On Failure of Oral Implants - Chrcanovic

BRUNO CHRCANOVIC
DOCTOR AL DISSERTATION IN ODONTOLOGY
ON FAILURE
OF ORAL IMPLANTS
ON FAILURE OF OR AL IMPL ANTS
Malmö University, Faculty of Odontology
Doctoral Dissertations 2017
© Bruno Chrcanovic 2017

ISBN 978-91-7104-766-3 (print)
ISBN 978-91-7104-767-0 (pdf)
Holmbergs, Malmö 2017
BRUNO CHRCANOVIC
ON FAILURE
OF OR AL IMPL ANTS
Malmö University, 2017

Faculty of Odontology
Department of Prosthodontics
Malmö, Sweden
This publication is also available at:
www.mah.se/muep
To my beloved wife Aleksandra,
my precious son Nathan,
and my mother and my father
This thesis is number 50 in a series of investigations on implants,
hard tissues and the locomotor apparatus originating from the
Department of Biomaterials, University of Gothenburg and
the Department of Prosthodontics/Material Sciences, Malmö
University, Sweden.
1. Anders R Eriksson DDS, 1984. Heat-induced Bone Tissue

Injury. An in vivo investigation of heat tolerance of bone
tissue and temperature rise in the drilling of cortical bone.
Thesis defended 21.2.1984. External examiner: Docent K-G.
Thorngren.
2. Magnus Jacobsson MD, 1985. On Bone Behaviour after

Irradiation.
Thesis defended 29.4.1985. External examiner: Docent A.
Nathanson.
3. Fredric Buch MD, 1985. On Electrical Stimulation of Bone

Tissue.
Thesis defended 28.5.1985. External examiner: Docent T.
Ejsing-Jörgensen.
4. Peter Kälebo MD, 1987. On Experimental Bone Regeneration

in Titanium Implants. A quantitative microradiographic and
histologic investigation using the Bone Harvest Chamber.
Thesis defended 1.10.1987. External examiner: Docent N.
Egund.
5. Lars Carlsson MD, 1989. On the Development of a new

Concept for Orthopaedic Implant Fixation.
Thesis defended 2.12.1989. External examiner: Docent L-Å
Broström.
6. Tord Röstlund MD, 1990. On the Development of a New

Arthroplasty.
Thesis defended 19.1.1990. External examiner: Docent Å.
Carlsson.
7
7. Carina Johansson Res Tech, 1991. On Tissue Reaction to
Metal Implants.
Thesis defended 12.4.1991. External examiner: Professor K.
Nilner.
8. Lars Sennerby DDS, 1991. On the Bone Tissue Response to

Titanium Implants.
Thesis defended 24.9.1991. External examiner: Dr J.E.
Davies.
9. Per Morberg MD, 1991. On Bone Tissue Reactions to Acrylic

Cement.
Thesis defended 19.12.1991. External examiner: Docent K.
Obrant.
10. Ulla Myhr PT, 1994. On factors of Importance for Sitting in

Children with Cerebral Palsy.
Harms-Ringdahl.
11. Magnus Gottlander MD, 1994. On Hard Tissue Reactions to

Hydroxyapatite- Coated Titanium Implants.
Thesis defended 25.11.1994. External examiner: Docent P.
Aspenberg.
12. Edward Ebramzadeh MScEng, 1995. On Factors Affecting

Long-Term Outcome of Total Hip Replacements.
Thesis defended 6.2.1995. External examiner: Docent L.
Linder.
13. Patricia Campbell BA, 1995. On Aseptic Loosening in Total

Hip Replacement: the Role of UHMWPE Wear Particles.
Thesis defended 7.2.1995. External examiner: Professor D.
Howie.
14. Ann Wennerberg, DDS, 1996. On Surface Roughness and

Implant Incorporation.
Thesis defended 19.4.1996. External examiner: Professor
P-O. Glantz.
8
15. Neil Meredith BDS MSc FDS RCSm, 1997. On the Clinical
Measurement of Implant Stability Osseointegration.
Thesis defended 3.6.1997. External examiner: Professor J.
Brunski.
16. Lars Rasmusson DDS, 1998. On Implant Integration in

Membrane-Induced and Grafter Bone.
Thesis defended 4.12.1998. External examiner: Professor R.
Haanaes.
17. Thay Q Lee MSc, 1999. On the Biomechanics of the

Patellfemoral Joint and Patellar Resurfacing in Total Knee
Arthroplasty.
Thesis defended 19.4.1999. External examiner: Docent G.
Nemeth.
18. Anna Karin Lundgren DDS, 1999. On Factors

Influencing Guided Regeneration and Augmentation of
Intramembraneous Bone.
Thesis defended 7.5.1999. External examiner: Professor B.
Klinge.
19. Carl-Johan Ivanoff DDS, 1999. On Surgical and Implant

Related Factors Influencing Integration and Function of
Titanium Implants. Experimental and Clinical Aspects.
Rosenquist.
20. Bertil Friberg DDS MDS, 1999. On Bone Quality and

Implant Stability Measurements.
Thesis defended 12.11.1999. External examiner: Docent P.
Åstrand.
21. Åse Allansdotter Johansson MD, 1999. On Implant

Integration in Irradiated Bone. An Experimental Study of the
Effects of Hyperbaric Oxygeneration and Delayed Implant
Placement.
Arvidsson-Fyrberg.
9
22. Börje Svensson FFS, 2000. On Costochondral Grafts
Replacing Mandibular Condyles in Juvenile Chronic
Arthritis. A Clinical, Histologic and Experimental Study.
Thesis defended 22.5.2000. External examiner: Professor Ch.
Lindqvist.
23. Warren Macdonald BEng, MPhil, 2000. On Component

Integration on Total Hip Arthroplasties: Pre-Clinical
Evaluations.
Thesis defended 1.9.2000. External examiner: Dr A.J.C. Lee.
24. Magne Røkkum MD, 2001. On Late Complications with HA

Coated Hip Arthroplasties.
Thesis defended 12.10.2001. External examiner: Professor P.
Benum.
25. Carin Hallgren Höstner DDS, 2001. On the Bone Response

to Different Implant Textures. A 3D analysis of roughness,
wavelength and surface pattern of experimental implants.
Thesis defended 19.11.2001. External examiner: Professor S.
Lundgren.
26. Young-Taeg Sul DDS, 2002. On the Bone Response to

Oxidised Titanium Implants: The role of microporous
structure and chemical composition of the surface oxide in
enhanced osseointegration.
Thesis defended 7.6.2002. External examiner: Professor J.E.
Ellingsen.
27. Victoria Franke Stenport DDS, 2002. On Growth Factors

and Titanium Implant Integration in Bone.
Thesis defended 11.6.2002. External examiner: Associate
Professor E. Solheim.
28. Mikael Sundfeldt MD, 2002. On the Aetiology of Aseptic

Loosening in Joint Arthroplasties and Routes to Improved
cemented Fixation.
Thesis defended 14.6.2002. External examiner: Professor N.
Dahlén.
10
29. Christer Slotte CCS, 2003. On Surgical Techniques to
Increase Bone Density and Volume. Studies in Rat and
Rabbit.
C.H.F. Hämmerle.
30. Anna Arvidsson MSc, 2003. On Surface Mediated

Interactions Related to Chemomechanical Caries Removal.
Effects on surrounding tissues and materials.
Thesis defended 28.11.2003. External examiner: Professor P.
Tengvall.
31. Pia Bolind DDS, 2004. On 606 retrieved oral and

craniofacial implants. An analysis of consequently received
human specimens.
Thesis defended 17.12.2004. External examiner: Professor A.
Piattelli.
32. Patricia Miranda Burgos DDS, 2006. On the influence of

micro- and macroscopic surface modifications on bone
integration of titanium implants.
Thesis defended 1.9.2006. External examiner: Professor A.
Piattelli.
33. Jonas P. Becktor DDS, 2006. On factors influencing the

outcome of various techniques using endosseous implants
for reconstruction of the atrophic edentulous and partially
dentate maxilla.
K.F. Moos.
34. Anna Göransson DDS, 2006. On Possibly Bioactive CP

Titanium Surfaces.
Melsen.
35. Andreas Thor DDS, 2006. On platelet-rich plasma in

reconstructive dental implant surgery.
E.M. Pinholt.
11
36. Luiz Meirelles DDS MSc, 2007. On Nano Size Structures for
Enhanced Early Bone Formation.
Lyndon F. Cooper.
37. Pär-Olov Östman DDS, 2007. On various protocols for direct

loading of implant-supported fixed prostheses.
Klinge.
38. Kerstin Fischer DDS, 2008. On immediate/early loading of

implant supported prostheses in the maxilla.
Arvidsson Fyrberg.
39. Alf Eliasson 2008. On the role of number of fixtures, surgical

technique and timing of loading.
Arvidsson Fyrberg.
40. Victoria Fröjd DDS, 2010. On Ca2+ incorporation and

nanoporosity of titanium surfaces and the effect on implant
performance.
J.E. Ellingsen.
41. Lory Melin Svanborg DDS, 2011. On the importance of

nanometer structures for implant incorporation in bone
tissue.
Thesis defended 01.06.2011. External examiner: Associate
professor C. Dahlin.
42. Byung-Soo Kang MSc, 2011. On the bone tissue response to

surface chemistry modifications of titanium implants.
Pan.
43. Kostas Bougas DDS, 2012. On the influence of biochemical

coating on implant bone incorporation.
Thesis defended 12.12.2012. External examiner: Professor T.
Berglundh.
12
44. Arne Mordenfeld DDS, 2013. On tissue reaction to and
adsorption of bone substitutes.
Thesis defended 29.5.2013. External examiner: Professor C.
Dahlin.
45. Ramesh Chowdhary DDS, 2014. On efficacy of implant

thread design for bone stimulation.
Flemming Isidor.
46. Anders Halldin MSc, 2015. On a biomechanical approach

to analysis of stability and load bearing capacity of oral
implants.
Brunski.
47. Francesca Cecchinato MSc, 2015. On magnesium-modified

titanium coatings and magnesium alloys for oral and
orthopaedic applications: in vitro investigation.
Thesis defended 20.11.2015. External examiner: Professor C.
Stanford.
48. Jonas Anderud DDS, 2016. On guided bone regeneration

using ceramic membranes.
Thesis defended 27.05.2016. External examiner: Professor S.
Lundgren
49. Silvia Galli DDS, 2016. On magnesium-containing implants

for bone applications.
J.E. Ellingsen.
50. Bruno Chrcanovic DDS MSc, 2017. On Failure of Oral

Implants.
Thesis to be defended 08.06.2017. External examiner:
Associate Professor B. Friberg.
see www.mah.se/muep
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TABLE OF CONTENTS
THESIS AT A GLANCE. . .................................................. 19
ABSTRACT................................................................... 23
POPULÄRVETENSKAPLIG SAMMANFATTNING................... 26
LIST OF PAPERS............................................................ 29
ABBREVIATIONS AND ACRONYMS................................. 31
INTRODUCTION........................................................... 34
OSSEOINTEGRATION.................................................... 37
REPORTED CLINICAL OUTCOME OF
OSSEOINTEGRATED IMPLANTS....................................... 44
RESEARCH METHODOLOGIES
– ADVANTAGES AND DISADVANTAGES AND
IMPACT ON IMPLANT SURVIVAL RESULTS. . ........................ 46
Clinical studies...................................................................... 46
Retrospective studies.......................................................... 49
Prospective studies............................................................ 50
Reviews................................................................................ 58
Narrative review............................................................... 58
Systematic review............................................................. 58
Data analysis........................................................................ 61
Survival analysis............................................................... 61
Binary logistic regression................................................... 69
Generalized estimating equation........................................ 71
Clinical factors...................................................................... 72
Time of follow-up.............................................................. 72
Sample size..................................................................... 72
Unaccounted for implants in drop out patients...................... 74
AIMS.......................................................................... 77
MATERIALS AND METHODS. . .......................................... 79
RESULTS AND DISCUSSION............................................ 83
Hardware............................................................................. 83
Implant length................................................................... 83
Implant diameter............................................................... 87
Implant design (non-threaded versus threaded,
cylindrical versus tapered).................................................. 91
Implant surface................................................................. 93
“Copycat” implants and implant systems that were
withdrawn due to clinical problems..................................... 96
Surface contamination....................................................... 99
Surgery.............................................................................. 101
Use of prophylactic antibiotics.......................................... 101
Insertion torque............................................................... 102
Primary stability.............................................................. 105
Fresh extraction sockets................................................... 108
Flapless surgery.............................................................. 112
Non-submerged implants................................................. 115
Immediate loading.......................................................... 118
Tilted implants................................................................ 120
Grafting......................................................................... 122
Reoperation................................................................... 124
Anatomy............................................................................ 126
Location – maxilla and mandible, anterior
and posterior regions...................................................... 126
Bone quantity and quality................................................ 127
Patient’s habits.................................................................... 131
Smoking........................................................................ 131
Snuff............................................................................. 136
Bruxism......................................................................... 137
Oral hygiene.................................................................. 146
Alcoholism..................................................................... 147
Narcotic drugs............................................................... 149
Health................................................................................ 152
Patient genetics............................................................... 152
Patient’s sex................................................................... 154
History of periodontitis.................................................... 158
Irradiation...................................................................... 164
Diabetes mellitus............................................................. 174
Pharmaceutical reasons for implant problems..................... 178
Titanium allergy.............................................................. 191
Prosthetic............................................................................ 196
Crown-to-implant ratio..................................................... 196
Number of implants per patient........................................ 198
Prosthetic rehabilitation type............................................. 199
Occlusal versus non-occlusal loading................................. 200
Prosthodontist experience/skill/judgment........................... 201
Surgeon............................................................................. 203
The surgeon’s experience................................................. 203
The surgeon’s skills.......................................................... 206
The surgeon’s judgment................................................... 207
Cluster behavior of failures................................................... 208
ON REASONS FOR MARGINAL BONE LOSS
AROUND ORAL IMPLANTS............................................211
The traditional theory of reasons for marginal bone loss........... 211
The immunologically based theory behind marginal bone loss.... 213
FRACTURE OF IMPLANTS..............................................214
CONTRAINDICATIONS FOR IMPLANTS...........................220
CONCLUSIONS. . .........................................................231
ACKNOWLEDGEMENTS...............................................233
REFERENCES...............................................................235
PAPERS I-IX.. ................................................................347
THESIS AT A GLANCE
Study Aim Study design Main findings
I To review the literature Systematic It is suggested that the following situations may increase
Reasons for failures of regarding the factors literature review the implant failure rate: a low insertion torque of implants
oral implants contributing to failures of oral that are planned to be immediately or early loaded,
implants. inexperienced surgeons inserting the implants, implant
insertion in the maxilla, implant insertion in the posterior
region of the jaws, implants in heavy smokers, implant
insertion in bone qualities type III and IV, implant insertion
in places with small bone volumes, use of shorter length
implants, greater number of implants placed per patient,
lack of initial implant stability, use of cylindrical (non-
threaded) implants and prosthetic rehabilitation with
implant-supported overdentures.
II To test the null hypothesis of Systematic It is suggested that the insertion of oral implants in
Smoking and no difference in the implant literature review smokers affects the implant failure rates, the incidence of
dental implants: A failure rates, postoperative and meta-analysis postoperative infections, as well as the marginal bone
systematic review and infection, and marginal loss.
meta-analysis bone loss for smokers or
non-smokers, against the
alternative hypothesis of a
difference.
III To assess the influence of Retrospective Smoking and the intake of antidepressants are suggested
Factors influencing local and systemic factors clinical trial to be potentially influencing factors to the occurrence of
early dental implant on the occurrence of implant implant failures up to the abutment connection.
failures failures up to second-
19
stage surgery (abutment
connection).
20
IV To analyze the complications Retrospective Bruxism may significantly increase both the implant
Bruxism and dental of dental implant treatment clinical trial failure rate and the rate of mechanical and technical
implant treatment in a group of patients complications of implant-supported restorations.
complications: presenting bruxism in
a retrospective comparison with a matched
comparative study of group of non-bruxers.
98 bruxer patients
and a matched group
V To investigate the association Retrospective The intake of proton pump inhibitors may be associated
The intake of proton between the intake of proton clinical trial with an increased risk of oral implant failure.
pump inhibitors is pump inhibitors and the risk
associated with an of dental implant failure.
increased risk of
dental implant failure
VI To investigate the association Retrospective The intake of selective serotonin reuptake inhibitors may
Is the intake of between the intake of clinical trial not be associated with an increased risk of oral implant
selective serotonin selective serotonin reuptake failure.
reuptake inhibitors inhibitors and the risk of
associated with an dental implant failure.
increased risk of
dental implant failure?
VII To assess the influence of the Retrospective Different levels of failure incidence of oral implants could
Impact of different placement of dental implants clinical trial be observed depending on the individual surgeons,
surgeons on dental by different dental surgeons occasionally reaching significant levels. Although a
implant failure on the implant failure direct causal relationship could not be ascertained, it is
prevalence. suggested that the surgeons’ technique, skills, and/or
judgment may influence the oral implant survival rates.
VIII To analyze the cluster Retrospective A cluster pattern among patients with implant failure
Analysis of risk factors behavior of dental implant clinical trial is highly probable. Shorter implants, turned implants,
for cluster behavior of failures among patients poor bone quality, younger patients, the intake of
dental implant failures and to assess the possible antidepressants and of proton pump inhibitors, smoking,
risk factors influencing this and bruxism were identified as suggested potential factors
phenomenon. exerting a statistically significant influence on the cluster
behavior of dental implant failures.
IX To assess the dental implant Retrospective Most of the implant failures occur at the first years after
A retrospective failure rates and marginal clinical trial implantation, regardless of a very long follow-up. Implants
study on clinical and bone loss of implants in different jaw locations, irradiation, and bruxism were
radiological outcomes followed up for a minimum of the factors suggested to affect the survival of implants.
of oral implants in 20 years. Marginal bone loss can be insignificant in long term
patients followed up observations, but it may, nevertheless, be the cause of
for a minimum of 20 secondary failure of oral implants in some cases.
years
21
ABSTRACT
Introduction
Nowadays oral implant placement is an effective and predictable
treatment modality for replacing missing teeth in both fully and
partially edentulous patients. Despite the high implant survival
and success rates, there is a general appreciation that some risk
factors predispose individuals to more complications and implant
failures and may result in lower implant survival and success rates.
Determining the exact elements that are critical for osseointegration
would be extremely useful. A better understanding of the factors
associated with implant failure provide data for the planning of
future studies, facilitate clinical decision-making, and may enhance
implant success. Once identified, the risks can then be avoided, or
an alternative intervention can be applied, implying in the least cost
to produce a given level of effectiveness in oral rehabilitation. The
general aim of the present thesis was to assess the impact of several
factors on the failure of oral implants.
Materials and Methods

The articles included in the present thesis consist of three types of
studies. First, a general overview was performed in order to identify
risk factors associated with the failure of oral implants (Study I).
Then, a systematic review of the literature with meta-analyses was
performed to analyze the influence of one risk factor (smoking) on the
failure of oral implants, marginal bone loss (MBL), and postoperative
infection around implants (Study II). The seven retrospective studies
(Study III-IX) were based on all 2,670 patients provided with 10,096
implants, consecutively treated on a routine basis at one specialist
23
clinic (Clinic for Prosthodontics, Centre of Dental Specialist Care,
Malmö, Sweden - Folktandvården Skåne AB, Specialisttandvård
Malmö) during the period from 1980 to 2014. The dental records
of all patients ever treated with implants in this clinic were read
in order to collect the data. The data were directly entered into a
SPSS file (SPSS software, version 23, SPSS Inc., Chicago, USA) as
the files were being read. Several anatomical-, patient-, health-,
and implant-related factors were collected. The clinical studies
included in the thesis focused on the association between implant
failure and bruxism, the intake of proton pump inhibitors and of
selective serotonin reuptake inhibitors and their relation to failure,
the impact of different surgeons, and the number of early failures,
cluster behavior of failures, and clinical and radiological outcomes
of implants followed up for a minimum of 20 years.
Besides descriptive statistics and tests for the comparison of 2
or of 3 or more independent and dependent groups of continuous
and categorical data, survival analyses, logistic regression models,
generalized estimating equation method, and multilevel mixed effects
parametric survival analysis were performed, depending on the study.
Results and Conclusions

After a systematic review of the literature, it may be suggested that
the following situations may increase the implant failure rate: a low
insertion torque of implants that are planned to be immediately or
early loaded, inexperienced surgeons inserting the implants, implant
insertion in the maxilla, implant insertion in the posterior region
of the jaws, implants in heavy smokers, implant insertion in bone
qualities type III and IV, implant insertion in places with small bone
volumes, use of shorter length implants, greater number of implants
placed per patient, lack of initial implant stability, use of cylindrical
(non-threaded) implants and prosthetic rehabilitation with implant-
supported overdentures. Moreover, it may be suggested that the
following situations may be correlated with an increase in the implant
failure rate but with a weaker association than the factors listed above:
use of the non-submerged technique, immediate loading, implant
insertion in fresh extraction sockets, smaller diameter implants. Some
recently published studies suggest that modern, moderately rough
implants may present with similar results irrespective if placed in
24
maxillae, in smoking patients or using only short implants (Study I).
The systematic review of the literature with meta-analyses suggested
that the insertion of oral implants in smokers affects the implant
failure rates, the incidence of postoperative infections, as well as the
marginal bone loss (Study II).
Smoking and the intake of antidepressants are suggested to be
potentially influencing factors with respect to the occurrence of
implant failures up to the second-stage surgery - abutment connection
(Study III). Bruxism may significantly increase both the implant
failure rate and the rate of mechanical and technical complications
of implant-supported restorations (Study IV). The intake of proton
pump inhibitors may be associated with an increased risk of oral
implant failure (Study V), but not so the intake of selective serotonin
reuptake inhibitors (Study VI). Different levels of failure incidence
of oral implants could be observed depending on the individual
surgeons, occasionally reaching significant levels. Although a direct
causal relationship could not be ascertained, it is suggested that
the surgeons’ technique, skills, and/or judgment may influence the
oral implant survival rates (Study VII). A cluster pattern among
patients with implant failure is highly probable. Shorter implants,
turned implants, poor bone quality, younger patients, the intake
of antidepressants and of proton pump inhibitors, smoking, and
bruxism were identified as suggested potential factors exerting a
statistically significant influence on the cluster behavior of dental
implant failures (Study VIII). Most of the implant failures occur at
the first years after implantation, regardless of a very long follow-up.
Implants in different jaw locations, irradiation, and bruxism were
the factors suggested to affect the survival of implants. Marginal
bone loss can be insignificant in long term observations, but it may,
nevertheless, be the cause of secondary failure of oral implants in
some cases (Study IX).
25
POPULÄRVETENSKAPLIG
SAMMANFATTNING
Introduktion
Behandling med orala implantat är idag en effektiv och fungerande
metod att ersätta bettfunktion vid partiell eller hel tandlöshet. Trots
höga överlevnads- och lyckandesiffror finns ändå riskfaktorer som
för vissa patienter kan resultera i implantatförlust. Man behöver
noggrant utreda olika faktorer som kan påverka benförankringen,
osseointegrationen, av implantaten för att ytterligare förbättra
lyckandesiffrorna. Om faktorer som leder till ökad implantatförlust
kan identifieras, skulle det underlätta för såväl tandläkare som för
patienten genom att man då får möjlighet att undvika eller kompensera
för individuella risker. Den här avhandlingen har haft som syfte att
presentera kända riskfaktorer bakom implantatförluster.
Material och metodik

Artiklarna som ingår i denna avhandling kan indelas i tre olika
sorters studier. Först gjordes en allmän översikt om kända faktorer
bakom implantatproblem (arbete I). Därefter utfördes en meta-
analys innebärande en genomgång av relevant litteratur för att mer
djupgående kunna analysera en selekterad riskfaktor, nämligen att
patienter som röker kan påverka såväl benförlust runt implantatet som
postoperativ infektionsrisk och implantatförlust.(Arbete II). Därefter
utfördes sju retrospektiva (tillbakablickande) studier(Arbeten III-IX)
baserat på 10.096 implantat, konsekutivt insatta på tillsammans 2670
patienter på en klinik – folktandvården i Skåne, specialisttandvården
26
Malmö under tiden 1980 till 2014. Efter godkännande från etisk
nämnd har det blivit möjligt att datorbehandla tandläkarjournaler
från detta patientmaterial. Data införs på en SPSS fil (SPSS software,
version 23, SPSS Inc, Chicago, USA). Anatomiska-, patient-, hälso-
och implantatrelaterade faktorer registrerades. De kliniska studier
som ingår i avhandlingen har fokuserats kring frågeställningar
som implantatförlust och bruxism(tandgnissling), medikamentell
behandling med protonpumps inhibitorer(magsårsmedicin) eller
serotonin(antidepressivt medel), lyckandedata för implantat
insatta av olika kirurger, tidiga förluster och s k klusterbeteende.
Klusterbeteende avser att implantatförluster inte är jämnt fördelade
bland patienterna, utan att det rör sig främst om ett fåtal patienter
som har många misslyckanden. Därtill utfördes röntgenologiska
beräkningar av benförlust runt implantat som varit insatta under
mer än 20 års tid. Olika statistiska modeller användes för att testa
om erhållna data var signifikant skilda åt i jämförelse med relevanta
kontroller.
Resultat och Diskussion

Den systematiskta genomgången av litteraturen antydde att det
fanns en serie faktorer som kunde påverka implantatutgången; t
ex lågt vridmoment vid implantatinsättningen om man samtidigt
avsåg belasta implantaten snabbt; att oerfarna eller dåligt skolade
kirurger har sämre kliniskt resultat än mer skolade kollegor;
implantatinsättning i överkäken; implantatinsättning i bakre delen
av käkarna eller i ben av dålig kvalitet/kvantitet; rökande patienter;
användning av korta implantat eller för många implantat; insättning
av icke gängade implantat eller användande av s k täckprotes. Därtill
fanns antydningar om andra faktorer som möjligen skulle kunna
påverka implantatframgången negativt, som att låta implantaten
ha direkt genomgång i slemhinnan utan tidigare vilofas, som
direktbelastning av implantaten, som insättning av implantat
direkt efter tandutdragning, som implantat med liten diameter. En
del senare studier antydde att moderna moderat råa implantatytor
kunde kompensera för risker med en del faktorer som insättning i
överkäken, användande av korta implantat eller vid direktbelastning
(Studie I). Den mer systematiska analysen av rökande patienter fann
en ökning av implantatförlusterna hos rökare och därtill påverkades
27
infektionsrisken efter implantatinsättningen och man fick ökad
benförlust runt implantaten när patienten rökte (Studie II).
Rökning kunde verifieras som riskfaktor i den kliniska analysen
och även om patienten åt antidepressiva tabletter av serotonin-
typ, så ökade i vart fall de tidiga implantatförlusterna (Studie III).
Patienter som gnisslade tänder hade signifikant ökning av implantat
förluster och fick därtill ökning av implantatfrakturer och brott på
tandbroar (Studie IV). Resultaten visade också att en vanlig typ av
magsårsmedicin; s k proton pumphämmare, resulterade i ökning av
antalet implantatförluster (Studie V). Man fann däremot inga säkra
tecken på ökad implantatförlust vad gällde sena resultat för de som
åt antidepressiva mediciner av serotonintyp (Studie VI). Vidare fanns
klara antydningar att vissa kirurger hade fler implantatförluster än
andra, något som kan ha att göra med vald kirurgisk teknik, kirurgisk
förmåga, kirurgiskt omdöme(vissa tänkta implantatpatienter skall
kanske inte operas utan få annan behandling) (Studie VII). Vissa
patienter med specifika karaktäristika som pekats på i studie I
förlorade klart fler implantat än medelpatienten (Studie VIII). Slutligen
noterades en mycket klar övervikt för tidiga implantatförluster
under de första två åren efter implantatinsättningen, varefter ytter
liga implantatförluster förekom men var långt mer ovanliga. En
särskild faktor som antytts ställa till stora kliniska problem, som
benförlust runt implantaten, visade sig i verkligheten sällan leda
till implantatförlust. De flesta implantat som uppvisade benförlust
fungerade trots detta utmärkt kliniskt (Studie IX).
Den övergripande målsättningen med denna avhandling har varit
att öka kunskapen om olika faktorer bakom implantatförlust för att
på så sätt kunna bidra till ytterligare förbättring av kliniska resultat
i framtiden.
28
LIST OF PAPERS
This dissertation is based on the following papers, which will be

referred to in the main text by their Roman numerals, except for
the Study I, which is a general review. Reference to the papers in the
text will not exacly appear in the numerical order shown below. The
papers are appended at the end of the thesis.
I. Chrcanovic BR, Albrektsson T, Wennerberg A. Reasons for

failures of oral implants. Journal of Oral Rehabilitation 2014
Jun;41(6):443-476.
II. Chrcanovic BR, Albrektsson T, Wennerberg A. Smoking

and dental implants: A systematic review and meta-analysis.
Journal of Dentistry 2015 May;43(5):487-498.
III. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.

Factors influencing early dental implant failures. Journal of
Dental Research. 2016 Aug;95(9):995-1002.
IV. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.

Bruxism and dental implant treatment complications: a
retrospective comparative study of 98 bruxer patients and
a matched group. Clinical Oral Implants Research. 2016.
In press.
V. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.

The intake of proton pump inhibitors is associated with
an increased risk of dental implant failure. International
Journal of Oral and Maxillofacial Implants 2016. Accepted
for publication.
29
VI. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.
Is the intake of selective serotonin reuptake inhibitors
associated with an increased risk of dental implant failure?
International Journal of Oral and Maxillofacial Surgery.
2017 Jun;46(6):782-788.
VII. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.

Impact of different surgeons on dental implant failure.
International Journal of Prosthodontics. 2017. Accepted for
publication.
VIII. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.

Analysis of risk factors for cluster behavior of dental implant
failures. Clinical Implant Dentistry and Related Research.
2017. In press.
IX. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A. A

retrospective study on clinical and radiological outcomes of
oral implants in patients followed up for a minimum of 20
years. 2017. Submitted.
All published and accepted papers were reprinted with permission

from the copyright holders.
Contribution by the respondent

The respondent performed most of the work of planning, and he
performed data collection and analysis of the data. The respondent
was also the main contributor to writing the manuscripts.
30
ABBREVIATIONS AND ACRONYMS
°C degree Celsius
95% CI 95% confidence interval
AB Aktiebolag (Swedish)
AG Aktiengesellschaft (German)
AIDS Acquired immune deficiency syndrome
AMSTAR Assessing the Methodological Quality of Systematic Reviews
ANOVA Analysis of variance
BIC Bone-to-implant contact
BMD Bone mineral density
BMI Body mass index
BMP-2 Bone morphogenetic protein 2
BP Bisphosphonate
BRONJ Bisphosphonate-related osteonecrosis of the jaw
c.p. Ti Commercially pure titanium
C/I ratio Crown-to-implant ratio
CCB Calcium-channel blocker
CCT Controlled clinical trial
CNC Computer Numerical Control
CsA Cyclosporin A
CSR Cumulative survival rate
CT Computed tomography
e.g. exempli gratia (Latin)
EU European Union
FEA Finite element analysis
g gram
31
GEE Generalized estimating equation
Gy Gray
HA-coated Hydroxyapatite-coated
HbA1c Glycosylated hemoglobin
HBO Hyperbaric oxygen
HIF-1α Hypoxia-inducible factor 1-alpha
HIV Human immunodeficiency virus
HR Hazard ratio
i.e. id est (Latin)
IL-1 Interleukin 1
IL-1α Interleukin 1 alpha
IL-1β Interleukin 1 beta
IL-6 Interleukin 6
IL-8 Interleukin 8
ISQ Implant stability quotient
KM Kaplan-Meier
LTT Lymphocyte transformation test
MBF Maximal bite force
MBL Marginal bone loss
MD Mean difference
MDMA 3,4-methylenedioxymetamphetamine
MELISA Memory Lymphocyte Immunostimulation Assay
mg milligram
MIP-1α Macrophage inflammatory protein-1 alpha
MIT Maximum insertion torque
mm millimeter
MMP Matrix metalloprotenase
MRT Maximum removal torque
MSC Mesenchymal stem cell
NCm Newton centimeter
nm nanometer
O2 Oxygen (dioxygen)
OR Odds ratio
PCP Periodontally compromised patient
PDGF-AA Platelet-derived growth factor-AA
32
PEEK Polyether ether ketone
PGE2 Prostaglandin E2
PHP Periodontally healthy patient
PICF Peri-implant crevicular fluid
ppb parts per billion
PPI Proton pump inhibitor
ppm parts per million
Preferred Reporting Items for Systematic Reviews
PRISMA
and Meta-Analyses
PTH Parathyroid hormone
QCT Quantitative computed tomography
RCT Randomized clinical trial
RFA Resonance frequency analysis
RR Risk ratio
SD Standard deviation
SEM Scanning electron microscopy
SPSS Statistical Package for the Social Sciences
SPT Supportive periodontal treatment
SSRI Selective serotonin reuptake inhibitor
TGF-β1 Transforming growth factor-beta 1
TiO2 Titanium dioxide
TNF-α Tumor necrosis factor alpha
VEGF Vascular endothelial growth factor
μm Micrometer
33
INTRODUCTION
Failures of oral implants are much less commonly described in the

literature than are surviving and successful cases. One reason for this
may certainly be that implants fare very well, provided documented
oral implant systems are placed by trained individuals. Since the
great majority of published papers indeed are authored by implant
scholars, this means that failures are few, typically in the range of
<5% over 10 years with modern, documented implants.1 Another
reason why failures are being discussed much less often than are
successful cases may relate to our inborn wish to remain positive.
Indeed, no clinic is particularly promoted if mainly failed implants
are being discussed.
But implant failures nevertheless occur. One way of categorizing
failures would be to separate early (primary) failures from secondary
ones. Some implants simply never osseointegrate; those are the
primary failures. They are not easy to explain. Palma-Carrió et al.2
presented a review over early failures with few possible conclusions,
even if factors such as patient smoking, implant posterior location or
poor bone quality or quantity seemed to be of some relevance. Sakka
et al.3 listed a lack of primary stability, surgical trauma and infection as
reasons for early failures. An odd reason for early oral implant failure
in form of low serum levels of vitamin D was analyzed by Mangano
et al.,4 however without finding clear statistics incriminating low
vitamin D levels. Secondary failures, i.e. implants that have lost a
previously established osseointegration, were explained by the sum
of the trauma due to patient smoking, patient genetic factors, poor
surgery, adverse loading, excess cement or intake of certain medicines
all leading to an immunologically derived shifted balance between
34
bone formation and bone resorption in favor of the latter.5 Sakka
et al.3 believed in occlusal overload, peri-implantitis, suboptimal
implant designs and improper prosthetic constructions to explain
later implant failure.
A lot has been written about an alleged disease entitled peri-
implantitis that supposedly hit implants in a similar way as teeth
suffer from periodontitis. Clearly inflated definitions of such a disease
have resulted in claims that up to 50% of all placed implants suffer
from it (for review see Qian et al.6). These theories are seemingly
impossible to couple to the clinical reality and, indeed, Jemt et al.7
who followed up a group of allegedly sick implants 9 years after
their preliminary diagnosis reported that clearly more than 90% of
them seemed to function quite well with no indications at all of an
imminent failure.
Chee and Jivray8 said that most implant failures can be classified
into four categories: (1) loss of osseointegration, (2) positional
failures, (3) soft tissue defects, and (4) biomechanical failures. Hadi
and co-workers9 listed a greater number of factors contributing to
implant failure, namely the medical status of the patient, patient
smoking, bone quality, bone grafting, irradiation, bacterial
contamination, lack of preoperative antibiotics, degree of surgical
trauma and operator experience. In addition, the authors listed
implant surface properties, roughness and premature loading to be
associated with failing patterns.
Another way of categorizing implant failure, but from the patient
perspective, was suggested by Penchas.10 Patient pain, swelling or
inflammation or a general feeling that the implant is loose were
summarized as patient factors.
This wide spectrum of factors believed to be associated with oral
implant failure in the literature was the background to the present
study. Although there were many viewpoints on reasons for failure
that had been suggested in the literature, a major study devoted
only to reasons for oral implant failures seemed to be missing in
the literature. In a series of meta-analyses or reviews the author
behind this thesis started by summing up the literature.11-31 However,
summarizing the literature only, of which two papers11,20 have been
inserted in this thesis, is far from satisfactory in an attempt to cover
the important topic of implant failure. The applicant, therefore,
35
decided to go through a consecutive series of 10,096 implants
placed at one Malmö clinic since 1980. Every clinical record
available from no fewer than 2,670 patients was carefully read and
data were computerized. To the knowledge of the present author,
thanks to the computerization of all data in dozens and dozens of
independent variables for each and every implant, this may be the
largest implant material ever possible to analyze in great detail, even
if I am certainly aware that the Brånemark clinic in Gothenburg has
access to about 40,000 implants in their clinical patient records. My
major motivation behind this thesis is to present an attempt to learn
more about oral implant failures to encompass even further increase
of implant success rates for the future.
36
OSSEOINTEGRATION
Oral implants of the past were anchored in soft tissues and had one
thing in common; they showed an intolerably poor clinical outcome.
No decent University had oral implants on their curriculum. Early
attempts to place implant with a direct bone anchorage had failed.32
Per-Ingvar Brånemark (Figure 1) of the Gothenburg University
in Sweden discovered in 1962 what was later referred to as
osseointegration, a direct bone anchorage of titanium implants (Figure
2), whilst working with experimental implants in rabbits. Brånemark
intended to use his implants for visualization of the microcirculation,
but noticed at the termination of his experiment that the implants
were most difficult to remove from the bone (Figure 3). Only 3 years
later, in 1965, Brånemark operated his first patient with oral implants
(Figure 4). His ideas were initially not very well received by dentistry,
but this was to change in Scandinavia in 1977 and internationally in
1982. There were different definitions offered of osseointegration;
one of them claimed “a structural and functional connection between
ordered, living bone and the surface of a load carrying implants”.33
Another early definition suggested that osseointegration was “a
process whereby clinically asymptomatic rigid fixation of alloplastic
material is achieved and maintained in bone during functional
loading”.34 Six factors were found important to control to achieve
reliable osseointegration; implant biocompatibility, design and
surface features, status of the host bed, surgical technique and what
was referred to as “loading conditions”.35 In case one or several of
those parameters were not controlled, implantation resulted in spit
out of the implant, i.e. a primary failure (Figure 5).
37
Figure 1. Per-Ingvar Brånemark. La Jolla, California, 1981.
Figure 2. Osseointegration represents a direct contact (at the light

microscopic level of resolution) between bone and implant.
38
Figure 3. This is a radiogram of the original chamber, placed in rabbit
bone, that led to the discovery of osseointegration in 1962.
Figure 4. One very early implant design with flanges used by P-I
Brånemark and his team between 1965 and 1970. The radiogram to
the right is a 30-year control.
39
Figure 5. Primary failure of an implant (from Albrektsson et al.44 Published
with permission Periodontology 2000).
Osseointegration meant an enormous breakthrough for the discipline

of jaw reconstruction. Today it is estimated that somewhat between
15 and 20 million oral implants are placed annually in the world.
Long term clinical success rates of more than 90% have been reported
in the literature.36 The present thesis is mainly built on a consecutive
series of 10,096 osseointegrated implants placed at one Malmö clinic
since 1980. This controlled material of oral implants is probably
the second largest in the world, second only to the implants placed
at the Brånemark clinic of Gothenburg where 39,077 oral implants
have been followed up and, to part, have had clinical results analyzed
under varying conditions.37 Clinical records of the entire Malmö
material have been computerized in several independent variables,
which is an advantage that enables simple long-term analysis of the
patient material.
With time the definition of and outlook on osseointegrated
implants changed; whereas in the early days titanium implants were
regarded to only result in a wound healing phenomenon38,39 due to
their superb biocompatibility, the general viewpoint today is that
titanium does represent a foreign body and is handled so by the
host tissues.40-42 The scenario is such that titanium is regarded as a
40
foreign body by the defense mechanisms and the response is to form
bone around the titanium to protect the body tissues from it. This is
indeed splendid for clinical dentistry since the newly formed bone will
improve loading of the implant. Our suggestion for a new definition
of osseointegration would be: “Osseointegration is a foreign body
reaction where interfacial bone is formed as a defense reaction to
shield off the implant from the tissues” (Figures 6 and 7).43
Figure 6. C.p. titanium is seen as a foreign body and the organism

protects itself by forming bone around titanium, a fact we can use
clinically to load our implants (from Albrektsson et al.44 Published with
permission Periodontology 2000).
41
Figure 7. Two clinical implants where bone condensation representing
foreign body bone is visualized.
The great majority of oral implants today are manufactured from

commercially pure titanium (c.p. Ti). Despite this material presenting
a foreign body reaction, it works very well with case reports of
clinical function of up to 50 years.44 Alternative materials for oral
implants have been hydroxyapatite coated titanium, titanium alloys
and zirconia. All these materials are biocompatible despite handled
as foreign elements by the defense mechanisms of the body. However,
hydroxyapatite-coated (HA-coated) implants of the first generation
failed and caused bone resorption, possibly due to the thick coats
of hydroxyl-apatite that were applied.45 Titanium-6Aluminum-
4Vanadium alloys have been used in relatively small numbers in oral
implantology with one clinical report claiming 83.3% success and
93.4% survival over 5 years of follow-up.46 Other titanium alloy
implants containing zirconia have, to the knowledge of the authors,
not yet been followed up for 5 years. The same is true for zirconia
implants47 and zirconia has the additional problem of increasing
42
brittleness due to ageing in the human body, even if it is unknown
whether we will see an increasing number of fractures of the implant
over time. In the present thesis, all 10,096 implants investigated were
manufactured from c.p. Ti.
43
REPORTED CLINICAL OUTCOME OF
OSSEOINTEGRATED IMPLANTS
Brånemark discovered the process of osseointegration in the 1960s

and placed the first dental implant in a patient about 50 years ago.48
Since then dental implants became an increasingly viable alternative
to conventional prosthodontic treatment options, supported by
evidenced-based data. Thousands of clinical studies on dental
implants were performed and published. Most studies present data on
implant and prosthesis survival, as well as on bone response adjacent
to the implants. However, many of the studies are on a relatively
short- or medium-term basis.49 There is an increase in the number
of dental implants being placed in the world annually and follow-up
is essential to determine and predict a future clinical course. The
patients receiving implants expect to keep them for years and years,
and therefore it is more reliable to have a basis for dental implants
prognosis with long follow-up studies.
One of the first studies to report at least 10 years of follow-up of
dental implants was the one published by Brånemark et al.50 At the
time, the Brånemark implant (Nobel Biocare AB, Göteborg, Sweden),
the so-called turned or machined original Brånemark implant, was one
of few available ones in the market. The study50 reported a survival
rate of 78.6% for implants placed in the maxilla and 92.6% for
implants installed in the mandible. Several studies of at least 10 years
of follow-up assessing the survival rates of the turned Brånemark
implants followed, with almost invariably showing higher survival
rates for implants placed in the mandible (usually around 95%) than
for implants placed in the maxilla (usually around 90%).49,51-62 More
44
recently, Chrcanovic et al.63 (Study IX) assessed the implant failure
rates of 1045 implants (98% of them Nobel turned implants) and
marginal bone loss (MBL) of 300 of these implants, all followed up
for a mean ± SD of 24.25 ± 2.8 years (min-max, 20.3-36.5). It was
observed a failure rate of 18.4% for implants placed in maxillae and
7.1% for implants placed in mandibles. The study observed that
59.3% the implant failures occurred at the three first years after
implantation, regardless of a very long follow-up.
Later, the Nobel Biocare launched implants with an oxidized
surface, the so-called TiUnite. Studies of at least 10 years of follow-up
with TiUnite implants64-66 showed improved survival rates than the
long-term studies with the turned Brånemark implants, sometimes
reaching 100% of survival. Other modern implants presented similar
positive long-term results, as the case of the SLA implants (Straumann
AG, Basel, Switzerland),67-75 TiOblast implants (Astra Tech AB,
Mölndal, Sweden),76-83 Osseotite implants (Zimmer Biomet Dental,
Warsaw, USA),84,85 and XiVE implants (Dentsply, York, USA).86
In general, modern oral implants have displayed better clinical
results than previously used devices, at least in maxillary cases or
when challenging factors apply such as patient smoking, direct or
rapid loading, the use of short implants, irradiation to tissues, or
bone grafting.1 After all, a clinical outcome of 95% or more of
modern implants when followed up for ten years or more44 suggests
most good a clinical outcome. However, as has been pointed out in
the past,1 this good an outcome may be limited to properly trained
clinicians placing controlled implant types and cannot automatically
be considered valid in all cases.
45
RESEARCH METHODOLOGIES
– ADVANTAGES AND
DISADVANTAGES AND IMPACT
ON IMPLANT SURVIVAL RESULTS
Research plays a vital role within biomedicine. Scientifically

appropriate research provides a basis for appropriate medical
decisions; conversely, inappropriate research may lead to flawed ‘best
medical practices’ which, when followed, contribute to avoidable
morbidity and mortality.87 Informed decision making requires health
professionals to combine their own clinical expertise and training with
high quality scientific evidence. New scientific knowledge is emerging
all the time and all health workers need to update their knowledge
continuously.88 Despite the advent of evidence-based medicine, many
research methods have become ‘standard’ even though there are
legitimate scientific reasons to question the conclusions reached by
such methods.87
In the present chapter some research methodologies are discussed,
pointing out their possible advantages and limitations, as well as
a discussion on some already established and other more recent
statistical methods used to evaluate dental implant survival and/or
failure. Moreover, the impact of some clinical factors on the study
results is examined.
Clinical studies
Study designs can be categorized as observational or interventional.
Observational studies, in which the investigator observes events
46
without attempting to influence them, are done to establish the
frequency of a disease or characteristic and/or to compare two groups.
Following a population over a period of time, and then analyzing the
differences between those who do or do not get a specific disease,
or the differences between patients who lose or did not lose dental
implants, are examples of observational studies. Observational
studies can identify an association between two variables. However,
they cannot establish a causal link.89
Types of observational studies include case–control, cohort, and
cross-sectional investifations.89 A case-control study is superior to
a case series because of the presence of a control group. Cases with
and without the condition of interest are identified. The degree of
exposure to a possible risk factor is then compared between the 2
groups. The case-control study design assumes that (1) cases differ
from controls only in having the disease, (2) exposure should be
equally distributed between cases and controls if the exposure does
not cause the disease, and (3) greater exposure among cases would
indicate that exposure increases the risk of the disease. The exposure
is determined retrospectively. Ideally, the data collectors are unaware
of whether a subject is a case or a control, and the data collectors
should be unaware of the study hypothesis. The cases and the
controls must be assessed for exposure in the same way.90 There are
both strengths and weaknesses in case-control studies. The strengths
include: a retrospective study has fewer constraints by the frequency
of the disease and it is easier to assess conditions where there is a
long latency between exposure and disease, and thus allows study
of rare occurrences, it has shorter waiting time than a prospective
cohort study, it is sometimes feasible when an randomized clinical
trial (RCT) is not and, as it uses existing records, it costs less and
has fewer practical restrictions. The weaknesses include: a less well
defined target population; risk of selection bias; and it is difficult
or impossible to ascertain cause-and-effect, because of confounding
factors.90 With a matched case-control study design, the control
subjects are selected so they resemble (match) the cases with regard
to certain characteristics (e.g., age, comorbidity, severity of disease).
The goal is to compare case and control patients who have similar
characteristics and thereby to adjust for potential confounders and
increase the precision of the comparison.90
47
In a cross-sectional study, the study sample is selected (e.g., the
population treated in a clinic), and the outcome variable (e.g., dental
implant failure) and the predictor variable (smoking) are measured
simultaneously. Because the data are collected at one point in time,
the investigator has no control over extraneous factors. In contrast to
a cohort study, there is no follow-up period in a cross-sectional study.
Cross-sectional studies are effective in determining the prevalence of
a disease (the proportion of the population that has a disease at a
particular point in time) and the coexistence of associated variables.
They do not give us information about disease/outcome incidence
(the proportion of the population that gets an illness or a failed dental
implant over a specified period of time).89
Cohort studies can also be used to establish the frequency of
a disease or event. A cohort is a group of patients with a specific
characteristic (e.g., patients being rehabilitated with dental implants).
An investigator may want to answer the question, ‘‘Do patients
who smoke present dental implant losses more often than patients
who do not smoke?” Using a retrospective cohort study design, the
investigator might look at all dental records of the cohort of patients
who lost an implant (the outcome variable), and match these records
with the cohort of patients without any dental implant lost. The
investigator can then review the records to see how often the presence
of smoking habits (the predictor variable) was documented in these
two cohorts. The retrospective nature of this study design means
the investigator is dependent on documentation of a dental implant
failure to properly classify patients. Cohort studies are particularly
effective at describing the incidence of disease and analyzing
associations between risk factors and outcomes, although it cannot
prove that the observed factor was the cause of the outcome.89 For
example, the result of an observational study may be that heavy
smoking and dental implant failure are associated with each other,
but the statement cannot be accurately made that heavy smoking
causes dental failure, based on the result of an observational study
alone.
Interventional studies, also known as clinical or experimental trials,
are used to address the question of causation. In this study type the
investigator intervenes in the events being studied by manipulating a
specific variable, and observing the effect of this manipulation on a
48
specified outcome.89 For example, a clinical trial might be designed to
investigate the effects of a drug agent added to a poor bone implant
site immediately before implantation on the implant survival. In such
a trial, the investigators would intervene in the management of the
implant site by the delivery of the drug or an appropriate placebo
in order to establish whether the use of the drug would result in an
improved osseointegration or clinical outcome.
Observational studies can be subdivided into retrospective and
prospective studies. The primary difference between these subdivisions
is the timing of the measurement of the outcome variable. In a
prospective study, the outcome variable has not yet occurred; the
investigator will measure it in the future. The investigator follows
the population over time, looking for the presence of the outcome
variable. All interventional studies are prospective.89
Retrospective studies
A retrospective study uses existing data that have been recorded for
reasons other than research. In health care these are often called
“chart reviews” because the data source is the medical record.90
A retrospective cohort study is based on a group of individuals
who are known to have been subject to a particular exposure or
intervention in the past, e.g. work environment, dental implants,
and about whom additional information has been collected from
existing sources, often medical records, concerning the consequences
of the intervention or exposure. Data for a retrospective study thus
suffer the limitation that they were originally collected and reported
in records but not standardized for a specific research purpose.
Retrospective cohort studies are usually less costly than prospective
cohort studies and also take less time to complete. However, they are
limited to studies of outcomes which have been documented insofar
as data are retrievable and reliable. Retrospective cohort studies are
especially suitable for studies of rare exposures, or where the latent
period between exposure and disease is long.
As advantages of this research design, the retrospective study can
help to focus the study question, clarify the hypothesis, determine an
appropriate sample size, and identify feasibility issues for a prospective
study. There are, however, several important disadvantages of a
retrospective study. First, the investigator depends on the availability
49
and accuracy of the medical record.90 There usually are gaps in
information and incomplete records. All data rely on the accuracy
of the original examination and documentation. Items may have been
excluded in the initial examination or not recorded in the medical
chart. Secondly, the retrospective study is subject to selection bias
because the investigator self-selects the cases.90 Thirdly, retrospective
studies are dependent upon the quality of information recorded by
the clinicians involved in the study. Since different clinicians may
practice differently, the retrospective study may demonstrate a larger
variability of techniques or materials.91 Fourthly, retrospective studies
tend to be conducted over longer periods of time. During those time
periods there is a greater likelihood that minor changes in materials,
techniques or designs can alter the therapy enough to create distinctly
different treatment groups. With these changes, survival data may also
change. If this is recognized, it is possible that the authors may describe
specific “before and after” data, but if it is not recognized, significant
improvements in design may not be apparent to the reader.91 An
actual example from many retrospective studies is implants followed
up over long time, without recognizing that machined implants were
used until one time period and modern, moderately rougher implants
from another time period. A potential benefit of the latter group may
“drown” in the information from the former group. Comparison of
pooled data in such a study could create erroneous impressions when
the reader compares the data to the results of other studies. For these
reasons, the use of time-dependent statistical analysis may be even
more critical to the establishment of meaningful conclusions with
retrospective studies.91
Prospective studies
In a prospective cohort study, the investigator is in the position to plan
and decide in beforehand what data to collect, when, and by which
method the data will be analyzed. Usually this type of study must
continue over a long period of time in order to observe a sufficient
number of cases, and thereby obtain a fairly reliable estimate of
incidence. The length of follow-up time required is dependent on the
incidence rate and the size of the population at risk.
Prospective studies generally have inclusion and exclusion criteria.
In some instances, prospective studies may be designed to eliminate
50
known risk factors that could contribute to higher failure rates. Well-
designed prospective studies consider the anticipated differences in
treatment outcomes when the number of subjects for enrollment is
considered; this is generally described as a power analysis.91
Prospective studies are generally more expensive to complete
since the study must enroll specific patients and must exclude
others. Data must be maintained. The dependence on personnel to
complete these tasks is greater with prospective studies. These studies
are generally performed over shorter time periods and often have
closer patient follow-up. The ability to discover late complications
or compliance related to complications with prospective studies is
thereby compromised.91
Clinicians and policymakers often distinguish between
the efficacy and the effectiveness of an intervention.
Efficacy trials (explanatory trials) determine whether an intervention
produces the expected result under ideal circumstances. Effectiveness
trials (pragmatic trials) measure the degree of beneficial effect under
“real world” clinical settings.92 Hence, hypotheses and study designs
of an effectiveness trial are formulated based on conditions of routine
clinical practice and on outcomes essential for clinical decisions.93
Of the principal methods available to measure effectiveness in
a prospective way, one important distinction is between non-
randomized studies and RCTs.
Controlled (non-randomized) clinical trial

A controlled clinical trial (CCT) is a clinical study that includesa
comparison (control) group. The comparison group receives a
placebo, another treatment, or no treatment at all. When the study
is not randomized, it is called non-randomized controlled trial or
simply CCT. The principal difference in design compared with an
RCT investigation is that participants in the trial are not allocated
at random to treatment.94 This kind of trial can detect associations
between an intervention and an outcome.
Because the trial participants are not randomly allocated to
treatment, the trial is liable to allocation bias. Allocation bias is a
systematic difference between participants in how they are allocated
to treatment.95 Because participants are not randomly allocated to
treatment and in case the treatment groups are not similar in the
51
number of participants, the two treatment groups are unlikely to be
similar in baseline characteristics. Therefore, the association between
treatment and outcome is prone to be confounding,94 in other
words, one cannot rule out the possibility that the association was
caused by a third factor linked to both intervention and outcome.96
Hence, the non-randomized controlled trial study design may not
promote internal validity.94 Internal validity is the extent to which
the observed results can be ascribed to differences in treatment and
not be confounding, thereby allowing the inference of causality to
be inferred.97
The potential contribution that non-randomized studies can make
to the evaluation of the effectiveness of healthcare interventions has
generated considerable debate. In particular, it has been suggested
that the lack of randomization in a non-randomized controlled trial,
which potentially leads to differences between treatment groups in
outcome owing to differences between treatment groups in baseline
characteristics, results in the study design having limited value.
However, in some trials random allocation may not be appropriate.94
Although not intrinsic to the design of non-randomized controlled
trials, when the trial is community based (an entire community within
the population is included in the trial), such an approach to sampling
of study participants promotes external validity, i.e. the extent to
which the study results can be generalized to the population that the
sample is meant to represent.97 This is in contrast to RCTs, which
often have stringent inclusion criteria and can recruit only those
patients who are willing to be randomized. This may introduce biases
that make the trial participants not representative of the population.94
Randomized clinical trials

RCTs are quantitative, comparative, controlled experiments in which
groups are randomly assigned to receive 1 of 2 or more educational
interventions. A large, well-designed and conducted RCT, in which
randomization is undertaken in a way that ensures that allocation
is actually random, will provide groups that can be expected
to be comparable in every way except for the intervention.98-100
Consequently, it is reasonable to attribute any significant observed
difference in outcome between the two groups to differences in
the effect of the interventions, provided both the practitioner and
52
patient are blinded and the outcome is assessed in a way that does
not introduce bias.98
The results of an RCT study can be analyzed and presented in
two ways: according to the treatment to which the patients were
randomized or according to the treatment they actually received.101
The planned treatment of the former demonstrates the efficacy of
a treatment, while the pragmatic latter alternative establishes its
effectiveness. The explanatory analysis is based on the principle that
avoidance of bias is a prime goal in the RCT study, that randomization
is the prime mechanism for avoiding bias, and that bias can arise
from any post-randomization made by patients or by investigators.102
More simply, the effectiveness study may be more prone to bias.
The disadvantage is that anything that happens to a patient after
a treatment has been randomly assigned is thereafter included in
the events ascribed to that treatment, regardless of why and how
the events occurred.103 Most RCTs adopt the explanatory analysis.
Therefore, clinicians should check the method of data analysis used
in the literature when they read the results of an RCT.91
Although randomization is considered the most powerful
experimental design in clinical trials, the method is not without
limitations. RCTs are more likely than observational studies to be
free of bias,104 but, because they usually enroll selected participants,
external validity may suffer. This problem of unsuitable participants
is also termed distorted assembly.102 Participants in RCTs tend to be
different (including being healthier105,106) than those who choose not
to take part, a function of the restricted entry criteria. Moreover,
the process of randomization can be compromised such that the
allocation results in biased groups of patients. A trial which has had its
randomization compromised may apparently show a treatment effect
that is entirely due to biased allocation. The results of such a study
are more damaging than results from an explicitly non-randomized
study, as bias in the latter is acknowledged and the statistical analysis
and subsequent interpretation takes this into account.107 In the past
attempts were not generally made to conceal randomization schedules
from investigators who recruited patients. However, unconcealed
randomization can lead to clinicians scheduling patients such that
patients with particular characteristics would receive a certain
allocation, thereby biasing the allocation.108 While much of the
53
evidence on subverting randomization is anecdotal, a review found
that randomization had been compromised in several controlled
trials.108 This review showed that trials which did not adequately
conceal randomization from the investigators demonstrated, on
average, a 41% increase in effect for the active treatment compared
with an adequately concealed trial.108 To avoid bias it is important that
randomization is well concealed. Recent evidence has questioned the
rigor of using local randomization (use on envelopes). Randomization
should be distant and separate from clinicians (telephone or internet
randomization) conducting the trial.107
RCTs are certainly not the most appropriate research design for
all questions.109 For example, for etiological questions, it would
neither be possible or ethical to randomize subjects to many harmful
exposures.88 Exposing patients to an intervention believed to be
inferior to current treatment is often thought unethical.96 In other
circumstances an RCT study may be ethical but infeasible - for
example, because of difficulties with randomization or recruitment.96
Randomization is unnecessary when the effect of an intervention
is so dramatic that the contribution of unknown confounding
factors can plausibly be ignored. Examples include penicillin for
streptococcal infection and defibrillation for ventricular fibrillation.98
Randomization may be inappropriate where a trial would have to be
of disproportionate size and duration, and thus expense, if it were
to detect very rare long-term adverse effects or the impact of policies
designed to prevent rare events.98 Randomization may be misleading
where the process of random allocation may affect the effectiveness
of the intervention. This can arise when the subjects cannot be
blinded to the intervention because the intervention requires their
active participation, which in turn will be affected by their underlying
beliefs and preferences.98 Strong patient preferences may also limit
recruitment and bias outcomes if not accommodated within the study
design.110
If a population contains many individuals with little ability to
benefit from the intervention in question and a few with a high ability
to benefit, even though the overall sample size is large, the latter
group may be very small and randomization may not ensure that
they are evenly distributed between the two arms. In this case, the
disproportionate effect exerted may lead to serious bias.111
54
Most evaluative studies fail to document adequately the
characteristics of eligible patients who do not participate. The
effect of non participation differs between RCTs that evaluate
interventions designed to treat an existing condition and those
directed at preventing disease.112 Participants in the former tend to
be less affluent, less educated, and more severely ill than eligible
patients who do not participate.113 In contrast, participants in RCTs
evaluating preventive interventions tend to be more affluent, better
educated, and more likely to have adopted a healthy lifestyle than
patients who decline.114 It is plausible that low participation in RCTs
of treatment may exaggerate treatment effects by including more
skillful practitioners and subjects with a greater capacity to benefit,
while RCTs of prevention may underestimate effects as participants
have selectively less capacity to benefit.115 Studies of RCTs with
varying quality of randomization have shown that inadequate or
unclear methods of treatment allocation exaggerate effect sizes.108
A large, inclusive, fully blinded RCT incorporating appropriate
subgroup analysis is likely to provide the best possible evidence
of effectiveness, but there will always be circumstances in which
randomization, especially on an inclusive basis, is unethical or
impractical.116 In circumstances where there are genuine reasons
for not randomizing,117 non-randomized studies can provide useful
evidence. In such studies, adjustment for baseline imbalances should
always be attempted, as rigorously and extensively as possible,
and the procedures should be reported explicitly to help readers’
evaluations.115
Randomized versus non-randomized studies

Evaluations of healthcare interventions can either randomize subjects
to comparison groups, or not. In both designs there are potential
threats to validity, which can be external (the extent to which they
are generalizable to all potential recipients) or internal (whether
differences in observed effects can be attributed to differences in
the intervention).115 Non-randomized studies face greatest risk to
their internal validity through allocation bias, though it may be
possible to overcome this during analysis, by either risk adjustment
or examination of comparable subgroups. The internal validity
of unblinded RCTs may also be threatened by the consequences
55
of patient preference, which may result in misleading estimations
of treatment effect.98 Threats to external validity have been seen
as of greater importance for RCTs, though the issue also arises in
non-randomized studies. This can be due to restricted eligibility
criteria, which can be addressed by expanding the criteria, or limited
participation by centers or by patients and practitioners, which can
be addressed by ensuring the design is pragmatic with less demanding
consent requirements. Potential subjects may not be invited to
participate in the research because of practitioner preferences for one
of the treatments or simply due to administrative oversight.98 Some
investigators have argued that RCTs tend to exclude, consciously or
otherwise, some types of patient to whom results will subsequently
be applied. Furthermore, in unblinded trials the outcome of treatment
may be influenced by practitioners’ and patients’ preferences for
one or other intervention. Though non-randomized studies are less
selective in terms of recruitment, they are subject to selection bias
in allocation if treatment is related to initial prognosis.115 Various
factors act through their effect on the distribution of the potential to
benefit among different groups. As patients are excluded or do not
participate, the study population becomes a progressively smaller
subset of the reference population, in principle increasing the scope
for selection bias and raising the question of whether it is valid to
apply the results obtained to the reference population.115 It is argued
that non-randomized studies, which often have more inclusive
entry criteria and procedures, may include subjects that are more
representative of the population to whom the results will be applied.
The process of recruitment, in which only individuals willing to be
randomized will be recruited, may introduce hidden biases that make
subjects unrepresentative of the reference population.98
An RCT study may produce a greater effect if the patients enrolled
in it receive higher quality care or are selected so that they have
greater capacity to benefit than patients in non-randomized studies.
However, the RCT study may produce a lower estimate of treatment
effect for several reasons: (1) in non-randomized studies, patients
tend to be allocated to treatments that are correctly considered most
appropriate for their individual circumstances; (2) exclusions from
an RCT create a sample with less capacity to benefit than in a non-
randomized study; (3) an unblinded RCT fails to capture patients with
56
strong preferences for a particular treatment who show an enhanced
response to treatment; (4) non-randomized studies of preventive
interventions include disproportionate numbers of individuals who,
by virtue of their health related behavior, have greater capacity to
benefit; (5) publication bias leads to negative results being less likely
to be published from non-randomized studies than from RCTs.115
The limited evidence indicates that the results of non-randomized
studies best approximate to results of RCTs when both use the
same exclusion criteria and when potential prognostic factors are
well understood, measured, and appropriately controlled in non-
randomized studies.118 The results of RCTs and non-randomized
studies of similar patients may not, after adjustment, be substantially
different in relative effect size. Any variations are no greater than
those between different RCTs or among non-randomized studies.
Differences in effect sizes could be due to chance or differences in
populations studied, timing, or nature of the intervention.115 Britton
et al.98 observed that within the limits of statistical significance, the
results obtained by the randomized and non- randomized studies are
frequently similar and that any differences were most often, but not
always, of similar magnitude of estimated treatment effect rather
than in the same direction, and only rarely did the two approaches
favor different interventions.
Evaluative research is undertaken predominantly in university or
teaching centers, but nonrandomized studies are more likely than
RCTs to include nonteaching centers, and criteria for participation
in RCTs may include the achievement of a specified level of clinical
outcome.115 The available evidence suggests that this may exaggerate
the measured treatment effect.119
When both randomized and nonrandomized studies have been
conducted it is important to ascertain whether estimates of treatment
effect are consistent for patients at similar risk across studies. If so,
it may be reasonable to accept the results of the less exclusive non
randomized studies. Differences in results cannot be assumed to be
solely due to the presence or lack of randomization - differences in
study populations, characteristics of the intervention, and the effects
of patients’ preferences may also affect the results.115
57
Reviews
Narrative review
Narrative reviews are the traditional approach and usually do not
include a section describing the methods used in the review. These
reviews are generally on a very broad topic, they use informal,
unsystematic and subjective methods to search for, collect and
interpret information, which is often summarized with a specific
hypothesis in mind, and without critical appraisal, and summarized
with an accompanying convenient narrative. Though these narrative
reviews are often conducted by people with expert knowledge of
their field, it may be the case that this expertise and experience may
bias the authors. The absence of a clear and objective method section
leads to a number of methodological flaws, which can bias the
author’s conclusions.120 Thus, it can be said that narrative reviews
are highly subjected to publication selection bias, and it can favor
one treatment in comparison of another one based on the author’s
biased preferences to choose the studies. Authors tend to choose
papers that agree with their point of view and also tend to effusively
quote themselves.
Systematic review
Systematic reviews of interventions require a thorough, objective and
reproducible search of a range of sources to identify as many relevant
studies as possible (within resource limits). This is a major factor in
distinguishing systematic reviews from traditional narrative reviews
and helps to minimize bias and therefore assist in achieving reliable
estimates of effects.121
By addressing the methods of the identified primary studies,
systematic reviews and meta-analyses can identify common
methodological weaknesses and errors that might materially affect the
results – these may be missed using a less systematic approach.88 By
weighting the trials and producing a pooled overall estimate, which
is a quantitative, rather than a qualitative assessment of the apparent
strength of the results, systematic reviews may often conclude that
the effect of a treatment is less impressive than a traditional narrative
review would conclude.88
There is evidence that systematic reviews improve the reliability
and accuracy of the conclusions, however the results are rarely
58
unequivocal and require careful appraisal and interpretation:122
clinicians therefore need to integrate the results with clinical expertise
and the patient’s preferences.
There are several forms of systematic bias that need to be
considered in reviews. One of the most important is selection bias,
in other words, a systematic bias in the selection of primary research
studies that are included in the review. For example, a reviewer may
only select those studies that support his prior beliefs. Selection bias,
however, may also be due to “publication bias” (the tendency of
investigators, reviewers and editors to differentially submit or accept
manuscripts for publication based on the direction or strength of the
study findings),123 “language of publication bias” (studies finding a
treatment effect are more likely to be published in English-language
journals, whilst opposing studies may be published in non-English-
language journals124 and biases introduced by an over reliance on
electronic databases (electronic databases do not offer comprehensive
or unbiased coverage of the relevant primary literature).88
Unfortunately, there is considerable evidence that key information
is often poorly reported in systematic reviews, thus diminishing their
potential usefulness.125 Systematic reviews may differ in quality, and
yield different answers to the same question.126 As a result, users
of systematic reviews should be critical and look carefully at the
methodological quality of the available reviews.127 Therefore, when
performing systematic reviews, it is important to make use of
instruments in order to attain certain methodological quality, such
as the AMSTAR128 or guidelines such as PRISMA,129 an evidence-
based minimum set of items for reporting in systematic reviews and
meta-analyses.
The use of meta-analysis

Systematic reviews usually, but not necessarily, apply meta-analysis
to examine a research question.130 Meta-analysis is the statistical
combination of the results of several studies into one pooled value
and can be a useful way of reducing random error and increasing
precision.88 Meta-analyses generally provide a greater degree of
precision when compared with other study types because the estimate
from the combined studies is based on a larger sample than any of
the individual studies. This will provide narrower 95% confidence
intervals than any study conducted on its own.131
59
A meta-analysis can be misleading unless it is performed in the
context of a systematic review of the literature to avoid systematic
biases. Whereas a systematic review can be applied to any form of
research question, a meta-analysis should not be used indiscriminately,
especially when the primary data are inadequate.88 The first stage in
conducting a systematic review is the formulation of a clear question.
The nature of the clinical question determines the optimal primary
study design and hence the a priori inclusion and exclusion criteria.88
The most reliable study design would be an RCT. Systematic reviews
of studies other than RCTs have their own methodological problems:
guidelines exist for undertaking reviews (and meta-analyses) of
diagnostic tests132 and the observational epidemiological designs used
in etiological research.133 A different approach would be to select
specific studies, but this has its problems as well and opens the door
to biased choices. The studies selected for meta-analyses are usually
all of high quality – often it is an inclusion criterion that they are
randomized and double blind.130
Meta-analysis may not always be appropriate. First of all, it is
necessary to ensure that the individual studies are really looking at
the same question: the criteria used to select including studies and
to assess the quality of the studies included should be explicit and
consistent with the focus of the review. Results from poor quality
studies can result in misleading conclusions and so inclusion of these
studies in a meta-analysis may bias the pooled result towards an
overestimate of the effectiveness of the intervention being evaluated.134
The methodological quality of the included studies is important even
if the results or quality of the included studies do not vary: if the
evidence is consistent but all the studies are flawed, the conclusions
of the review would not be nearly as strong as if consistent results
were obtained from a series of high quality studies.88
Potential biases are likely to be greater for non-randomized studies
compared with RCTs, so results should always be interpreted with
caution when they are included in reviews and meta-analyses.121
So what was the reason to include non-randomized studies in the
present meta-analysis? The issue is important because meta-analyses
are frequently conducted on a limited number of RCTs.135 Shrier136
gave fundament to this observation by reviewing a random 1%
sample of meta-analyses published by the Cochrane Collaboration
60
in 2003 and found that 6 of 16 reviews included two studies or fewer.
Furthermore, 158 of 183 analyses conducted in 7 additional studies
were limited to two or fewer studies. Given the limited number
of RCTs included in 13/16 reviews, the inclusion of other types
of evidence — for example, cohort, case-control, basic science —
would probably have provided a stronger foundation for a rational
decision of treatment.136 In meta-analyses such as these, adding more
information from observational studies may aid in clinical reasoning
and establish a more solid foundation for causal inferences.135 In
a meta-analysis, homogeneity implies a mathematical compatibility
between the results of each individual trial. Narrowing the inclusion
criteria increases homogeneity but also excludes the results of more
trials and thus risks the exclusion of significant data. In the Cochrane
Review approach, if one RCT is available then all ‘‘weaker’’ data are
ignored. However, it is not clear how much stronger the data needs
to be to ignore ‘‘weaker’’ data.137 Further, it ignores the fact that other
types of studies could help the reviewer discuss treatment effectiveness
in other populations — for example, different age groups — or
similar but not identical conditions.136 Cochrane Reviews currently
enjoy a credibility level that may not be warranted. Reviews that are
based on zero, one, or two RCTs without reference to other types
of evidence may be omitting important information that would be
useful to a clinician who needs to treat actual patients.136
A drawback associated with meta-analyses includes lack of
accepted or consistent methodology in a scientific study(s), which
can bias the results. This can lead to inaccurate estimates of the
effectiveness of clinical procedures. Important caveats to consider
in a meta-analysis include pooling of data and conflicting results of
studies, which can influence outcomes. In addition, the consistency
in clinical and research methodology that has been used, the sample
sizes, number of variables in a study design, and the probability for
error or bias in the results of clinical studies need to be considered
when performing a meta-analysis.131
Data analysis
Survival analysis
With any study there is a need for data analysis. Whether data are
followed forward (prospective study) or backward (retrospective
61
study), they must be collated and evaluated in such a way as to make
them meaningful. Raw data can be easily distorted to demonstrate
results that do not adequately describe clinical performance. Statistical
analysis of data, particularly time-dependent analysis, is more valuable
if there is a risk of time-dependent deterioration, complication, or
failure.91 Studies of how patients respond to treatment over time are
fundamentally important to understanding how therapies influence
quality of life and progression of disease during survivorship.138
Survival analyses are statistical methods used to examine changes
over time to a specified event. It follows comments on some of the
used methods of survival analysis.
Life table
The most straightforward way to describe the survival in a sample
is to compute the life table, or the Cutler-Ederer method.139 The life
table technique is one of the oldest methods for analyzing survival
data. The distribution of survival times is divided into a certain
number of intervals. For each interval we can then compute the
number and proportion of cases or objects that entered the respective
interval ‘alive,’ the number and proportion of cases that failed in the
respective interval (number of terminal events, or number of cases
that died, or number of dental implants that failed), and the number
of cases that were lost or censored in the respective interval. Based
on those numbers and proportions, several additional statistics can
be computed, such as, the number of cases at risk, proportion failing,
proportion surviving, survival function, hazard rate, and median
survival time. This procedure is used for larger samples where the
time intervals are large enough to be broken down into smaller
units.140
The advantages of the life-table analysis were listed by Ferguson:141
(1) the method uses the data of all patients; (2) calculations are simple
enough to be performed by a non-statistician and by hand; (3) it does
not require knowledge of exact follow-up times; (4) hypothesis testing
is based on distribution-free methods. That is to say, no assumption
is required regarding the distribution of survival times and, therefore,
the form of the survival distribution need not be known. This is
particularly important, since in general it is not known; (5) results
can be represented graphically, promoting comprehension and
62
simplifying communication of results. This is particularly important
when the target audience consists of non-statisticians; (6) life tables
can suggest which factors are important for establishing a prognosis,
for example, by comparing life tables in separate patient categories
based on treatment, gender, etc; (7) the log-rank test is optimal for
assessing the equality of life tables when the event rate in one group
consistently exceeds that of another; (8) the log-rank tests can be used
to compare more than two groups; (9) it is possible to adjust survival
comparisons for the confounding effects of prognostic variables by
means of a stratified log-rank test. However, the potential to do so
is limited compared with other techniques, for example, regression
based on the proportional hazards model.
As disadvantages of the life table, it can be said that141 (1) the life-
table analysis shows cumulative event-free survival and, therefore,
does not directly show changes in the event rate; (2) it does not take
into account the exact ordering of dental implant losses within each
interval; (3) it is an approximation to the Kaplan-Meier product-limit
survival estimate and owes its popularity, in some measure, to the
relative ease of calculations performed in large data sets. However,
this is no longer an important consideration given the ubiquity of
computers; (4) survival estimates are somewhat arbitrary in that
they depend on the time intervals chosen. This is not a problem
with the Kaplan-Meier product-limit method of survival analysis;
(5) large steps and long flat regions in the survival curve can result
from small numbers of patients at risk. These distortions are not
biologically significant; (6) the most recent observations are the least
reliable because of the decreasing number of patients at risk for the
event of interest; (7) the log-rank test is relatively insensitive to early
differences in event-free survival. Consequently, it is less likely than
the Gehan test to detect these.
More specifically to the implant dentistry, it is possible to report
5-year cumulative survival rate (CSR) results before all implants have
been followed up for a full of 5 years, i.e. a considerable advantage
for those who wish to report results as rapidly as possible. Hence, the
CSR technique involving the use of so called life tables presents a quite
good way of reporting clinical outcome with one major exception;
the treatment of so called drop-out patients that are assumed to have
the same results as those remaining in the study. This may be true for
63
patients who have not, as yet, had the chance of being followed up for
the decided time period, it may further be true for those patients who
die with their implants in situ, but it is a great risk that it is untrue for
many other patient categories where patient drop outs may coincide
with more actual implant problems compared to those who remain in
a study. In the drop-out category, it is possible that a number of high
risk patients may be lost to follow-up. Similarly dissatisfied patients
are unlikely to return for follow-up care which further underestimates
the number of failures experienced in the patients who do not return.
If high risk and dissatisfied patients are lost their higher incidence of
implant failure would not be recorded thereby providing the reader
with the impression that a higher number of implants succeed than
is actually the case. The solution to this potential misrepresentation
is to count all “dropouts” as clinical failures and let data so handled
present the lower confidence interval and then to conversely count
all “dropouts” as successes and record this as the upper confidence
interval. The way that most articles are reported today is to ignore the
dropouts entirely and simply report the performance of the known
or followed patients. When reporting this, the authors are making a
concerted effort to describe in the life table all the known data but
may not recognize that this method likely inflates the results. We are
likely to have an overrepresentation of drug abuse and other risk
patients and, furthermore, dissatisfied patients who do not wish to go
back to the treating dentist that well may represent double the failure
rate compared to those who remained in the study.
One more disadvantage of life tables as used in implant dentistry is
that too few implants have been included that are actually followed
up for the full study period, hence a study that is titled as a “five-year
cumulative survival analysis” frequently presents results in which
only a very small percentage of patients treated in the study have
reached the described five-year time frame. A more appropriate title
might describe a mean survival with up to a maximum of five years.
The presented 5 year CSR-outcome has a substantial uncertainty in
that it is assumed that these very few implants reflect the reality for
each and every implant of the study. Another substantial shortcoming
of commonly used simple CSR tables in most dental implant reports
is that too little data is being presented in the tables that, at best,
present a survival rate.
64
It is also important to stress that life-table analyses are based
mainly on criteria that are easy to evaluate (e.g. implant function
and immobility, no pain) instead of criteria that are more difficult
to evaluate (e.g. peri-implant pocket depth, bleeding disposition,
and bone loss), but which would provide more information about
peri-implant soft and hard tissue health.142 Life-table analyses that
consider multiple implants placed in one patient produces data that
are not independent (i.e., they have some common variables that may
predispose to failure). Thus, statistics based on each implant as the
index of analysis may lead to bias. Others have suggested selecting
one implant at random for each patient providing independent
data,143 but this method discards much of the data collected144 and
has the drawback of falsifying the result depending on false positive
or negative choices.142
Kaplan-Meier analysis
The Kaplan-Meier (KM) method is maybe the most prevalent in the
dental literature.91 Kaplan and Meier145 first described the approach
and formulas for the statistical procedure that took their name. The
method permits estimation of subject survival over time, even when
subjects are lost to follow-up or followed for different lengths of
time.91 Incomplete observations often occur because contact with
some sample members is lost before the event, some other intervening
variable affects the event, or insufficient time has passed to observe
the event in all sample members. Any of these cases would result in
a participant being censored.138 At each time point, the KM method
typically involves computing the number of subjects that had died at
each time point (numerator) divided by the total number of subjects
that were still in the study at that time point (denominator). The
censored cases, i.e. the subjects who are lost to follow-up, are no
longer included in the denominator from the first time point at which
they were lost.91 The KM method allows the practitioner to estimate
the probability of a subject surviving at a given time point, e.g., 5
years, from the cumulative probability of a subject surviving each
preceding time interval (years 1, 2, 3, and 4). Therefore, although a
probability calculated in a given interval may not be accurate because
of a relatively small number of subject deaths in that interval, the
overall probability of surviving to each time point is more accurate.91
65
The KM method is not without limitations. Missing data is a
problem that can potentially bias data analyses and statistics. An
important assumption is that censored patients have the same
likelihood of survival as those continuing in the study (an assumption
not easily testable), and that survival probabilities are the same
whether individuals enter a study early or late.146 One important
way to deal with this is to track the numbers of patients in each
arm who withdraw and reasons for withdrawal and to include this
information in research reports.138 In most studies some subjects drop
out for reasons unrelated to the condition under study (for example,
emigration). If, however, for some patients in this study censoring was
related to failure to conceive this would have biased the estimated
survival probabilities downwards.147 Completeness of follow-up is
important, especially in clinical trials, since unequal follow-up in the
treatment groups can bias the analysis of results. In survival studies,
information on participants who do not complete the study is often
omitted because their data can be included up to the time at which
they were lost to follow-up.148
A second assumption would be that the survival probabilities are
the same for subjects recruited early and late in the study.147 In a
long term observational study of patients with dental implants, the
cohort may change over the period of recruitment, or there may
be an innovation in treatment, for example, turned implants were
installed at the beginning years of the study and then enlarged-surface
implants were adopted. A third assumption is that the event happens
at the time specified. This is not a problem for the conception data,
but could be, for example, if a dental implant failure was detected at
a regular examination. All we would know is that the event happened
between two examinations. This imprecision would bias the survival
probabilities upwards.147
Most clinical trials have a minimum follow-up time, at which point
the status of each patient (implant) is known. The survival rate at
this point becomes the most accurate reflection of the survival rate
of the group. Survivor function at the far right of a Kaplan-Meier
survival curve should be interpreted cautiously, since there are fewer
patients remaining in the study group and the survival estimates are
not as accurate.149 After the first patient is censored the survival curve
becomes an estimate, since we do not know if censored patients would
66
have experienced an event at some point later in their life. Thus, the
more patients censored in a study (especially early in the study), the
less reliable is the survival curve. Ludbrook and Royse150 showed that
the KM approach underestimates the cumulative survival probability.
The KM method for estimating survival or incidence is unsuitable for
use when there are two competing risks. It occurs because if relapse
is the event of interest, then according to the KM method, both those
who are dead and those alive should be censored. But unlike the
case in which there is only one event and observations are censored
because the subject is alive or is inaccessible to further follow up,
death precludes the possibility of relapse.150 However, the presence
of competing risks is more common in cancer studies, not in dental
implant studies. As examples of competing risks,148 there would be
death from a cause “not tumor related”, precluding the observation
of death from cancer, death precluding the observation of time to
diagnosis of a second cancer in lymphoma patients after high-dose
chemotherapy and stem-cell transplants, and analysis of local and
distant recurrence.
Likewise, it is helpful to know why patients were censored. If many
patients were censored in a given group(s), one must question how
the study was carried out or how the type of treatment affected the
patients. This stresses the importance of showing censored patients
as tick marks in survival curves.149
Moreover, the shape of the KM survival curve is important to
evaluate. Curves that have many small steps usually have a higher
number of participating subjects, whereas curves with large steps
usually have a limited number of subjects and are thus not as accurate.
Concerning the amount of censored subjects and the distribution of
censored subjects, if there is a large number of censored subjects one
must question how the study was carried out or if the treatment was
ineffective resulting in subjects leaving the study to pursue different
therapies. A curve that does not demonstrate censored patients should
be interpreted with caution.149
Cox Proportional Hazards Regression

Cox proportional hazards regression is widely used to assess the
influence of multiple factors on time to event.151 It is one of the most
popular regression models in medical research. The model enables
67
one to assess a relationship between patients’ (or dental implants’)
survival time and one (univariable) or multiple (multivariable)
explanatory variables. Additionally, it allows an estimated risk of an
event occurrence for an individual to take into account statistically
significant prognostic variables.152 Similarly to other regression
analyses, Cox regression produces coefficients which provide an
estimate of size of effect due to the variable of interest as well as
confidence intervals. These estimates are called hazard ratios (HR)
and represent the chance of the event (e.g. dental implant loss)
occurring in those with the variable of interest (e.g. smoker) as a
ratio of the hazard of the event occurring in those without (e.g.
non-smoker). Therefore a HR of 1 represents no difference while a
HR of 3 implies that at any time point the event will occur 3 times
more commonly in those with the variable of interest compared to
control participants. In the case of continuous predictor variables
the HR represents the ratio of hazards for each unit of change in
the predictor variable. The HR does not provide information about
speed of time to event (or recovery) so it is incorrect to interpret a
HR of 3 as saying people with the treatment will recover 3 times
faster than those without the treatment.153 In other words, the HRs
of two people are independent of time, and are valid only for time-
independent covariates. This means that the hazard functions for
any two individuals at any point in time are proportional.140 If an
individual has a risk of having a dental implant failure at some initial
point in time that is twice as high as that of another individual, then
at all later times the risk of implant failure remains twice as high.
Then, a key assumption when performing Cox regression is that the
HR for the explanatory variable is relatively constant across time.154
When the HR for the explanatory variable is not constant
across time (the curves cross in the plot of survival curves, and the
HR clearly changes over time), then there is strong evidence the
proportional hazards assumption is violated.154 An example would
be a trial comparing steroid injection to exercise therapy in people
with sub acromial impingement as the HR would likely change over
time. The event of interest could be time to 50% reduction in pain.
In the short term (e.g. day 1) you would expect more people to have
the event if they received steroid injection, however, at a later time
point (e.g. 6 weeks) it is likely a larger number of people receiving
68
exercise therapy will have the event. This is a clear violation of the
proportional hazards assumption. Cox regression cannot be used
in this case without modifications.154 One strategy to deal with
situations where the proportional hazards assumption is violated is
to divide the time interval.155 In other words the HRs are generated
for smaller intervals of time where the HR is more constant.
Multilevel mixed effects parametric survival approach

The multilevel mixed effects parametric survival model is a very
recent survival statistical analysis. The model is used in the analysis of
clustered survival data, such as repeated events, multicenter clinical
trials, and individual participant data meta-analyses, to investigate
heterogeneity in baseline risk and covariate effects.156 It takes into
consideration that the occurrence of clustered survival data is
commonplace in medical research, where event times are clustered
within groups of the same or similar individuals, which means event
times from the same group are likely to be correlated. It considers
situations where a researcher wants to make an average inference
across all clusters while accounting for any heterogeneity between
clusters.156
The method is very recent, and as the developers of this statistical
model stated, further work is needed to evaluate the estimation
methods in clinically realistic scenarios, to investigate how well it
performs for varying effect sizes, heterogeneity standard deviation
sizes, number of clusters, and number of participants per cluster.156 A
deeper discussion about the advantages and limitations of the method
would be, statistically speaking, too complex, which goes beyond the
scope of the present text.
Only few studies have used the method in the dental literature for
the analysis of implant failures.157-161
Binary logistic regression

Logistic regression models are used to study effects of predictor
variables on categorical outcomes and normally the outcome is binary,
such as presence or absence of disease, in which case the model is
called a binary logistic model.162 An event is a binary variable that
can only have a yes or no value (e.g., dental implant failure, death,
69
hospital discharge or readmission, heart attack, recovery from an
infection, relapse from smoking cessation, etc.).138
Logistic regression may include only one or multiple independent
variables, although examining multiple variables is generally more
informative because it reveals the unique contribution of each variable
after adjusting for the others.163 And this is important in implant
dentistry, since implant failure frequently involves many different
factors. For a logistic regression model with only one independent
variable, the odds ratio (OR) is considered ‘‘unadjusted’’ because
there are no other variables whose influence must be adjusted for or
subtracted out. In contrast, if the logistic regression model includes
multiple independent variables, the ORs are now ‘‘adjusted’’ because
they represent the unique contribution of the independent variable
after adjusting for (or subtracting out) the effects of the other variables
in the model. As a result, adjusted odds ratios are often lower than
their unadjusted counterparts.163
Carefully selecting one’s independent variables is an essential step.
While logistic regression is quite flexible in that it accommodates
different variable types, including continuous (e.g., age, implant
length), ordinal (e.g., local bone classification in quantity or quality),
and categorical (e.g., implant surface, implant system, reason for
tooth extraction before implantation), one must always justify
variable selection using well-established theory, past research,
clinical observations, preliminary statistical analysis, or some sensible
combination of these different options.163 One must always keep in
mind that too many independent variables in the model may lead to
a mathematically unstable outcome, with decreased generalizability
beyond the current study sample.164,165 Thus, it is suggested that first
a univariate effect of each factor on implant failure is evaluated and
then only the factors that shown to have a statistically significant
effect size in the univariate logistic regression would be included in
the multiple/multivariate analysis.
Concerning the selection of the independent variables, the
challenge is to select the smallest number of independent variables
that best explains the outcome while being mindful of sample size
constraints.164,165 For instance, if one selects 50 people for the study
sample and includes 50 independent variables in the logistic regression
analysis, the result is an overfit (and therefore unstable) model.
70
An overfit model has estimated beta coefficients for independent
variables that are much larger than they should be, as well as higher
than-expected standard errors.164
What, then, is the correct number of outcomes for avoiding an
overfit model? While there is no universally accepted standard, there
are some common “rules of thumb” based in part on simulation
studies. One such rule states that for every independent variable,
there should be no fewer than 10 outcomes for each binary category
(e.g., lost implant ⁄ survived implant), with the least common outcome
determining the maximum number of independent variables.166,167 For
example, in a dental implant failure study, assume that 30 patients
lost dental implants and 600 patients did not lose any implant. The
logistic regression model could reasonably accommodate, at most,
three independent variables (since 30 is the smallest outcome).
However, the issue has not been definitively settled, and some would
argue that fewer than 10 outcomes per independent variable may be
appropriate in certain research contexts.164
Generalized estimating equation

In clinical dental research, each participant often contributes multiple,
potentially clustered observations to a database. For example, in dental
implants, multiple implants placed within the same individual will be
clustered or correlated. It is common practice for those conducting
dental research to assume independent outcome observations in
survival analyses.168,169 These approaches tend to underestimate the
variability of the estimated covariate effects or survival probabilities,
because the possible within-cluster correlations are overlooked. To
account for correlation, many authors have recommended randomly
selecting 1 implant per person, and the use of only the subset for
analysis.53,170 However, this approach does not fully utilize all the
available information, and thus may be inefficient. This gives rise
to the need for the application of other methods that can efficiently
analyze clustered dental survival data.171
Responses measured on the same subject are usually assumed to
be correlated and, therefore, a proper modeling approach is needed
that accounts for within subject correlation.172 One of the most
important approaches is the generalized estimating equation (GEE)
proposed by Liang and Zeger.173 Particularly in implant dentistry,
71
the method accounts for the fact that repeated observations (several
implants) can be available for a single patient. Because the outcome
relating to implants within a single patient must be more closely
correlated to each other than implants in separate patients, ignoring
these correlations could result in a bias in p-value computations.174
A deeper discussion about the advantages and limitations of
the method goes beyond the scope of the present text, being
very complex and specific to advanced statistics. Literature
about it has been published.175,176
Clinical factors
Time of follow-up
When a reader compares studies, it is critical to compare similar time
periods and time intervals. If a study begins many years prior to a
second study, it is distinctly possible that results of the two studies
may differ simply because of changes in the standards of practice that
occurred during the time period covered by the two studies. When two
studies are conducted in two distinctly different time periods, even if
the duration of the studies is similar, distortion of results is possible.
It is distinctly possible that the earlier study may represent a different
generation or version of the device being tested and therefore may
have little relevance to the more current study. Materials, devices,
and techniques used in the 1980s study may not even be available
for use a decade and a half later. Therefore, comparisons that lead
to conclusions about the two different approaches should not be
made.91
Moreover, when studies differ in follow-up periods, a longer
follow-up period can lead to an increase in the failure rate, especially
if it extended beyond functional loading, because other prosthetic
factors can influence implant failure from that point onward. This
might lead to an underestimation of actual failures in some studies.
Long-term survival rates of implants are critical for clinicians to
consider before they can make decisions to place them in their
patients.
Sample size
A research can be conducted for various objectives. It may be done
to establish a difference between two treatment regimens in terms
72
of predefined parameters like beneficial effects, side effects, and risk
factors of these regimens. It may also be carried out to prove similarity
between groups. Sometimes, the purpose may be to achieve certain
estimation in the population, such as the prevalence of a disease.
Whatever the aim, one can draw a precise and accurate conclusion
only with an appropriate sample size. A smaller sample will give a
result which may not be sufficiently powered to detect a difference
between the groups and the study may turn out to be falsely negative
leading to a type II error. A study on a small sample is quite tempting
for obvious reasons, but it is a waste of time and money as the result
will be invariably inconclusive. Very often, a small sample size is
decided arbitrarily based on the researchers’ convenience, available
time, and resources, resulting in a null trial due to insufficient number
of subjects studied. The underpowered studies should be interpreted
cautiously and the ‘absence of evidence’ in these studies should not be
taken as ‘evidence of absence’. Only for a rare disease or indication
is an underpowered study justified, due to logistics as the data from
such a study is helpful in meta-analysis.177
Concerning implant dentistry, because implant survival rates
are generally high, sample sizes need to be large to demonstrate
statistically significant differences for meaningful clinical differences
in implant survival performance.91 When a new dental implant is
evaluated for its clinical efficacy, there might be conflicting results
from the published literature. For instance, two different studies
might have reported opposite conclusions about the dental implants
being good for their patients. However, one of the studies might have
placed the implants in a smaller group of patients (e.g., 20 patients)
by a single surgeon, while the second study might have carried out
a larger RCT (e.g., 2000 patients). The conclusions from the second
study might carry more validity in terms of being more acceptable to
clinicians, while the first study’s conclusions might constitute a mere
opinion from a clinician’s experience. When appraising the literature,
the dentist needs to consider these previously mentioned factors so
that the more valid study results can be used clinically.131 A power
analysis would permit a clinician researcher to predict the number
of implants that need to be included in a study for it to provide data
that can be analyzed in a statistically meaningful manner.91
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Unaccounted for implants in drop out patients
The probability of missing data is particularly high in longitudinal
epidemiological studies.178 Subject loss to follow-up is a form of
selection bias that is particular to the cohort design.179,180 It occurs
when subjects are permanently lost to follow-up.181 Loss to follow-up
is inevitable in most cohort studies and commonly leads to bias
and loss of statistical power.182,183 Loss to follow-up can severely
compromise a study’s validity. Incomplete follow-up biases the
results when either the dropout rates are different between study
groups or the patients who drop out are different from those who
do not drop out. These situations make a difference because in each
situation, those lost to follow-up often have a different prognosis
than those who complete the study.184 For example, patients with
dental implants may not return for follow-up because they might
think that there is no problem and felt no need to return to see the
surgeon. Conversely, some patients may not return because they had
a particularly bad outcome or complication and had chosen to go
to another dentist instead, or because they died. In either case, bias
can affect the validity of the inferences drawn from the study. Some
have suggested that <5% loss of follow-up leads to little bias, while
>20% poses serious threats to validity.185 This may be a good rule of
thumb, but keep in mind that even small proportions of patients lost
to follow-up can cause significant bias.186 In the presence of missing
data, the choice of analytical method has important implications on
the estimates of the outcome response and of the relationship of the
outcome to predictors. That is, the effect of missing data on inference
depends on the underlying missingness process.178
When it comes to the implant dentistry, Albrektsson and Zarb187
suggested that each and every implant should be evaluated as part
of a four-grade scale representing success, survival, unaccounted for,
and failure. The success category includes implants that meet (and
have been tested for) all of the success criteria, including stability
tests and individual radiograms. The survival category encompasses
those unattached implants that were not checked for mobility, where
periapical films were not used, or where the prosthesis was not
removed at the evaluation for other reasons. Such implants can never
be regarded as successful because there are not enough data to evaluate
them as such. Implants in the unaccounted for category include all
those in patients who died or dropped out of the study, or who were
74
not available at a specific recall appointment. Naturally, the larger
the number of unaccounted for implants, the more uncertain will
be the estimates of implant success or survival. The failure category
includes all removed implants irrespective of the cause of their failure
or removal. Even an individual implant that has been lost (e.g., in a
motor vehicle accident) must be categorized as a failure. Correctly
applied, it is believed this new type of evaluation will encompass an
improved diagnosis of the outcome of oral implants.
In their article, the authors187 describe an example of how to apply
the categories (Figure 8): 100 consecutively placed implants are to
be evaluated with respect to their outcome for 1, 3, and 5 years. At
the 1-year recall, 78 of those implants were diagnosed as successful
based on the listed criteria. Four implants were impossible to evaluate
radiographically because of poor radiograms, 4 were placed in a
patient who subsequently died, 4 others were placed in a patient
who suddenly dropped out of the study, 6 were reported to be
painful, 2 were mobile, and the remaining 2 had been removed. This
would result in a 1-year outcome of 78% success, 10% survival, 8%
unaccounted for, and 4% failure.
Figure 8. Four-field diagram for evaluating the outcome of an implant

procedure (from Albrektsson and Zarb187). An example of 100
consecutively placed implants where 78 implants passed the success
criteria. Ss = success, SI = other survivals, U = unaccounted for, F =
failure. All figures in percent.
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As a final remark, it can be said that a well-constructed statistical
model is not the sole determinant of high quality research—developing
a clinically relevant and objectively measurable hypothesis,
implementing an appropriate study design and statistical analysis
plan, and accurately reporting both outcomes and conclusions are all
important considerations. Therefore, readers who pay close attention
to the parameters of their statistical analysis within the context of
a well-designed and soundly executed study will make the most
meaningful contribution to evidence-based dentistry.163
76
AIMS
The general aim of the present thesis was to investigate and identify
factors associated with the failure of oral implants, by performing
systematic reviews and clinical trials including the population
rehabilitated with dental implants at the Clinic for Prosthodontics,
Centre of Dental Specialist Care, Malmö, Sweden (Folktandvården
Skåne AB, Specialisttandvård Malmö).
The specific aims were:
1. To identify risk factors that may contribute to failures of oral

implants, in a systematic review of the literature (Study I);
2. To analyze the influence of one risk factor (smoking) on the

failure of oral implants, marginal bone loss, and postoperative
infection, in a systematic review of the literature with meta-
analysis (Study II);
3. To assess the influence of local and systemic factors on the

occurrence of oral implant failures up to second-stage surgery -
abutment connection, in a retrospective clinical trial (Study III);
4. To analyze the complications of oral implant treatment in a group

of patients presenting bruxism in comparison with a matched
group of non-bruxers, in a retrospective clinical trial (Study IV);
5. To investigate the association between the intake of two types of

medicaments, i.e. proton pump inhibitors and selective serotonin
reuptake inhibitors, and the risk of oral implant failure, in
retrospective clinical trials (Studies V and VI);
77
6. To assess, among other factors, the influence of the placement of
oral implants by different dental surgeons on the implant failure
prevalence, in a retrospective clinical trial (Study VII);
7. To analyze cluster behavior of oral implant failures among

patients, to assess the possible risk factors influencing this
phenomenon, and to describe and compare this group of patients
with one not presenting this behavior, in a retrospective clinical
trial (Study VIII);
8. To assess the dental implant failure rates and marginal bone

loss of implants followed up for a minimum of 20 years, in a
retrospective clinical trial (Study IX).
78
MATERIALS AND METHODS
The articles included in the present thesis consist of three types of

studies. First, a general overview was performed in order to identify
risk factors associated with the failure of oral implants (Study I).
Then, a systematic review of the literature with meta-analyses was
performed to analyze the influence of one risk factor (smoking) on
the failure of oral implants, MBL, and postoperative infection around
implants (Study II). Details about the procedures performed in these
two reviews are described in the articles included at the end of this
thesis.
The other studies consisted of retrospective clinical observations
(Studies III-IX). In general, these are the materials and methods for
these seven clinical trials:
Materials. The retrospective studies were based on all 2,670 patients

provided with implants, consecutively treated on a routine basis at
one specialist clinic (Clinic for Prosthodontics, Centre of Dental
Specialist Care, Malmö, Sweden - Folktandvården Skåne AB,
Specialisttandvård Malmö) during the period from 1980 to 2014.
The study protocol was approved by the regional Ethical Committee,
Lund, Sweden (Dnr 2014/598; Dnr 2015/72).
Definitions. An implant was considered a failure if presenting signs

and symptoms that led to implant removal. Thus, a failed implant in
our study is equal to a lost implant. The failures were classified into
two types: (1) implants lost due to lack/loss of osseointegration and
(2) fractured implants. Primary failures were those occurring until/at
the day of the 2o stage surgery (abutment connection).
79
Inclusion and exclusion criteria. Patients with all modern types of
implants with cylindrical or conical design were included. Zygomatic
implants were not included in the study, as well as implants detected
in radiographies, but without basic information about them in the
patients’ files.
Data collection. The dental records of all patients ever treated with
implants in the aforementioned clinic were read in order to collect the
data. The data were directly entered into a SPSS file (SPSS software,
version 23, SPSS Inc., Chicago, USA) as the files were being read. The
following data were collected:
(a) Implant-related factors: implant system, implant surface

(turned/machined or enhanced surfaces, the latter including
sandblasted, acid-etched, sandblasted + acid-etched, anodized,
hydroxyapatite-coated surfaces), implant diameter and length,
and implant design (cylindrical or conical), number of implants
in maxilla and mandible;
(b) Site-related factors: implant jaw location (maxilla/
mandible), anterior or posterior location of the implant (sites
from right canine to left canine teeth were considered anterior
location), bone quantity and quality of the implant sites, which
were classified at the time of surgery according to the Lekholm
and Zarb188 classification, implant sites with previous implant
failures (reoperation), elements adjacent to the implant (both
sides edentulous, one tooth + edentulous, two teeth, implant +
edentulous, two implants, one tooth + one implant);
(c) Patient-related factors: patient’s sex, age of the patient at
the implant insertion surgery, general health, and behavioral
history. The presence of a medicament list in the patients’ records
was also used to correlate the use of certain drugs to specific
health conditions. Health factors assessed: diabetes types I
and II, hypertension, hypercholesterolemia, hypothyroidism,
asthma, psoriasis, chemotherapy, and irradiation of the head
and neck region. The patients were also classified according to
the intake of the following medication types: antidepressants,
immunosuppressives, bisphosphonates, antithrombotic agents
(antiplatelet, anticoagulant, thrombolytic drugs), hormone
replacement therapy in women, and medicaments to reduce
80
the acid gastric production (proton pump inhibitors - PPIs).
The behavioral factors assessed were smoking habits, use of
snuff, and bruxism;
(d) Other factors: surgeon who performed the implant surgery,
prescription of antibiotics (the prophylactic antibiotic regimen
was usually starting 1-2 hours before surgery and going from
5-7 days postoperatively), bone graft procedures, reason for
tooth extraction (periodontal disease, tooth fracture, trauma,
advanced caries, tooth agenesis, other), type of implant-
supported prosthetic restoration (single crown, partial bridge
with 2-6 prosthetic elements, partial bridge with 7-10 prosthetic
elements, full-arch, overdenture), number of days until failure,
time between loss of an implant and replacement by another
one, and follow-up time.
Statistical analyses. The SPSS software version 23 (SPSS Inc.,

Chicago, USA) was used for the statistical analyses. In general,
the mean, standard deviation, and percentages were presented as
descriptive statistics. The Kolmogorov–Smirnov test was performed
to evaluate the normal distribution of the variables, and Levene’s test
evaluated homoscedasticity. The performed tests for the comparison
of continuous data of two independent groups were Student’s t-test or
Mann-Whitney test, depending on the normality. The performed tests
for the comparison of continuous data of two dependent groups were
paired-samples t-test or Wilcoxon signed-rank test, depending on the
normality. The performed tests for the comparison of three or more
independent groups were one-way analysis of variance (one-way
ANOVA) or Kruskal–Wallis test for continuous variables, depending
on the normality. Pearson’s chi-squared test or Fisher’s exact test
was used in the analysis of contingency tables of categorical data of
independent groups, and McNemar’s test for dependent groups. The
degree of statistical significance was considered p < 0.05.
• The use of other statistical analyses varied among the
articles included in the thesis:
• Survival analyses: life table and Kaplan-Meier analysis;
• Logistic regression models: used at the patient-level as well
as at the implant-level;
81
• Generalized estimating equation (GEE) method: used at
the implant-level to account for the fact that repeated
observations (several implants) were available for a single
patient;
Multilevel mixed effects parametric survival analysis: with a binomial

distribution and a logit link function, while assuming an exchangeable
working correlation structure.
Details specific to each of the seven retrospective clinical trials are
described in the articles included at the end of this thesis.
82
RESULTS AND DISCUSSION
In my work about oral implant failure I have decided to include 9

different scientific papers. However, since the topic or oral implant
failure is so huge, this means that I have had to select 9 papers from
the 33 papers11-31,44,63,158,160,161,189-195 I have actually authored and
published on this topic. I have, therefore, decided to present the
results and discussion by thematic headlines going through my own
results and those of others and discussing them in the same part of
the thesis. In this chapter, the influence of several factors on implant
survival/failure will be discussed. The aim is not to cover every
possible factor affecting osseointegration, but the main issues. The
papers included in the thesis will be referred to in the following text
by their Roman numerals (see ‘List of Papers’). Study I is not referred
to in the following text, since it is a general review.
Hardware
Implant length
Many implant models are available for specific clinical applications,
with varying lengths and diameters. The choice of implants depends
on the type of edentulism, the volume of residual bone, the amount
of space available for the prosthetic reconstruction, the emergence
profile, and the type of occlusion.196 The use of implants may be
restricted where there are limitations imposed by the geometry and
volume of the alveolar bone. These restrictions are more common
in the posterior regions of the maxilla and the mandible.197 Surgical
treatment options to overcome these limitations include either
supplementary bone augmentation procedures or the use of implants
83
reduced in length.198 The advantages of using short implants include
the avoidance of invasive bone augmentation surgery associated with
donor site morbidity, additional treatment duration and financial
burden.199
Some articles showed clearly that short implants failed more
often than longer implants.200-205 Telleman et al.206 observed in their
review that there is a tendency towards an increasing survival rate
per implant length. The meta-analysis of Pommer et al.207 observed
increased failure rates of short implants compared to longer implants
with significant differences observed in the anterior and posterior
maxilla. Another review observed that the failure rate appeared to
be higher in shorter small diameter implants than in longer ones.208
However, others reported that implant length did not appear to
significantly influence the survival rate.169,209-211 Some factors have
been suggested to explain the difference found in some studies, such
as the quality of the patient’s bone, amount of bone-to-implant
contact (BIC), crown-to-implant ratio, and stress on bone.
In sites associated with poor bone density and jaw bone resorption,
a prevalence of short implants and/or wide-diameter implants might
be used. In these particular situations, failure rates may be increased.
Jaw shape and bone density must be considered as one of the most
influential factors in implant survival. It should be understood that
the length of the implant, in most of the studies reflects the state
of jaw bone resorption.212 When the relationship between implant
length and available jaw bone were examined, Herrmann et al.205
found that 29.4% of the 7-mm implants were placed in jaws with jaw
shape E and 25.5% were placed in jaw with jaw shape D, according
to the Lekholm and Zarb188 classification.
Compared with longer implants, there is less BIC when short
implants are used, because of the smaller implant surface.211 However,
as some studies show comparable survival rates for short and long
implants observed,169,209-211 the difference in the total implant surface
might not be crucial for implant survival.
Concerning crown to implant ratio, because of the extensive
resorption in the posterior region, a higher crown to implant ratio
is created over short dental implants,211 which might in theory
contribute to an increase in implant failure rate.206
84
Several researchers213-218 have stated that short implants produce
higher stress and strain over the bone because of the smaller
contact area at the implant–bone interface in combination with a
less homogenous stress distribution.219 Rubo and Capello Souza220
showed that the stress decreased ≈14% when the implant length
increased from 10 mm to 13 mm. Petrie and Williams221 reported
that an increase in the implant length might facilitate a decrease
in bone deformation and maximum stress compared with short
implants.217 However, a finite element analysis (FEA) study conducted
by Pierrisnard et al.222 found that the shear stress during oblique
loads in implants is concentrated on the first 7 mm and observed no
differences related to the implant length. It appears that, whatever the
implant length is in the cancellous bone, stress is always located at
the implant neck level and has a slight influence on the peri-implant
bone stress values.222 A study of fixed single-unit restorations showed
that a relationship between implant length and success may not exist,
especially over 13 mm in length.223 No relationship between initial
mobility and implant length has been established, and mechanical
analyses have supported the view that increasing the implant length
may only increase the success rate to a certain extent.224 Moreover,
according to Geng et al.,225 if the bone is of good quality (bone type I),
the implant length does not influence the treatment success because
the degree of inequality in the stress distribution over the interface
depends on the difference in the elastic modulus of both structures;
with better bone quality, there is less difference in the stiffness of
these two structures. Some have stated that in the long term, the
length of the implant could be more important than the diameter,
because before oral cavity exposure and loading, vertical osseous
loss is present, and it can be close to 0.2 mm per year; in the future,
the implant may lose important contact between bone and implant
surface.226,227
For immediate implant cases, the literature reports contradictory
statements about the influence of implant length on bone
biomechanics based in finite element analyses. In a clinical follow-up
study of Schnitman et al.,228 the authors conclude that 50% failures
of immediately loaded external hexagon implants during 10 years
were related with utilization of implants shorter than 10 mm.
Miyamoto et al.229 stated that length is a weak factor for primary
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stability in immediate implants cases. However implants longer than
10 mm may result in a considerable strain reduction.230 Kong et al.231
concluded that greater implant length can reduce the cortical and
cancellous bone stress and the implant displacement during axial
loads in immediate implant cases.
Surface treatment may have some influence on the results of short
implants. The review of Renouard and Nisand197 demonstrated a
trend toward an increased failure rate with short- and wide-diameter
implants. However, they identified that out of the 12 studies which
have documented an increased failure rate with short implants, 11
used of machined-surfaced implants.53,200,202,204,205,212,232-236 In the other
hand, out of the nine studies which have indicated that implant length
did not influence the survival rate, six168,169,209,237-239 were performed
with textured-surfaced implants. As an example, Feldman et al.209
demonstrated survival rates of 91.6% and 97.7%, respectively, in a
the 5-year survival rate of short machined-surfaced and short dual-
acid-etched surfaced implants. In this study a statistically significant
difference in CSR was found between short machined-surfaced
implants and standard machined-surfaced implants. It is noteworthy
that this difference increased dramatically in the posterior maxilla.
For the dual-acid-etched implants, no statistically significant
differences were demonstrated between short and standard-length
implants. When comparing, the CSRs in poor bone density, Feldman
et al.209 demonstrated that short dual-acid-etched implants provided
better outcomes than machined-surfaced implants (96% and 86.5%,
respectively). Kotsovilis et al.240 concluded from their systematic
review that the placement of short rough-surface implants is not
a less efficacious treatment modality compared with the placement
of conventional rough surface implants. In the meta-analysis of
Pommer et al.207 turned implants demonstrated a significant impact
of implant length overall as well as in the anterior and posterior
maxilla. However, no significant overall effect could be substantiated
for rough-surfaced implants.
It is worth mentioning that short implants should not be compared
with long implants placed in good bone density, but should then
be compared with the failure rates and morbidity of advanced
surgical procedures such as bone grafting, sinus lifting, and alveolar
nerve lateralization. Thus both survival rates and morbidity must
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be considered when comparing the outcomes of short implants and
advanced surgical procedures to allow adequate comparisons.197 A
RCT aimed to evaluate whether short dental implants could be an
alternative to bone augmentation together with placement of longer
implants in posterior atrophic jaws; results revealed that, 1 year after
loading, short implants achieved similar results compared with longer
implants placed in augmented bone.241 The authors concluded that
short implants might be a preferable choice to bone augmentation
because the treatment is faster, less expensive, and associated with
less morbidity.
A review197 analyzing 53 human studies observed that studies which
have used surgical preparation adapted to the bone density, textured-
surfaced implants, and modified case selection have reported survival
rates for short implants and for wide-diameter implants which were
comparable with those obtained with long-implants and standard-
diameter implants.
It is important to stress that there is still no consensus in the
literature on the definition of a short implant.211 Some authors
consider 10 mm the minimal length for predictable success; thus, they
consider any implant <10 mm in length as short.242 Others defined an
implant length of 10 mm also as a short Implant.198
Implant diameter
The original standard Brånemark System implant was 3.75 mm
in diameter, but owing to treatment needs, i.e. the adaptation of
the implant to the existing anatomy, implants of several other
diameters were introduced as well. Today, many types of implants are
available, which have different external designs, surfaces, platforms,
connections, diameters and lengths.
It has been said that the diameter of the implant could be considered
the most effective factor when compared with the length.243-245 It
has been suggested that increasing the implant diameter appears to
compensate for the implant length,246,247 even though the results of a
meta-analysis207 found no influence of implant diameter on the failure
rate of short implants.
Availability of bone in the edentulous ridge determines the implant
dimensions that can be used in that site.248,249 The main 2 advantages
of narrow implants are the ability to apply less invasive surgical
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procedures when there are circumferential bone deficiencies and the
ability to place narrow implants in reduced interradicular spaces, such
as the edentulous ridge of the mandibular incisors.250,251 Thus, narrow
implants are indicated in areas with reduced horizontal ridge width
or mesio-distal prosthetic space.252 Conceptually narrow implants are
often placed in compromised clinical scenarios or subjected to higher
risks of increased implant body fracture possibility or prosthetic
complications.253,254
In some cases, surgeons try to use narrow implants, which are
advantageous in treating bone defects and avoiding anatomical risk
areas.255 In the use of narrow diameter implants, the similarity of the
survival rates to those of regular implants does not extend to their
mechanical behavior.248,256 Biomechanically, the implant diameter
appears to influence the stress concentration at the implant as well
as at the surrounding bone and, hence, affects the success rate.213,257
In vitro studies and finite element analyses have illustrated that stress
values affecting the crestal cortical bone are reciprocal to the dental
implant diameter, which means that especially small diameters result
in disadvantageous stress peaks at the implant-bone interface.258 Ding
et al.259 showed that the stress values at the implant-bone interface
rise more significantly by reducing the diameter from 4.1 mm to 3.3
mm, compared to reducing the diameter from 4.8 mm to 4.1 mm. As
a biological implication, inadequate overloading of narrow-diameter
implants might possibly lead to disadvantageous peri-implant crestal
bone resorption resulting in clinical complications. The implant itself
is also more prone to fatigue fracture as a result of a reduced implant
diameter.253 An increase of the implant diameter, comparing the same
load, produces a decrease in stress in the implant and the peri-implant
bone.244,258-262 Lower stress values in the bone and the implant have
been observed in implants with larger diameter, which is justified as a
better distribution by the largest contact area between the implant and
peri-implant bone.215,262,263 The usefulness of small-diameter implants
has to be discussed with an awareness of their potential limitations.
It has been estimated that a 3.3-mm-diameter, screw-shaped, c.p. Ti
implant possesses 25% less resistance to fracture when compared
with a similar regular-diameter implant.264 Decreasing the diameter
also means increasing the risk for implant fracture because of reduced
mechanical stability and increasing the risk for overload.265
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An increase in the implant diameter produces significant stress
reduction, particularly in the cortical bone,262 whereas the length of the
implant has a certain influence on the stress patterns in the trabecular
bone implant interface.258,266 Iplikcioglu and Akça267 demonstrated
that the implant length does not influence stress reduction over
the peri-implant bone, in contrast to the implant diameter. When
the implant diameter increases by 0.25 mm, the contact surface is
augmented by ≈10%.268 In a direct comparison, the use of a 5.0
mm diameter implant that is 6 mm long increases the surface area
available to contact the bone similar to that of a 3.75 mm diameter
implant that is 10 mm in length.201 An increased implant surface
area of wider implants can engage more cortical bone. It has also
been shown in a study in rabbit tibia that wider implant diameters
resulted in increased removal torque values.269 In 1994, Lazzara270
recommended the immediate placement of a wide-diameter implant
after extraction. The volume of the alveolus is best filled by increasing
the diameter of the implant to provide adequate primary stability.
Finite element studies suggest that implants with a wider diameter
are more favorable in reducing the stress distribution in bone
surrounding the implants compared to more narrow implants.271,272
The use of wider diameter implants allows engagement of a maximal
amount of bone and improved distribution of stress in the surrounding
bone,254 providing more BIC, bicortical engagement, and immediate
placement in failure sites.211 The use of wider components also allows
for the application of higher torque in the placement of prosthetic
components. The use of wide implants, however, is limited by the
width of the residual ridge and esthetic requirements for a natural
emergence profile.273
Implants of 5- and 6-mm diameter are, respectively, three and
six times more resistant to fracture than standard implants. The
supporting surface of the top area of 5- and 6-mm implants is
increased by 122% and 281%, respectively, compared with standard
implants.274 This feature allows better distribution of occlusal forces.
Petrie and Williams221 concluded that the increase of the implant
diameter decreases the stress in the alveolar crest 3.5-times, with
a better effect for short and tapered implants because the diameter
predominates over the length and taper. Kong et al.275 reported that
the narrowing of the implant neck also induces a more favorable
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stress distribution in the bone. It is hard to say whether all the
biomechanical advantages of wider implants may result in more
advantageous clinical conditions when it comes to MBL. A review197
analyzing 53 human studies observed that there was no relationship
between MBL and implant diameter in most of the studies, which
reported rather low changes in crestal bone levels.
Wide-diameter implants are indicated in cases of poor bone
quality and inadequate height of bone and to replace nonintegrated
or fractured implants. Wide-diameter implants can be used in special
situations in which they can increase the surface area available for
implant anchorage and improve their primary stabilization. Such
wide implants provide a means of managing difficult bone situations,
such as inadequate quality and/or height of bone.226,270,274 A biological
impediment to the use of wide-diameter implants can be a lower
blood supply because of minimum existing cancellous bone.276 Wider
implants are used when bone is scarce and the influence of diameter
on BIC may not translate into a clinical advantage.277
Some studies involving implants of various diameters reach the
conclusion that failure is more common for the 5.0-mm implant as
compared to the 3.75-mm and 4.0-mm standard design.277,278 As
possible causes for the outcome, the 5.0-mm implant was frequently
placed as a rescue implant in poor quantities of low-quality bone
without utilizing an adapted surgical technique and without extended
healing time,277,279 and the use of this implant diameter when primary
stability could not be achieved with a standard-diameter implant.277
This view was supported by the study of Mordenfeld et al.280 in
which wide-diameter implants were placed in unfavorable situations
such as poor bone density, and compromised bone volume. As such,
in some studies a trend could be drawn with a prevalence of early
failures.223,277,281
Moreover, implants of wider diameter are usually placed in
the posterior areas of the jaws. Due to the anatomical limitations
(maxillary sinus, inferior alveolar canal), these implants are also
shorter. Some studies have observed that shorter implants have a
higher failure rate than longer implants.200-205 And in posterior
partially edentulous arches it is often difficult to achieve implant
stability because of both compromised bone quality and/or quantity.
Initial implant stability has been pointed out as another parameter
of importance for establishing osseointegration.35
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Furthermore, the 5.0-mm-diameter implant usually lacks a neck
and has a differently threaded profile, compared to standard and
4.0-mm-diameter implants. Certainly, this might also have had an
impact on the treatment results, both with regard to implant survival
and MBL. The implant neck may play an important role in stabilizing
the implant during its final tightening when placed, especially in poor
quality bone and in combination with a thin marginal compact bone
layer.277
There are no significant differences in failures rates when
narrow-diameter implants are compared to their regular-diameter
counterparts, according to two literature reviews on the subject.207,208
It is worth mentioning again that the review of Renouard and
Nisand197 including 53 human studies observed that studies which
have used surgical preparation adapted to the bone density, textured-
surfaced implants, and modified case selection have reported survival
rates for short implants and for wide-diameter implants which were
comparable with those obtained with long-implants and standard-
diameter implants.
Implant design (non-threaded versus threaded, cylindrical

versus tapered)
When considering only studies comparing the survival rates between
cylindrical non-threaded and threaded implants, four studies showed
that there is a greater risk of implant failures with insertion of non-
threaded implants when compared to threaded implants.168,227,238,282
The statistical analysis of four other studies indicated that the type
of implant did not influence the failure rate of the implants.210,283-285
It is worth to mention the case of the German IMZ implant, a solid
non-threaded cylindrical implant with a plasma sprayed titanium
surface. Life table analysis revealed an extremely low CSR for
maxillary implants (37.9% at 100 months of follow-up) in a clinical
study.286 According to Karoussis et al.,282 the possible reasons for
inferior survival rates of non-threaded implants in comparison to
threaded implants are largely unknown and may only be speculated
upon.
However, others have hypothesized that the differences could be
related to accumulation of stress around the implant neck. Implant
design has been proven to have an effect on peri-implant bone when
loaded.287 Implants with threaded designs are preferred because they
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have a greater ability to reduce shear force than cylindrical non-
threaded implants.287,288 In general, stresses developing in the neck
region of threaded implants are lower than those around cylindrical
implants.289 Moreover, studies288,290,291 have suggested that the use
of threaded implants decreases implant mobility at the time of
placement, disperses interfacial stresses, and increases the contact
area between the implant and bone.
Another possible explanation for the extremely poor clinical
results of the cylindrical implants relates to the most common surface
modification used at the time for this implant design, the plasma
sprayed surface. This surface modification presented extremely high
values of roughness, which was a short-term disadvantage for bone
tissue.292
Concerning cylindrical and tapered implants, it has been proposed
that tapered implants favor load distribution to surrounding bone
by mimicking the natural root form.293 The theory behind the use of
tapered implants is to provide for a degree of compression of the cortical
bone in a poor bone-implant site.294 Some studies have investigated
the difference between these two different implant designs. O’Sullivan
et al.294 analyzed the mechanical performance and the primary
and secondary stability characteristics of tapered implants when
compared with the standard Brånemark parallel-walled design
placed in rabbits, and observed that the tapered implants resulted in
a better primary stability. Sakoh et al.295 investigated the differences
with respect to primary stability between a conical implant and a
cylindrical screw-type implant, in an in vitro study. The conical
implant showed significantly higher primary stability than the
cylindrical hybrid implant using the insertion torque, Periotest,
and push-out tests. In an experimental study on dogs, Kim et al.296
compared the mechanical properties of tapered and parallel-walled
implants in terms of the success rate. Maximum insertion torque
(MIT) and maximum removal torque (MRT) were assessed. The
results showed significantly high values of MIT and MRT for tapered
implants than parallel-walled implants.296 Romanos et al.297 placed 90
parallel-walled and 90 tapered implants in freshly slaughtered cow
ribs and noticed that tapered implants achieved greater stability than
parallel-walled implants, measured by resonance frequency analysis
(RFA).297 Similar results were reported in another experimental study
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performed by the same group.298 Toyoshima et al.299 observed that
the mean MIT and implant stability quotient (ISQ) were significantly
higher for tapered implants than for cylindrical ones in an ex vivo
model. The general results that tapered implants may present higher
primary stability than cylindrical implants might have an impact on
the implant survival rates, as it has been stated that primary stability
is a crucial prerequisite for achieving osseointegration.299
Implant surface
To achieve successful BIC (i.e. osseointegration), oral implants placed
according to a two-stage surgical protocol have been advocated to
remain unloaded for a healing period of 3–6 months.300 The biological
rationale supporting this approach resides predominantly in the fact
that implant micro-movements caused by premature loading during
wound healing may promote connective tissue encapsulation of the
implant rather than healing by direct BIC.300 Numerous efforts have
been made to make implant therapy more appealing for potential
patients by simplifying clinical procedures. One of these efforts has
been a general reduction of the healing period using new titanium
surfaces that shorten and improve the osseointegration process.301
Nevertheless, this reduction of the initial osseointegration period
should not result in a higher failure rate of the dental implants
inserted with the chosen loading protocol.302
To improve its functional properties, the titanium implant surface
is generally modified by increasing the surface roughness on the
titanium surface or by altering the crystal structure and chemical
composition (Figure 9). Dental implant surfaces are modified in
an attempt to optimize the cell and tissue interactions.303 When a
biomaterial is inserted into living body, it absorbs proteins before
cells adhere to its surface.304 These proteins significantly affect the
attachment, adhesion, and spreading of osteoblasts, the cells that form
bony tissues.305 For such cells, the implant’s surface-charge influences
their reactions to the implant, by affecting the type and amount of
proteins attached on its surface.306 The moderately enlarged surfaces
provide better possibilities for micro-biomechanical retention due to
larger tissue contacts and thus more retention for proteins (on the
nanoscale level) to attach and new bone formation.307-311
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Figure 9. High resolution SEM images of TiOblast (top image) and
Osseospeed (middle upper image) implant surfaces (Scale bar 2 μm).
High power SEM images of SLA (middle lower image) and SLActive
(bottom image) implant surfaces (Scale bar 200 nm). There are clear
nanopatterns on Osseospeed and SLActive implant surfaces.
94
In addition to surface roughness, the surface physics is another
factor important for peri-implant bone apposition, because it
influences surface charge and surface wettability. Surface wettability
is largely dependent on surface energy, and influences the degree
of contact with the physiologic environment. Increased wettability
enhances interaction between the implant surface and the biologic
environment.312 Textor et al.313 concluded that a certain similarity of
the clean hydrophilic titanium oxide surface to water can be assumed
as a consequence of extensive hydroxylation/ hydration of the oxide
layer. This leads to high wettability by water314 and to an interaction
of the surface with the water shell around biomolecules such as
proteins. Such an interaction might accelerate and enhance bone
deposition and therefore osseointegration.315 In addition, this also
increases removal torque values during this early healing phase.316
This in turn might allow for further reductions in the time needed
for healing around the implant or might provide more stability early
in the course of healing, when the stability of the implant is generally
decreased.301
In the late 1980s and 1990s, several research groups started to
examine altered titanium surfaces, and focused on subtractive
surface techniques such as sandblasting and/or acid-etching
procedures.292,317-325 Various techniques have been used over the years,
such as sandblasting,292,320-323 acid-etching,326-329 a combination of acid-
etching and sandblasting,318,330,331 oxidation methods,332,333 anodic
plasma-chemical treatments,334 calcium phosphate and hydroxyapatite
coatings on the titanium surface,335 the fabrication of nanotubular
structures on a titanium surface by anodic oxidation,336 fluoride
modification of the titanium surface,337-339 the addition of calcium on
the surface,340,341 and the incorporation of magnesium.342-345 Several
of these experimental studies demonstrated that the new titanium
surfaces had better bone integration than machined titanium surfaces.
It was also showed a significantly higher removal torque values and a
greater percentage of BIC adjacent to moderately roughened titanium
surfaces, compared with plasma sprayed, machined or polished
titanium surfaces. Clinical studies evaluating implants with rougher
surfaces usually show short- and long-term higher survival rates when
compared to turned implants,28,37,191,346,347 (Study III included) but this
was not always the case.76,210,348-351 An extremely rough surface may
95
not be ideal for osseointegration. It was shown that a highly increased
surface roughness compared to a moderately increased one is a short-
term disadvantage for bone tissue.292,320-322 So the correct development
was not to produce “rougher surfaces” but to achieve a moderately
rough surface. Plasma-sprayed rough implants did seem to give rise
to more MBL than did smoother implants.352,353
When it comes to MBL, it was reported that a surface roughness
of more than 2 μm (Sa) is associated with a higher risk of peri-
implantitis.354 Rougher implant surfaces are more susceptible to
accumulation of bacteria on hard surfaces.355,356 Bacterial infection,
characterized as bacterial colonization and biofilm formation on
dental implants, is an important risk factor for peri-implantitis. A
roughened surface does not only increase the susceptibility for peri-
implantitis, but also reduces the treatment efficacy of the bacteria
biofilm.357 The progression of ligature induced bone resorption
in dogs is more pronounced at implants with a moderately rough
surface than at implants with a turned surface.358 These results must
be carefully interpreted due to the animal model. However, this could
mean that with rough surface, the prevalence of peri-implantitis is
not higher but once there is a peri-implantitis the progression is
increased compare to the turned surface.359 Hence, moderate surface
modifications may improve implant therapy in terms of speeding up
the treatment, but may be disadvantageous for the patients prone
to peri-implantitis.360 However, it must be pointed out that these
viewpoints so far are speculative in nature. There is no clinical
evidence available that moderately rough surfaces see more clinical
problems with peri-implantitis of other surfaces.361
“Copycat” implants and implant systems that were

withdrawn due to clinical problems
Some dental implant companies have been researching the science
of dental implants for years and years. There are copycat companies
that are manufacturing cheap, low-quality knock-off implants that
are marketed to dentists as low-cost dental implants. Often these
copycat implants look very similar but unfortunately do not carry
guarantee of high standards and research based quality, i.e. they
are not all subject to the same rigor of material quality control and
continuing quality verification. Therefore, they might not ensure an
identical outcome.
96
Many implant companies try to take advantage of research
undertaken by the more established providers, stating “we use
the same materials” or “the principles are the same for all dental
implant systems”, when clearly it is not acceptable to make such
claims about systems that are not supported by their own research.362
Good two-way communication can be an excellent way to find out
more about the products available, and the choice should be based on
known and extensive research with comprehensive documentation.
It’s unlikely that cheaper copycat products will have this scope
of evidence.362 Although is supposedly assumed that the copycat
implants might not perform as well as the dental implants that have
been on the market for years, clinical studies on the performance of
copycat implants are lacking.
Some implant systems with designs of their own have failed in
the long run and been withdrawn from the market. In some cases
the precise reason for the system failing was easy to pinpoint, but
in the majority of cases it must be regarded as uncertain whether
one implant characteristic or a combination of characteristics was
responsible for the poor clinical outcome. The crystalline bone screw
of aluminum oxide had poor strength and the estimated 5 year success
rate was only 25%.363 The Frialit implant of aluminum oxide was
introduced in the 1980s with, for its time, very good clinical research
behind it.364,365 However, a 4 ½ year follow-up (average) reported
only 87% survival rate.366 Other authors confirmed the poor rate
of long term success with Frialit 1 and the aluminum oxides did
not meet the expectations in terms of long term stability and was
finally withdrawn from marketing.367 Single crystal aluminum oxide
implants marketed by Kyocera of Japan was allegedly most popular,
but when clinical results were scrutinized implant fractures resulted
in quite poor 5- and 10-year outcomes of, respectively, 75.7% and
64.7%368 and the system disappeared.
The Core Vent implant, allegedly the most commonly used brand in
the US around 1990, was a hollow cylinder of titanium 6 aluminum 4
vanadium material, with some threads in the construction. However,
when tested in a clinical study369 analyzing 47 consecutively placed
core vent cylinders, the survival of 1-4 years was only 71% and the
success rate over the same time was estimated to 9%. The implants
lost marginal bone at a most rapid rate and were unable to maintain
the osseointegrated state and the system was withdrawn in 1991. It is
97
possible that the problems with Core Vent implants were associated
with the hollow cylinder design, but precise data documenting this
hypothesis are lacking.
IMZ was a German solid cylinder implant with a plasma sprayed
titanium surface. When analyzed clinically without a radiographic
documentation, the system seemed to function quite well,370 but
this was not the case at all over longer times of follow up when a
severe resorption of marginal bone was documented.352,353 The IMZ
implants never displayed even close to a steady state situation with
respect to MBL that was documented to 0.5 mm annually (average)
between year 1 and year 5 and accelerated thereafter.371 A clinical
report finding only 37.9% survival of maxillary IMZ implants
100 months of follow-up286 was followed by withdrawal of this
oral implant system in 1997. Reasons for MBL may have been the
cylindrical shape without threads of the implants in combination
with the plasma sprayed surface. Another solid cylindrical implant
with a plasma sprayed HA-coated surface was the Calcitek implant.
It likewise failed to display maintained marginal bone levels45,372 and
were withdrawn from sales due to this, even if short term reports
without bone loss evaluations were quite positive.373 The type of
HA-coatings used in those days was plasma sprayed with a minimal
thickness of some 50-75 µm. In animal studies it was demonstrated
that such thick HA-coatings were attacked by macrophages/foreign
body. Giant cells that initiated resorption of the bone as well335 which
may have been an additional problem with the Calcitek cylinders.
The Bicortical screw implant caused major problems in form of
MBL possibly due its design in form of a needle-like device with
threads. Attempts to place this implant in patients ended up with
major problems due to the loss of harboring bone and most implants
were removed at nearby University clinics. This implant design with
due clinical problems resulted in Scandinavian court cases with
banning of its further usage.374
The clinical problems observed with Nobel Direct implants375,376
was probably due to strange clinical recommendations to grind the
implant down in situ and, thereafter, loading it directly. Such actions
resulted in large bone loss and implant failure in one third of cases
at 18 months of follow-up,377 presumably due to vibrations from the
rotating instruments in combination with later direct loading of the
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implants. The Swedish control body; Läkemedelsverket, forbade the
sales of this implant until instructions for its use were re-written.378
Quite acceptable clinical results with the same Nobel Direct implant
was reported for devices not ground down in situ.377
Surface contamination
In order to discuss the factor of surface contamination, it would be
impossible to not mention the work that Dr. Dirk Duddeck has been
conducting. His work focuses in investigating the quality of dental
implant surfaces, which depends on a number of different factors.
Surface contamination is one of them.
Once the titanium implant blank has been computer numerical
control (CNC)-machined, it is further processed using different
techniques that ultimately result in the product’s specific surface
structure.379 There must be a distinction between the manufacturing
process, from the CNC-machined blank with product-specific surface
processing, and the handling of the sterile-packaged implant. Various
production processes ultimately contribute to product quality: the
production itself, the cleaning steps, post-production handling
(i.e., quality control), packaging and sterilization processes and the
packaging itself.379 The packaging itself may also be a source of
organic contamination of the implant surface.380
Several implants in the study that did not feature contact-free
packaging but were delivered in soft sealed polyethylene bags
exhibited various amounts of organic contaminants or plastic residue,
depending on their surface roughness.380 The manufacturers and
users of implants which in the study of Duddeck and Neugebauer380
exhibited some organic contaminants report clinical success rates
that do not differ from those of implants by other manufacturers.
Statements such as “Our success rates are high, so what is the
problem?” may be fully justified when discussing statistical
average. But the question remains: What happens to those organic
contaminants once in the bone? It is hard to imagine that those organic
contaminants should have a positive influence on osseointegration.
At best, there will be areas with a lack of osseointegration, i.e.
smaller areas or entire outer thread edges with less bone contact,
because the osteoblasts will have better things to do than to settle on
polyethylene residue. Or macrophages cause phagocytosis of these
99
materials during the first remodeling phase, which would amount to
biological purification of industrially manufactured surfaces. What
then becomes of the phagocytized materials is another question.380
Particles with a diameter of less than 10 μm are susceptible to uptake by
macrophages through phagocytosis.381 Particle-induced macrophage
activation is associated with an increased osteoclastogenesis and
may therefore cause increased bone resorption.382 Implant debris
activates macrophages to secrete TNF-α, IL-1β, IL-6, and PGE2,
which stimulates differentiation of osteoclast precursors into mature
osteoclasts and increases peri-prosthetic bone resorption, which is
not replaced by new bone.383,384
It is possible that residue on implants is tolerated in healthy patients.
But can we be sure that this is also the case in immunocompromised
high-risk patients? How about extended augmentation sites?
Therefore, surfaces ought to be properly cleaned to avoid increasing
the clinical risks with implants. These questions, however, should
actually not arise in the first place, because impurities are preventable,
as this study clearly shows.380
There is also the concern of the inorganic impurities. There is
continuing concern regarding the release of soluble metal ions
[aluminum (Al), chromium (Cr), vanadium (V), cobalt (Co), and
titanium (Ti), among others], which bind to proteins, remain in
solution, and disseminate into the surrounding tissues, bloodstream,
and remote organs.381 At least when it comes to orthopedic implants,
patients with titanium-base alloy implants have demonstrated elevated
titanium, aluminum, and vanadium levels in joint pseudocapsules
(with up to 200 ppm of titanium, six orders of magnitude greater
than that of controls, 880 ppb of aluminum, and 250 ppb of
vanadium).385 Implant debris can elicit inflammation, osteolysis,
hypersensitivity, and neuropathy. Concerns about implant debris
becoming carcinogenic and toxic, or either, persist.381
The clinical relevance of minuscule particles and contaminants on
dental implants remains speculative. Parameters such as total surface
area and particle size do matter, and the most important determinant
of inflammation is probably particle load, i.e. concentration of
phagocytosable particles per tissue volume, assuming particles are
under 10 μm and able to be phagocytized by cells. However, it is
important to note that all particles are not equally bioreactive.381
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Surgery
Use of prophylactic antibiotics
The risk of infection in any dental implant surgical procedure
depends on several patient factors, management procedures during
implant placement, and the care of the surgical team in maintaining
the basic principles of surgery and asepsis.386,387 Although many
surgeons believe that antibiotic coverage for implant placement is
not necessary, they continue to use them to protect against claims
of malpractice.388 However, the benefits of antibiotic prophylaxis in
relatively normal patients undergoing routine surgical procedures,
such as the placement of endosseous dental implants, remain a
controversial issue,389 even for the placement of implants into
infected sites.189 Moreover, there is a general trend of providing
inappropriate antibiotic prescriptions in dental practice, usually in
excess, therapeutically as well as prophylactically.390
Among the possible disadvantages of routine antibiotic prophylaxis
are the risk of drug-related complications (such as hypersensitivity
and anaphylaxis), which may be greater than the risk of postoperative
infection occurring with that particular operation, and the possibility
that its use may lead to lax surgical techniques and actual increase of
complications.389 In addition, in view of the growing concerns that
health care professionals have regarding the potential for an increase
in new antibiotic-resistant bacteria, antibiotic prophylaxis guidelines
are being reviewed and modified by health care professionals.388
The indiscriminate use of antibiotics may produce unwanted
adverse effects in patients, cause unnecessary costs, and may add
to the increasing emergence of resistant bacterial strains. The recent
increases in resistant bacteria observed in the health care environments
represents a major concern that requires all health care professionals
to closely examine each procedure in which prophylactic antibiotics
are frequently used in order to determine their true effectiveness.391
Even though oral surgeons often prescribe antibiotics routinely
following implant surgery, the usefulness of pre- and post-operative
antibiotics in reducing the failure rates of endosseous implants remain
unclear.11 Most of the conclusions about the use of prophylactic
antibiotic regimen in implant dentistry originate from retrospective
analyses, with multiple operators, different antibiotic prescriptions,
and different regimens. Despite the widespread use of oral implants
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in dentistry, we are still lacking a clear guideline on if, when, and how
to prescribe antibiotics for this type of surgery.392
A recent systematic review and meta-analysis on subject14 suggested
that the difference between the use versus nonuse of antibiotics
significantly affected the implant failure rates (p = 0.0002), with a
risk ratio (RR) of 0.55 (95% CI 0.41-0.75). This means that healthy
patients taking prophylactic antibiotics for implant placement
surgery may experience a 45% lesser risk of having an implant loss
in comparison to healthy patients not taking prophylactic antibiotics
for the same procedure. Moreover, there were no apparent significant
effects of prophylactic antibiotics on the occurrence of postoperative
infections in healthy patients receiving implants (p = 0.520).
It is also important to mention another variable, the surgeons’
surgical experience, which was evaluated together with the use of
prophylactic antibiotics in one study.389 When implant survival rates
were compared according to surgeons’ previous implant surgery
experience and use or non-use of preoperative antibiotics, those
surgeons with greater than 50 implant placements prior to the study
had a slightly higher implant survival rate (2.9%) when preoperative
antibiotics were used. There was an even greater increase in survival
rate (7.3%) when less experienced surgeons (<50 previous implant
placements) used preoperative antibiotic coverage, which would
suggest that as surgical skill increases with experience, there is less
reliance on antibiotics for survival of implants. However, this should
not be interpreted that antibiotics will make up for lax and poor
surgical techniques.
Although the exact mechanism by which prophylactic antibiotics
has a significant effect on implant survival is not known, it may be
that a more aseptic local environment during the time of implant
placement and in the immediate perioperative period results in
improved healing and, ultimately, a better state of osseointegration.389
Insertion torque
The goal of achieving primary stability at the time of implant
placement is to limit excessive micromotion at the bone-implant
interface, which could prevent osseointegration.393,394 The use of a
slightly narrower final drill with a tapered implant design has been
often associated with elevated insertion torque395-399 and localized
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bone compression,400 and these factors may help to increase primary
implant stability.401 The achievement of high insertion torque is likely
related to the achievement of higher primary fixation402 and to the
amount of micromotion.403 The measurement of insertion torque
values to quantify primary implant stability has been reported. Some
examples follow.
Maló et al.404 assessed implants placed in the esthetic zone, of
which only those reaching a minimum installation torque of 32
NCm were immediately loaded. With the CSR of 96% after only
2 years, the authors stated that the minimum installation torque
used in the study was safe for immediate function. Hui et al.405
studied immediate placement of single-tooth implants in the esthetic
zone with a minimum installation torque of 40 NCm, with an
immediate provisional protocol. No failures were reported, however,
the implants were observed between 1-15 months. Lorenzoni et
al.406 evaluated the immediate loading of single implants placed in
fresh extraction sockets in the anterior maxilla, and recommended
immediate provisionalization for single implants inserted into fresh
extraction sites only when a minimum torque value of 32 Ncm is
reached. Nikellis et al.399 observed that the immediate loading of
all 190 dental implants in their study with a minimum of 32 NCm
resulted in no failures after a follow-up up to 2 years. It is important
to mention that these studies did not attempt to insert implants with
less than 32 NCm, which would be more appropriate for direct
comparisons.
Ottoni et al.402 compared implants restored immediately (test group)
with implants restored after a healing period (the control group), and
primary stability was standardized with a minimum insertion torque
of 20 Ncm. The test group included 10 failed implants, of which
9 had been placed with an insertion torque of 20 Ncm. Only one
implant from the control group failed during the 24-month follow-up
period. The authors concluded that immediate loading in single-
tooth indications should only be considered if the implant can be
placed with an insertion torque greater than 32 Ncm. In the animal
study of Neugebauer et al.,407 four to six immediately loaded and
unloaded dental implants with a microstructured surface were placed
in the mandible and the maxilla in seven minipigs. Implants showed
osseointegration if the average insertion torque of the implants within
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one bridge was >35 Ncm. If the primary stability of the bridge was
<35 Ncm, all implants in the quadrant were lost after 4 months.
Grandi et al.408 conducted a study very similar to Hui et al.405 and
Lorenzoni et al.406 One implant failed and was removed 3 weeks after
placement because of progressive mobility. The failed implant had a
final insertion torque of 35 Ncm, whereas all the successful implants
had a final insertion torque ranging between 50 and 80 Ncm. It was
reported that the implant was inserted in D3 quality bone and the
authors hypothesized that the presence of micromovements at the
implant-bone interface probably led to the formation of a soft-tissue
encapsulation around the fixture, causing its failure.408 Khayat et al.401
assessed the clinical outcome of 42 implants placed with an insertion
torque ≥70 Ncm. All implants were clinically stable after 2-3 months
of non-submerged healing. The use of high insertion torques (up
to 176 Ncm) did not prevent osseointegration. The implants were
followed for 1 year, and no signs of pressure necrosis, crestal bone
change, or untoward healing were noted compared with the control
group. An increased static strain in the bone not only creates higher
implant stability at the time of insertion, but also generates increased
implant stability throughout the observation period of 3-24 days.409
It seems there is no consensus on the minimal insertion torque
required for some kinds of treatments with dental implants. When
it comes to the maximum insertion torque, traditionally, implants
were preferably placed with a torque not exceeding the empirically
set limit of 45 Ncm because excessive strain on the surrounding
bone was thought to negatively affect osseointegration.396 Excessive
tightening creates important compression forces in the surrounding
bone. This has been theorized to disturb microcirculation and lead
to bone resorption, but the theory has never been scientifically
investigated. However, there seems to be no limits concerning the
maximal insertion torque allowed provided of course that the bone
does not fracture, according to the results of the study of Khayat et
al.401
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Primary stability
Implant stability, an indirect indication of osseointegration, is a
measure of the clinical immobility of an implant.325,393 It can occur
at two different stages: primary and secondary.410 Primary stability
of an implant is attained at implant placement and is determined
by numerous factors, including density and mechanical properties
of the bone, the implant design, site complications, and the
surgical technique.411-415 It has been stated that primary stability is
a crucial prerequisite for achieving osseointegration.299 Secondary
stability depends on the further reaction of surrounding tissue
to the implantation and offers biological stability through bone
regeneration and remodeling.325,393,415,416 In case of premature loading
of an implant, lack of primary stability may result in micromotion at
the tissue-implant interface, which may lead to fibrous encapsulation
rather than bone formation. Therefore, if good primary stability can
be obtained in small amounts of dense bone, for instance, by using
an adapted surgical technique with narrower drills and self-tapping
implants, it is possible that the implant can remain stable during
functional loading.417 The conventional method is to insert the
implant into a hole of a smaller diameter than usual. This leads to the
generation of compressive forces along the implant-bone interface and
results in enhanced implant stability.299 The results of Toyoshima et
al.299 showed that the mean MIT, ISQ, and push-out tests for implants
with standard drilling in corticocancellous bone were significantly
higher than those with undersized or standard drilling in cancellous
bone. Another approach in cases with insufficient bone is to choose a
tapered implant for insertion into a standard parallel-sided hole.298,418
The idea behind this approach is to induce controlled compressive
forces in the cortical layer of bone when the implant is inserted.297
These forces would be expected to increase the primary stability of
the implant.294,419 Still, the implants could be fabricated with a shorter
thread pitch in order to increase the available surface area.420 As
pitch distance is inversely related to the number of threads, implants
with a shorter pitch should carry an increased surface area. This, in
turn, should lead to a higher degree of BIC, improved mechanical
anchorage, and improved primary stability, which are vital in cases
with insufficient bone.421 A three-dimensional FEA study showed that
105
implants with threads of 0.8 mm pitch offered stronger resistance to
vertical loads than those with 1.6 or 2.4 mm pitch.422
Overloading may also play a role and result in complete loss of
osseointegration and replacement of bony by fibrous tissue, which
has been demonstrated.423-428 Then it may be assumed that immediate
or early loading of implants, especially in situations with very loose
trabecular bone, may also result in primary instability of the implants,
thus jeopardizing the establishment of a direct BIC.429 The results of
Balshi et al.415 suggest that initial bone quality at implantation can
affect the rate of bone remodeling and thus secondary stability. There
are some studies in literature supporting these statements.
For instance, Friberg et al.212 reported that implants placed in
extremely soft bone and/or lacking initial stability, as evidenced
by “lack of resistance during final tightening of the cover screw or
mobility of the fixture mount when still on the implant,” constituted
32% of the implant failures recorded in their study. However, they
did not report the integration rate of implants that were mobile at
placement or their long-term survival rates.
In the study of Orenstein et al.430 with Core Vent Spectra System
implants, 93.8% of the implants that were mobile at placement
were clinically integrated at uncovering, compared with 97.5% of
the implants not mobile at placement. The 3-year postplacement
survival for the implants that were mobile at placement, however, was
significantly lower (79.8%) than for implants that exhibited primary
stability (93.4%) at the time of placement. In the study of Morris et
al.414 with Ankylos implants, of the implants mobile at placement,
97.7% were stable at uncovering. The 3-year postplacement survival
of initially mobile implants was 84.1% compared with 96.8% for
implants not mobile at placement.
Glauser et al.431 observed that only 66% of implants placed in
poorly mineralized trabecular bone in the posterior maxilla were
successfully integrated after 1 year following immediate loading in
comparison with 91% successful implants placed in mineralized
bone. Glauser et al.431 studied machined implants.
In the study of Lioubavina-Hack et al.,429 titanium implants were
placed in rats in a secluded space created for the formation of new
bone, either in contact with the bone surface of the mandibular
ramus, being stable, or not, could easily be moved. All primarily
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stable implants presented increasing percentages of direct BIC during
the experimental period, reaching about 80% of the entire implant
length after 9 months. Primarily unstable implants, on the other
hand, failed to present osseointegration at any observation time,
despite the formation of considerable amounts of new peri-implant
bone inside the capsules. The authors stated that this finding would
indicate that primary implant stability is a prerequisite for obtaining
osseointegration of titanium oral implants.
In addition, it has been stated that secure primary stability
leads to predictable secondary stability.432 However, primary
implant stability, while desirable, is not a prerequisite for achieving
osseointegration.414,430 Implants that are mobile at placement may
benefit significantly if given more time to integrate without loads than
those implants that are stable at placement.414 Progressive loading of
implants has been shown to improve Periotest values433 and may also
promote more complete osseointegration of initially mobile implants.
Moreover, the low values of RFA obtained from implants placed in
softer bone seem to increase over time and match the RFA values
of the implants placed in more dense bone sites.434 Thus, the most
important factors to affect osseointegration could be a matter of how
unstable the implant is right after placement and how soon, strong,
and frequent is the load to which the implant is subjected to.
Based on the findings of several studies,398,415,434-441 a table of RFA
ISQ ranges was developed based on bone type, implant location, and
patient gender that can be used as a guideline for determining the
specifics of immediate loading.442 An ISQ value below the predictor
range may indicate that the implant does not have sufficient primary
stability to undergo immediate functional loading. An ISQ value above
the predictor range may represent either an inaccurate identification
of bone quality at the implant site or an incorrect resonance frequency
measurement technique.415 However, these guidelines should be used
with caution. There is a need to maintain a consistent protocol in the
measurements, as the ISQ level was often influenced by orientation
of the transducer to the axis of the alveolar ridge. It was observed
that measurements in one orientation (for instance, perpendicular or
parallel) may have ISQs equal to or higher than the measurements
made in different orientations.415 The distance from the transducer to
the first bone contact435,443 is another factor of potential importance,
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such as the abutment length and possible marginal bone resorption
as well.434 The application of the Periotest as a clinical diagnostic
aid to measure implant stability has been contested by some,444 due
to the sensitivity of the device to clinical variables including striking
heights and hand-piece angulation.
Fresh extraction sockets

The insertion of dental implants immediately after teeth extractions
has become a routine clinical procedure in implant dentistry. Tooth
extraction results in a reduction of the bone quantity, which may
prevent placement of an implant because of the decreased bone
volume. Therefore, some authors advocate immediate placement.
Several studies mainly of moderately rough-surfaces implants have
reported that successful osseointegration is possible when implants
are inserted immediately after tooth extraction, with similar survival
rates when compared to implants inserted in healed sites, with or
without the help of guided bone regeneration procedures. Placing an
implant immediately after tooth extraction offers several advantages,
including a decrease in rehabilitation treatment time, fewer surgical
sessions, the ability to place the fixture in an ideal axial position,
positive psychological impact on the patient, and enhanced hard
and soft tissue maintenance.445,446 However, some other studies have
shown that implants placed in fresh extraction sockets shows higher
failure rates than when inserted in mature bone.404,447-452 A systematic
review and meta-analysis was conducted18 in order to address the
conflicting clinical data, and observed that the insertion of dental
implants in fresh extraction sockets increased the implant failure
rates (p < 0.0001), with a RR of 1.58 (95% CI 1.27-1.95) when
compared to placement in healed sites.
A suggested explanation for this is the fact that implant placement
in fresh extraction sockets is technique-sensitive because primary
implant stability is critical; these implants are usually not in direct
contact with the alveolar bone because the extraction socket is broader
than is the implant. The anatomic characteristics of the socket after
tooth extraction are different from the socket environment after 1
year of healing. Implants placed immediately into fresh extraction
sites engage precisely prepared bony walls only in their apex, whereas
the coronal space is filled by the end of the healing phase.453 It has
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been stated that the procedure should be limited to alveoli with
sufficient bone for primary stability, which is generally achieved by
exceeding the apex by 3 to 5 mm or by using implants that are wider
than the alveolus.454 To achieve these conditions, a minimum of 4 to
5 mm of alveolar crest width and a residual bone length no less than
10 mm are recommended.455 Simultaneous bone regeneration may
be required.456
It is also suggested that periodontitis-affected tissues may have a
negative local influence on the failure rates due to the presence of
infrabony defects, which could increase the gap between bone and
implant,457 or jeopardize the achievement of primary stability458 at
immediate implant placement.
The aforementioned review18 observed a higher failure rate of
immediate implants in relation to non-immediate implants in the
maxilla in comparison to the mandible, which may be attributed to
the low density of medullary bone and thin cortical plates,448 which
may have resulted in significant reduction in insertion torque for
implants in the maxilla and less implants with primary stability, and
further resulted in a lack of resistance to mechanical stresses.450
Concerning the influence of the prosthetic rehabilitation on
the failure rates, a statistically significant difference between the
placement of implants in fresh extraction sockets and healed sites was
found when studies only evaluating patients with implant-supported
single crowns were pooled, the same not happening when full-arch
prostheses were the only prosthetic rehabilitation performed.18 From
a biomechanical point of view, single implants may be at higher risk
of overloading,459 because of the lack of splinting. The splinting of
the implants in full-arch prostheses allows a more even distribution
of the occlusal forces, thereby reducing stresses at the bone-implant
interface460 as well as micromotion.461
Moreover, it is suggested that the healing/loading period may
also influence the implant failure rates and immediate loading
may appear to be at a higher risk of failure than conventionally
loaded ones. It was believed that too-early loading of an implant
leads to an interfacial formation of fibrous tissue instead of bone.462
Presently, it appears that premature loading per se does not lead to
fibrous tissue encapsulation. Rather, it is due to an excessive amount
of micromotion at the bone–implant interface, during the healing
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phase.440 Most of the included studies exclusively evaluating implants
being rehabilitated with single crowns or with full-arch prostheses
applied immediate loading to the implants. The splinting of the
implants in the full-arch prostheses might have influenced the results.
A study450 comparing the survival rates of implants subjected to
immediate or delayed restoration in periodontally susceptible patients
observed that the stratification of the implants between extraction
and non-extraction sites revealed no statistically significant difference
between the groups in either insertion torque, insertion ISQ (Implant
Stability Torque), or change in ISQ from insertion to 12 months.
Based on these data, primary stability did not contribute to implant
failure in extraction sites.
Some studies specifically addressed this issue of MBL when
implants were placed immediately in extraction sockets. In a
prospective clinical study, Schropp et al.463 observed that both delayed
and immediate approach resulted in statistically significant reduction
in bony defects. Another study found that the amount of resorption
has been reduced in immediate implants compared to the delayed
implants.464 Raes et al.465 observed that a trend toward bone gain
was found following insertion in fresh extraction sockets, which may
be explained by the fact that the gap between the original bone and
implant diminishes during healing, and the BIC increases in coronal
direction during the healing phase. These findings can be related to a
coronal bone remodeling around immediate implants and a healing
pattern with new bone apposition around the neck of the implants.466
These studies did not lead to a clear conclusion about the subject,
and the possible influence of several factors42 makes it difficult to
estimate the real effect of the insertion of implants in fresh extraction
sockets on the marginal bone level. The meta-analysis of Chrcanovic
et al.18 found no apparent significant effect of implants inserted in
fresh extraction sockets on the magnitude of MBL in comparison
with implants placed in mature bone.
One important factor to consider is the implant position in relation
to the extraction socket crestal bone level. A study467 observed
that there are reasons to suggest that either crestal bone loss or its
preservation may be partly due to the crestal or subcrestal implant
position. The study also showed that there is a marked hard tissue
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alteration during the 8-week healing period following tooth extraction
and immediate implant placement, which affected both buccal and
lingual bone plates. The experiment of Caneva et al.468 installed
immediate implants into extraction sockets in the mandibles of six
dogs and concluded that implants should be positioned approximately
1 mm below the alveolar crest and in a lingual position in relation to
the center of the alveolus to reduce or eliminate the exposure above
the alveolar crest of the endosseous rough portion of the implant.
In a clinical trial using a multivariate model to analyze factors that
may affect bone alterations during healing after immediate implant
placement, Tomasi et al.469 observed that the position of the implant
opposite the alveolar crest of the buccal ridge and its bucco-lingual
implant position influenced the amount of buccal crest resorption.
Furthermore, the thickness of the buccal bony wall in the extraction
site and the vertical as well as the horizontal positioning of the
implant in the socket must be considered because these factors will
influence hard tissue changes during healing.
Another factor that may determinate the amount of bone
loss that will occur at crestal bone level is the implant-abutment
design.470 The influence of different microgap configurations can
cause different amount of bone loss, even before prosthetic loading.
Subcrestal placement of a butt-joint microgap design may lead to
more pronounced bone loss at least at early times of follow up.471,472
It is suggested that grafting procedures may also exert some
influence on the marginal bone levels. The marginal gap that may exist
following implant placement in an extraction socket may be resolved
by hard tissue filling during healing, which can possibly change the
results, but the literature shows conflicting results. A preclinical
study473 on beagle dogs demonstrated that socket grafting modified
the process of hard tissue healing, provided additional amounts of
hard tissue at the entrance of the previous socket and improved the
level of marginal BIC. In contrast, an animal study474 on mongrel
dogs demonstrated that such procedure resulted in significant buccal
bone loss with low osseointegration. Last but not least, the use of
different radiological techniques to assess changes in crestal bone
level is an additional influencing factor on the results.
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Flapless surgery
When placing dental implants, a flap is traditionally elevated
to better visualize the implant recipient site, providing that some
anatomical landmarks are clearly identified and protected. When a
limited amount of bone is available, a flap elevation can help implant
placement to reduce the risk of bone fenestrations or perforations.475
More recently, the concept of flapless implant surgery has been
introduced for patients with sufficient keratinized gingival tissue and
bone volume in the implant recipient site. In a flapless procedure,
a dental implant is installed through the mucosal tissues without
reflecting a flap. The alleged reasons to choose the flapless technique
are to minimize the possibility of postoperative peri-implant tissue
loss and to overcome the challenge of soft tissue management during
or after surgery.476 Other alleged advantages of the flapless implant
surgery include less traumatic surgery, decreased operative time,
rapid postsurgical healing, fewer postoperative complications and
increased patient comfort.477,478 A disadvantage of this technique is
that the true topography of the underlying available bone cannot
be observed because the mucogingival tissues are not raised, which
may increase the risk for unwanted perforations which in turn could
lead to esthetical problems or implant losses.479 Moreover, there is
the potential for thermal damage secondary to reduced access for
external irrigation during osteotomy preparations.478
A systematic review and meta-analysis on the subject12 suggested
that there is a statistically significant difference in implant failure
rates when implants are inserted through the flapless approach in
comparison to an open flap surgery (RR 1.75, 95% CI 1.07-2.86;
p = 0.03).
Currently, some software systems using computed tomography
(CT) scans have been proposed to aid in planning surgery and to
produce surgical drilling guides to transfer the planned position to
the surgical field. These guides are manufactured in such a way that
they match the location, trajectory, and depth of the planned implant
with a high degree of precision. As the dental practitioner places the
implants, the guides stabilize the drilling by restricting the degrees of
freedom of the drill trajectory and depth.480,481 It was stated that by
using computer-assisted surgery predictability, precision and safety
in flapless dental implantology are ensured.482
112
However, the precision of the whole procedure depends largely
on the ability to position accurately the drill guide, and to maintain
that stable position during the whole procedure.480 In the case of the
placement of implants in completely edentulous jaws, there must be
a way to assure the stability of the drill guide, and this is done by
fixing the surgical guide onto the bone using osteosyntheses screws.
Asymmetric distribution of the screws or uneven tightening of the
screws could bring the drilling template out of balance. Furthermore,
a certain error is induced as the diameter of the steel tubes is slightly
larger than the drill diameter.480 Finally, the largest error is probably
due to the fact that the final step in the procedure is carried out
manually, depending on the surgical guide used. In these cases,
implant placement cannot be done through the surgical drill guide
because of present mechanical limitations. The drill guide, therefore,
has to be removed before the implant is actually inserted, leaving the
possibility of additional deviation.480 Because of these reasons, the
surgical drill guide may provide a false security in decreasing the risk
of bone fenestrations or perforations. This may be one of the reasons
why the review of Chrcanovic et al.12 observed a higher percentage
of implant failures with the flapless technique when compared with
the open flap surgery.
Still concerning the precision of the implant insertion, it is worth
commenting about the technique used by the study of Sennerby et
al.376 They made use of a slide-over guide sleeve to evaluate and
determine the position of the implant. This system is based on the
surgeons’ imprecise opinion of what is the exact direction of the
implants to be placed and it is subjected to flaws, which may have
led to an increasing incidence of implant bone plate fenestrations
or perforations, and consequently higher implant failure in this
group (7.9% versus no failure in the open flap surgery). Correct bur
angulation is critical in the procedure.480 With the CT-guide surgery,
it is possible to verify in advance the presence of concavities of the
vestibular and lingual/palatal bone plates surrounding the planned
implant surgical site, thus planning the correct bur angulation and
decreasing the chance of implant bone fenestrations or perforations.
Moreover, one in vitro study483 analyzed deviations in position and
inclination of implants placed with flapless surgery compared with
the ideally planned position and examined whether the outcome was
113
affected by the experience level. The authors observed that the three-
dimensional location of implants installed with flapless approach
differed significantly from the ideal, although neighboring teeth
were present and maximal radiographical information was
available. The outcome was not influenced by the level of experience
with implant surgery. It was suggested that these deviations would in a
clinical situation lead to complications such as loss of implant stability,
as well as aesthetical and phonetical consequences. The authors
recommended the performance of more precise measurements of soft
tissue in situ or additional use of guiding systems.
Since flapless implant placement generally is a “blind” surgical
technique, care must be taken when placing implants. Angulation of
the implants affected by drilling is critical so as to avoid perforation
of the cortical plates, both lingually and buccally, but with presumed
more problems with the lingual side in the mandibular molar area
and the anterior maxilla.484 Therefore, the surgeon must weigh the
benefits of the flapless technique against the increasing risk of implant
bone fenestrations or perforations, which allegedly may impair
implant success or increase the implant failure rates.485 Violation of
the dental implant beyond the alveolar housing may result in infection
and ultimate loss of the implant.486 There should be no problem if the
patient has been appropriately selected and an appropriate width of
bone is available for implant placement.484 Some authors484 suggested
a minimum of 7 mm of bone width and substantial training to use
the appropriate technique.
Another hypothetical drawback of the flapless procedure is that
it could interfere with osseointegration because of implant surface
contamination and the deposition of epithelial and connective cells
from the oral mucosa in the bone during surgical preparation.487
On the other hand, a flapless procedure could have a positive effect
on the early bone remodeling process, because during the surgical
procedure, the bone remains covered by the periosteum. However, the
strongly tightened surgical template used to insert implants in totally
edentulous jaws may hinder access of saline water and proper cooling
during the drilling procedure, which could negatively influence the
implant surrounding the bone and the remodeling process during
healing.488
114
Concerning the MBL, one may expect that the open flap surgery
may cause higher MBL due to decreased supraperiosteal blood
supply because of the raising the tissue flap during the surgical
procedure. Studies have demonstrated that flap reflection often
results in bone resorption around natural teeth.489 However, it was
showed in five studies that the flapless technique generated more
MBL around the implants.479,490-493 The authors of some of the articles
here reviewed provided some reasonable explanations for this. De
Bruyn et al.479 suggested that this was probably caused in their study
due to overdoing of the countersinking procedure. More extensive
widening of the crestal bone was necessary to remove enough
bone as to allow proper placement of the healing abutment. By
countersinking wider and deeper, the coronal portion of the implant
is not always in intimate contact with the bone. In the flapped sites,
the countersinking procedure was more controlled according to the
guidelines of the manufacturer because visual inspection in situ was
possible. Rousseau492 discussed that this is due to implants being
installed blindly, and thus implants are installed more deeply with
the flapless technique than with the open flap technique. Therefore,
a portion of the transmucosal (supracrestal) part of the implant is
slightly below the crestal bone level. Because the coronal part of the
implant is smooth titanium, rearrangement of bone around the neck
of the implant is normal. When an open flap technique is used, the
implant is installed under visual control directly at the right crestal
bone position, which results in less bone rearrangement around the
implant neck.492 The results found in the study of Van de Velde et
al.493 may be related to the fact that the implants inserted through
the flapless technique were immediately loaded, whereas the implants
inserted through open flap surgery were loaded only after 6 weeks.
Non-submerged implants
Historically, the original Brånemark protocol for placing implants
prescribed a two-stage surgery with a submerged healing period of
at least 3 months in the mandible and 6 months in the maxilla,35
allowing the implant to osseointegrate without being exposed to
external forces. After bone healing, a second surgery is performed
to connect a healing abutment. One of the main reasons for implant
insertion in the two-stage procedure was to minimize the risk of
115
infection, since the peri-implant tissue is allowed to heal separately
from the oral microbial environment.494 The predictable outcome of
this two-stage installation technique was verified in several clinical
trials that reported high success and survival rates for implants that
were initially submerged. Extended treatment times, two surgical
interventions, and the need for interim prostheses during healing are
disadvantages of conventional implant treatment.495
With time, the concepts of implant placement in fresh extraction
sockets,189,496 immediate loading, and non-submerged implants were
introduced, focusing on shorter and less invasive procedures. To
reduce the treatment time and offer the patient early function and
esthetics, it is necessary to use a one-stage surgical procedure and
to load the implants as soon as possible. In the one-stage surgical
approach (non-submerged implant), the coronal part of the implant
is positioned above the gingiva level in case of one-part implants,
or transmucosal healing abutments are placed in case of two-part
implants. In the one-stage surgical approach the implant can be
immediately loaded or not. The encouraging early experiences of
immediate loading in the mandible and the development of new
implant designs and surfaces have inspired researchers to further
explore applications of immediate loading.497
Inserting implants in one stage has several advantages. Only one
surgical intervention is required, which is convenient for the patient,
especially for the medically compromised patient. In addition, there is
a considerable cost-benefit advantage. The prosthetic phase can start
earlier because there is no wound-healing period involved related to a
second surgical procedure. Furthermore, the implants are accessible for
clinical monitoring during the osseointegration period.498 It allows for
a healed peri-implant mucosa at the time of prosthetic rehabilitation.
Although immediate loading of implants shortens treatment duration
and also provides patients with an acceptable esthetic appearance,
there is concern that immediate loading may increase the risk of
implant failure. However, reports have shown that immediate loading
can lead to clinical and histological osseointegration.499,500
In a meta-analysis, Chrcanovic et al.21 compared dental implant
failures in patients being rehabilitated with immediately loaded non-
submerged dental implants versus delayed loaded submerged implants. It
was observed that the difference between the procedures significantly
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affected the outcome (p = 0.02), with a higher implant failure rate
for the immediately loaded non-submerged implants (RR 1.78, 95%
CI 1.12, 2.83). However, the results of the analysis may have been
influenced by the fact that all implants in the non-submerged group
were immediately loaded.
A possible explanation for the possibility of a difference in MBL
between submerged and non-submerged implants could be that the
trauma of the second operation is avoided by preservation of the
biologic width by means of a more superficial placing of implants.501
A less extensive countersinking in the non-submerged implants may
also contribute to less bone resorption.501 The presence of a microgap
between the implant and the prosthetic abutment when two-part
implants are used is another hypothesis. It has been observed that
bacteria colonize the inner region of two-part implants following
abutment connection and that this, in turn, may result in MBL.502,503
Weber et al.504 demonstrated that in one-stage implants a large
percentage of initial bone loss occurred during the first months,
whereas in two-stage implants 40% of initial bone resorption was
found after re-entry. The authors explain their findings with bacterial
colonization of one-stage implants and the additional surgical trauma
in two-stage protocols. However, a comparison of MBL between
one- and two-piece implants was performed in the study of Engquist
et al.501 and the results suggest that the microgap has no obvious
effect on the clinical outcome. Putative periodontal pathogens have
been implicated in the onset and progression of peri-implantitis, but it
remains unclear whether these bacteria always constitute a risk factor
for the maintenance of dental implants.505 In fact, in some studies506,507
no correlation was established between the frequency of any group
of microorganisms and the clinical parameters of peri-implantitis.
Although suspected periodontal pathogens were identified at implant
sites in these latter studies, the clinical parameters were not indicative
for deteriorating support, suggesting that the presence of potential
periodontal pathogens around implants may not always be associated
with future attachment loss or implant failure. As it was observed in a
review, there are many original reasons for MBL around oral implants,
reasons not associated with any primary infection or overloading
alone, but instead coupled with the used hardware, clinical handling,
and different patient factors or dependent on foreign body reactions.6
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Immediate loading
A healing period of 4 to 6 months was initially proposed to ensure
osseointegration of endosseous dental implants.38 The desire for
fewer surgical interventions and shorter implant treatment times has
led to the development of revised placement and loading protocols.
With the improvements in oral implantology resulting in improved
prognosis and outcomes, the traditional protocol for implant dentistry
has been constantly reevaluated. Recent steps were the reduction of
the treatment time by immediate placement of implants into fresh
extraction sockets18,189 and by loading the implants immediately.508
In 1990, Schnitman et al.509 reported on the fabrication of immediate
(immediately following stage I surgery) fixed mandibular interim
prostheses supported by 2-stage threaded implants. These authors
felt that the use of threaded implants in these cases was important
in order to achieve “immediate stabilization within cortical bone.”
Immediate loading protocols have since been extensively discussed in
the literature and found to be a viable treatment approach in selected
cases.500
In a meta-analysis, Chrcanovic et al.21 compared dental implant
failures in patients being rehabilitated with immediately loaded non-
submerged dental implants versus delayed loaded submerged implants. It
was observed that the difference between the procedures significantly
affected the outcome (p = 0.02), with a higher implant failure rate
for the immediately loaded non-submerged implants (RR 1.78, 95%
CI 1.12, 2.83). However, things are not as black and white as they
might see, as the authors discussed in their article.
Concerning the immediate loading, that might have influenced
the results, Pilliar et al.510 observed that an amount of 150 μm of
micromovement may be a critical level above which healing would
undergo fibrous repair rather than the desired osseous regeneration.
Micromotion or motion of the implant surface relative to the bone can
result from functional overloading immediately after implantation.
It has been for long believed that micromotion can also disturb
the early remodeling phase, and a critical degree of micromotion
caused by overload can result in fibrous repair at the interface
rather than osseous regeneration and osseointegration.511 However,
reports have shown that immediate loading can lead to clinical
and histological osseointegration.499,500 It is therefore justifiable to
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question whether this healing period is an absolute prerequisite to
obtaining osseointegration, or if under certain circumstances this
period can be shortened without jeopardizing osseointegration
and long-term results.512 Moreover, several implant features, like
geometry of the implant body specially designed for critical bone
conditions and implant surfaces combined with high insertion torques
during bone healing may have minimized the risk of early failure of
immediately loaded implants. The immediate loading of implants
installed according to the non-submerged procedure might inhibit
osseointegration, although implants inserted in the submerged way
sometimes fail to osseointegrate as well. Thus, the true reason for the
failure to osseointegrate largely remains obscure.494
Speculatively, the immediate loading may cause a greater MBL in
comparison with delayed loading. However, early functional loading
to a determined, controlled extent during the healing phase may
instead have a positive effect on marginal bone levels.513 Early loading
stimuli at the bone-implant interface leads to functional adaptation
of the bone to the loading situation (remodeling) and to an improved
differentiation of the bone structures, resulting in a higher marginal
bone level.393,514
Furthermore, the peri-implant bone reactions around delayed
and immediately loaded implants have been evaluated in an animal
study. Histologic and histomorphometric observations and data have
already been published515 and showed no histologic differences in the
two loading groups. It should be noted that the lack of statistically
significant differences between the two loading groups does not mean
that the peri-implant conditions are the same,516 because the sample
size in most of the studies with available information on MBL were
relatively small.
It has been suggested that it is not the absence of loading per se that
is critical for osseointegration, but rather the absence of excessive
micromotion at the interface.517 Micromotion consists of relative
movement between the implant surface and surrounding bone during
functional loading and above a certain threshold excessive interfacial
micromotion early after the implantation interferes with local bone
healing, predisposes to a fibrous tissue interface, and may prevent
the fibrin clot from adhering to the implant surface during healing.440
Splinting of the provisional restoration might have protected these
implants from micromotion.461
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The biological differences in peri-implant tissue responses between
immediate nonfunctional loading and immediate functional loading
implants were already analyzed in animal models, and no difference
was observed between the ultrastructural morphology of the cells
at the interface of implants from both groups in the early phases of
the osseointegration in minipigs,518 and no statistically significant
differences in the BIC percentages between the groups, in a study
performed in dogs.519
Tilted implants
The loss of posterior teeth, particularly at an early age, leads to
the loss of alveolar bone with a relative surfacing of the inferior
alveolar nerve in the mandible, thus often prohibiting placement
of implants in the posterior regions.520 Bone grafting and the use
of short implants have been proposed to overcome these anatomic
limitations. An alternative could be the inferior alveolar nerve
lateral transposition521,522 or the use of tilted implants, which
allows for maximum use of the existing bone and placement of
posterior fixed teeth with minimum cantilevers, in a region where
bone height and nerve proximity does not allow for the placement
of axial implants.520 Concerning the upper jaw, implant anchorage
in the totally edentulous maxilla is often restricted owing to bone
resorption, which is especially frequent in the posterior region of
the maxillary arch, where bone grafting is often indicated.523 There
is also the problem of the pneumatization, an inferior expansion of
the maxillary sinus in relation to fixed anatomic landmarks which
develops with time after the extraction of the posterior maxillary
teeth. Pterygomaxillary and zygomatic implants could be used, but
these techniques present considerable surgical complexity.27,480,524,525
The use of tilted implants in the anterior or posterior maxillary sinus
walls leads to the exclusion of maxillary sinus elevation or bone
grafts, resulting in a simpler and less time-consuming treatment and
significantly less morbidity, in decreased financial costs associated
with those procedures, and in a more comfortable postsurgical period
for the patients.526,527
A recent systematic review17 focused on comparing the effect of
tilted versus axially placed implants on the implant failure rates. A
meta-analysis observed that the difference between the procedures
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did not significantly affect the implant failure rates (RR 1.14, 95% CI
0.84-1.56; p = 0.40). This suggests that tilted implants may achieve
the same outcome as implants placed in an upright position. This
result is associated with biomechanical advantages in the case of
fixed full-arch prostheses with splinted implants, the most common
rehabilitation observed in the studies here included, since in this
protocol implants are placed in strategic positions from a load-sharing
point of view. Placement of two or more well-anchored posterior
tilted implants together with anterior axially oriented implants can
provide a predictable foundation for implant-supported full-arch
prostheses.527 A FEA study concluded that there is a biomechanical
advantage in using splinted tilted distal implants rather than axial
implants supporting a higher number of cantilever teeth.528 Tilting
of the implants may allow using longer implants that may engage
greater quantity of residual bone, which is beneficial to implant
stability.529,530 Moreover, a more even distribution of stress around
implants is achieved when implants with longer length are used.221
It is also important to make some consideration about the splinting
of the implants. It has been suggested that immediate loading would
not be as critical for osseointegration as the presence of excessive
micromotion at the interface. Micromotion consists of relative
movement between the implant surface and surrounding bone
during functional loading and above a certain threshold excessive
interfacial micromotion early after the implantation interferes with
local bone healing, predisposes to a fibrous tissue interface, and may
prevent the fibrin clot from adhering to the implant surface during
healing.440 Splinting of the implants in the case of the immediate-
loaded fixed full-arch prostheses might have protected these implants
from micromotion.461 Splinting allows a more even distribution of
the occlusal forces, thereby reducing stresses at the bone-implant
interface.460 It was also suggested that the reason for the high survival
of tilted implants may be the increased contact between cortical
bone and tilted implants, increasing the initial stability,531 which
may be true for the maxilla, but not necessarily for the mandible.
However, when a sensitivity analysis was performed pooling the
studies evaluating implants inserted in maxillae only, a statistically
significant difference was observed, favoring axially placed implants.
This might be associated with the lower bone density encountered
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at the posterior regions of the edentulous maxilla, where the tilted
implants were inserted.
Concerning MBL, it was suggested by FEA studies which reported
accentuated stresses around non-axially placed implant necks532-534
that unfavorable loading direction could in theory induce greater
bone resorption around tilted implants as compared to axially placed
ones. Tilted implants may be also subjected to bending, possibly
increasing marginal bone stress.535 On the other side, it was shown
in FEA studies for full-arch prosthesis that the reduction of the
cantilever length achieved by tilting of the distal implants allows for
a more widespread distribution of the occlusal forces under loading,
and consequently for a reduction of the stresses at the implant
neck.528,536,537 It is interesting to note that photo elastic and FEA
studies analyzing single angulated implants532-534 showed increase
of stress in the surrounding bone, whereas FEA studies528,536,537
analyzing tilted implants in splinted full-arch prostheses observed
more favorable results for tilted implants concerning MBL, due to the
splinting effect. The cantilever length of the prosthesis also has some
influence, as shorter cantilevers have been correlated to a reduced
peri-implant bone loss.538 The meta-analysis of Chrcanovic et al.17
did not find an apparent significant effect of tilted dental implants
on the occurrence of greater MBL in comparison with axially placed
implants. The fact that fixed full-arch prostheses with splinted
implants were the most common rehabilitation observed in several
studies might have collaborated to these findings. However, these
results should be interpreted with caution due to the lack of use of a
standardized technique aiming to obtain a precise and reproducible
bone loss measurement, and further due to the variability of the
follow-up period among the studies.
Grafting
The insertion of dental implants requires sufficient bone volume
to achieve primary stability539 and ensure good long-term results.
The reconstruction of defective mandibles using non-vascularized
bone grafts and dental implant insertion was originally described
by Brånemark et al.540 and has become a well-established procedure
for prosthetic rehabilitation.539,541,542 Interpositional bone grafting,543
vascularized bone grafting,544,545 and nerve repositioning, including
lateralization and transposition techniques,522 represent valid
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alternatives to non-vascularized bone grafting procedures. In cases of
non-vascularized procedures, and depending on clinical conditions,
endosseous implants can be inserted at the time of reconstruction as
long as there is sufficient residual bone to ensure primary stability.546,547
Alternatively, implants may be inserted later, in a delayed procedure,
after the graft has been left to consolidate for 3 to 6 months.542
Many authors have advocated the delayed protocol,548-557 stating
that the immediate placement of implants exposes the patient to some
risks, such as partial or total loss of the graft in the case of wound
dehiscence, membrane or onlay graft exposure and/or infection,
and non-integration of implants related to the immediate placement
into avascular bone. As it would be possible to place implants
in a revascularized graft when a delayed protocol is performed,
and since the regenerative capacity of bone is determined by the
presence of vessels, bone marrow, and vital bone surfaces, a delayed
approach would permit a better integration of implants (higher
values of BIC) and stability of implants as compared with immediate
implant placement.549,558,559 Although it is difficult to determine a
clear indication for immediate or delayed implant placement, the
majority of authors suggest immediate implant placement when the
residual alveolar bone presents adequate quality and quantity.560
Thus, primary stability of dental implants would be closely related
to these parameters.561
A systematic review561 comparing success rates in immediate
and delayed dental implant placement following guided bone
regeneration or onlay bone block ridge augmentation observed that
these two procedures are reliable techniques, providing sufficient
bone volume to allow implant placement in the case of vertical and/
or horizontal defects of partially or totally edentulous patients.
Most studies demonstrated that success rates of implants placed in
the augmented areas by means of GBR or onlay graft techniques
are similar to those reported for implants placed in pristine bone.
Another review562 observed that implants placed in onlay or inlay
graft procedures presented a very low failure rates, and that the
marginal bone conditions around implants in grafted sites were
comparable to what has generally been reported for non-grafted sites.
Specifically to the superior jaw, maxillary sinus floor augmentation
is a technique that is widely used to enable the placement of dental
implants in the severely resorbed posterior region. The success of the
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maxillary sinus lift procedure is determined by the amount of vital bone
formation after maturation of the graft and the long-term survival rate
of the implants placed in that region.563 A recent systematic review on
the subject564 observed that the most frequently reported reasons for
the loss of implants were instability during implant insertion565-569 and
the placement of implants after dental extraction in alveolar regions
with less than 2 mm of height,570 demonstrating the importance of
primary stability in the rehabilitation of regions by sinus lift.
Reoperation
Replacement of implants in sites where previous implants have failed
has often been the main treatment alternative in most cases.571 It
was suggested more than 30 years ago that when a dental implant is
lost, a flap should primarily cover the entrance to the site, and after
9 to 12 months a new implant could be replaced.300 More recently,
it was suggested that a 1-year healing period may not be necessary,
provided that the socket can be prepared to eliminate thread grooves
and invasive soft tissue, the replacement implant is larger in diameter
than the original implant, and sufficient available bone remains for
the procedures.572
Failed implant sites present a challenging therapeutic dilemma
to the clinician because the alveolar bone in these sites is usually
further reduced due to marginal bone resorption, resulting in greater
difficulties for integration of yet another implant. Implant therapy is,
however needed for a fixed prosthetic reconstruction in most cases.573
Chrcanovic et al.192 assessed the survival of dental implants placed
in sites of previously failed implants, and observed that the survival of
implants placed at the same location after implant failure was 73%
compared to the 94% survival rate of traditionally placed implants in
the original cohort. These results are in agreement with other studies.
Grossmann and Levin574 observed that 9 of 31 (29%) re-operated
implants failed in their study. Machtei et al.573 reported an overall
survival rate of 83.5% for re-operated dental implants. Kim et al.575
found a lower failure rate (11.7%) for reimplantation, similar to the
results of Alsaadi et al.576 with 12.1% failure rates (7 of 58 implants),
and Wagenberg and Froum577 of only 3.92% failures (2 of 51). Kim
et al.575 reported that few implants failed the second time and were
replaced with a third implant, this time with good results. However,
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these were only a few implants, which were only followed up for
a short period of time. The lower survival rate observed in these
studies represents three- to fourfold increase in the proportions of
lost fixtures compared with the rate often reported for non-affected
first-time implant sites.577
The lower survival rate for implants placed in previously failed
sites suggests site- or patient-specific risk factors.571,573 The site-
specific theory is mainly supported by the finding that failed implants
are often found in patients where other implants were successfully
osseointegrated and in function.229 Machtei et al.573 concluded that
the lower failure rate observed for re-operated implants in their study
was not related to any of the common implant- or patient-related
factors. Thus, they have suggested a possible site-specific negative
effect that might be associated with this phenomenon. A greater
percentage of lost implants in the study of Chrcanovic et al.192 were
placed in bone sites having been classified as quantities D and E and
qualities 3 and 4, according to the Lekholm and Zarb188 classification.
Moreover, bone quality in the area with failed implants is usually
further reduced and is poor compared with other areas without
implants.575 There was a statistically significant higher failure rate for
turned (machined) implants versus surface enlarged implants in cases
of replaced failed implants.192 The same was observed in the study
of Alsaadi et al.576 The mean Implant diameter was rather similar in
the original operation and the reoperations. Evaluating the length
of the original and replacement implants, it could be observed that
the mean length of the replacement implants were actually shorter
than the original ones. Furthermore, some implants were replaced a
short period after the explantation.192 These two factors may have
also contributed to the higher failure rates. It has been suggested
that the success of replacement may be increased by improving the
implantation site with bone augmentation and the use of larger
implants with improved surfaces,576 although recent evidence has
criticized bone augmentation.578 It has been reported that implants
with an enlarged surface experience faster bone apposition in relation
to turned (machined) implants, which allows the former to achieve
a proper fixation even if a remaining endosseous lesion tends to
compromise the osseointegration process.579 This difference in bone
apposition may be relevant for replacing implants.576
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On the other hand, the cluster phenomenon supports the patient-
specific factor as a possible explanation for failure of implants.580
Concerning this issue, there is a general appreciation that risk factors
predispose individuals to more complications and implant failures
and may result in lower implant survival rates.11 Chrcanovic et al.192
found no clear relationship between the patients’ habits and systemic
conditions and failures of the re-operated implants. However, this
does not necessarily mean that these variables are not risk factors for
dental implants, but it is suggested that the substantial negative effect
of these sites with previous failures outweighs these patients’ and
environmental variables, thus masking their effect.573 It is important
to stress that, once an implant has failed, replacement of that implant
is subjected to at least all the initial factors that led to the failure.574
Anatomy
Location – maxilla and mandible, anterior
and posterior regions
According to its structure, jawbone can be classified as cortical
or trabecular. With respect to osseointegration, cortical bone is
beneficial to implant stability, whereas trabecular bone is beneficial
to blood supply.581 Their relative proportion strongly affects implant
survival.582 In general, there is a tendency to have more bone tissue
in anterior than in posterior regions.583 In the posterior maxilla, there
is commonly thinner cortical bone combined with thicker trabecular
bone compared to the mandible.583-585 This higher failure rate in
this region may be attributable to a combination of the demanding
preconditions often present in the posterior maxilla, such as barely
sufficient bone volume, poor bone quality, and high functional
forces.431 The cortical layer of both jaws tends to become thinner
and more porous posteriorly. Moreover, posterior implants have
to withstand the heaviest loading and are in general short due to
insufficient quantity of available bone (the maxillary sinus and the
inferior alveolar nerve are the main anatomical limitations). The
high survival rates presented in the canine and/or premolar maxillary
area in some studies212,577,586,587 could be attributed to favorable bone
density and adequate bone quantity due to relatively rare anatomic
limitations. A study577 found high failure rates in the mandibular
anterior region, which was suggested to be caused by overheating of
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the bone when long implants (15-18 mm) were placed.577 The cortical
bone that is very hard with a low blood supply and the trabecular
bone with a low density do not provide favorable host conditions for
good prognosis of dental implants.588 Implant survival rates can be
significantly associated with implant location. Clinical studies have
reported dental implants in the mandible to have higher survival
rates compared to those in the maxilla, especially for the posterior
maxilla.346,589 Bone quality has been considered as the basic cause of
this difference.
Bone quantity and quality

Bone quality is often referred to as the amount and their topographic
relationship of cortical and cancellous bone in which the recipient site
is drilled.590 There are two main reasons for assessing jawbone tissue in
dental implant treatment: first, as a diagnostic tool to assess whether
the jawbone tissue is sufficient for implant treatment, and second,
as a prognostic tool to predict the probability of success or failure,
as the bone tissue characteristics of quality, quantity and density are
considered important with regard to treatment outcomes.212
A poor bone quantity and quality have been indicated as the main
risk factors for implant failure as it may be associated with excessive
bone resorption and impairment in the healing process compared
with higher density bone.205,590,591 Therefore, methods used prior to
dental implant placement are valuable as diagnostic tests for the
planning of implant placement in bone tissue.592
Chrcanovic et al.30 performed the so far only meta-analysis
comparing the survival rate of dental implants, when these were
inserted in bone sites of different qualities and quantities, according
to the Lekholm and Zarb188 classification. The results suggest that
dental implants inserted in bone quality 1 have a higher failure rate
in comparison with implants inserted in bone qualities 2 and 3, the
insertion of implants in bone quality 3 have a higher failure rate
in comparison with implants inserted in bone quality 2, and the
insertion of implants in bone quality 4 have a higher failure rate
in comparison with implants inserted in bone qualities 1, 2 and 3.
These results are hypothesized to be related to some factors. It has
been shown that achieving optimum primary stability in bones with
poor densities is difficult, and this is related to a higher implant
127
failure rate.590,593 There is a strong correlation between bone density
and dental implant stability.594 Dental implant stability is positively
associated with the thickness of cortical bone.229 Bone quality is
not the only factor, and stability is also influenced by the surgical
technique, the surface implant morphology, or its diameter, bone
compaction techniques and cortical anchor for implant placement.
Wide diameters that increase the contact area between the treated
bone and implant surface treated will increase primary stability.
The results of the review30 in relation to the bone quantity suggest
that dental implants inserted in bone quantity A have a higher
failure rate in comparison to implants inserted in bone quantities B
and C, but failure less when compared to implants placed in bone
quantity D. Implants in bone quantity B have a lower failure rate
in comparison with implants inserted in bone quantities C and D.
Implants in bone quantity C have a lower failure rate in comparison
with implants inserted in bone quantity D. Implants in bone quantity
E have a higher failure rate in comparison with implants inserted
in all other bone quantities. The higher failure rate of implants
inserted in bone quantity A in comparison with implants inserted
in bone quantities B and C may be related to the heat generation
during implant site preparation. One in vitro study595 measured in
blocks of bovine cortical femur bone the thermal changes elicited
during drilling and tapping procedures used in site preparation for
implants. Significantly greater temperature increase was noted at the
8-mm depth versus the 4-mm depth with drills. Dentists tend to use
longer implants for sites with more available bone. This increases
the probability of a thermal injury at the implant site. Frictional heat
generated during uncontrolled surgical preparation of hard tissues
at implant sites produces a zone of devitalized bone around the bur
holes. The extent of this necrotic zone varies exponentially with
the magnitude of temperature reached and the duration of thermal
injury.596 Eriksson et al.597 performed histological, histochemical and
vital microscopic study in the rabbit and established a threshold of
47 °C for 1 minute to cause thermal necrosis of the cortical bone.
Also they evaluated the effects of defined temperature rise on bone
regeneration and found that heating of the test implants (titanium) to
47 °C or 50 °C for 1 minute caused a significant reduction in the bone
formation in the implants while no significant effects were observed
128
when the heating was done to 44 °C for 1 min. These results reflected
the importance of controlling the heat generated during the surgical
process that hampers the proper bone regeneration. Concerning the
case of bone quantities D and E, the poor bone volume does not allow
the placement of longer implants with presumably high degrees of
BIC, which may lead to a difficulty to attain primary stability.
Some things must be said about the classification system presented
by Lekholm and Zarb.188 This classification was chosen for several
reasons: (1) it is well known; (2) it describes jawbone tissue from
both qualitative and quantitative aspects; and (3) results indicate
a good correlation with bone mineral content.598 However, the
classification is not perfect. It does not provide quantitative data
about bone quality and density.599,600 The original publication by
Lekholm and Zarb188 contains no definitions of bone characteristics.
The suggestion that anatomical features of bone tissue be considered
before the preparation of implant sites was based on experience.
The foundation for five groups of jaw shapes or four groups of
bone quality was not discussed.601 In a systematic review to evaluate
the evidence for the diagnostic accuracy of clinical methods to
assess bone density, quantity, or quality prior to and during dental
implant placement,592 the authors observed that no study examined
the accuracy of the method originally described by Lekholm and
Zarb.188 The authors concluded that the evidence for the efficacy
of clinical methods to assess jawbone tissue prior to and during
endosseous dental implant placement is sparse. This emphasizes the
need for studies that incorporate accepted methodological criteria
for diagnostic efficacy.592 In a later review,601 the same authors
observed that though it had become routine to include the reference
by Lekholm and Zarb,188 apparently there was no knowledge of the
original description of either bone characteristics or the recommended
assessment methods. This is an inadequate approach to research as
inaccuracy of measurements can affect the reported results of any
intervention.601 Authors should describe how these outcomes have
been measured and whether any particular steps have been taken to
increase the reliability of the measurements.602,603
The reliability of surgeons’ perceptions of bone quality during
surgery is difficult to investigate.601 Shapurian et al.604 found the
observer agreement of two examiners to be low when assessing
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bone quality as correlated with Hounsfield units values (r = 0.65,
p < 0.001), concluding that their finding underscored the subjective
nature of the Lekholm and Zarb188 classification system. The fact
that there are no guarantees against operator errors, coupled with the
notion that there are no clear-cut boundaries assigned between poor,
moderate, and good bone quality, opens the door to the possibility
of variability.605
Besides being a subjective nonspecific technique to determine bone
density,606 there is a lot of overlap between its various categories.599,600
For example, the results obtained from the study of Rokn et al.607
show that the Lekholm and Zarb188 classification as a preoperative
predictor and the tactile sense of the surgeon as an indicator at the
time of surgery significantly distinguish quality bones 1, 2, and 3
from each other but fail to differentiate quality bones 3 from 4.
Other studies608-611 demonstrated a similar overlap between quality
2 and 3 in bone classification, making it difficult to distinguish these
2 bone types by subjective evaluations. In this regard, Lindh et al.608
demonstrated a higher interobserver accuracy when the clinicians
classified the bone density according to trabecular bone pattern and
in 3 categories.
On the other hand, the applicability of the Lekholm and Zarb188
classification of bone quality was supported by the results of four
studies. In the first study,612 panoramic radiographic appearances
of bone quality assessed according to Lekholm and Zarb188 were
found to be correlated with bone mineral density of the body of
the mandible as measured by dual energy X-ray absorptiometry. In
two other studies,610,613 implant sites were assessed by quantitative
computed tomography (QCT) where the QCT bone density values
were compared to the Lekholm and Zarb188 classification system.
An overall correlation between the QCT values and the subjective
density scores was observed. In the fourth study,598 bone mineral
density measurements from CT and RFA were used to assess bone
quality. Bone classification significantly correlated with mean bone
mineral density and mean RFA values, and bone mineral density
was higher at implant sites where torque was ≥35 Ncm at implant
placement.598 However, none of the included studies in the review of
Chrcanovic et al.30 had performed dual energy X-ray absorptiometry,
CT, or RFA in order to validate their findings.
130
Although subjective assessments of the implant recipient area are
relatively accepted methods for determining bone quality clinically,600
a more accurate evaluation should be used to determine bone quality,
especially in patients in whom bone quality is more important in
the treatment plan, such as patients needing early or immediate
loading.607 CT has been regarded as the best radiographic method for
analyzing the morphological and qualitative analysis of the residual
bone.600,614,615 CT is also a valuable means for evaluating the relative
distribution of cortical and cancellous bone.613 Hounsfield units can
be determined on CT scan images and is an objective and reliable
technique for the evaluation of bone density.606,613
Bone quality as a term is a potentially ambiguous one. Bone quality
recordings of the osteotomy site at the time of implant placement
are subjective and based upon a surgeon’s assessment usually
accomplished by visual and tactile inspection/palpation at the time
the osteotomy site is prepared. Clinicians would benefit from an
objective measure to reliably predict osseointegration.605 Accurate
analysis of the bone content and architecture would facilitate clinical
decision-making regarding patient selection, implant type and
surface, and the surgical technique used.613 Classification systems
are needed in order to provide a framework for the orderly, scientific
study of treatment and treatment outcomes.601 Similar assessment
methods, classification systems and measurement units are essential
prerequisites for comparing the results of different studies and for
improving our understanding of treatment outcomes in relation to
different bone characteristics. If there is no distinct and generally
accepted definition of bone tissue characteristics, comparisons of
results cannot be trusted.601
Patient’s habits
Smoking
Nicotine is the most important constituent among more than 4,000
potentially toxic substances in tobacco products. It is the main
chemical component responsible for tobacco addiction, appears
to mediate the hemodynamic effects of smoking,616 and has been
implicated in the pathogenesis of numerous diseases.617
When it comes to the negative effects in bone, smoking, especially
nicotine, impairs new bone formation, reduces calcium absorption,
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and decreases bone mineral density transiently.618 Chen et al.619
observed that mean union rates were 7.1 months in smokers and 4.1
months in non-smokers, in a study of healing after orthopedic surgery
to the arm. Moreover, six smokers (30%) and no non-smokers
experienced delayed union or nonunion. Osteoporosis is usually
observed in long-term smokers who routinely show lower bone density
than non-smoking cohorts.620-622 One study showed that smokers
and ex-smokers had lower trabecular bone mineral content when
compared to never-smokers.623 In a study of 41 pairs of twins, those
who smoked more heavily had bone mineral density values 5% and
10% lower at the femoral neck and lumbar spine, respectively, for each
20 pack-year difference (the lifetime tobacco use was calculated as the
total number of years of smoking multiplied by the average number
of cigarettes smoked per day, divided by 20, and expressed as pack-
years of smoking).624 Glassman et al.625 studied the effect of cigarette
smoking and smoking cessation on spinal fusion in a retrospective
review of 357 patients, and found that the nonunion rate was 14.2%
for non-smokers and 26.5% for patients who continued to smoke
after surgery (p < 0.05). Patients who quit smoking after surgery for
longer than 6 months had a nonunion rate of 17.1%. Bain626 found
that patients following a smoking cessation protocol (complete
cessation of smoking for 1 week before and 8 weeks after initial
implant placement) presented statistically significant less failure rates
than smokers who continued to smoke. These results may help to
validate the hypothetical assumption that postoperative smoking
cessation helps to reverse the impact of cigarette smoking on bone
healing. However, it is important to notice that there is much more
evidence of the detrimental effect of smoking on implant outcomes
than there is on the potential benefit of stopping smoking.627
Besides the implication in several systemic diseases, various clinical
studies have also demonstrated the detrimental effect of smoking on
oral health. Tobacco smoke is associated with the poorer healing
of the socket post tooth extraction,628 tooth loss,629 marginal and
alveolar bone loss,630 and periodontal diseases.631 Concerning the
dental implant interface, the deleterious effects of tobacco smoke
reflects a series of direct and indirect systemic and local effects on
bone metabolism.632 It has been strongly suggested that local exposure
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of the peri-implant tissues to tobacco products is the main factor
leading to an overall increase in implant failure rate in smokers.631
A systematic review and meta-analysis on the effect of smoking
on dental implants20 (Study II) suggested that the insertion of dental
implants in smokers affects the implant failure rates. Sensitivity
analyses suggested that smoking also significantly affects the survival
of implants inserted only in the maxilla or in the posterior regions
of the jaws, implants receiving single-crown restorations, implants
in full-arch implant-supported fixed prostheses, implants that
received immediate loading, and of implants submitted to any surface
modification here reviewed (turned, acid-etched, sandblasted and
acid-etched, sandblasted and fluoride-modified, and oxidized). The
lack of statistical significance for the mandible was surprising but is
most likely explained by the limited number of studies633-637 reporting
implant survival for smokers and non-smokers exclusively in the
inferior jaw. Moreover, a previous review638 on the subject suggested
that smoking may be a significant risk factor with an adverse effect
on implant survival and success in areas of loose trabecular bone,
but may not be as significant for good bone sites. A recent clinical
study191 (Study III) assessed the influence of local and systemic factors
on the occurrence of dental implant failures up to the second-stage
surgery (abutment connection). As the study of failures only before
the abutment connection limits the observation to the stage before
the prosthetic treatment, some confounding factors are eliminated.
Smoking was one of the two variables to exert some significant effect
on the failures during this pre-prosthetic period.
The increase of implant failure rates due to smoking is hypothesized
to be related mainly to the effect of smoking in osteogenesis and
angiogenesis. Concerning the effects on osteogenesis, Ma et al.639
showed that nicotine inhibited the gene expression of BMP-2, TGF-β1,
PDGF-AA and VEGF in osteoblasts. BMP-2 is the most potent
osteogenic induction factor regulating osteoblast differentiation, ALP
expression and subsequent mineralization.640 TGF-β1 is produced
by osteoblasts and incorporated into the bone matrix. During bone
remodeling, TGF-β1 plays an important role in the regulation
of osteoblast proliferation, differentiation and apoptosis, with
subsequent important effects on bone formation and remodeling.641
PDGF and VEGF have angiogenic effects during bone healing.642
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Whereas their expression can be detected in osteoblasts, they are
considered to be able to regulate osteoblast activity as well. VEGF
can interact synergistically with bone morphogenetic protein (BMP)
to promote skeletal development and bone healing by enhancing cell
recruitment, prolonging cell survival, and increasing angiogenesis.643
BMP acts as an important regulator that stimulates production of
VEGF in osteoblasts.644 Therefore, the inhibitive effect of nicotine on
osteoblastic activity may contribute to the failure of dental implant
osseointegration.639
In addition, some studies showed that osteogenesis and
angiogenesis are tightly coupled during bone formation, and
angiogenesis plays a pivotal role in skeletal development and bone
repair.645-647 Besides carrying oxygen and nutrients to bone tissue,
blood flow play an active role in bone formation and remodeling by
mediating the interactions among osteoblasts, osteocytes, osteoclasts,
and vascular cells at a variety of levels.648 The deleterious effects of
smoking have not only been shown on osteoblasts, but also on the
microcirculation, including morphologic aspects, particularly vessel
wall injury and capillary loss and functional aspects, predominantly
changes in tissue perfusion and its regulatory mechanisms,
notable reactive hyperemia, and sequestration of blood cells in the
microcirculation.649 Studies650,651 demonstrated that nicotine exposure
has direct effects on blood vessels, producing vasoconstriction and
systemic venoconstriction, which decreases blood perfusion and
causes low oxygen and ischemia, which is the major stimulus for
initiating the angiogenic cascade.652 Hypoxia and ischemia owing
to nicotine exposure could stimulate HIF-1α expression, leading
to an increased expression of VEGF, which, in turn, stimulates
angiogenesis. However, the enhanced vessel formation is incapable
of compensating for the adverse effect of the reduced blood flow
possibly caused by nicotine-induced vasoconstriction.651 And even
though the increased expression of VEGF caused by hypoxia and
ischemia may stimulate angiogenesis, it may also contribute to the
compromised bone healing, due to the fact that excessive VEGF
may lead to impairment in bone formation, possibly by promoting
mesenchymal stem cell differentiation toward an endothelial
lineage,653 consequently reducing the availability of mesenchymal
stem cells (MSCs) for osteogenic differentiation.654 Alternatively,
excessive VEGF may increase recruitment of osteoclasts into the
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bone-regeneration sites and lead to an excessive bone resorption.654
Another fact that should also be taken into consideration is that the
inflammatory response to bone trauma plays an important role in
initiating the repair cascade. The trauma activates downstream factors
such as cytokines and growth factors that recruit osteoprogenitor and
mesenchymal cells to the injury site.653,655 The problem is that nicotine
is an anti-inflammatory agent.656
Moreover, it is known that the surface properties of dental implants
such as topography and chemistry are relevant for the osseointegration
process influencing ionic interaction, protein adsorption and cellular
activity at the surface.311 In a meta-analysis performed more than 10
years ago, Bain et al.627 examined the outcomes of clinical studies
that monitored the performance of turned and acid-etched surface
implants, also isolating the effect of smoking, and it was observed that
there was no significant difference between smokers and non-smokers
with either type of surface, but there was a significant difference
between turned and acid-etched surface in both smokers and non-
smokers. Balshe et al.657 observed that smoking was not identified
as significantly associated with implant failure among the rough-
surface implants, while it was associated with implant failure among
the group with smooth-surface implants. More recently, Sayardoust
et al.658 showed that turned implants failed more frequently and lost
more marginal bone in smokers, and that oxidized implants showed
similar failure rates and bone loss in smokers and never-smokers. In
the review,20 however, a higher RR was observed for implants with
roughened surfaces in comparison with turned implants in smokers.
These contrasting results indicate that there is a need for more studies
to evaluate the long-term outcome of implants with altered surface
characteristics in smokers.638
It is important to stress that some studies on the subject have a
short-term follow-up period, of up to 3 years. In 12-month follow-up
study, Kan et al.659 reported a 93.04% success for non-smokers and
an 82.82% success for smokers. In a second study by the authors,660
but now with a 60-month follow-up, the success rate for the non-
smokers was 82.7% and for smokers was 65.3%. Thus, if one
considers the difference in success rates for smokers and non-smokers
with implants placed in loose trabecular bone sites that are followed
over a longer period of time, the adverse effect of smoking may be
more evident.
135
The fact that the insertion of dental implants in smokers statistically
affected the MBL20 may be related to the deleterious effects of smoking
in osteogenesis and angiogenesis. Lindquist et al.633 correlated the
amount of cigarette consumption to the greater MBL in smokers
than in non-smokers. The multivariate analyses performed in their
study observed that the smoking habit was the most important factor
among those analyzed for association with MBL. Cigar and cigarette
smokers have significantly greater loss of bone height than matched
non-smokers.661 Moreover, a higher MBL in smokers in comparison
to non-smokers could be partially explained by the elevated levels
of pyridinoline (a molecule specific to the collagen matrix of bone
and cartilage) in the crevicular fluid associated with dental implants
of smokers662 and suggest that smoking may affect implant success
in part through alterations in the levels of bone resorption. A
strong correlation between pyridinoline levels and radiographic and
histologic signs of tissue destruction has been demonstrated.663
Snuff
Whereas the effect of smoking on periodontal health is abundantly
documented, little is known about the possible effects of non-smoked
tobacco products, which are mainly used as chewing tobacco and
snuff.664 Like other smokeless tobacco products, snuff is rapidly
delivering high doses of nicotine, which leads to dependence.665,666
The nicotine is readily absorbed via the mucosal membrane by
passive diffusion.667,668
Localized oral manifestations, such as gingival recessions and
mucosal lesions (snuff dipper’s lesion) at the site of snuff placement, are
common in users of moist snuff.669-673 After cessation of use, however,
mucosal lesions seem to heal clinically as well as histologically.672,674,675
However, the use of snuff was not associated with the presence of
periodontal bone loss.664,676,677 Cigarette smokers were found to have
a statistically significant higher risk of severe periodontitis than non-
tobacco users and users of snuff. Using snuff did not seem to be a
risk factor for periodontitis.676 It is hard to tell whether the effect of
snuff on teeth would reflect the same periodontal results on implants,
because studies on the effect of snuff on dental implants are rare.
Chrcanovic et al.191 (Study III) and Chrcanovic et al.193 (Study VIII)
found no influence of snuff on dental implant failures in multiple
136
regression analyses assessing factors that could influence dental
implant failures up to the abutment connection and cluster behavior
of dental implant failures among patients, respectively.
Bruxism
Occlusal parafunction includes bruxism (clenching, grinding), lip
biting, thumb sucking, and abnormal posturing of the jaw. In contrast
to functional behaviors such as mastication, deglutition, or speaking,
activities classified as “parafunction” appear to have no functional
purpose.678 Concerning the overloading related to parafunction, it can
cause various complications, such as occlusal surface wear (Figures
10 and 11), fracture, loosened screws, or abutment and implant
fracture.679 As the frequency of parafunction is very common,678
the usage of implants in patients with parafunctional habits is
unavoidable. Moreover, a significantly high percentage of newly
gained parafunction was reported in patients with implant-supported
superstructures.680 Some authors have suggested that overloading of
implants or abnormal occlusal stress, as seen in patients with bruxism
habits, may contribute to failure.681 As the possible occurrence of
parafunctional habits is evident in any stage of dental treatment, the
risks for implant therapy must be considered.679 Therefore, bruxism is
often considered a contraindication for implant treatment, although
the evidence for this is usually based on clinical experience only.682
Bruxism has been suggested to cause excessive occlusal load of
dental implants and their suprastructures, ultimately resulting in bone
loss around the implants or even in implant failure,682 even though
some studies on the subject have not provided clear conclusions on
the issue,199,452,683 or have not supported bruxism as a causative effect
of dental implant failures.514 The only meta-analysis on the subject23
found a statistically significant difference when comparing dental
implant failures in bruxers and non-bruxers. However, the included
studies have a lot of limitations, thus being not possible to suggest
that the insertion of dental implants in bruxers affects the implant
failure rates.
Two clinical studies158,190 evaluating the effect of bruxism on dental
implants and implant-supported prosthetic restorations were recently
published. The first one190 (Study IV) analyzed the complications of
dental implant treatment in a group of 98 patients with bruxism
137
in comparison with a matched group of 98 non-bruxers. The odds
ratio of implant failure in bruxers in relation to non-bruxers was
2.71 (95% CI 1.25, 5.88; p = 0.01). Considering the same number of
patients with the same total number of implants equally distributed
between groups, the bruxers group had a higher prevalence of
mechanical complications (Figures 12, 13, 14, and 15) in comparison
to the non-bruxers group. The second study158 used multilevel mixed
effects parametric survival analysis to test the association between
bruxism and risk of implant failure adjusting for several potential
confounders. The statistical model showed that bruxism (among
other factors) was a statistically significantly risk factor to implant
failure (HR 3.396; 95% CI 1.314, 8.777; p = 0.012).
138
Figure 10. Severe occlusal surface wear in bruxers (middle and bottom
images: Courtesy of Dr. Jenö Kisch).
139
Figure 11. Severe occlusal surface wear in a bruxer patient
(Courtesy of Dr. Jenö Kisch).
140
Figure 12. Mechanical complications observed in the same bruxer
patient: screw fracture, abutment fracture, implant fracture, and implant
exfoliation (Courtesy of Dr. Jenö Kisch).
Figure 13. Fracture of implants in a bruxer patient

Figure 14. Fracture of ceramic abutment in a bruxer patient

141
Figure 15. Fracture of prosthetic work in bruxer patients
142
Even though the cause-effect relationship still needs to be confirmed
by more studies, it worth reminding that a high and unpredictable or
uncontrolled loading of the implant could lead to micromotions above
the critical limit, resulting in fibrous encapsulation of the implant
instead of osseointegration.513 It is also important to stress that the
periodontal ligament of natural teeth provides the central nerve
system with feedback for sensory perception and motor control.684
Proprioception around dental implants is limited because of the
absence of a periodontal ligament, causing lower tactile sensitivity.
Consequently, the proprioceptive feedback mechanisms to the jaw
closing muscles are limited as well. In addition, the perception of
forces is limited in implant patients.685 It is, therefore, not unlikely
that forces that are applied to implants during bruxism are even larger
than those exerted during mastication,682 making them more prone
to occlusal overload and possible subsequent failure.684 Chewing is
supposed to be a physiological load for dental implants; bruxism, an
overload.682
When it comes to MBL, contrary to early failures, late biological
failures are characterized by pathological bone loss after full
osseointegration was obtained at an earlier stage. Late biological
implant failures are, among other reasons, associated with
overload.682 Occlusal overloading has been suggested to cause peri-
implant MBL and constitutes a high risk for early implant failure.686
Natural teeth have a lower detection threshold of minimal pressure
compared to implants, but stresses are distributed evenly around
them, whereas stresses around implants tend to concentrate at the
crestal bone region instead of distributing themselves evenly.687 In case
of overload, equilibrium between bone resorption and deposition is
being disturbed, thereby causing fatigue-related micro-fractures at,
and around, the bone–implant interface.688
In a clinical human study, Lindquist et al.538 showed that
parafunctional activity such as bruxism, reported as tooth clenching
and occlusal wear on the prosthesis, led to increased bone loss
around Brånemark implants. Animal studies also evaluated the
relationship between implant occlusal overload and MBL. Miyata
et al.689 investigated the relationship between occlusal overload and
peri-implant tissue and suggested that there is a possibility of bone
resorption around the implants caused by excess occlusal trauma,
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even when there is no inflammation in the peri-implant tissue. Duyck
et al.690 showed that dynamic overload generated by the grinding
of teeth resulted in severe angular bone loss. In a recent review,691
the authors pointed out that animal experimental studies indeed
suggested the potential detrimental effect of excessive mechanical
load on peri-implant bone, although RCTs or CCTs of treatment
interventions of oral implants designed to study overload are lacking.
The authors also observed that the level of evidence of the studies
on bone response to implant loading is weak and does not indicate
that overload can lead to peri-implant bone loss, except in case of
inflammation. Thus, the subject is still controversial.
It is important to say that there is still a lack of agreement about
the definition of bruxism, which makes it sometimes difficult to
unequivocally interpret the available evidence.682 The clinical features
for diagnosis of bruxism include complaint of jaw muscle discomfort,
fatigue, stiffness, and/or occasional headaches, the presence of tooth
wear, tooth sensitivity, muscle hypertrophy, TMJ clicking or jaw lock,
and tongue indentation. The clinical diagnosis of bruxism is based
on orofacial examination and is usually supported by patient history,
self-reports, or parental/partner reports. Considering that many sleep
bruxism patients are not aware of grinding if they sleep alone or
with a partner who sleeps deeply,692 and that the overall prevalence
of daytime clenching awareness has been reported by approximately
20% of the adult population,693 this may misguide the clinician
to the correct clinical diagnosis.692 Polysomnographic analysis has
been proposed for a more accurate diagnosis,679 even though the
process of diagnosing sleep bruxism by means of polysomnography is
considered to be complicated by some authors.694 Thus, there appears
to be a need to establish more accurate and objective methodology
for detecting bruxism.679 Many clinical studies199,431,452,514,634,695-697 did
not even report the adopted criteria to classify a patient as having
bruxing habits, i.e. the mode of bruxism determination is not given
at all.
In the study of Chrcanovic et al. (Study IV),190 the authors followed
the definition of bruxism proposed by Lobbezoo et al.698: “Bruxism is
a repetitive jaw-muscle activity characterized by clenching or grinding
of the teeth and/or by bracing or thrusting of the mandible. Bruxism
has two distinct circadian manifestations: it can occur during sleep
(indicated as sleep bruxism) or during wakefulness (indicated as
144
awake bruxism).” The self-conscience of the condition was evaluated
with some questions, according to suggestions of a previous study,699
questions like the following were asked: (a) Are you aware of the fact
that you grind your teeth during sleep? (b) Did anyone tell you that
you grind your teeth during sleep? (c) On morning awakening or on
awakenings during the night, do you have your jaws thrust or braced?
(d) Do you clench your teeth whilst awake? (e) Do you grind your
teeth whilst awake? All questions could be answered with either ‘yes’
or ‘no’. The patients were instructed to answer ‘yes’ if considered their
habit to be frequent enough to be clinically relevant (e.g. frequency
of more than thrice a week and/or several hours per day).699 The
clinical condition was re-evaluated to assess possible bruxism-related
signs and symptoms. The sign and symptoms of bruxism were listed
according to the International Classification of Sleep Disorders700:
(a) presence of regular or frequent tooth grinding sounds occurring
during sleep, (b) abnormal tooth wear consistent with above reports
of tooth grinding during sleep, (c) transient morning jaw muscle
pain or fatigue; and/or temporal headache; and/or jaw locking on
awakening consistent with above reports of tooth grinding during
sleep. Moreover, clenching or grinding of the teeth and/or by bracing
or thrusting of the mandible during wakefulness was also considered,
according to a recent international consensus.698 As reliable and valid
diagnostic tools for bruxism are scarce,698 a diagnostic grading system
of ‘possible’, ‘probable’ and ‘definite’ sleep or awake bruxism was
used, as suggested for clinical and research purposes.701 According
to an international consensus,698 ‘possible’ sleep or awake bruxism
should be based on self-report, by means of questionnaires and/or the
anamnestic part of a clinical examination. ‘Probable’ sleep or awake
bruxism should be based on self-report plus the inspection part of a
clinical examination. ‘Definite’ sleep bruxism should be based on self-
report, a clinical examination, and a polysomnographic recording,
preferably along with audio/video recordings. As electromyography
and/or polysomnography were not used due to high cost and limited
availability, the patients of the study of Chrcanovic et al.190 (Study
IV) would only fall into the categories ‘possible’ or ‘probable’. Thus,
a patient was considered as presenting bruxism based on self-report
of clenching/grinding during sleep or during wakefulness, plus the
inspection part of a clinical examination.
145
Without a definitive diagnosis of bruxism having been established,
it is acknowledged that some of the outcomes illustrated in some of
the clinical cases may be due to such load-increasing or materials-
related factors, rather than to bruxism per se.694 Therefore, the
possible cause-and-effect relationship between bruxism and implant
failure do not yield consistent and specific outcomes. This is partly
because of the large variation in the literature in terms of both the
technical aspects and the biological aspects of the study material.682
It is also important to comment that when overload occurs, the
level of stress concentration at the implant-bone interface depends
on several factors related to load transfer, such as the direction of
the functional loads, the resiliency properties of the implant and
alveolar bone, the implant macrogeometry and microgeometry, and
the quality of the bone support,702 and it is impossible to control
these all variables.
Although a hard stabilization splint for nightly use (night guard)
will not prevent a parafunctional habit from occurring, it contributes
to optimally distributing, and vertically redirecting, the forces that go
with nocturnal teeth grinding and clenching.679,703
Oral hygiene
A proportion of implants are unsuccessful due to various
inflammatory pathoses in peri-implant tissues. These include two
main disease entities: peri-implant mucositis, which is a condition
limited to the mucosa surrounding the implant, and peri-implantitis,
characterized by a loss of peri-implant bone.704 Some studies
showed that experimentally induced mucositis was reversible at
the clinical and biomarker level once the biofilm was disrupted and
oral hygiene procedures were reinforced.705,706 On the other side,
mechanical debridement alone has shown limited efficacy for peri-
implantitis.707,708 Gingivitis of natural teeth and peri-implant mucositis
of implants would be the precursors of periodontitis and peri-
implantitis, respectively.709 Therefore, prevention and management
of peri-implant mucositis are critical in long-term maintenance of
implants.710 In contrast, some researchers see mucositis as a possible
indication of an immunological reaction, not in itself dependent on
oral hygiene.5
146
A clinical study showed that the absence of preventive maintenance in
individuals with pre-existing peri-implant mucositis was associated
with a high incidence of peri-implantitis. Clinical parameters, such
as bleeding on peri-implant probing, periodontal probing depth and
the presence of periodontitis were associated with a higher risk of
developing peri-implantitis.711 Others have reported that bleeding
on probing and probing depth are meaningless tools for diagnosis
of disease.712 Aguirre-Zorzano et al.713 observed that the MBL
around implants in patients with treated chronic periodontitis is
minimal if they are in a controlled supportive periodontal therapy
program and there is individual control of plaque index. Rinke
et al.714 observed an association between regular prophylaxis/
supportive periodontal therapy and the reduction of the risk for
peri-implantitis by more than 11 times.
When it comes to peri-implantitis, adjunctive measures (e.g. local
antibiotics/antiseptics, laser application) may be effective in arresting
disease progression at initial sites, however, moderate to advanced
peri-implantitis lesions commonly require a more demanding
surgical intervention (e.g. resection of the bony wall, filling of the
defect or surface modifications of the implant) or even removal of
the implant.708,715 In contrast, there is currently published evidence
claiming that the reported frequency of peri-implantitis is grossly
exaggerated.1
There are several studies showing that maintenance therapy
decrease the risk of tooth loss.716-719 However, the same cannot be
said about studies on implants. In the field of implant dentistry there
is still a lack of long-term longitudinal studies to determine the actual
significance of the effect of maintenance therapy to minimize implant
loss.
Alcoholism
Alcohol abusers are defined by consumption of at least five drinks
(more than 60g of ethanol) per day for several months or years.720 After
consumption, alcohol is readily distributed throughout the body in the
blood stream and crosses biological membranes, affecting virtually all
biological processes inside the cell.721 Excessive alcohol consumption
substantially promotes adipogenesis and inhibits osteogenesis.722-724
Moreover, both chronic and binge consumptions of ethanol are
147
known to cause suppression of bone formation and enhancement of
bone resorption. Chronic alcoholism is associated with increased risk
of fracture and incidence of osteoporosis.725,726 Bone metabolism is
affected by alcohol consumption because alcohol inhibits osteoblast
proliferation.727,728 Several in vitro studies investigating the effects
of alcohol on bone have demonstrated diminished osteoblast
numbers and function.721,727,729-736 Other in vitro studies indicated
a possible increase in osteoclast numbers resulting in increased
resorption.737,738 One of these studies738 showed that ethanol, even
at blood concentrations experienced by the social drinker, has an
immediate direct effect on bone cells in vitro, resulting in increased
resorption by osteoclasts. According to the results of their rat model
study, Trevisiol et al.739 concluded that reduced osteoinduction may
contribute to impaired bone healing in alcoholics.
Moreover, the consumption of alcohol was found to be associated
with suppression of activation and proliferation of T lymphocytes,
as well as with adherence, mobility, and phagocytic activity of
monocytes, macrophages, and neutrophils.740,741 As these cells
populations are crucial in the initiation, regulation, and propagation
of cellular immunity, alcoholism may as well be associated to an
increased risk of postoperative infection. Although most of these
immunological changes have been demonstrated to be related to
alcohol, other factors, such as malnutrition and cigarette smoking,
may contribute to the increased susceptibility to infection in alcohol
abusers.720
Few studies have studied the effect of high consumption of alcohol
on the osseointegration and peri-implant tissues of oral implants.
Bombonato-Prado et al.742 evaluated the effect of alcoholic beverage
administration on reparative bone formation around hydroxyapatite/
tricalcium phosphate implants inside the alveolar sockets of rats. A
significant delay in reparative bone formation was detected in the
alveolus of alcoholic rats by a histometric differential point counting
method. Koo et al.743 evaluated bone formation in alcohol-fed rabbits
following the insertion of dental titanium implants and compared the
results with a control group. Their results showed that the alcoholic
rabbits demonstrated significantly less bone density and direct BIC.
Galindo-Moreno et al.744 conducted a prospective clinical study to
explore the possible link between peri-implant bone loss and the
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widespread habits of tobacco smoking and alcohol consumption.
Their results showed that peri-implant MBL was significantly
related to a daily consumption of >10 g of alcohol, tobacco use
and increased plaque levels and gingival inflammation. Torricelli
et al.736 investigated the proliferation and synthetic activity of
osteoblasts isolated from the trabecular bone of rats previously
exposed to 7-week intermittent exposure to ethanol vapor when
cultured on standard c.p. Ti. Their results suggest that alcohol
abuse affects bone repair and decreases the ability to form bone
around standard c.p. Ti. Alissa and Oliver745 assessed whether
alcohol consumption, among other risk indicators, was associated
with patients with at least one implant failure using a case-control
study design. Heavy drinkers (>5 units/day) had a statistically higher
percentage of implant failure compared with nondrinkers and
patients who reported consumption of a lesser amount of alcohol
(<5 units/day). de Deco et al.746 evaluated osseointegration of
implants in femurs of rats fed with alcohol and presenting
induced estrogen deficiency. Their results showed that
the combination of alcohol intake and estrogen deficiency, and the
combination of estrogen deficiency and reduced ingestion of food can
negatively affect osseointegration in rats.
Narcotic drugs
Narcotics are chemical agents that induce stupor, coma or, as in the
case of morphine, methadone, and codeine, insensibility to pain.
These drugs are also used to affect mood or behavior and some are
sold illegally for nonmedical purposes, such as cannabis, heroin,
and cocaine. Legally speaking, the term “narcotic” is imprecisely
defined and typically has negative connotations.747 In the medical
community, however, the term is more precisely defined and generally
does not carry the same negative connotations. Any substance that
can affect bone metabolism could, in theory, have some influence on
the osseointegration of oral implants. Several studies evaluated the
effect of narcotics on bone status and metabolism.
Analgesic therapy with opioids and the use of opioid drugs seem to
induce the inhibition of gonadotropin-releasing hormone production,
and chronic hypogonadism is an important cause of osteoporosis
in both sexes.748 Hypogonadism in young women can subsequently
149
cause amenorrhea. This endocrinological misbalance is a well-known
negative factor for bone mineral density (BMD) metabolism.749-754 In
addition, opioids may contribute to increased fracture risk by directly
interfering with bone formation.748,755-757 Prolonged heroin addiction
was associated with accelerated bone turnover and osteopenia in
cortical bone without evidence of metabolic bone disease.758 Opioids
were associated with significantly reduced BMD.759 One study760
observed that the chronic abuse of opioid drugs may be associated
with altered bone metabolism and reduced trabecular bone mass,
attributable, at least in part, to gonadal deficiency. However,
these alterations seem reversible after drug discontinuation.
Another study showed that 83% of the patients enrolled in
a methadone maintenance treatment had low BMD.761
A role for the endocannabinoid system (membrane receptors
for the psychoactive principle in Cannabis) in the regulation of
bone mass has been demonstrated, because mice lacking either
of the cannabinoid receptors CB1 or CB2 have abnormal bone
phenotypes.762 Furthermore, cannabinoid receptor agonists and
inverse agonists reduce bone loss in mice following ovariectomy and
have direct effects on both osteoclasts and osteoblasts in vitro.763-
766
Bourne et al.767 found no association between cannabis and
bone mineral density of the hip or spine in adults, for any level of
use. On the other hand, the study of Sophocleous et al.768 found that
heavy cannabis use is associated with low bone mineral density, low
body mass index (BMI), high bone turnover, and an increased risk of
fracture. Heavy cannabis use negatively impacts on bone health both
directly and indirectly through an effect on BMI.
Balabanova et al.769 observed that daily administration of cocaine
in sheep caused elevations in plasma parathyroid hormone (PTH) and
calcitonin. However, these effects could only be maintained for 10
days of treatment before lack of a response was noted. These authors
acknowledged that a physical tolerance may have been reached and
that graded increase in cocaine been administered further release of
these calciotropic hormones. Given the osteolytic response to high
circulating levels of PTH, the consequences of long term cocaine use
may include reduced bone mass.
Rico et al.770 evaluated osteocalcin by radioimmunoassay at the
time of delivery in mothers and in the umbilical arteries of newborns
150
in a group of pregnant drug users (eight heroin users and seven cocaine
users) and compared with findings from a group of 18 normal mothers
and their newborns. Osteocalcin, a vitamin K-dependent protein
synthesized by osteoblasts,771,772 is a major noncollagenous protein
found in bone matrix.773,774 Serum concentrations of osteocalcin have
been shown to correlate well with histologic parameters of bone
formation.774 The results of the study of Rico et al.770 suggest a toxic
effect of these drugs on the osteoblast, which could account for the
lower birth weights and skeletal alterations reported in the infants
of drug users.
Seifert and Church775 examined the long term effects of prenatal
cocaine exposure on femoral growth and mineralization in male rats.
Femur dry weight, ash weight, organic matrix weight and density
were significantly reduced in these animals compared to normal or
pair-fed controls. The authors stated that their results suggested that
prenatal exposure to cocaine may have long term postnatal impact
on bone cell or mineral metabolism.
Only one clinical study776 observed a possible association
between narcotic abuse and oral implant outcome, showing
addiction to narcotics in a group of patients presenting multiple
implant failures. An in vivo study investigated whether marijuana
smoke influences bone healing around titanium implants in rats.777
A group of marijuana smoke inhalation rats was compared to a
control group. A negative effect of marijuana smoke was observed
in cancellous bone for BIC and bone area. The authors of the study
suggested that the deleterious impact of cannabis sativa smoke
on bone healing may represent a new concern for implant success/
failure. Other studies focused on alveolar bone loss and periodontitis.
Nogueira-Filho et al.778 noticed that cannabis smoke may impact
alveolar bone by increasing bone loss resulting from ligature-induced
periodontitis in rats. Breivik et al.779 investigated the effects of long-
term exposure (4 weeks) to the widely used narcotic drug and putative
neurotoxicant “ecstasy” (3,4-methylenedioxymetamphetamine
- MDMA) on neuronal transmitter transport and progression of
experimental periodontitis in rats. Their results showed that long-
term exposure to MDMA affects the serotonergic and dopaminergic
transport systems in the rat brain and increased the susceptibility to
the psychosomatic ailment periodontitis following disturbances of
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brain immune-regulatory systems. It is a matter of debate whether
similar results could occur around implants, in an experimental
peri-implantitis.
We know very little, if anything, on narcotic drug abuse and its
possible effects on oral implants, but that we cannot ignore the
possibility that some drugs may cause implant problems.
Health
Patient genetics
The fact that implant losses tend to cluster in a specific group of
individuals193 (Study VIII) could indicate specific host characteristics
that disturb the osseointegration process and are influenced by
genetic factors.780 Most of the genetic research in the oral disease
has focused on gene polymorphisms that play a role in the immune
response, tissue destructive process, or metabolic mechanism.781
A combination of the Greek words poly (meaning multiple)
and morph (meaning form), polymorphism is a term used in genetics
to describe multiple forms of a single gene that exist in an individual
or among a group of individuals. A gene is said to be polymorphic if
more than one allele occupies that gene’s locus within a population.782
In some situations, genetic polymorphisms could cause a change in
the protein or its expression, possibly resulting in alterations in innate
and adaptative immunity and may thus be deterministic in disease
progression.781 On the other hand, genetic polymorphisms may also
act like a protector or a destructive factor for a disease.783-786
The genetic variants in the interleukin-1 (IL-1) gene region can
be listed as an example of the suggestive influence of genetics on
implant dentistry. IL-1 is a potent proinflammatory mediator that
is mainly released by monocytes, macrophages, and dendritic
cells. Immunological reactions are believed to cause abnormal
tissue destruction leading to periodontitis. Inflammatory cytokines
are involved in the initiation and continuation of such immune
reactions.787,788 Involvement of IL-1 in the pathogenesis of periodontal
disease has long been suspected because of similarities between its
known biological effects and the manifestations of the disease, as well
its presence in the lesions.789 Feloutzis et al.790 investigated the relation
between specific IL-1 gene polymorphisms and peri-implant bone loss
at dental implants. The results of the study suggested that in heavy
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cigarette smokers, carriage of a functionally significant IL-1 gene
complex polymorphism is associated with an increased risk for peri-
implant bone loss following prosthetic reconstruction and during the
supportive periodontal care phase of the treatment. Gruica et al.791
reported a follow-up study using the increased number of patients
in the same institution as Feloutzis et al.790 They observed that there
is a synergistic effect between a positive IL-1 genotype and smoking
that puts dental implants at a significantly higher risk of developing
biologic complications during function. Laine et al.792 results provide
evidence that IL-1RN gene polymorphism is associated with peri-
implantitis and may represent a risk factor for this disease. Petkovic
et al.793 examined the peri-implant crevicular fluid (PICF) levels of
IL-1β, tumor necrosis factor α (TNF-α), interleukin-8 (IL-8) and
macrophage inflammatory protein-1α (MIP-1α) in patients with non-
manifesting inflammation, early and late stages of mucositis. Their
results suggest that cytokines could be prognostic markers of implant
failure. Vaz et al.781 analyzed the association between polymorphisms
in the IL-1 gene cluster and failure of dental implants, and showed
that the alleles 1 and 2 of IL-1α gene and the alleles 1 and 2 of IL-1β
gene were statistically associated with the success or no success of
the dental implants. The study of Shimpuku et al.794 suggested that
the IL-1β-511 2/2 genotype has a significant association with the
incidence of early MBL around implants.
Studies suggesting a lack of association between IL-1 gene
polymorphisms and dental implant biological problems have also
been published. Wilson and Nunn795 could not find statistical
association with positive genotype for IL-1 in their group of failed
implants (27 patients who had lost implants or had implants with
at least 50% of bone loss on radiographs). In addition, Rogers et
al.796 could not find any statistical association with combined positive
genotype of IL-1 in the group of failed implants (19 patients with
failed implants).
It is suggested that peri-implantitis implant success and survival
may also be influenced by other gene polymorphisms. Nosaka et al.797
observed that patients with a type calcitonin receptor genotype were
20 times more likely to suffer buccal MBL around implants in the
mandible than patients with another calcitonin receptor genotype.
Shimpuku et al.798 showed that BMP-4 genetic polymorphism
153
influences early MBL around implants. The results of Santos et
al.799 suggested a possible relationship between polymorphisms in
the promoter region of human matrix metalloprotenase 1 (MMP-1) or
a C-1562T substitution in the MMP-9 gene and early implant failure.
Later, the same group of researchers800 observed similar results with
polymorphism in the same gene. Casado et al.801 investigated the
association between BRINP3 genetic variation and expression and
susceptibility to chronic periodontitis and peri-implantitis. The
study showed that a BRINP3 polymorphic variant and the low
level of BRINP3 expression are associated with peri-implantitis,
independently from the presence of chronic periodontitis.
However, not every gene polymorphism seems to be associated with
dental implant problems. For example, Dos Santos et al.802 observed
that polymorphisms in the TGF-β1 gene are not associated separately
or in haplotype combinations with early implant failure, suggesting
that the presence of those single nucleotide polymorphisms alone do
not constitute a genetic risk factor for early implant failure. Cury et
al.803 did not find an association between a specific polymorphism
in the tumor necrosis factor TNF-α gene and peri-implant bone loss
following prosthetic reconstruction.
Although a review on the association between genetic predisposition
and dental implant biological complications804 pointed out that a
small number of properly designed studies have been performed
to address the genetic susceptibility to implant failure in terms of
biological complications and that methodological and study design
issues restrict the possibility to draw robust conclusions, the matter
of a possible genetic influence on dental implants cannot be ignored.
It seems that we are still incipient on this issue, and further research
is needed.
Patient’s sex
In humans, biological sex is determined by some factors present at
birth, such as the presence or absence of a Y chromosome, the type
of gonads, the internal reproductive anatomy, the external genitalia,
and the proportion of the different sexual hormones.805 The biological
sex is important, as the function of cells and organs depends on their
sex, determined by the interplay among the genome and biological
and social environments. Sex has profound effects on physiology and
154
the susceptibility to disease.806 Even though success and survival rates
for osseointegrated dental implants are well documented, it is still
unknown whether there is influence of sex on the clinical outcomes
of the therapy with endosseous dental implants.
The only systematic review and meta-analysis on the subject22
with more than 52000 implants suggested that when implants are
inserted in men, failures are 1.21 times likely to happen than failures
when implants are inserted in women (RR 1.21, 95% CI 1.07,
1.37; p = 0.002). The difference in failure rates between the sexes is
hypothesized to be related to some factors.
Osteoporosis is one of them. After the early to mid-20s, a slow
but steady decline in bone mass takes place in both men and women.
This is because less than 100% of the bone that is resorbed every
180 days is replaced by newly forming bone. Over the years, this
slight shortfall in bone renewal adds up to a significant loss of
bone mass.807 It is heightened in women because after menopause
natural levels of estrogen are greatly reduced, and estrogen is one of
the requirements for osteoblast differentiation from bone marrow
osteoprogenitor cells.808 Therefore, postmenopausal women undergo
a more rapid and significant decline in bone mass.809 Furthermore,
more women stay with less strong bone than men. Therefore, it takes
longer time for males to suffer the consequences of biological bone
loss with increasing age. Compromise of systemic bone metabolism
may be a risk factor affecting osseointegration and maintenance of
osseointegration. One study retrospectively evaluated 13 patients
with osteoporosis of the axial or appendicular skeleton, including
the jaw bone, that were subjected to oral implant treatment.810 The
results of the study showed that implant placement in patients in
whom the average bone density showed osteoporosis in both lumbar
spine and hip as well as poor local bone texture may be successful
over a period of many years. The study did not compare the result
between sexes.
If a higher degree of osteoporosis may be more prevalent in
women than in men, the same does not happen with periodontitis.
Epidemiologic studies provide broad-based evidence that men are at
greater risk of developing severe periodontal disease than women.811,812
A study estimated the prevalence, severity and extent of periodontitis
in the adult US population with data from the a national survey and
155
observed that after adjustment for the effect of age, total periodontitis
was significantly higher in men than in women aged 30 years and
older (males = 57%; females = 39%), with males showing a 3%, 7%
and 8% higher prevalence of mild, moderate and severe periodontal
disease, respectively, compared with women.813 Freitag-Wolf et
al.814 investigated interactions of single-nucleotide polymorphism
genotypes with male and female sex with respect to the risk for
aggressive periodontitis on a genome-wide scale, and observed an
increased risk of aggressive periodontitis in men and a decreased risk
in women. Moreover, the results of a systematic review and meta-
analysis15 suggest that an increased susceptibility for periodontitis may
translate to increased susceptibility for peri-implantitis. We do not
know the mechanisms that connect periodontitis with increased rates
of peri-implantitis and loss of implants. Periodontitis is a complex
genetic disorder that shows clear differences to the genetics of peri-
implantitis.815 Hence, the connection between a disease of teeth and
an immunological reaction affecting foreign body implants787,788 may
depend on quite different gene patterns and not necessarily being
indicative of a similarity between these two conditions. Whatever the
reason, the increased rate of peri-implantitis could possibly explain
the higher failure rates we found in men.
Concerning the association between gender and recall compliance
to supportive periodontal treatment (SPT), there is no common
consensus on this issue, and the variance in the studies outcomes
may be explained by differences in the study populations, variations
in the observation periods, levels of maintenance measures and the
use of different criteria to define periodontitis/peri-implantitis.816
Even though many studies817-821 demonstrated that no significant
relationship was found between degree of compliance and gender,
several others822-827 revealed a predominance of females in compliance
with SPT. After the incorporation of implant-supported restorations,
special oral hygiene measures are known to be necessary for
preventing inflammation, peri-implant diseases, and even implant
loss. This suggests that the difference of compliance between implant
patients of different sexes to SPT may also play a role in the different
implant failure rates.
A survey conducted in the United States reported that, in 2005,
the current cigarette smoking prevalence of the population aged ≥18
156
years was higher among males (23.9%) than females (18.1%). These
numbers were 20.5% and 18.1% for males and females, respectively,
in the survey conducted in 2013 including 34,557 respondents.828 A
study tried to identify predictors of implant failure and peri-implant
bone loss, and observed that only smoking and recall compliance
had a significant influence on implant failure, based on multivariate
analysis.829 The results of a recent meta-analysis analyzing 107
clinical trials suggest that the insertion of dental implants in smokers
statistically affects the implant failure rates.20 These findings suggest
that a higher prevalence of smokers among men may, to some degree,
be associated with the higher risk of implant failure in men than in
women. However, in some societies such as Sweden, females today
smoke more than men and it will be interesting to follow up whether
this fact will influence future failures or not.830
Another explanation behind the noticed difference in implant
failure between the sexes may be related to the fact that men are
prone to load their implants more strongly than females. Under
normal conditions the extra load may not be problematic, but in
case of complicating factors or rapid onset of extra load such as the
case of suddenly failed teeth around an implant, then overloading
may be a significant factor behind the greater implant loss reported
in men. According to a recent review on the subject,831 total loss of
osseointegration appears possible with an already osseointegrated
dental implant, when the applied force exceeds the biological
adaptable limit, but this has been very rarely documented, and
this threshold is currently unknown. The fact is that bone response
to functional load depends on a complicated interaction of strain
magnitude and time.832 Strain (deformation of the bone) is defined as
the relative change in the length of the bone and the amount of strain
is directly correlated to the stress applied to the bone; for example,
occlusal loading, but it is also dependent on the mechanical properties
of the bone.831 It is reasonable to assume that with different bone
types and composition, the thresholds of destructive strain values
will be different for each individual, while age and sex might play a
significant role in this diversity.831
When it comes to sex differences of bite forces, a study observed
that the voluntary maximal bite force (MBF) values for men were
one third higher than for women.833 This sex-related difference in
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MBF may be a result of anatomic differences. Tuxen et al.834 used
electromyography and biopsy to further explore why MBF is higher
in men than in women. The men’s masseter muscles had type II fibers
with larger diameter and sectional area than those of the women, and
the authors suggested that hormonal differences might contribute to
the composition of the muscle fibers. The results of Cosme et al.833
showed that voluntary MBF was no different between bruxers and
non-bruxers when controlling for some potential confounders. One
possible explanation may be that the voluntary MBF is different from
the MBF exerted during bruxism.
Concerning bruxism, this parafunctional habit has been for many
years considered a reason for implant failure or MBL after successful
bone-to-implant osseointegration. A recent systematic review on
epidemiology of bruxism in adults835 observed that bruxism was not
found to be a disorder related to sex, since sex differences were not
relevant for any of the bruxism activities, even though a female-to-
male ratio was reported only in a few studies.
History of periodontitis
The question if patients with a history of periodontitis are more
at risk for peri-implant disease has received increasing attention in
the last years.836 There is some evidence that patients treated for
periodontitis may experience more implant loss and complications
around implants including higher bone loss and peri-implantitis than
non-periodontitis patients.837 A history of treated periodontitis does
not seem to adversely affect implant survival rates but it could have
a negative influence on implant survival/success rates, particularly
over longer periods.638
Some clinicians assume that periodontally compromised patients
(PCPs) present a potentially higher risk for implant failure. The
reason for this assumption is that a similar pathogenous bacterial
flora forms around diseased teeth and diseased implants, though with
some differences in partially and completely edentulous patients.838
Implants are rapidly colonized by indigenous periodontal pathogens
in partially dentate patients harboring periodontal lesions.838 An
association between periodontal and peri-implant conditions over
10 years in partially edentulous patients was showed. Marginal bone
level at 10 years was significantly associated with smoking, implant
158
location, full-mouth probing attachment levels, and change, over
time, in full-mouth probing pocket depths.839 However, Cecchinato
et al.840 who evaluated the progressive MBL that had occurred at
implants and teeth in the same segment of the dentition following
implant placement in partially dentate subjects, reported that when
implants lost bone teeth bone was stable and, vice-versa, when teeth
lost bone implant bone seemed stable.
A systematic review and meta-analysis15 comparing PCPs
and periodontally healthy patients (PHPs) suggested that an
increased susceptibility for periodontitis may also translate to an
increased susceptibility for implant loss, loss of supporting bone,
and postoperative infection. The difference between the patients
significantly affected the implant failure rates (RR 1.78, 95%
CI 1.50-2.11; p < 0.00001), also observed when only the CCTs
were pooled (RR 1.97, 95% CI 1.38-2.80; p = 0.0002). There
was significant effects of dental implants inserted in PCPs on the
occurrence of postoperative infections (RR 3.24, 95% CI 1.69-6.21;
p = 0.0004) and in MBL (MD 0.60, 95% CI 0.33-0.87; p < 0.0001)
when compared to PHPs.
This observation is not surprising if one assumes that periodontal
disease not only decreases available bone volume, but also affects the
capacity of osseous tissue to remodel.841 In patients in whom teeth
were lost for periodontal reasons, the disease may have decreased the
available bone following tooth extraction or resulted in the necessity
to place the implant with a more exposed surface to achieve ideal
prosthetic position. Both of these situations could result in a greater
implant failure rate.577 Other factors may also exert influence on
the fact that implant failure is more frequent in patients classified in
the aggressive periodontitis group. De Boever et al.842 noticed that
it is apparent that in these patients a combination of this form of
periodontitis, current smoking habits and general (systemic) diseases
was often observed. It should be stressed that the classification used
by De Boever et al.842 to classify periodontitis as ‘aggressive’ may not
be the same as used in other studies.
Here is important to mention the possible high influence of
smoking habits on the implants failure rates. Tobacco smoking is
considered the principal environmental risk factor affecting the
pathogenesis of periodontitis. Tobacco smokers were shown to
159
be more prone to developing periodontitis compared with non-
smokers.843 Furthermore, the results after periodontal therapies are
less predictable in smokers compared with non- or former smokers844
and the risk of periodontitis recurrence appears to be higher as well.845
Karoussis et al.846 showed in their study that there was a tendency for
a poorer survival rate of implants in smokers versus non-smokers in
patients with a history of periodontitis, indicating that the smoking
patient susceptible to periodontitis yields a documented higher
risk for implant loss than the non-smoking periodontitis patient or
the patient not susceptible to periodontitis at all. In the study of
Koldsland et al.,847 the combination of tobacco smoking and a history
of treated periodontitis was significantly associated with implant loss
after a mean observation time of 8.4 years. Aglietta et al.848 showed
that tobacco smokers with a history of treated periodontitis displayed
lower implant survival rates and higher MBL rates compared with
smokers PHPs, independent of other factors such as implant type,
healing modality and operator, and despite the fact that smokers
PCPs were treated for their periodontal conditions before implant
placement and were regularly enrolled in a SPT.
A relationship between marginal implant bone loss and smoking
habits was also observed. In the study of Feloutzis et al.,790 IL-1 gene
polymorphisms were determined and compared to the annual rate
of bone loss in periodontally susceptible patients. It was revealed
that IL-1 genotype positive smoking patients yield a higher risk for
peri-implant bone loss than IL-1 negative smokers. Heavy smoking
patients, which in this study were the patients smoking 20 cigarettes
per day, also significantly demonstrated higher rates of peri-implant
alveolar bone loss than non-smokers. Nitzan et al.849 showed a
higher incidence of marginal implant bone loss in their study in the
smoking group, which was more pronounced in the maxilla. Hardt
et al.850 observed that the amount of longitudinal peri-implant bone
loss is related to pretreatment experience of loss of periodontal bone
support. The exact relationship between periodontitis and peri-
implantitis remains unknown; we really do not know whether these
two types of disease are similar in origin at all since a demonstrated
positive correlation between PCP and implant failure in itself does
not prove such a connection. In some studies PCPs demonstrated
higher implant failure rates but this difference did not reach statistical
160
significance. Obviously, treatment of periodontal infections before
implant placement would seem important to avoid placing an implant
in an infected bed.
No difference was found for implant failures and the MBL around
implants between the PHPs and patients with chronic periodontal
disease in the aforementioned meta-analysis.15 This is likely due to the
thorough supportive maintenance program in which patients from
almost all studies were enrolled, and also due to the more mild nature
of the chronic periodontitis in comparison with the aggressive ones.
In some studies PCPs demonstrated higher implant failure rates but
this difference did not reach statistical significance, which could be
attributed to the fact that the patients were treated in a periodontal
clinic and their periodontal condition was “controlled.” Obviously,
treatment of periodontal infections before implant placement,
achievement of high levels of oral hygiene and enrollment of patients
in a regular supportive therapy program contributed to the positive
outcomes (or less difference) in some studies. The lack of adhesion
to SPT is associated with a higher incidence of bone loss and implant
loss, as it has proven to be a key factor in enhancing long-term
outcomes of implant therapy by controlling re-infection.836 These
results may underestimate the value of the SPT in enhancing long-
term outcomes of implant therapy, particularly in subjects affected
by severe periodontitis.836
However, the compliance to SPT cannot always be counted as a
factor to decrease or avoid possible periodontal complications. A small
number of periodontal maintenance patients seem to be refractory to
treatment and go on to experience continued and significant tooth
loss. These subjects also have a high level of implant complications
and failure.851 Moreover, long-term outcomes demonstrated that
implants in non-smoking PCPs previously treated for periodontitis
were more prone to developing MBL compared with those in PHPs.852
These results were obtained despite the fact that all patients were
regularly enrolled in and compliant with a SPT program over 10
years.852 Furthermore, Fardal and Linden851 observed that smoking,
stress and a family history of periodontal disease were identified as
factors associated with a refractory outcome, and these variables
remained significant after multivariate analysis.
161
Analysis of the data disclosed different patterns regarding the
distribution of the implant losses over time in the two categories
of patients. In the study of Hardt et al.,850 while the number of
implants lost during the first year were similar in the two groups,
there was subsequently only one implant lost in PHPs compared
to five implants (four patients) in PCPs, all with a length of ≥10
mm. Rosenberg et al.853 observed that failure up to 1 year of loading
occurred relatively frequently in both the PCP group and the PHP
group, with no significant differences, indicating that a history
of periodontitis in a particular patient does not affect the healing
process of osseointegration. On the other side, failure significantly
occurred more frequently in the PCP group than in the PHP group
after 1 year of loading. Gianserra et al.854 observed in a retrospective
study that patients with a previous history of periodontitis did
not lose significantly more implants after 5 years in function than
PHPs. However, Roccuzzo et al.836 showed that the difference
between PHP and PCP is negligible during the first 5 years, but
becomes more pronounced later on, being in accordance with the
findings of Karoussis et al.,846 who first demonstrated that a 5-year
follow-up is usually not sufficient to evaluate the differences in the
clinical outcomes of the various groups of patients. In particular, the
difference in the survival rates was not obvious during the first 6 years
of follow-up, whereas during the later 4 years, a higher implant loss
was observed in PCP.846 In the study of Levin et al.,855 the extended
Cox model revealed that until around 50 months, periodontal status
is not a significant factor but after 50 months, the hazard for implant
failure is eight times greater for the severe PCP. This means that a
higher susceptibility for the loss of implants in patients with a history
of periodontitis compared to patients with no such history may first
become evident after prolonged observation periods of 5–10 years.
Rosenberg et al.853 hypothesized that one possible explanation for
the difference between the 2 groups in this pattern of failure is the
influence of the host, which plays an important role in the variable
inflammatory process and may be significant in patients with a
history of periodontal disease. Another possible explanation could be
related to local factors. A reduced quantity of hard tissue in the PCP
group may be related to periodontal loss prior to tooth extraction.853
162
A problem in comparing these studies is the fact that the studies
used different definitions for the presence of periodontal disease,
depending on the threshold chosen for the definition of periodontitis,
or which conjunct of characteristics may be considered a periodontal
disease, i.e., the diagnostic criteria are less clear. Periodontitis
comprises a variety of pathologic conditions that affect the health
of the periodontium, with patients usually exhibiting gingival
inflammation and loss of the connective tissue attachment to teeth,
but sometimes also loss of the periodontal ligament, disruption
of its attachment to the cementum, and resorption of the alveolar
bone can also occur.856 Thus, a clear classification system needs to
be implemented with clinical evaluation related to a more specific
pathology. Moreover, the outcome measures were not related to the
type of periodontitis in every study. When it was reported, there was
a statistically significant difference concerning the implant failure
rates, favoring the less aggressive type of periodontitis in comparison
with the more aggressive one.
It has been stated that endodontic problems associated with teeth to
be extracted may affect the long-term survival of implants immediately
placed into the same sites.857 However, a systematic review189 on
the subject got to the conclusion that the high survival rate and the
normal marginal bone changes obtained in several studies support the
hypothesis that implants may be successfully osseointegrated when
placed immediately after extraction of teeth presenting endodontic and
periodontal lesions, provided that appropriate clinical procedures are
performed before the implant surgical procedure. Moreover, primary
closure over immediately placed implants is another variable that
could influence the outcome. Although gingival grafts may be placed
over the socket if primary closure is not achieved, in numerous cases
the socket may have had exposure to the oral environment during
healing.858 Numerous implants in some studies857 were placed at the
same time as periodontal surgical procedures were being carried out.
The influence of this co-therapy on implant contamination during
the procedure has not been investigated. At the immediate and early
implant placement it can be speculated that periodontitis-affected
tissues might have had a negative local influence due to the presence
of infrabony defects; this could increase the gap between bone and
implant457 or jeopardize achievement of primary stability.458
163
It has been reported that in partially edentulous patients, periodontal
pathogens may be transmitted from teeth to implants, implying that
periodontal pockets may serve as reservoirs for bacterial colonization
around implants.838,859 At sites of implants having been in function for
3–4 years, deeper probing depths and higher detection frequencies of
periodontal pathogens were observed compared to sites of implants
having been in function for only 1–2 years, thus providing evidence
for the spread of pathogens with time.860 The similarity in microbial
flora responsible for periodontitis and peri-implantitis supports the
concept that periodontal pathogens may be associated with peri-
implant infections and failing implants.861 However, more recent
studies show different results. Carcuac and Berglundh862 performed
histologic and immunohistochemical analysis of soft tissue biopsies
sampled from patients with severe forms of periodontitis or peri-
implantitis. They observed that the peri-implantitis lesions were larger
and comprised greater proportions of plasma cells, macrophages and
polymorphonuclears than the periodontitis lesions. They suggested
that peri-implantitis and periodontitis lesions exhibit critical
histopathological differences, which contribute to the understanding
of dissimilarities in onset and progression between the two diseases.
Moreover, the study of Cecchinato et al.840 evaluated the MBL that
occurred at implants and teeth in the same segment of the dentition
following implant placement in partially dentate subjects and showed
that MBL at implants and teeth in many partially dentate subjects
might be independent phenomena.
Irradiation
Following radiation and surgical resection of oral cancer most patients
suffer from defects of soft and hard tissue resulting in functional
disabilities and esthetic deformity. These maxillofacial defects are
usually reconstructed with vascularized and non-vascularized flaps.
This treatment modality alters hard and soft tissues, and the oral
cavity in particular is influenced in its integrity by the surgical
reconstruction and the adverse effects of the radiotherapy. Dental
rehabilitation by conventional prosthesis may be hampered because
of the fact that reconstructive surgery changes oral anatomy and
radiotherapy results in vulnerable mucosa, xerostomia and bone
healing disturbances. Therefore, in most patients a conventional
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prosthetic rehabilitation is unsatisfactory or may not even be a
possibility. In this situation dental implants are potentially a more
effective oral rehabilitation with regard to mastication, esthetics and
speech function.863 As dental implants have been increasingly used
in oral cancer patients, it is important to know how much irradiated
patients in the head and neck region are more at risk of losing dental
implants.
Radiotherapy is largely used for treatment of head and neck
cancer, as primary therapy, adjuvant to surgery, in conjunction with
concurrent chemotherapy or as palliative treatment for late stage and
unresectable head and neck malignancies. Although the radiotherapy
can increase cure rates, the irradiated patient is susceptible to
secondary effects and a series of potential orofacial complications.
Radiotherapy may result in progressive fibrosis of blood vessels and
soft tissues, in xerostomia, in osteoradionecrosis, and in reduction of
bone-healing capacity, among others.864-866 Because of the cumulative
effects of radiation on bone vascularity, the regenerative capacity
of these tissues is limited, which may have a deleterious impact on
subsequent implant osseointegration.867
A recent systematic review and meta-analysis24 assessed the
influence of radiotherapy on dental implants. The meta-analyses
performed suggest that irradiation negatively affects the survival rates
of dental implants, and that implants placed in irradiated maxillae
perform much worse than implants placed in irradiated mandibles.
The study has failed to support the effectiveness of hyperbaric oxygen
(HBO) therapy in irradiated patients requiring dental implants. It
also suggests that there is no statistically significant difference in
survival when implants are inserted before or after 12 months after
the radiotherapy. Moreover, it was observed a tendency to a lower
survival rate of implants inserted in the patients submitted to higher
irradiation doses.
The significantly higher failure rates in irradiated compared to
non-irradiated patients might be caused by the long-term effects of
reduced vascularization compromising the implantation site.863 In
general, radiation therapy has two antagonistic effects with regard
to recovery of irradiated tissue: a short-term positive cellular effect
resulting in the improvement of reduced bone-healing capacity,868
and a long-term negative effect resulting in permanent damage of
165
osteoprogenitor cells869 and a gradual, progressive endarteritis
obliterans, with thrombosis of small blood vessels, fibrosis of the
periosteum and mucosa and damage to osteocytes, osteoblasts and
fibroblasts.870 Moreover, irradiation of tissues that contain integrated
implants increases the risk of soft tissue dehiscences around the
implants, and osteoradionecrosis may lead to loss of the implants.871
This failure difference after radiation therapy was observed in several
studies, although the radiation dosage and observation period varied
in the majority of these cases.
Another aspect to consider is the use of HBO. There is no strict
consensus about the use of adjunctive HBO therapy but many studies
stressed the advantages of HBO treatment for wound healing in
the irradiated soft and hard tissue.863 As a result, some authors use
HBO as an additive therapy when implant therapy in irradiated
bone is planned. It is stated in the literature that HBO results in
an increased oxygen tension in the irradiated ischemic bone and
provokes capillary neoangiogenesis869 and bone formation.872 The
exact correlation between HBO dose and duration of antifibrotic
response is not yet settled. It has been convincingly demonstrated that
such treatment dramatically decreases the risk of trauma-induced
osteoradionecrosis by promoting vascular proliferation, collagen
synthesis, bone remodeling activities, and healing of bone wounds in
irradiated tissues.873 Moreover, HBO therapy increases the amount of
force necessary to unscrew integrated titanium implants in irradiated
bone,874 which suggests that promoted integration has occurred.
Larsen et al.872 showed a difference of 13.9% in mean percent of
integration after 4 months in the osseointegration surface of irradiated
and non-irradiated animals. This difference dropped to 6.38% when
animals received HBO before and after implantation. The difference
was shown to be significant, though without establishing whether
this reduction is of significance in relation to implant support. As
long as the direct bone-implant interface is sufficiently large to
support the suprastructure, it can be argued that additional support
to the implant surface is unnecessary, particularly in light of patient
inconvenience and the cost of HBO treatment.875 HBO therapy
needs expensive equipment, requires significant patient compliance
and involves financial costs per patient treatment. In addition, HBO
therapy is not without risks and adverse effects like barotrauma,
166
particularly of the middle ear, O2 seizures or a change in the refractive
power of the lens.876 Moreover, results from animal experiments
may only partly be extrapolated to clinically relevant conditions for
endosseous implants in irradiated bone. Apart from considerable
methodological limitations in the simulation of the therapeutic reality
and temporal restrictions, events during the follow-up (induction
of neoplasms, loss of implants, osteoradionecrosis, etc), differences
related to cell cycles, structural peculiarities of the bone matrix, the
periosteal situation, and the enzyme system of the species have to be
taken into account.877 It is no less important to mention that several
studies875,878-898 demonstrated a high survival rate for the implants
placed in irradiated jaws without the use of adjunctive HBO therapy.
It might have been expected a significantly higher failure for patients
submitted to HBO, since most of the patients selected for HBO could
have been at a higher risk for osteoradionecrosis due to a higher
irradiation dose, and consequently at a higher risk of implant loss.
For example, the difference in implant survival between the HBO and
non-HBO treated patients observed in the study of Schoen et al.894
was remarkable, but was mainly caused by one HBO treated patient
who developed osteoradionecrosis and subsequently lost all four
implants. However, the meta-analysis of Chrcanovic et al.24 found no
statistically significant difference when comparing implant failures in
irradiated patients receiving HBO or not; this is most likely the result
of the small sample size in many studies and selection bias. There are
still no randomized, controlled, double-blind studies conducted to
prove that HBO really has a significant osseointegration stimulating
effect in irradiated patients. However, there are certain technical
difficulties related to designing such a study, such as blinding a
chamber treatment and the design of the placebo treatment.899
The time span between the irradiation and the implant surgery may
influence the survival of the dental implants, and recommendations
for an optimal time interval are inconsistent. Dental implants can be
inserted during the ablative surgery or after completed radiotherapy.
When the implants are inserted during the ablative surgical session, a
large part of the integration will occur in the period between surgery
and radiotherapy, i.e. within 4-6 weeks.900 However, a large majority
of studies reviewed by Chrcanovic et al.24 report on implants installed
after radiotherapy. The advantage of placement after radiotherapy
167
is that the anatomical situation, residual function and prognosis can
be taken into account in the decision of whether to use implants
or not. Moreover, tumor recurrence has been reported to occur
most often between 8 and 12 months after surgery according to one
study,901 or within 2 years according to another one;879 thus oral
rehabilitation may be delayed until this period of highest risk has
passed. The disadvantage is that patients are often psychologically
and physically weakened by the therapy, resulting in postponement
or even cancellation of prosthetic rehabilitation.902 Moreover, after
radiotherapy the vascularization and regenerative ability of the
irradiated tissues can be decreased, which may lessen the prospect
of successful osseointegration of the dental implants.903 The subject
is controversial. King et al.904 indicated that blood vessels that were
destroyed radiologically show partial recovery after 3 to 6 months.
Wächter and Stoll905 conducted histomorphometric studies, the results
of which state that implantation can be performed, at the earliest,
12 to 18 months after the conclusion of irradiation. Jacobsson868
reported an improvement in the bone healing capacity by a factor
of almost 2.5 during a 12-month period following irradiation.
According to the author, functional self-regeneration of the damaged
tissue would provide sufficient implant healing and osseointegration
capacities of the bone 1 year after radiation therapy. On the other
side, Marx and Johnson869 stated that after 6 months, fibrosis is
expected to start in the irradiated tissues as a result of reduced cell
reproducibility and progressive ischemia. This process will increase
with time, especially when curative doses of radiotherapy have been
given. The meta-analysis of Chrcanovic et al.24 found no statistically
significant difference when failure of implants was compared for the
implants installed before and after a period of 12 months from the
radiotherapy, and this is most likely dependent on the fact that only
three studies863,906,907 performed this comparison. Two other studies
did not report defined time points to enable the comparison, but did
not find any influence of time of implantation on the implant failure
rates.883,891
Named advantages of implant installation during ablative tumor
surgery include900: (1) Implant surgery in an area compromised
by radiotherapy can be avoided, thus reducing the risk of late
complications, such as development of osteoradionecrosis; (2) initial
168
implant healing (osseointegration) will take place before irradiation;
(3) the patient can benefit from the support of the implants at an
earlier stage after treatment, e.g. concerning the rehabilitation of
speech and swallowing. Prosthetic rehabilitation can start early
providing the patient with a more timely improvement in oral
function; (4) there is no need for adjunctive prophylaxis such as
the long-term use of antibiotics or hyperbaric oxygen therapy.
The risks of installing implants during ablative surgery have to be
named as well: (1) improper implant positioning, especially when
ablative surgery will result in gross alterations in the anatomical
situation and/or intermaxillary relationship, e.g. after mandibular
continuity resections or if the anatomical situation is changed due to
reconstructive surgery; (2) interference with or delay of oncological
therapy including radiotherapy; (3) development of post-treatment
complications caused by installation of implants during ablative
surgery; and (4) lack of use of implants, due to early tumor recurrence
or patients refusing abutment connection surgery.900 The advantages
of placement of implants sometime after ablative and reconstructive
surgery include the ability to make detailed assessment of disease
status, oral function, motivation, and rehabilitation requirements of
the patient before commencing radiotherapy treatment.144
Concerning the radiation dose, the implants inserted into locations
irradiated with ≥50 Gy in four studies879,906-908 had a lower survival
rate than implants in locations that are irradiated with <50 Gy. The
same happened in another study,909 but comparing different dose
thresholds (>54 versus <54 Gy). Generally, high radiation doses
>50 Gy have been reported to result in chronic complications like
radioxerostomia and impaired wound healing.910 Also, irradiation
doses above 65 Gy may significantly increase the risk of development
of osteoradionecrosis,911 which may also be a reason for implant
failures. Moreover, it was shown that there is a distinct dose-dependent
relationship between the duration and extent of irradiation and the
resulting reduced osteogenesis.912 Bone healing was delayed at lower
doses of radiation with the formation of more impaired fibrous tissue
and non-lamellar bone, but severely disturbed at radiation doses
used to treat head and neck cancer.913 However, the meta-analysis
of Chrcanovic et al.24 did not find a significant higher risk of losing
an implant in patients receiving higher doses of radiotherapy. Once
169
again, this result may have been influenced by the limited number
of studies performing this comparison. The comparable survival
rates of both groups in the study of Niimi et al.886 and even a higher
survival rate of implants inserted into locations of higher doses in
the study of Shaw et al.144 might be caused by the effects of reduced
vascularization that compromises both irradiated and non-irradiated
locations.869
Another circumstance that may increase implant failure is the
anatomy of the implantation site. Oral anatomy may change after
ablative surgery and eventually following reconstruction by grafts
and flaps, and the resulting defects and bulky areas or the presence
of insufficient soft tissues for coverage may compromise prosthetic
rehabilitation.914,915 One could speculate that the bony section of
the graft may have been non-vital from the time of placement or
that placement of implants in the grafted block of bone may have
compromised the vitality of the block.916 Some studies on this topic
address the increased implant loss in augmented bone to the reduced
primary stability of dental implants due to impaired mechanical bone
quality as well as to increased bone resorption kinetics.544,558,917 The
lower survival of implants in the grafted bone may be the result
of differences in bone quality, bone volume and revascularization
compared with the original residual bone. There is also a difference
when it comes to the graft type. Vascularized bone flaps maintain
their viability even following prolonged periods of ischemia provided
that the medullary nutrient blood supply is later restored.918 This is
unlike nonvascularized cortical bone grafts, where implant placement
must await a lengthy delay to allow for ‘creeping substitution’645 to
occur. Even with all these disadvantages, Chrcanovic et al.24 found
no statistically significant difference concerning failures of dental
implants when inserted in irradiated grafted bone or in irradiated
native bone. This could be related to the assumption that the clinical
courses of implants may not be affected by the presence of grafted
bone once the graft has succeeded.915 However, this is difficult to
ascertain, as not every study included in the review of Chrcanovic
et al.24 provided detailed information about grafting procedures. On
the other side, when the failure rates were compared in irradiated
versus non-irradiated patients,24 there was a statistically significant
difference for implants inserted in grafted bone and in native bone.
170
Once again, when the term ‘irradiation’ is inserted into the equation,
there are significant differences.
Concerning the different jaws, it was observed in one study906
that the most dominant variable influencing implant survival in
irradiated bone is the implant’s location in the maxilla or mandible.
The side effects of radiotherapy appear to be more serious in the
mandible than in the maxilla because of its inferior blood supply.883
However, it appears that implant failure in the maxilla follows a
similar course in irradiated and non-irradiated patients.24 The results
comparing implant failures in irradiated and non-irradiated maxilla
and in irradiated and non-irradiated mandible must be interpreted
with caution, due to the limited number of studies reporting this
information (2 and 4, respectively). It is also important to consider
whether all implants had been inserted in the field of irradiation, even
though this information was rarely provided by the studies. In the case
of the mandible, for example, the external beam radiation therapy for
oral malignancies does not always include the whole mandible and,
hence, implants inserted anterior to the mental foramina might be
inserted in a field of lower radiation dose. This will naturally affect
the outcome for the implants.899
When it comes to postoperative infection, soft tissue may be
affected by irradiation, and the causes might be the post-operative
and post-irradiation xerostomia, different saliva quantity and quality
and altered microflora as well as the presence of scar tissue after
reconstruction and the loss of attached and keratinized gingiva
adjacent to the implants.863,891 It may be suggested that stable soft
tissue conditions are crucial for the possibility to perform oral
hygiene and can influence the clinical performance of the implants
in irradiated patients.896 This could influence the incidence of peri-
implantitis and consequently the MBL. Chrcanovic et al.24 observed
a statistically significant difference between the irradiated versus
non-irradiated patients concerning the MBL, favoring non-irradiated
patients. However, this result must be interpreted with caution, due
to the limited number of studies that evaluated the condition. The
same can be said about the meta-analysis results for the outcome
postoperative infection.
There are a considerable number of confounding factors that might
also influence therapy with dental implants in irradiated patients.
171
First, bone resections may result in unfavorable prosthetic
circumstances by producing bulky and soft areas. In these situations,
(removable) prosthetic appliances are often complicated and may
cause overloading of the implants.914 This negative influence may
be responsible for lower survival rate of implants inserted into jaws
treated with bone resections, compared with that of implants inserted
into jaws that did not undergo bone surgery.906
Second, the percentage of patients who had received postoperative
radiotherapy may have decreased over time among the survivors, as
it was observed in many studies, which could have contributed to
the relatively low failure rate of implants in irradiated bone. Those
patients selected to be submitted to radiotherapy may be the patients
with cancers of worse prognosis.
Third, in the analysis of implant survival, it is important to
ascertain whether the implants that were placed and considered
osseointegrated were, in fact, used for the final implant-supported
prosthesis.919 A longer follow-up period can lead to an increase in
the failure rate, especially if it extended beyond functional loading,
because other prosthetic factors can influence implant failure from
that point onward. This might have led to an underestimation of
actual failures in some studies. However, it is hard to define what it
would be considered a short follow-up period to evaluate implant
failures when comparing these techniques.
Fourth, most oral cancer patients have a history of smoking, drinking
poor oral hygiene.920 The local environment is less favorable to dental
implants than in healthy subjects. Saliva quantity and quality as well
as oral microflora change considerably after salivary gland resection.
Landes and Kovács891 observed that plaque and peri-implant bleeding
indices remained typically high compared with non-cancer patients.
Oral hygiene and compliance were limited although patients received
individual oral hygiene instruction. On the other hand, a rapid plaque
accumulation and bleeding tendency was concomitant with post-
operative and post-irradiation xerostomia, altered microflora, saliva
quantity and quality, smoking and drinking. Irradiation leaves a less-
viable bone that is prone to infection; furthermore, oral xerostomia
post-radiotherapy complicates the situation.909
Fifth, as oral cancer represents around 3% of the total cancer
incidence,921 most of the studies were not able to create a homogenous
172
collective for more than the factors such as oral squamous cell
carcinoma, edentulousness or severely reduced tooth number. By
breaking down the study by each variable, the authors of the studies
may had had serious doubts regarding the clinical value in a study
that is totally homogenous in tumor staging, Gy of irradiation,
etc. It can be said that in order to have sufficient group sizes and a
clinically relevant conclusion, groups in the studies were therefore
not supposedly broken down further. Homogenous or matched
collectives somewhat have a higher significance but they tend to be
inhibited by small case numbers.891
Sixth, it is known that the surface properties of dental implants such
as topography and chemistry are relevant for the osseointegration
process influencing ionic interaction, protein adsorption and cellular
activity at the surface.311 The studies here included made use of
implants with different brands and surface treatments. Titanium
with different surface modifications shows a wide range of chemical,
physical properties, and surface topographies or morphologies,
depending on how they are prepared and handled,922 and it is not
clear whether, in general, one surface modification is better than
another.311
Seventh, there was a great variation of the implant healing time
before the prosthetic loading. In irradiated tissue, the local healing
ability is impaired886,909 and the vulnerable time period following
insertion becomes jeopardized with early loading. The overloading
of the implants, induced by altered oral anatomy following ablative
surgery or reconstruction by grafts and flaps may also increase
implant failure in malignant cancer patients compared with healthy
patients.913 The optimal head and neck oncology treatment-related
healing time of implants before loading is still in need of further
research and probably can be shortened significantly.895
Eighth, patients in some studies were subject to adjunctive
chemotherapy. The effect of chemotherapy on the osseointegration
and survival of endosteal implants is not well established, even
though it was shown that the risk of irradiation-induced bone
damage is increased by chemotherapy.923 It is suggested by animal
model studies that chemotherapeutic agents have an adverse effect on
normal physiological bone turnover, especially osteoblastic activity,
and would also be expected to alter fracture-healing and bone-
173
allograft incorporation by these same mechanisms.924,925 However,
chemotherapy did not have a detrimental effect on the survival and
success of dental implants in some studies,142,896,926 even though
implant insertion in these studies was performed at least 6 months
after chemotherapy. Thus, it is unknown whether the time point of
chemotherapy might be decisive.
Ninth, it is important that the patients are followed-up long enough
before reporting implant success in irradiated bone.899 However,
since the life-span prognosis for most patients with oral malignant
tumors is rather poor and the 5-year survival rate is reached by only
approximately 50% of the patients, it is difficult to collect long-term
data on implants placed in these patients.903 Moreover, one study927
showed that the early dropout after the final prosthetic treatment
is high and that some patients were hindered to attend the regular
recall sessions due to serious health conditions, which makes it even
more difficult to collect substantial data on the long-term situation.
It is also important to stress that the patients with better oral and
general health conditions are usually the ones who are more willing
to pay a recall visit.
The failure of dental implants in irradiated patients is therefore
subjected to many considerations and predictability is dependent
upon issues like the use of HBO and chemotherapy, the timing of
the implant placement in relation to radiation therapy, the radiation
dosage, the insertion of implants in native of grafted bone, selection
of anatomic site, the patients’ oral hygiene conditions and habits
(smoking, drinking), the implant surface treatment, the prosthetic
loading conditions, the type of prosthetic restoration, the period of
follow-up, and risk of osteoradionecrosis.24
Diabetes mellitus
Dental implant survival is initially dependent upon successful
osseointegration following placement. Any alteration of this biological
process by excessive surgical trauma, infection or metabolic upset may
adversely affect treatment outcomes.928 Subsequently, as an implant
is restored and placed into function, bone remodeling becomes a
critical aspect of implant survival in responding to the functional
demands placed on the implant restoration and supporting bone. The
critical dependence on bone metabolism for implant survival may be
174
heightened in patients with diabetes.929 Diabetes is a chronic disease
that occurs when the pancreas does not produce enough insulin,
or when the body cannot effectively use the insulin it produces.
The number of people with diabetes increased from 153 (127–182)
million in 1980, to 347 (314–382) million in 2008.930 These trends
highlight the urgency for a better understanding of diabetes as well
as for improving the care of patients with diabetes.
Diabetic patients have increased frequency of periodontitis and
tooth loss,931 and together with the fact that diabetes is associated with
delayed wound healing,932 prevalence of microvascular disease,933 and
impaired response to infection,934 diabetes has been considered a risky
condition for dental implants. Accordingly, it has been stated that
diabetes remains a relative contraindication for implant therapy;935
well-controlled diabetic patients may be considered appropriate for
implant therapy while diabetic patients lacking good glycemic control
may be denied the benefits of implant therapy.929 Decreased levels of
implant osseointegration have been demonstrated in hyperglycemic
animals consistent with untreated type 1 diabetes.936,937 However,
the subject is contradictory, since there are numerous studies that
offer indirect evidence for diabetes patients to benefit from oral
rehabilitation using dental implant therapy.
It has been suggested that the relative contraindication for implant
surgery is related to the stability of the diabetic’s blood sugar level.
Unfortunately, the application of the finding from many studies
to clinical practice is limited by the lack of specific information
characterizing the subjects’ diabetic status. While most of these
studies describe the subjects’ diabetes as being ‘well-controlled’,
the authors do not report how they assessed glycemic control.938
A systematic review and meta-analysis assessing the influence of
diabetes on dental implants therapy16 identified two938,939 of the 14
publications included855,928,938-949 in the study in which patients lacking
acceptable glycemic control (through the estimation of glycosylated
hemoglobin – HbA1c) were included. Five studies940,942,944-946
reported that the patients’ diabetes was under control, but it was not
mentioned the level of control, whereas the other studies included in
the review did not provide any information about glycemic control.
In the study of Moy et al.,950 even patients with controlled diabetes
were almost 3 times as likely to develop implant failure compared
175
to other patients. Glycemic control is a primary consideration for
patients with diabetes, and there is a clear correlation between
glycemic control and the development of microvascular and
macrovascular complications.951 Tissue hyperglycemia impacts
every aspect of wound healing by adversely affecting the immune
system, including neutrophil and lymphocyte function, chemotaxis,
and phagocytosis.952 This also leads to a greater predisposition to
infection of the wound. Moreover, animal studies showed negative
effects of hyperglycemia, not only on bone formation, but also on
bone strength and fracture healing.936,953,954 These effects are suggested
to affect the osseointegration. However, a prospective evaluation of
58 patients with presumably well-controlled diabetes who received
mandibular implants reported that glycemic control was not related
significantly to implant success over five years.955 Dowell et al.938 and
Tawil et al.939 also observed that compromises in glycemic control
may not affect implant success in human subjects.
Heterogeneity in eligibility criteria for implantation in different
diabetic populations may explain the wide between-study variations.
The true differences in metabolic effects between type 1 and type 2
diabetes remain unclear.929 It has been proposed that diabetes leads
to decreased bone turnover, with reductions in both resorption and
formation and that it is the difference in ages of onset of types 1
and 2 diabetes relative to bone growth patterns that lead to these
distinctions in outcomes.956 Because type 1 has an earlier onset than
type 2 diabetes, one can assume that implant loss is more frequent
in patients with the former form of diabetes. One possible reflection
in oral implantology was observed by Alsaadi et al.,945 who detected
a significant effect of diabetes type 1 on early implant failures (p
= 0.02), the same not happening with diabetes type 2 (p = 0.39).
However, it is important to observe that in the study of Alsaadi et
al.,945 only one implant was placed in the only patient with diabetes
type 1 in the study, and this implant failed, whereas 25 implants
were inserted in patients with diabetes type 2, with only one failure
(694 implants were placed in non-diabetic patients, with 13 failures).
One of the possible problems in including patients with diabetes type
1 in dental implant clinical studies is its prevalence: over 90% of
people with diabetes have type 2. Since implant outcomes for patients
with type 1 diabetes may differ from those for patients with type 2
176
diabetes, it is important for studies that include both patients’ types
to report the outcome data separately for each group.638
In animal studies it was shown that uncontrolled diabetes hinders
bone formation, bone remodeling, and wound healing957 and causes
reduction in BIC and bone thickness,958 while insulin upregulates bone
formation936 and maintains BIC.959 The effects of a hyperglycemic state
have been shown to include inhibition of osteoblastic cell proliferation
and collagen production during the early stages of callus development,
resulting in reduced bone formation, as well as diminished mechanical
properties of the newly formed bone.953 Reduced BIC may indicate
a poorer healing response and may predict a reduced ability of the
implant to withstand bacterial and load challenges. If the lack of
BIC is carried to the extreme, osseointegration would be deemed to
have failed and the implant would be found to be mobile at stage-
two surgery.928 Oates et al.960 demonstrated alterations in implant
stability consistent with impaired implant integration for persons
with type 2 diabetes mellitus in direct relation to hyperglycemic
conditions. It was observed that persons with HbA1c ≥ 8.1% had a
greater maximum decrease in stability from baseline and required a
longer time for healing, which also suggests alterations in the biologic
integration of the implants in direct relation to glycemic control.960 It
seems reasonable to postulate that an implant demonstrating reduced
BIC may be less able to withstand functional stresses placed upon
it during the healing phase. Further breakdown of the peri-implant
bone could therefore ensue and this could result in a loosening of the
implant and its ultimate failure.928 However, this has not yet been
clinically proved, since most of the studies reviewed by Chrcanovic
et al.16 did not inform of the times which the implants placed in
diabetics were loaded. The study of Tawil et al.939 was the one only
in which some implants (n = 58) inserted in diabetic patients were
submitted to immediate loading, but no failure was observed after a
mean follow-up of 42 months.
In some dental implant studies including diabetic patients,938,945 the
patients were followed for a short period (up to 6 months). Thus,
even though it is especially during the healing time, up to abutment
surgery, that systemic factors can be most easily identified as other
risk factors that occur after abutment surgery do not apply,961 only
early failures could be assessed. A longer follow-up period can lead
177
to an increase in the failure rate. Moreover, the results found in the
studies differed from each other, and this difference could be due to
factors such as differences in the patients included in the study or the
clinicians placing and restoring the implants. For example, Olson
et al.955 observed that implant failure had a statistically significant
association with an increase in years of diabetic history. The authors
hypothesized that, as duration of diabetes is associated with increased
classic microvascular complications, this increase in microvascular
disease may be postulated to have contributed to implant failure.
However, Tawil et al.939 divided the patients with well-controlled
diabetes into four groups (with reference to duration of diabetes),
and the results showed no significant differences in implant survival
rates between the groups.
The study of Morris et al.941 was the only one associating some
variables to diabetes and implant failure rates. They reported improved
implant survival for patients who were treated with antibiotics in
comparison to those treated without prophylactic antibiotics, but
the survival improvement was greater in diabetic patients (97.1%
versus 86.6%) than in non-diabetic patients (95.1% versus 90.6%).
The same happened in diabetic and non-diabetic patients when the
use or non-use of chlorhexidine rinses was evaluated.
In the meta-analysis of Chrcanovic et al.,16 the difference between
the insertion of dental implants in non-diabetic and diabetic patients
did not statistically affect the implant failure rates. However, the
authors suggested that is believed that this lack of difference applies
only when well-controlled type 2 diabetes patients are considered.
They also detected that studies which include both patient types with
a larger sample size and report the outcome data separately for each
group are lacking.
Pharmaceutical reasons for implant problems

Effects of antidepressants and clinical depression
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs
that are typically used as antidepressants in the treatment of major
depressive disorder and anxiety disorders. There is evidence suggesting
a relationship between some neuroendocrine mechanisms related to
the serotonin system and the impairment of bone metabolism.962-964
Therefore, the intake of SSRIs could in theory interfere with the
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osseointegration process. In the case of dental implants in particular,
the findings of recent studies157,191 (Study III included) suggest that
the treatment with antidepressants is associated with an increased
failure risk of osseointegrated implants, while others944,945,965 did not
find a relationship between these two factors. Thus, there is still no
clear consensus on the influence of antidepressants on the risk of
dental implant failure.
It is possible that neuroendocrine mechanisms related to the
serotonin system could regulate osteoclast differentiation/activation,
because osteoclasts derive from hematopoietic cell precursors and
a relationship between bone and the immune system has been
established.962-964 Studies have identified a functional serotonin
system in osteoblasts and osteoclasts,966-968 in which the serotonin
transporter and several receptors are expressed in osteoblasts as well
as in osteoclasts.966,967 The presence of serotonin receptors and the
serotonin transporter in bone raises the question whether medications
that antagonize serotonin reuptake could influence bone metabolism.
It has been shown in in vitro studies that activity of the serotonin
transporter is required for osteoclast differentiation. While blockage
of the serotonin transporter reduced osteoclast differentiation when
fluoxetine, an antidepressant, was administered to produce μM
concentrations,968,969 there was an increase in osteoclast differentiation
for the same medicament in the nM concentrations.969 In vivo
studies demonstrated detrimental effects of fluoxetine on trabecular
architecture970 and on bone mineral density970,971 in mice. Another in
vivo study showed that serotonin acts on osteoblasts inhibiting their
proliferation.972 These studies in animal models indicate a negative
effect of SSRIs on bone mass and suggest that these antidepressants
may possess direct anti-anabolic skeletal effects, through the
pharmacological inhibition of the serotonin transporter.
In the field of dentistry, some studies have already assessed whether
the intake of antidepressants might be associated with an increased
risk of implant failures. Alsaadi et al.945 and Alsaadi et al.965 evaluated
the impact of local and systemic factors on the incidence of oral
implant failures up to abutment connection, finding no relationship
between these two factors. The same group of researchers944
evaluated the impact of the same factors on the incidence of late
oral implant failures as well, also finding no relationship. However,
179
these three studies did not specify whether this kind of medication
was limited to the class of SSRIs. A more recent study191 (Study
III) evaluated a cohort study on the same conditions as these two
previous studies, i.e. failures up to abutment connection, having
several implant- and health-related factors as confounders, and not
limiting antidepressants to the SSRIs class. In contrast to Alsaadi et
al.,944,945,965 they observed an increased failure risk of implants with
the use of these medicaments (in this study,191 an increased failure
risk up to abutment connection was also associated with smoking).
Wu et al.157 was the only study among these previous publications
that evaluated only SSRIs, excluding other classes of antidepressants,
and they found a statistically significant association. However, it is
important to make a few more considerations about the study of
Wu et al.157 A table in their publication included 9 factors except the
intake of SSRIs, which was presented alone and in a different table.
It is not entirely clear from the publication whether they included
the intake of SSRIs in this final model or whether they analyzed
the factor SSRIs alone in a crude model. If they didn’t analyze the
factor SSRIs in the model with the other 9 factors, this could generate
a misspecified model, i.e. one that is not complete - it is missing
key/important explanatory variables and so it does not adequately
represent what one is trying to model or trying to predict. Supposing
that the variable SSRI was not included in the model together with the
other confounders, and if it were, the interaction of other confounders
of strong effect on the outcome (implant diameter and smoking, in
this case in particular) could have influenced the significance of the
factor SSRIs. It may happen that when there is the inclusion of a new
variable into a model, something that was previously statistically
significant becomes not significant.973 Thus, the results of the study
of Wu et al.157 must be analyzed carefully.
Chrcanovic et al.160 (Study VI) used several statistical methods
to test the association between SSRIs exposure and risk of implant
failure adjusting for several potential confounders. Patients were
included in the study if there were only taking SSRIs and no other
medicament, and did not present any other systemic condition.
Thus, the authors tried to isolate the status ‘taking SSRIs’ as much
as possible from the potential influence any other systemic condition
or medication. Even though descriptive statistics had pointed out that
180
the implant failure rates were statistically significant higher for SSRIs
users in comparison to nonusers (12.5% versus 3.3%, p = 0.007), the
same being observed by Kaplan Meier analysis (p < 0.001), the other
two statistical methods used in the study (multivariate GEE method
and a multilevel mixed effects parametric survival analysis) did not
detect any statistically significant difference between the groups. This
was due to differences in the statistical methods applied. The Fisher’s
exact test found a statistically significant association between the
intake of SSRIs and an increased risk of implant failure. However,
this test does not take into consideration the other confounders and
the factor time. The Kaplan Meier analysis showed a statistically
significant difference in the CSRs between SSRIs users and nonusers.
Even though this test considers the factor time, it does not count
the influence of the other variables. The multivariate GGE did not
find a statistically significant association, but even analyzing the
influence of the other confounders on the failures, the model only
takes the factor time as a simple confounder. The multilevel mixed
effects parametric survival analysis could be the best analysis, and it
showed no statistically significant association between the intake of
SSRIs and the risk of dental implant failure.
It is important to take into consideration that the alleged higher
risk of dental implant failures could be associated with the patient’s
mental condition rather than by the intake of antidepressants per
se. Some studies have demonstrated that psychosocial stress may
induce neglect of oral hygiene974,975 and that people suffering from
psychosocial stress may show resistance to periodontal therapies.976
Thus, it is suggested that psychosocial stress may be an important risk
factor in defining the progression of periodontitis, even if the patient
is undergoing therapy.977 Moreover, a study showed that depression
was associated with more extensive periodontitis, with continuous
periodontal breakdown, and with differences in serum antibody titers
to pathogens associated with periodontitis.978 It is a matter of debate
whether the results relating depression to periodontitis (around teeth)
could be similar around implants (peri-implantitis).
Effects of proton pump inhibitors

Proton pump inhibitors (PPIs) are in widespread use for the treatment
of acid-related disorders, such as gastroesophageal reflux disease or
181
gastric ulcer disease. They exert their curative effects by inhibiting
the acid output of the stomach. The higher probability of losing an
implant in patients taking medicaments to reduce the acid gastric
production is suggested to be related to observations indicating that
a reduction of gastric acidity may impair effective calcium uptake
through the intestines.979 As the calcium balance is essential for the
maintenance of bone health, among a multitude of other physiological
processes, it seems reasonable to believe that the unbalance of calcium
may to some degree affect osseointegration.
A recent clinical study161 (Study V) investigated the association
between the intake of PPIs and the risk of dental implant failure.
The implant failure rates were 12.0% (30/250) for PPIs users and
4.5% (148/3309) for nonusers (p < 0.001). The multilevel mixed
effects parametric survival analysis performed in the study showed
that the intake of PPIs significantly affected the implant survival rate
(HR 2.811; 95% CI 1.139, 6.937; p = 0.025), among other factors.
Some reasons could theoretically account for the suggested
association between PPIs intake and the increased likelihood of
dental implant failures. The most prominent hypothesis assumes that
the reduced acidity in the stomach impairs the intestinal absorption
of dietary calcium. Thus, there can be a decreased calcium absorption
under PPI therapy.980-982 Graziani et al.980 observed in eight healthy
volunteers that postprandial calcium concentrations did not increase
in subjects on a PPI regime (omeprazole 20 mg 3x daily), whereas
control subjects demonstrated a clear spike in serum calcium levels.
They as well observed that the urine calcium excretion in the
PPI group was also reduced in comparison to the control group.
O’Connell et al.981 measured the intestinal calcium absorption and
reported that 7 days of PPI (omeprazole 20 mg once a day) intake
significantly reduced calcium absorption in elderly women under
fasting conditions compared with the placebo group. Schinke et
al.982 showed that genetically manipulated mice to be achlorhydric
(with absence of hydrochloric acid from gastric juice) presented
decreased serum calcium levels and developed osteoporosis and
secondary hyperparathyroidism in an effort to maintain calcium
balance. As the calcium balance is essential for the maintenance
of bone health, among a multitude of other physiological processes,
it seems reasonable to believe that the unbalance of calcium may to
some degree affect osseointegration.
182
Effects of bisphosphonates
Bisphosphonates (BP) are a class of drugs that prevent the loss
of bone mass, used to treat osteoporosis and malignant diseases
involving bone resorption, such as bone lesions of multiple myeloma
and metastatic bone diseases. BP inhibits osteoclast-mediated bone
resorption and renewal, therefore retaining existing bone. This
increases mineralization under normal function, resulting in an
increase in bone mineral density and theoretically an increased
resistance to osteoporosis-related fractures.983 However, more recent
studies has been showing that preventing osteoclast-mediated bone
resorption/renewal results only in the retention of old bone, which
lives out its natural life span and becomes brittle and thus even more
prone to fracture.984 Removing osteoclasts and their useful function
in skeletal homeostasis by drugs can be expected to result in the same
complications seen in the genetic loss of osteoclast function in the
disease known as osteopetrosis, such as exposed bone in the maxilla
and/or mandible and leg fractures.985 In the case of use of BP, it is not
a matter of genetic expression but one of dose and accumulation in
bone over time.807
BPs are incorporated into mineralized structures and released during
mineral resorption. Upon release, BPs are internalized by osteoclasts.
The non–nitrogen-containing BPs are metabolized by osteoclasts into
cytotoxic analogs of adenosine triphosphate.986 Once concentrated
within the osteoclast, the analogs induce osteoclast apoptosis. The
final outcome from this process is a decreased quantity of osteoclasts,
resulting in less bone resorption.987 Nitrogen-containing BPs work
by a separate pathway. Once ingested, nitrogenous BPs bind to the
enzyme farnesyl diphosphate synthase in the 3-hydroxy-3-methyl-
glutaryl-CoA pathway and block the synthesis of farnesol and
genanylgeraniol. The end result is osteoclast cellular dysfunction and
death.988,989
The increase of implant failure rates to BP is hypothesized to be
related mainly to the impairment and cellular death (apoptosis) of not
only adult osteoclasts but osteoclast precursors in the bone marrow by
BP.990,991 In the normal bone, in areas of greater stress, the osteoblasts/
osteocytes reduce their secretion of osteoprotegerin, which is a decoy
receptor for the receptor activator of nuclear factor-kappaB ligand
(RANKL). Osteoprotegerin is also known as osteoclastogenesis
183
inhibitory factor and inhibits both differentiation and function of
osteoclasts. The osteoblasts/osteocytes also increase their secretion of
RANKL, so that the area can resorb and re-form to accommodate this
greater stress; an adaptive response.992 If the now-stimulated osteoclast
attempts to resorb this stressed bone that contains a BP, it begins to
do so but dies off before completing the resorption. This disrupts the
resorption-renewal cycle. The osteocytes then succumb to the stress
and die before their usual 180-day life span, or they live out their
life span but are not replaced. The bone may first become sclerotic
(overmineralized), but then it often becomes necrotic and exposed.807
Moreover, an animal study demonstrated that alendronate (a type of
oral BP) inhibited the repair of normal bone microdamage, leading
to the accumulation of microdamage and possible osteonecrosis.993 It
has been hypothesized that as bone remodeling is decreased by BPs, an
infection into the bone exposure site or microcrack area might lead to
a continuous and deeper progression of the inflammatory process and
infection, which are not always observed in peri-implantitis, where
bone resorption exists along with the bone–implant interface. Thus,
when bisphosphonate-related osteonecrosis of the jaw (BRONJ) is
not triggered by peri-implantitis or surgical trauma but developed at
the well-functioning implant, bacterial infection to the microcrack
area in peri-implant trabecular bone might contribute to the en
bloc sequestration of a BRONJ lesion.994 All the above mentioned
mechanisms could presumably interfere with the healing process after
implant placement, and consequently increase the failure rates.
It is important to stress that the differences in the BP therapy also
interfere with the occurrence of osteonecrosis, which may directly
influence the implant survival rates. Considering the different ways of
BP administration, for example, osteonecrosis caused by intravenous
BPs is more prevalent and more severe than osteonecrosis induced
by oral BPs,995 being a result of the immediate uptake and binding
of BPs to bone via the intravenous route, as compared to the oral
route, where less than 0.7% is absorbed through the gastrointestinal
mucosa before it circulates and binds to bone.996 Thus, it can be
said that intravenous BPs load and accumulate in bone at a rate
142.8 times higher than oral BP.807 As none of the studies included
in a meta-analysis on the subject25 provided information about the
evaluated patients taking intravenous BPs, an underestimation of the
184
implant failure rates can exist. Still, the meta-analysis suggested that
BPs affect the implant failure rates.
A second point concerning the BP therapy is that variations in the
chemical molecular structure of the BPs confer different degrees of
potency, with zolendronate being the most potent of the intravenous
BPs and alendronate being the most potent of the oral BPs, therefore
causing the majority of the cases of osteonecrosis of the jaws for
intravenous997 and oral types,998 respectively. The action of a BP also
depends on the drug’s chemical structure. The two main categories
are the non–nitrogen-containing BP and the nitrogen-containing
BP.999 The addition of an amine group to the end of a side chain
increases the drug’s potency.1000
A third point is the fact that the effect of patient compliance
and adherence to their medication regimens is unknown. Evidence
indicates that adherence to BP therapy at 6 months may be less than
50% for both once-weekly and daily dosing regiments.1001 Fourth,
studies involving a retrospective chart review do not usually provide
information regarding the duration of BP usage. This would have
been an important variable to examine, as the absorbed nitrogen-
containing BPs remain bound to their bone targets until they are
released when the bone is resorbed.1002 This limitation prevents one
from stratifying the population of oral BPs users by duration to
analyze the effect of increasing duration on implant failure rate. Fifth,
much of the research in the field is limited by small cohort sizes and
short follow-up periods. The occurrence of osteonecrosis can also
exert some influence on the implant survival rates.994 Some studies
show that effects of BP persist for extended periods, which could
explain why osteonecrosis appears after long-term treatment and
even in cases in which BP treatment was discontinued.1003,1004 This
is some concern because oral BP are intended for ongoing use over
several years in, for example, postmenopausal women. However, it
is hard to define what would be considered a short follow-up period
to evaluate implant failures in patients taking BP.
Concerning MBL, several studies showed that BPs may
not only cause apoptosis of osteoclasts cells, but also inhibit
angiogenesis.990,991,1005,1006 These processes may lead to increased
amounts of avascular and acellular bone that may be less tolerant
to oral bacterial insult and lead to increased MBL.1007 Moreover,
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the microdamage accumulation reduces the mechanical properties of
bone, enhancing the effect of occlusal forces and leading to increased
MBL.993 Although animal studies1008,1009 have shown that BPs may be
useful in minimizing MBL around osseointegrated implants, those
implants were placed in rat tibia. Thus, those findings may not be
directly comparable to results of clinical trials since occlusal forces
and bacterial flora are absent and may not be directly applicable to
humans.
The only meta-analysis assessing the intake of BPs and dental
implants failure rates25 suggested a statistically significant risk ratio
for implant failure (RR 1.73, 95% CI 1.21-2.48, p = 0.003) in
patients taking BP in comparison to patients not taking this class
of medicaments. However, the authors stressed that conclusions are
difficult due to a limited number of published studies,577,947,995,1007,1010-
1020
all characterized by a low level of specificity, and most of them
dealing with a limited number of cases without a proper control
group. Therefore, the real effect of BPs on the osseointegration and
survival of dental implants is still not well established. Still, there
are recommendations for the discontinuation of oral BP therapy for
three to six months prior to implant insertion, and also for several
months following implant insertion, which may allow bone turnover
to recover.1021 It must be pointed out that these results apply to oral
consumption or parenteral administration of BPs and may not be
relevant for BP-coated implants.1022 Abtahi et al.1022 compared the
effects of the local delivery of BP from the implant surface and
the effects of systemic BP on the fixation of dental implants in an
animal study in rats, and observed that local BP treatment appears
to improve implant fixation in a setting where systemic treatment
caused osteonecrosis of the jaw.
It is believed that future controlled studies with a larger number of
patients in the BP group (several studies included far fewer patients
taking BP than patients not taking BP) are required to determine the
real effect of this medicament on the dental implant outcome. Given
the large number of post-menopausal women, and an increasing
number of elderly men, who are being treated for osteopenia or
osteoporosis with BPs medications, whether dental implant therapy
leads to lower survival rates is important information to discuss
with patients during the treatment planning phase.1014 There is
186
also a need to weigh the benefits of a “drug holiday” (a temporary
discontinuation of a bisphosphonate to allow bone marrow recovery
and the formation of new osteoclasts to repopulate the population
that has been depleted by the bisphosphonate807 for implant therapy
against the risk of progression of osteoporosis in the absence of oral
BP therapy.1019
Effects of chemotherapeutic agents

Implant placement in patients after ablative surgery for malignant
disease and benign tumors presents special difficulties. Resection
results in an unfavorable environment for dental implants. Radiation
therapy for treatment of oral cancer further endangers implant
placement.142 Chemotherapy is the third standard treatment method
for cancer patients. All the different antineoplastic agents cause
severe acute side-effects in many tissues, e.g. bone marrow, kidneys,
and oral mucosa (stomatitis/mucositis). As a late side-effect, vascular
cells may be altered and thereby cause malnutrition of the bones.1023
It was also shown that the effect of chemotherapy with cisplatin is a
diminished bone remodeling, especially at implant-host interfaces in
orthopedic surgery.925 However, the real effect of chemotherapy on
the osseointegration and survival of endosteal dental implants is still
not well established, with most of the reports dealing with a limited
number of cases without a control group.
The effect of chemotherapy on the osseointegration and survival
of endosteal implants is not well established, even though it was
shown that the risk of irradiation-induced bone damage is increased
by chemotherapy.923 In the study of Friedlaender et al.,924 the effects
of the chemotherapeutic agents on trabecular bone were quantified
with respect to changes in total bone mass, new-bone formation, and
resorption, in a rat model. Both drugs used in the study significantly
and profoundly diminished bone-formation rates by nearly 60%.
The toxic effect on osteoblasts was also reflected in reduced volume
and thickness of osteoid, but the total numbers of osteoblasts and
the percent of trabecular surface covered by bone-forming cells were
not affected. Young et al.925 investigated the influence of cisplatin
chemotherapy on the bone turnover analyzing bone markers in
a dog model, and their results showed that significant effects of
cisplatin were observed at the site of active cellular induction and
187
proliferation, such as implant-host interface, and fewer effects were
seen at the sites of normal bone turnover. Thus, it is suggestive
that chemotherapeutic agents have an adverse effect on normal
physiological bone turnover, especially osteoblastic activity, and
would also be expected to alter fracture-healing and bone-allograft
incorporation by the same mechanisms.924 In the second publication
of the study, a biomechanical and histologic analysis on the effects of
chemotherapy either pre- or postoperatively, Young et al.1024 observed
that postoperative chemotherapy resulted in less bone formation, but
extracortical capsule formation was not inhibited, while preoperative
chemotherapy did not alter the formation of new bone. Animal
experiments are difficult to translate into a clinical setting, but
formation of peri-implant connective tissue would be detrimental to
the osseointegration of dental implants. In the study of Karr et al.,1025
many patients who have undergone chemotherapy with pre-existing
implants have suffered serious complications and lost multiple
implants. On the other hand, as claimed by other reports, implants
have been successful with chemotherapy treatments before and after
implant placement.1026-1028 However, in the study of Moy et al.,950
data analysis revealed a success rate of 90% (RR = 0.63) in patients
undergoing chemotherapy treatment. Although the sample size for
these patients was small, no significant increase in implant failure
was seen when compared with the healthy population. Moreover, in
three other studies142,896,926 chemotherapy did not have a detrimental
effect on the survival and success of dental implants, even though
implant insertion in these studies was performed at least 6 months
after chemotherapy. It is still unknown whether the time point of
chemotherapy might be decisive. The only meta-analysis on the
subject26 did not show that the implant failure rate was affected by
the fact that the patients were submitted or not to chemotherapy. The
authors concluded that, as there are a limited number of published
clinical series with patients being rehabilitated with dental implants
and submitted to chemotherapy,142,875,879,897,926,942,1029,1030 and most of
them deal with a limited number of cases without a well-defined
control group, the real effect of chemotherapy on the osseointegration
and survival of endosteal dental implants is still not well established.
Considering gender of the patients, women with breast cancer
have an increased risk for osteoporosis because of treatment-
188
induced premature ovarian failure and the direct effects of cytotoxic
chemotherapy.1031 Estrogens limit bone resorption, and decreases in
available estradiol levels can accelerate bone resorption, resulting in
overall bone loss.1032 Clinically significant bone loss may continue
during 2–5 years following chemotherapy, in women who experienced
permanent ovarian failure.1033 Therefore, the long term follow-up is
also important. In the case of men, androgen deprivation–induced bone
loss is a significant clinical concern in patients with hormone-sensitive
prostate cancer receiving long-term androgen deprivation therapy,
which decreases circulating levels of estrogen and testosterone, both
of which maintain bone mass through suppression of bone resorption
and promotion of bone formation.1032,1034 To which extent this may
affect the osseointegration of dental implants is unknown, since a
study assessing the chemotherapy effects on implants taking into
account the patients’ gender is lacking.
Effects of immunosuppressives
Immunosuppressive drugs/agents are drugs that inhibit or prevent
activity of the immune system. They are mainly used to prevent or
reduce the chance of rejection of transplanted organs and tissues,
and to treat autoimmune diseases. Cyclosporin A (CsA) is the most
commonly used immunosuppressant agent for preventing graft
rejection. Its major effect on the immune system is inhibition of T-cell
action and proliferation, thereby altering the T-cell-mediated immune
response. It has also been shown to affect a subset of B cells.1035
CsA has also been associated with deleterious effects upon bone
metabolism.1036 The precise mechanisms underlying the CsA effect
on bone metabolism are still unknown. However, it may be suggested
that CsA affects the immune system by selectively influencing the
lymphokine-monokine cascade and it has been recognized that
cytokines, such as IL-1, are among a number of products of the
lymphokine-monokine cascade that affects bone metabolism.1037
Moreover, it is known that the immune system actively participates
in bone mineral metabolism and that the T lymphocytes play a
critical role in the development of CsA-induced osteopenia.1038 This
is not surprising, as the T cell is the traditional target of CsA and
naturally occurring T-lymphocyte perturbations are implicated in the
development of primary osteoporosis in humans.1038 T-lymphocyte
189
suppression results in a high bone-metabolism state where the bone
formation is supplanted by the bone resorption leading to a decrease
in the trabecular bone volume.1038,1039
In vivo studies observed that CsA administration may result in a
severe high turnover osteopenic state,1040-1042 which is dependent on
both the dose and duration of the therapy.1039 In vitro studies indicate
that CsA inhibits bone resorption and osteoclast formation.1043 Fu
et al.1044 observed an increased osteoclasia in periodontal sites and
reduced bone formation in symphyseal sites in rats exposed to CsA
compared to the controls. Two in vivo studies1045,1046 in a rabbit
model suggested that the administration of immunosuppressive drugs
may negatively influence bone healing around titanium implants.
Moreover, it was observed that the administration of CsA may impair
the mechanical retention of dental implants previously integrated to
the bone.1047
The effects of immunosuppressives on bone metabolism may be
different when there is concomitant use of calcium-channel blockers
(CCB). CCBs have been successfully utilized for the control of CsA-
induced toxicity.1048 A number of clinical and experimental studies
have suggested that the effects of CCBs are not only limited to
the cardiovascular system but might also involve skeletal calcium
metabolism, due to the presence of calcium channels in bone cells.1049-
1051
The results of a study1052 suggested that short-term administration
of CsA, associated with nifedipine, may not influence bone density
in a lateral zone to the titanium implant surface inserted in rabbits.
Gu and Yu1053 published a case series of 13 liver transplant patients
who received 45 implants and were followed up for 3 years, with no
implant losses. They reported that MBL and Periotest values were
within acceptable ranges without bleeding on probing or pathological
probing depth. Montebugnoli et al.1054 published which was probably
the first controlled clinical study in humans. The authors concluded
that the bone response around submerged dental implants in
immunocompromised organ transplant patients (n = 10) does not
differ from that observed in control patients (n = 10). However, the
study had a follow-up of only 3 months. A couple of years later
the authors published further results of the study, now with 3 more
patients in each group and 1 year after prosthetic loading.1055 The
authors came to the same conclusions as in their previous publication.
190
However, even though they had followed the patients for a longer
period, actual follow-up time was limited.
It is a matter of debate whether the implications proposed by the
results of these studies could have some significant clinical impact
on dental implants in human beings in the long run, due to the lack
of long-term controlled clinical studies with a considerable number
of patients regarding the effect of immunosuppressive agents on the
osseointegration process around titanium implants.
Titanium allergy
Various types of metallic and organic materials have been used for
dental prostheses. Some of these materials have been reported to
have pro-allergenic properties.1056 Mercury,1057-1059 nickel,1059,1060
chromium,1061 palladium and cobalt1060,1061 are classic allergens.
When it comes to dental implants, the most commonly used systems
nowadays are manufactured of c.p. Ti.
Titanium implants are covered by a protective adherent oxide
layer, composed primarily of titanium dioxide (TiO2), created upon
exposure to air and biological fluids, which provides pure titanium
and titanium-based alloys with outstanding resistance to corrosion.1062
Nevertheless some corrosion of titanium from oral implants has been
demonstrated.1063 Release and in vivo studies have proven that the
oxide layer can be compromised, and ions and particles are indeed
released from c.p. Ti and titanium alloys into biological fluids and
tissue (Figure 16).1064 Incorporation of other metals in the TiO2
passive layer might weaken the protective properties, and this might
explain the poorer stability of titanium alloys than of TiO2 materials,
and explain the differences in stability between different titanium
alloys despite formation of the oxide layer.1064
191
Figure 16. Leaked out titanium from a clinical implant. Black dots
represent titanium in the implant-near tissues.
Cadosch et al.1065 showed that human osteoclast precursors are able

to grow and differentiate to form mature osteoclasts on titanium
and aluminum, and that the mature cells are able to directly corrode
the metal surface and take up corresponding metal ions, which
may subsequently be released and thereby induce the formation of
osteolytic lesions in the peri-prosthetic bone, contributing to the
loosening of the implant.
Several studies of humans and animals with inserted implants
showed an increased presence of titanium ions in serum,1066-
1069
in surrounding tissue,1070 urine,1067 peri-implant tissues,1070
regional lymph nodes,1071-1073 spleen,1071 adjacent muscle,1071 and
lungs,1071,1073,1074 particularly in combination with loosened implants.
On the other hand, there are studies that found no statistically
significant difference on the increased release of titanium between
test and control human1075,1076 or animal groups,1063,1077-1079 or in in
vitro studies.1080,1081
192
Notwithstanding, whether dental materials comprising titanium
are associated with allergic symptoms is controversial. Titanium is
known to possess good biocompatibility. However, recent studies have
reported cases of allergic symptoms caused by titanium-based dental
materials. For example, Müller and Valentine-Thon1082 investigated the
potential of titanium to induce hypersensitivity in patients chronically
exposed to titanium-based dental or endoprosthetic implants. Fifty-
six patients who had developed clinical symptoms after receiving
titanium-based implants were tested. Although all patients that
were patch-tested accused negative reaction to titanium, these same
patients showed remarkable clinical improvement following removal
of the implants. Moreover, 15 of these patients were retested in the
optimized lymphocyte transformation test (LTT) MELISA and showed
clinical improvement correlated with normalization in MELISA
reactivity. Thomas et al.1083 reported a patient who developed eczema
upon titanium-based osteosynthesis. Patch testing gave no reactions
to titanium or to nickel, chromium, or cobalt. However, in the LTT,
the patient’s lymphocytes showed markedly enhanced proliferation
in vitro to titanium. After removal of the titanium material, fracture
healing was achieved and the eczema cleared. Parallel to this,
in vitro hyperactivity to titanium disappeared.1083 Egusa et al.1084
reported facial eczema in association with a titanium dental implant
placed for a mandibular overdenture supported by 2 implants. The
patient showed positive LTTs index for titanium. LTTs have been
recently validated for metal sensitivity testing, including testing for
titanium hypersensitivity.1082,1085,1086 Complete remission was achieved
by the removal of the titanium material. Sicilia et al.1087 evaluated
the presence of titanium allergy by the anamnesis and examination
of 1,500 patients, together with the selective use of cutaneous
and epicutaneous testing, in patients treated with or intending to
receive dental implants of such material. They observed that nine
patients (0.6%) displayed positive reactions to titanium allergy tests.
Five of these nine patients proved to have suffered some form of
acute reaction, post-implant surgery allergic reaction or short-term
complications, or spontaneous rapid exfoliation of an implant.
Hosoki et al.1056 reported a case that exhibited allergic symptoms
(eczema) after orthopedic surgery. The titanium screws used in the
orthopedic surgery that he underwent were removed 1 year later, but
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the eczema remained. The patient clearly exhibited positive reactions
to many reagents (patch tests), including titanium. After removal
of dental implants, the eczema disappeared completely. Degidi et
al.1088 compared the inflammatory profiles of peri-implant soft tissues
adjacent to either c.p. Ti or experimental zirconia healing abutments
in five human subjects after 6 months of healing. They observed
significant elevations in pro-inflammatory infiltrates (lymphocytes,
plasma cells, and histiocytes), as well as increased expression of
VEGF and nitric oxide synthase isoforms 1 and 3 adjacent to titanium
healing abutments, as compared to zirconia abutments.
Contrastingly, there are studies showing no effect of titanium-
based dental materials on tissue reactions. Barwacz et al.1089 assessed
differences in the pro-inflammatory cytokine and bone metabolism
mediator protein expression in the PICF adjacent to transmucosal
abutments, made of either c.p. Ti or zirconia. No significant differences
in pro-inflammatory cytokine or bone metabolism mediator profiles
were observed biochemically, with the exception of leptin (a protein
that has been demonstrated to induce osteoblastogenesis and inhibit
osteoclastogenesis1090,1091), for the abutment biomaterials of titanium
or zirconia. The authors concluded that the molecular PICF findings
of their study support the observed clinical biocompatibility of
both titanium and zirconia abutments. Moreover, Flatebø et al.1092
histologically evaluated non-perforated mucosa covering submerged
maxillary titanium implants with regard to induced tissue reactions,
and tissue sensitivity reactions to titanium implants were not
disclosed.
Of course that with data from non-experimental studies such
as some of the aforementioned, cause-effect relations cannot be
established, and so the conclusions must be interpreted as hypotheses
to be confirmed later on. Still, the clinical evidence is suggestive,
and some of these clinical studies were supported by in vitro and
laboratorial tests.
It is also important to remember that one component containing
titanium, the TiO2, is one of the most popular pigments in use
today.1093 TiO2 is authorized as a food color in the European Union
(EU) as E 1711094 and is commonly used as a food additive.1095 TiO2 is
used as an additive in a plethora of food groups, such as confectionery
(chocolate products, sweets, candy bars, chewing gum), fine bakery
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wares (cake, pies, pastries, cookies and biscuits), sauces (dressings
and savoury sauces), milk products (cheeses (soft and hard), coffee
creamer and milk powder, ices and desserts, cappuccino, dairy
drinks), drinks (sports and soft drinks, fruit drinks), and cereal
products (popcorn and rice, breakfast cereals).1095-1097 It was observed
that there is a constant intake of nanoparticles TiO2 by humans, and
the products contributing most this are toothpaste (in young children
only), candy, coffee creamer, fine bakery wares and sauces.1098 TiO2 is
also applied in paints, coatings, plastics, papers, inks, drugs, cosmetics
(e.g. sunscreens, creams, lip balm) and toothpaste.1099,1100 Recent oral
studies with TiO2 nanoparticles indicate that these particles can have
toxic effects1100-1102 and repeated oral exposure to these particles may
result in tissue accumulation in the long run.1103 However, there is an
enormous lack of epidemiological data regarding TiO2 nanoparticles
in spite of its increased production and use.1100
Prevalence of allergy-positive reactions against titanium reagents
is far lower than that for other materials such as chromium, mercury,
palladium and nickel. No patient has exhibited an allergy-positive
reaction only for a titanium reagent. In light of this, it can be suggested
that titanium is a relatively safe material that causes allergic symptoms
rarely. However, one must bear in mind that as hypersensitization can
take months or even years to develop,1104 along with the fact of its
infrequency and the uncertainty of its symptomatic expression,1105 it
is difficult to perform deeper studies in this field. As titanium allergy
is barely recognized in the field of implant dentistry, some authors
have suggested that this could just be the very tip of the iceberg, and
advocate further awareness.1106-1108 Possible restrictions deriving from
the use of cutaneous and epicutaneous tests,1085 the fact that some
hypersensitive reactions appear over the long-term and the differences
between cutaneous reactivity and that of other organs,1109,1110 as well
as the potential yet unlikely appearance of immunological tolerance
or non-specific immunosuppression caused by implant degradation
products,1105 may contribute to underestimate the actual prevalence
rate of titanium allergy. Moreover, dental implants have special
conditions that could prevent them from being affected by an allergic
reaction despite developing a cutaneous reaction: the implant–host
contact surface is very limited,1111,1112 the prosthetic structures and
implants are partially isolated by a layer of glycoproteins1113 and the
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bone and oral mucosa have a low reactivity.1109,1110,1113 Last but not
least, it is not entirely known whether the titanium alloys usually used
to manufacture orthopedic implants may have the same reactivity as
c.p. Ti and the titanium alloys usually used to manufacture dental
implants and titanium-based dental materials, respectively.
If the allergy to titanium would be diagnosed in a patient, the
surgeon must then determine whether it is suitable to place a
titanium implant in patients with a positive reaction to it, given the
potential medical and legal complications that could derive from
such a procedure.1087 Some alternative materials could be considered,
such as tantalum,1114,1115 hydroxyapatite,1116-1118 zirconium,1119,1120 or
polyether ether ketone - PEEK.1121
Prosthetic
Crown-to-implant ratio
The crown-to-root ratio is defined as the physical relationship
between that portion of the tooth within the alveolar bone and that
portion not within alveolar bone, as determined by a radiograph.1122
The crown-to-root ratio is determined by dividing the length of the
tooth coronal to the bone by the length of the root that resides in
bone.1123
Dentists use the crown-to-root ratio as an important prognostic
indicator to determine the suitability of a tooth to act as an abutment
for a fixed or removable partial denture. Furthermore, the crown-
to-root ratio is used as a prime indicator of the long-term prognosis
of a given tooth.1124,1125 It extrapolates the biomechanical concept
of a class I lever for evaluating abutment teeth with the fulcrum
lying in the middle portion of the root residing in alveolar bone.
As progressive bone loss occurs, the fulcrum moves apically, and
as a result, the tooth is more susceptible to harmful lateral occlusal
forces.1126 Newman et al.1127 reinforce this by stating that because of
disproportionate crown-to-root ratios and the reduced root surface
available for periodontal support, the periodontium may be more
susceptible to injury by occlusal forces.
The concept of crown-to-root ratio was then extrapolated to the
dental implant field, coining the term crown-to-implant (C/I) ratio.
The ‘‘anatomic’’ crown-to-implant ratio is measured from the bottom
of the fixture to the implant-abutment connection and then from
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that point to the top of the crown. The ‘‘clinical’’ crown-to-implant
ratio is measured from the top of the crestal bone in contact with the
implant to the top of the crown; thus the implant length is measured
from the bottom of the fixture to the top of the crestal bone in contact
with the implant. This is an important difference because of the fact
that an implant of conventional length (>10 mm) may exhibit a large
C/I ratio if the crestal bone has remodeled to a level far below the
implant-abutment connection.1123
From the biomechanical viewpoint, long- and wide-diameter
implants with low C/I ratios provide better peri-implant tissue
stability in the long-term because of favorable distribution of occlusal
forces.218,224,1128 On the other hand, the limited surface area of short
implants with high C/I ratios could be a biomechanical disadvantage
in the long-term because such implants may be less resistant to
detrimental nonaxial occlusal forces.1129-1131 Increased C/I ratio, higher
bite forces, and bone density in posterior area are common factors
that increase stress and may explain the reasons of the higher failure
rates of short implants.1132 Excessive C/I ratios have been reported as
being detrimental to the long-term stability of peri-implant bone and
implant survival,197,1133 and is generally associated with higher stress
values in the peri-implant region.249
However, disproportionate C/I ratios have also been associated
with predictable long-term prognosis. Neither C/I ratio nor
estimated implant surface area (small or large) affected steady-state
crestal bone levels in the study of Rokni et al.1134 that evaluated
partially edentulous patients with implant-supported fixed prostheses
in a follow-up study of almost 4 years. Blanes et al.1135 suggested
that implant restorations with C/I ratios between 2 and 3 may be
successfully used in the posterior areas of the jaw, a 10-year follow-up
study. Contrary to what would be expected according to the
biomechanical viewpoint, Blanes et al.1135 found a positive correlation
between increasing crown-to-implant ratios and increasing first BIC
levels over 1 year. Higher clinical crown-to-implant ratios showed
lower average bone loss when compared with lower crown-to-
implant ratios. This may be attributed to the design of the non-
submerged implants, the clinical crown-to-implant calculations, or
the fact that most of the restorations were splinted.1123 Schulte et
al.1136 observed that the crown-to-implant ratios of those implants
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that were in function were similar to those implants that failed. The
results of the study of Birdi et al.1123 suggest that a C/I ratio of 2.0:1
and even greater can produce a stable favorable outcome. However,
this study had a mean follow-up of only 20.9 months. Urdaneta
et al.1137 observed that larger C/I was associated with a significant
increase in prosthetic complications but had no significant effect on
crestal bone levels on single-tooth locking-taper implants. According
to a review,1138 a higher C/I ratio could be considered a risk
factor for some mechanical complications of implant-supported
rehabilitations as screw loosening, porcelain fractures loosening
of maxillary anterior crowns, fractures of 2-mm-wide implant
abutments supporting single crowns in posterior areas,697,1137 but an
increased C/I ratio cannot be considered a risk factor for biological
complications around dental implants and implant failure.1138 Sun et
al.1139 observed in patients who had been treated with single Astra
implants for replacement of missing premolars and molars that the
higher C/I ratio and anatomical crown length did not increase the risk
of peri-implant MBL during 6 years of functional loading. Instead,
they noticed that higher anatomical crown lengths are associated
with higher technical complications, the same as observed in other
studies.1140,1141 It has been hypothesized that implant restorations with
high anatomical crown length overload the prosthetic components,
which increase the risk of technical complications such as screw
fracture, screw looseness, loss of retention, and veneering fracture.1139
In a study with extra-short implants,1142 there was a significant
positive correlation between bone loss and crown height space,
but not between MBL and the crown-to-implant ratio. A possible
explanation for this is that an increase in crown length from 10 to
20 mm will increase the occlusal forces on an implant by 100%.1143
Moreover, a crown height space higher than 15 mm has been reported
as unfavorable and to result in higher stress concentrations at the
bone-implant interface.1140,1141
Number of implants per patient

One may hypothesize that placing multiple implants requires
more mucoperiosteal stripping, compromising blood supply, more
operating time, and more contamination of the wound, all of which
may contribute to the increased complication rate.1144 Only few
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clinical studies corroborate this hypothesis. Smith et al.1144 studied
313 implants, and the univariate analysis of risk factors showed
that the number of implants placed per patient did correlate with
implant failure. The patients receiving from 4.1 implants had a
greater probability of having failures than the patients receiving
until 2.2 implants (p = 0.016). Naert et al.202 studied the outcome of
1,956 implants, and according to their results, the higher the number
of implants a patient has, the higher the hazard rate (p = 0.005).
Increasing the number of implants by one increases the hazard rate
0.14 times. However, there are also examples of studies in which the
number of lost implants was independent of the number of implants
placed per patient.53,1145
Prosthetic rehabilitation type

Several studies observed statistically significant difference in the
implant failure rates between implants used to support different
prosthetic configurations, being overdentures versus fixed full-arch
prostheses, favoring fixed prostheses,235 overdenture versus fixed
partial prostheses, favoring fixed prostheses,372 overdentures versus
all types of fixed prostheses (single-tooth, partial, full-arch), favoring
fixed prostheses,1146-1148 overdentures versus fixed full-arch bridges,
favoring fixed prostheses (but only in the maxilla),1149 overdentures
versus all types of fixed prostheses, favoring overdentures and
full-arch fixed prostheses,1150 and single- versus multiple-implant
supported fixed prostheses, favoring single-tooth prostheses. 376
Many studies did not observe statistically significant differences in
the implant failure rates between implants used to support different
prosthetic configurations, being fixed prosthesis versus single-tooth
restorations,52 single crowns versus fixed partial prosthesis,202
overdenture versus fixed full-arch prosthesis,1151 single- versus
multiple-implant supported fixed prosthesis,577 and all-ceramic
versus metal-ceramic implant-supported single-tooth restorations.1152
Generally speaking, it is difficult to say which type of prosthetic
restoration type would be better than the other, since several
influencing factors may play a role in the implant failure rates.
One of the important decisions in implant prosthodontics is the
choice of the connection type of the final restoration to the implant
via the screw-retained abutment. The restorative connection can
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be either screw- or cement-retained. Four controlled studies1153-1156
evaluated the differences in the clinical outcomes between cemented
versus screw-retained implant restorations, and all 4 observed no
statistically significant difference in implant failure rates between the
two techniques. Concerning MBL, three of these four studies compared
MBL between cemented and screw-retained implant restorations.
Nissan et al.1153 observed that the mean MBL was statistically
significantly higher (p < 0.001) for screw-retained (1.4 ± 0.6 mm) than
for cemented (0.69 ± 0.5 mm) restorations. Crespi et al.1156 found no
statistically significant differences in MBL between cemented versus
screw-retained implants restorations, the same in the study of Vigolo
et al.1155 at the 10-year follow-up appointment.
Occlusal versus non-occlusal loading

Within immediate loading, two types of have been described in the
literature. One is the immediate functional loading, or immediate
occlusal loading, which refers to the use of a temporary or definitive
prosthesis seated the same day as the surgery in occlusal contact with
the opposing arch.1157 The other one has been proposed to modify
the immediate temporary restoration to avoid occlusal contact in
centric and lateral excursions, in order to reduce the early risks of
mechanical overload caused by functional or parafunctional forces,
the immediate nonfunctional loading, or immediate non-occlusal
loading.1158 Thus, the modified restoration would still be involved in
the chewing process, but the mechanical loading stress is reduced.1159
Chrcanovic et al.13 tested the null hypothesis of no difference in the
implant failure rates between these two procedures in a meta-analysis.
The results showed that the procedure used (nonfunctional versus
functional) did not significantly affect the implant failure rates (RR
0.87, 95% CI 0.44, 1.75; p = 0.70).
The idea behind the concept of keeping temporary restoration
out of occlusion is to control the load on the prosthesis in order to
allow undisturbed healing. The role of tongue pressure and perioral
musculature may be an underestimated factor in immediately
provisionalized but non-loaded implants. Moreover, occlusion might
not be the only determinant of implants survival1160 because there
was no statistically significant difference between the immediate
nonfunctional loading and immediate functional loading. The
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increase of load, applied to the prosthesis caused by the presence
of the normal occlusal contact, seems to be unable to jeopardize or
alter the healing process of the implant.1159 Some factors may have
contributed to this outcome in some studies: the use of a resilient
acrylic resin for the fabrication of the temporary restoration, the
exclusion of parafunctional bruxist patents, and the splinting of the
temporary prosthetic work.
Prosthodontist experience/skill/judgment
The experience of the surgeon may affect the survival rates of
implants, and the same is true for the experience of the prosthodontist
performing the restorative part of the dental implant rehabilitation.
The construction of an inadequate implant-supported restoration,
which could be a result of an oral prosthetic rehabilitation conducted
by a less experienced and less skilled prosthodontist, among other
factors, might jeopardize the implant long-term survival. It has been
suggested that the passiveness of the framework fit, for instance,
may have an influence on implant failures and/or delayed component
failure.233,300,1161-1163 Passive fit is supposedly one of the prerequisites
for the maintenance of the bone-implant interface. To provide passive
fit or a strain-free superstructure, a framework should, theoretically,
induce absolute zero strain on the supporting implant components
and the surrounding bone in the absence of an applied external
load.1164 However, there is no longitudinal clinical study that reports
implant failure specifically attributed to framework misfit. Moreover,
first, it is hard to tell what level of misfit is clinically important,
beyond which damage is likely to occur, and second, passiveness
of a framework is not an easy task to measure it in a clinical
situation.1165 And yet, although more recent procedures such as laser
welding, framework cemented on prepared abutments and other
methods have minimized the misfit of structures on implants,1166,1167
an absolute passive fit cannot be obtained.1168
Another factor to consider is the establishment of a balanced
occlusion, which is, in most part, verified, controlled and corrected
by the prosthodontist. The application of an external load on an
implant-supported prosthesis induces stresses within the entire load-
bearing system and stress reactions in the supporting bone which
are theoretically the same in magnitude, but in opposite directions.
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During clinical loading of an implant, the direction of forces almost
never coincides along its central long axis, providing an absolute axial
loading. On the contrary, the occlusal force is applied at different
locations and frequently, in a direction that creates a lever-arm, which
causes reacting forces and bending moments in the bone.1169,1170 This
bending moment is the force times the orthogonal distance between
the force direction line and the counter-acting support. The longer
the distance, the greater will be the bending moment.1171 Accordingly,
the fraction of force transmitted to implants and the induced stresses
are dependent particularly on where the load is applied on the
prosthesis.1172,1173 Hence, it is of paramount importance that the
prosthodontist do not overlook a non-balanced occlusion, i.e. do
not neglect to establish an equilibrium between acting and counter-
acting forces.
The aforementioned conditions are hypothetical situations in which
the prosthodontist could negatively influence the implant-prosthetic
rehabilitation work, and most of the studies assessing the influence
of the experience of the practitioner on the implant survival concern
the dentists who surgically place the implant, not the prosthodontist.
The only one, perhaps, to somehow address the issue of the influence
of the prosthodontist on implant clinical performance was Bryant.1174
He observed that the crestal bone loss during the first to fourth year
of loading and after the first year of loading, and the estimated crestal
bone level at 10 years after loading among prosthetic sites varied with
differences in the dentist who placed the first prosthesis.
There are, however, some studies correlating the prevalence of
restorative complication in implant-supported prostheses with
the experience of the professional performing the restorative part
of the treatment. Wang et al.,1175 for example, found a correlation
between screw loosening in single-implant crowns and operator
experience (measured by number of implants restored during the
study period), with more experienced operators suffering fewer
screw-loosening complications. They also observed that increased
operator experience is associated with reduced food packing and
contact point complications.
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Surgeon
Some studies have assumed that the operator skill and/or experience
is of importance for achieving high implant success rates and that
a learning curve does exist for dental implant therapy.452,1176-1178
However, this subject is not without controversy, and a significant
association of ‘experienced surgeon-less implant failures’ was not
verified by all studies. Melo et al.1179 found no statistically significant
difference in implant survival rates among oral and maxillofacial
residents of different levels of training. However, the authors stressed
that this observation may be due to the fact that more complicated
cases were assigned to surgeons with more experience in implant
surgery. Another study456 observed that clinical experience had no
significant impact on implant survival, at least not on the basis
of multivariate analyses. The authors suggested that a significant
difference in favor of inexperienced surgeons based on univariate
methods could be explained by the fact that the more challenging
cases with poor bone quality and/or quantity had been treated by the
academic staff; whereas, standard cases had been usually treated by
clinicians-in-training. Considering the assumption of no difference
in the implant failure rates between beginners and experienced
surgeons, what could possibly be influencing the difference in failure
rates between different surgeons?
The surgeon’s experience

Weyant1180 showed that the surgeon’s experience was associated
with implant health; as a provider’s experience grows, the likelihood
of peri-implant soft tissue health problems decreases. A study1176
comparing treatment outcomes in implant therapy between surgeons
with a minimum of 2 years implant experience and surgeons just
beginning involvement in implant techniques observed that the
surgeon’s experience had a major impact on the failure probability of
unloaded implants. The authors suggested that the loading conditions
and the design of the prosthesis may be the decisive determinants for
the probability of success with loaded implants, but also pointed out
that it is likely that implant positioning, angulation, and technique
will affect the result for the entire lifespan of the restoration.1176
Moreover, the authors observed that the surgeons’ learning curve
showed that after 2 years of function, the probability of success
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of the prosthesis remained constant, which might be biased since
increased experience might have caused the operator to adopt a
more selective approach toward prosthodontic solutions. Lambert
et al.1177 observed that implants placed by inexperienced surgeons
(<50 implants) failed twice as often as those placed by experienced
surgeons (> or = 50 implants). Similar results were observed by
Morris et al.1178 Ji et al.452 reported in their study that the implant
failure rate for 2 surgeons with >5 years of surgical experience was
2.4% (2 of 85 implants), whereas the remaining 18 surgeons, that is,
those with ≤5 years of surgical experience, incurred an implant failure
rate of 12.2% (26 of 212 implants). On the other hand, Morris et
al.941 noticed an only slightly greater survival for implants placed by
the more experienced dentists in their study, evaluating more than
2,600 implants followed up for 3 years. Melo et al.1179 found no
statistically significant difference in implant survival rates among oral
and maxillofacial residents of different levels of training. However,
the authors stressed that this observation may be due to the fact
that more complicated cases were assigned to surgeons with more
experience in implant surgery. Another study456 observed that clinical
experience had no significant impact on implant survival, at least not
on the basis of multivariate analyses. The authors suggested that a
significant difference in favor of inexperienced surgeons based on
univariate methods could be explained by the fact that the more
challenging cases with poor bone quality and/or quantity had been
treated by the academic staff; whereas, standard cases had been
usually treated by clinicians-in-training.
There is also a relationship between procedure volume and clinical
outcomes. Although surgical volume is less important for simple
procedures, it might be for complex procedures. Procedure volume
may be linked to other delivery factors associated with surgical
outcomes, but it has been assumed that volume is important in
large part because it serves as a proxy for operative proficiency.1181
A study1182 examined mortality rates for 12 surgical procedures of
varying complexity in 1,498 hospitals to determine whether there
is a relation between a hospital’s surgical volume and its surgical
mortality, and observed that hospitals in which 200 or more of
these operations were done annually had death rates, adjusted for
case mix, 25 to 41% lower than hospitals with lower volumes. The
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results may reflect the effect of volume or experience on mortality, or
referrals to institutions with better outcomes, as well as a number of
other factors, such as patient selection. Another study1183 examined
the relations between operative mortality and surgeon volume and
hospital volume (each in terms of total procedures performed per
year), with adjustment for characteristics of the patients and other
characteristics of the provider. The study results showed that the
surgeon volume was inversely related to operative mortality for all
eight procedures assessed.
A systematic review on the subject31 found only 8 studies reporting
and comparing implant failure rates between groups of (relatively)
more and less experienced surgeons. In the first meta-analysis
performed in the study, including four retrospective comparative
studies that defined experienced professionals as specialists, the
experience of the surgeon did not significantly affect the implant
failure rate (OR 1.24, 95% CI 0.62, 2.48; p = 0.54). In the second
meta-analysis, including two retrospective studies that defined
experienced surgeons as those professionals that had placed more
than 50 implants, the expertise of the surgeon did significantly affect
the implant failure rates (OR 2.18, 95% CI 1.40, 3.39; p = 0.0005).
However, based only on the results on this study it is not possible to
state that the insertion of dental implants by experienced surgeons
would result in a lower risk of implant failures in comparison to non-
experienced surgeons, due to a limited number of published studies.
A recent clinical study194 (Study VII) assessed the influence of
several factors on dental implant failure prevalence, with special
consideration on the placement of implants by different dental
surgeons. Only the data of patients and implants treated by surgeons
who had inserted a minimum of 200 implants at one clinic were
included. The differences between the survival curves of each of the
10 eligible surgeons were statistically significant. The surgeon with
the highest absolute number of failures was also the one who inserted
most implants in sites of poor bone and used turned implants in
most cases, whereas the surgeon with the lowest absolute number
of failures used mainly modern implants. There were statistically
significant differences in cumulative survival when separate survival
analyses of turned and modern implants were stratified for the
individual surgeon. The study also identified the surgeon among the
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statistically significant factors affecting the implant survival rates
when a binary logistic regression analysis was performed using a
GEE method.
The surgeon’s skills

Besides the procedure volume and experience of the surgeon, the skill
is another important factor to take into consideration. A considerable
body of research suggests that some surgeons have better results than
others, with some studies showing wide variation in risk-adjusted
patient mortality across surgeons.1181,1184,1185 To quote an example, a
study assessing the influence of the surgical skill on the complications
rates after bariatric surgery1181 observed that the technical skill of
practicing bariatric surgeons varied widely, and greater skill was
associated with fewer postoperative complications and lower rates
of reoperation, readmission, and visits to the emergency department.
Surgical skill was strongly related to procedure volume, but not
related to years in bariatric surgery practice, status with respect to
completion of a fellowship in advanced laparoscopy or bariatric
surgery, or practice at a teaching or nonteaching hospital.
In many procedures, the technical skill of the operating surgeon
may be an important determinant of the outcomes.1186 A high
level of surgical skill may be essential in preventing intraoperative
problems, such as failure to properly maintain or use equipment and
instruments that may compromise drilling precision. If an imprecise
implant site is prepared or if tapping procedures are excessive,
initial implant stability and subsequent osseointegration may be
compromised. A bony dehiscence or defect may occur as a result of
implant placement too facially or lingually. Moreover, an excessive
countersinking may result in the loss of a superior cortical bone plate
to stabilize the implant. The failure to preserve keratinized gingiva
was even mentioned as a factor, as it may compromise maintenance
of peri-implant tissue health in the long-term.1187 Because failure to
osseointegrate can, in part, be related to imprecise surgical technique,
it follows that these complications are more likely to occur after
operations performed by less skilled surgeons.
The impact of stress on the surgeon’s skill must also be considered.
According to Renouard et al.,1188 everyone will, at one time or another,
experience the negative impact stress can have on their capacity to
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perform a procedure or deliver a treatment to the best of their ability.
Moreover, in the event of acute stress, people may regress mentally
and completely lose their ability for rational decision-making.1189-1191
The surgeon’s judgment

It is important to take into consideration some facts concerning
the observed statistically significant difference in implant failure
rates between some surgeons in the study of Chrcanovic et al.
(Study VII).194 The success of a technique depends on careful and
scrupulous adherence to the prescribed clinical protocol by the
combine surgical-prosthodontic team. The surgeon might be addicted
to bad/bold habits and bad choices, as for example, risk too much in
inserting implants in and/or choosing patients with sites with poor
bone quantity/quality. The level of complexity of cases treated by
different dentists may vary, and some professionals may be more
willing to take more risky cases. The surgeons may overestimate their
ability to execute a complex or high-risk procedure.347,1174,1188 There
are some categories of behavior that are frequently cited to increase
the likelihood of one or more complications occurring during the
implementation of a procedure, and such behaviors are also relevant
in the dental/medical field and may make the surgeon less careful.1192
In the study of Chrcanovic et al.194 (Study VII), a separate analysis
showed a far unequal distribution of implants placed in sites of
poor bone (bone quantity D/E, bone quality 4) among the surgeons.
The surgeon with the highest absolute number of failures was also
the one who mostly inserted implants in sites of poor bone. It was
suggested that one of the most important factors responsible for
implant failures is probably the local anatomic structure regarding
bone quality and quantity, or rather the lack thereof.776 Clinicians
may embark on a particular course of treatment to address a complex
case despite less-than-ideal conditions from a patient safety point
of view.1188 Some surgeons might have had considerable experience
with some implant systems but not with other systems. Moreover,
some surgeons used old implants more often than other surgeons,
but this is also related to the fact that some surgeons inserted more
implants on the 1980’s and 1990’s. Modern implants having an
enlarged surface had a statistically significant lower probability to
fail in comparison to turned implants. It has been shown that the
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osseointegration process is influenced by several factors, among
them the surface texture.1193,1194 There is supportive evidence for
a positive relationship between an improved bone healing around
implants and its surface roughness,1195 which enhances the process
of osseointegration. However, it is also important to note that the
group of turned-surface implants had statistically significant longer
mean follow-up time than the group of enlarged surface implants,
which can lead to an increase in the failure rate.
Unfortunately, it was not possible for Chrcanovic et al.194 (Study
VII) to assess implant survival based on dentist experience in implant
surgery, as this information was not archived in the records. Dentists
from the specialist clinic where the study was based on come with a
diverse background; some enter the specialist training program after
only 2 years of working in general practice after leaving the dental
school (minimum requirement to enter a specialist program in the
country), whereas others come from a long private dental practice.
It is important to remember that Chrcanovic et al.’s194 study includes
implants placed as long ago as 1980, and some of the surgeons
are already retired. It was not possible to know for every surgeon
whether the initial implants placed for each of them occurred at
the clinic in particular, and how many implants were placed outside
the clinic. Moreover, some surgeons with less experience might have
had more opportunity to gain additional experience than those with
more experience, i.e. those with less experience might have put more
implants after a couple of years than the more experienced surgeons.
Another important issue is the fact that the experience of the surgeon
may be masked by that of the restorative dentist. With the existing
data forms, the particular experience of each surgeon was difficult
to ascertain, and any conclusions regarding experience drawn from
these data must be considered with caution in mind. However, if
one hypothetically assumes that the surgeons analyzed would have
the level of experience, and assuming all other factors equal, the
variations in the failure rates could be, in part, explained by the
surgeons’ skill and/or judgment.194
Cluster behavior of failures

Results of some studies indicated that implant failures are commonly
concentrated in few patients, rather than to be evenly distributed
208
among all treated patients.776,1196-1200 Implant failures are not randomly
distributed in all patients and a cluster behavior can occur.1198 Cluster
was once defined as more than one implant failure per patient, not
necessarily in the same area or quadrant.1199 As such, these failing
patients have been described as “cluster patients,” and even though
they have seemingly been observed in a randomized pattern, it is
reasonable to assume that the patient with failing implant has certain
individual characteristics that separate them from the more successful
implant patients,1198 i.e. these implant loss clusters happen in specific
high-risk groups and individuals.1201
One recent study193 (Study VIII) analyzed the cluster behavior of
dental implant failures among patients and assessed the possible risk
factors influencing this phenomenon. Only patients receiving at least
three implants were included. There were 1,406 patients with three
or more implants, totaling 8,337 implants, with 592 implant failures.
Sixty-seven (4.77%) of these patients were identified as presenting
cluster behavior, who received 620 implants, of which 331 failed.
The 67 cluster patients had a mean implant failure rate of 53.4%
(range 20-100%), and they presented 56% of all failures in the study.
Twelve patients lost all their implants. The intake of antidepressants
and bruxism were identified as potential negative factors exerting a
statistically significant influence on a cluster behavior at the patient-
level. The negative factors at the implant-level were turned implants,
short implants, poor bone quality, age of the patient, the intake of
medicaments to reduce the acid gastric production, smoking, and
bruxism. The authors concluded that a cluster pattern among
patients with implant failure is highly probable. Factors of interest
as predictors for implant failures could be a number of systemic
and local factors, although a direct causal relationship cannot be
ascertained.
It is important to stress that some patients should have been treated
differently than what was done in the first place. Grafting procedures
might have been advantageous in the cases with poor bone quantity
and quality that displayed large number of failures. Parameters that
can be available before the surgical and prosthodontics treatment
would certainly be of importance to identify information to allow
a careful discussion regarding risks and problems prior to surgery,
and also to allow for measures to be taken to reduce the risk by, for
209
example, choosing other surgical or prosthodontic techniques.1198
The indication for the use of oral implants should sometimes be
reconsidered when alternative prosthetic treatments are available
and when possibly multiple interfering systemic or local factors are
identified.
210
ON REASONS FOR MARGINAL BONE
LOSS AROUND ORAL IMPLANTS
MBL around oral implants has been recognized as a potential

problem for long time survival of the implant. Therefore, it was
natural to include a MBL parameter in the criteria for success of
oral implants presented in 1986.919 With respect to MBL as handled
in those criteria, a successful implant must display less than 0.2 mm
annually of MBL following the implant´s first year of service. The
reason why the authors did not include MBL during the first year
in their criteria was the fact that knowledge from the first year was
lacking in the then available clinical material due to the fact that
Brånemark did not endorse radiograms during the initial phase of
implant incorporation. In a publication from 1993, an acceptable
MBL during the first year was considered to be 1 mm accumulated.187
The traditional theory of reasons for marginal bone loss

The success criteria described by Albrektsson et al.187,919 were behind
what was regarded as a dangerous MBL by author such as Roos-
Jansåker et al.1202 and Fransson et al.1203 These authors in their initial
reports accepted 1.8 mm of MBL1202 or three threads of MBL1203 but
deemed larger bone loss as pathological if coupled to bleeding on
probing and pus on probing. With these definitions they regarded
6.6%1202 or 12.8%1203 of all placed Brånemark implants followed up
over respectively 9-14 years and 5 to 20 years to suffer from a disease
entitled peri-implantitis. With time the same authors, then using more
liberal criteria for pathological MBL, reported between 18 and 43.3%
of all implants to suffer from peri-implantitis. A consensus report1204
211
reported that peri-implantitis is an infectious disease, which affects
the supporting bone as well as the mucosa. Mucositis occurs as a
response to bacteria, originating either from surgical contamination
during implant placement or from a later occurring infection. The
bacteria will secondarily lead to marginal bone resorption. In parallel
to the clinical studies, experimental investigations with ligatures were
conducted.1205 Albouy and co-workers1206-1208 performed a series of
experimental studies with ligatures placed around commercially
available implants. The ligatures provoked progressive bone
resorption and were then removed. Whereas turned implants
spontaneously saw no further bone resorption after ligature removal,
the other commercially available implants nevertheless saw continued
MBL. The investigators then mechanically cleaned the implants and
were able to stop further bone resorption around two of the tested
implants, but not around the third type of implant that had a porous
surface structure allegedly more difficult to clean mechanically. One
may certainly question the clinical relevance of such ligature studies,
but they remain one mode of investigating MBL.
The studies by Roos-Jansåker et al.1202 and Fransson et al.1203 have
been criticized for making pathology of MBL that in many cases
may spontaneously stop without really resulting in risk of implant
loosening. Jemt et al.7 reported of the long term fate of the allegedly
sick implants in the Fransson et al.1203 study when analyzed a further
9.1 years after the completion of the original 5-20 year clinical
follow up study. Jemt et al.7 reported that 91.3% of the allegedly
sick implants had seen no significant further bone resorption and
that 95.4% of the implants were still clinically functioning, thus
questioning the actual clinical problems with the majority of the
implants suffering from peri-implantitis. Coli et al.712 have questioned
the use of Bleeding on probing and probing depth around implants
in the diagnosis of MBL. Albrektsson et al.1 questioned the high
rates of reported disease. Based on 10 different 10-year studies of
modern implants, only 1-2% of the implants had problems with MBL
and the authors concluded that peri-implantitis is not as common
as previously reported, at least if properly controlled oral implant
systems are used by trained individuals.
212
The immunologically based theory behind
marginal bone loss
During the first decades of using osseointegrated titanium implants,
the general concept was that titanium implants worked very well
and were incorporated into bone in the manner of a simple wound
healing. However, this theory has not been supported by biomaterials
research; instead the titanium implant is perceived by the bodies as
a foreign element and osseointegration represents the body´s defense
mechanism in encapsulation of the foreign material.5,40-42,44,1209,1210
This means that when the osseointegration of an implant is
threatened, immunological reactions are likely to participate in the
process. In fact, a recent PhD thesis of orthopedic implants analyzed
the reason for what orthopedic researchers have called aseptic
loosening of implants. The aseptic loosening was found to be caused
by immunological reactions, with evidence of both an innate and
adaptive immune response as incriminating agents.1211 Landgraeber
et al.1212 mainly believed in innate immune system reactions.
According to the immunologically based theory, the initial reason
behind MBL is due to immunological reactions, but this does not
necessarily prevent that bacteria play a role in the bone response as
well.788 There are principally three different theories concerning the
role of interfacial bacteria; that they merely represent a secondary
opportunistic colonization,1213 that they recruit the same bone
resorbing cells as those recruited by immunological agents788 or that
the bacteria themselves are perceived as foreign elements leading to
activation of the bone response.5
The immunologically based theory has been criticized by those
who believe that Periodontitis around teeth and peri-implantitis
around implants are similar forms of disease. However, recent
evidence speaks strongly against this suggestion.815 Furthermore,
Cecchinato et al.840 reported that teeth and implants in the same
patient did not see bone resorption simultaneously; if teeth displayed
bone resorption implants showed a steady state situation of the
marginal bone and alternatively if implants lost bone, then teeth had
a steady state marginal bone status. In only 3% of analyzed cases,
did the investigators see simultaneous bone resorption around teeth
and implants.
213
FRACTURE OF IMPLANTS
Knowledge regarding the types of complications that can occur in

dental implant oral rehabilitations is an important aspect of the
post-treatment care. Among the mechanical complications, implant
fractures offer a challenging situation because of their functional,
restorative, surgical, and emotional implications.1214 Implant fracture
is the most catastrophic failure of implant components because it
usually causes the loss of the implant and prosthesis.1215 Fortunately,
they do not occur as frequently as abutment screw or prosthesis gold
screw fractures.190,1216 (Study IV included) Implant fractures were first
described by Brånemark et al.,38 who reported on 13 fractured of a
total of 1,618 osseointegrated implants. Chrcanovic et al.195 observed
a 0.40% implant fracture rate among more than 10,000 implants.
The prevalence in several studies altogether is reported to be around
1.0-1.5% according to two review papers,1214,1216 mostly when older
Brånemark implants were considered. However, one study of 157
ITI implants (Straumann AG, Waldenburg, Switzerland) that were
followed up for a mean of 40 months reported a 1.9% fracture
rate.1217
Several factors have been implicated as potential causes of implant
fracture.
(a) Bending overload. Bending overload is defined as the load on

an implant-supported prosthesis that exerts a bending moment on
the fixture cross-section at the crestal bone level, leading to MBL
and/or implant fatigue fracture.1218 The mechanism of fracture
has a multi-factorial etiology; when number, position, dimension,
design of implant and restoration are inadequate to the site needing
214
rehabilitation, the situation of bending overload is present and an
initial bone loss around the implant begins.1219 If no correction of the
prosthesis is introduced, the coronal screws become soon exposed
and a crater-like appearance of the surrounding bone is observable.
At this time, the coronal portion of the implant represents a locus
minoris resistensiae (i.e., a site of lesser resistance), being the implant
internally filleted and consequently extremely thin, upon which
overstress promotes the creation of numerous micro-fractures that
can result,1220-1223 after a variable time range, in a complete fatigue
fracture. Ideally, implants with internal abutment connection should
be more suitable to this complication.1219
Previous case series and reports, involving investigations of
fractured implant surfaces, revealed fatigue striations1214,1215,1219,1221,1224
consistent with those obtained in vitro when implants were cyclically
loaded to fracture.1221 An interesting case is the one from Capodiferro
et al.,1219 who performed an accurate analysis of a removed fractured
implant both by stereomicroscopy and making a three-dimensional
reconstruction by confocal laser scanning microscopy. The histological
evaluation of the peri-implant bone showed no signs of peri-
implantitis or fibrous integration of the implant. After removal of the
bone, the fracture surface presented the typical features of the fatigue
fracture observed by other studies using fractography with scanning
electronic microscopy - main transversal fracture surface with a
variable number of fatigue striations indicating the advancement of
the crack front under cycling loading.53,1225,1226 Moreover, numerous
surface irregularities were also detected on the roots of the screw
thread of the well-osseointegrated apical portion of the implant,
which the authors defined as microfractures or cracks of the apical
portion of the implant despite adequate osseointegration.1219 This
would suggest that bending overload and resultant fatigue failure to
be the usual mode of fracture of an implant.1227
(b) Restoration design. Cantilever design bridges increase the stress

upon an implant, and have been found to be associated with fractured
implants,1221,1224,1225,1228,1229 even though fractured fixtures have also
been reported to occur more frequently in single implant supported,
single unit restorations.1224,1225,1229-1232 Implant fractures associated
with a combined dento-implant supported restoration have also been
reported.1214,1225,1233,1234 In addition, an implant supporting a bridge
215
has a smaller tendency to fracture than an implant supporting a
removable prosthesis.1196
(c) Accuracy of fit of restoration. Stress caused by screw joint

connections to the implants from an ill-fitting prosthetic framework
may result in constant shear load on the implant, predisposing it to
fracture. Frequently, loosening of the screw(s) on the supraimplant
component precedes implant fracture and may be a warning sign
that the framework needs re-evaluation.1228 Some studies have shown
implant fracture in partially edentulous fixed prostheses particularly
with older, less passively fitting prostheses.300,1235-1237
(d) Number of implants, positioning. A higher incidence of implant

fractures has been reported in fixed partial dentures supported by
only 2 implants.232,1238-1241 Theoretical models suggest the effects of
loading on implant supported restorations to be significantly reduced
by the placement of additional implants, the use of wider platform
fixtures and the avoidance of implants being positioned in a straight
line.1224,1225,1242 In a survey by Rangert et al.,1225 most fractured
implants occurred in single or double implant–supported restorations
in posterior partially edentulous jaws where occlusal loads were
higher. Thus, it was suggested that implant fixed partial dentures be
supported by 3 implants placed in a tripod alignment to minimize
stress and torque distribution.1225,1241 The proximity of the molar to
the temporomandibular joint creates a mechanically unfavorable
situation because of the high magnitude of force transmission. In
a similar sense, the molar has a larger occlusal table than premolar
or anterior teeth. The larger occlusal surface, supported by a single
implant, will create forces that are not in line with the long axis of the
implant. These tipping forces may lead to chronically high, complex
force patterns that contribute to implant fracture.1224
(e) Marginal bone loss. Implant fractures have been associated with
increased MBL.1214,1221,1224,1225,1228,1230,1231 According to a review on
clinical complications of implants,1216 most fractures of implants
reported in the literature occurred between the third and fourth
implant thread, which corresponds to the last thread of the abutment
screw.1243,1244 Bone resorption exceeding three threads in the apical
direction will expose the weaker portion of the implant apical to the
abutment screw engagement, which may become the fulcrum for the
216
loading, and thus contributes to an overload of the implant.1225,1245
This may particularly be the case in fixtures whose design features
incorporate a significant void in this region.1230-1232 It has been
shown in an animal study that craterlike bone loss will occur around
implants with excessive dynamic loading690 and this loss of bone
support will allow flexing of an implant under loading and possibly
contribute to a fatigue stress fracture. Moreover, any significant bone
loss at the crestal level increases the unsupported coronal length of
the implant, increasing the crown to implant ratio, resulting in the
fixture becoming more at risk to bending forces.1227 Morgan et al.1221
analyzed the surface of in vivo fractured implants and compared to
new titanium implants fractured in the laboratory under monotonic
and cyclic loads. The researchers concluded that the failure mechanism
was fatigue and that the failures were associated with MBL, which
was thought to have been induced by overload before the fracture
occurred.1221 Implant fracture involves progressive fatigue failure until
the implant lacks adequate strength to maintain integrity, culminating
in a catastrophic failure. During the progression of the fracture
process, it is possible that an infective process may be involved in the
observed pattern of bone loss, i.e. when an implant begins to fracture,
it becomes secondarily infected which causes the accelerated MBL. In
the former situation, bone loss is an etiologic factor for the fracture,
while the latter instance would have the fracture causing bone loss.1224
It is unclear whether MBL is a cause or an effect of implant fracture,
or if they are both consequences of unfavorable loading.1224,1225
(f) Bruxism. Implant fracture has been associated with parafunction.

A parafunctional occlusal habit can contribute to the potential
overload, as load magnitude, duration, frequency, and direction
are increased by such activity. Six of the eight fractured implants in
the study of Balshi1228 supported posterior prostheses and all eight
fractured implants occurred in patients with parafunctional habits.
The results of the clinical study of Chrcanovic et al.190 (Study IV)
suggest that bruxism may be an important contributor to the rate of
mechanical complications in implant-supported restorations, as well
as for a higher prevalence of implant fracture. The study compared
groups of bruxers and non-bruxers having the same number of
patients (n = 98) with the same total number of implants (n = 427)
equally distributed between them. Bruxers presented 16 fractured
217
implants, whereas non-bruxers did not present any case of implant
fracture. In another study, specifically assessing implant fractures,
Chrcanovic et al.195 observed that bruxism was one of the factors
presenting a statistically significant influence on the prevalence of
implant fractures, according to a multivariate GEE statistical model.
(g) Chemical factors. Titanium implant components adsorb hydrogen

in the biological environment and it has been suggested that this makes
them more brittle and prone to fatigue.1223 Hydrogen embrittlement
of titanium is associated with the formation of a brittle hydride
phase.1246 Amongst the factors that determine the service life of a
titanium device for medical use may therefore be the rate of hydrogen
absorption in the device and the rate of diffusion of hydrogen in the
alloy.1247
(h) Implant composition. In the study of Eckert et al.,1224 all of the

fractured implants were made from c.p. Ti grade 1. The use of a
different implant material provides a higher threshold for fatigue
failure, since fatigue appears to have some relationship with the tensile
strength of the implant material.1248 Because c.p. Ti is ductile and the
implant will thus bend, it is not possible to fracture a c.p. Ti implant
in situ with just one loading cycle. With repeated load, however,
the material may start to develop internal microcracks, which may
increase in size with the number of load cycles. The fatigue strength
determines the capacity for withstanding such repeated loads.1225
The fatigue strength of grade 1 c.p. Ti is practically independent
of its tensile strength.1249 The tensile strength may be increased by
work hardening to surpass the minimum strength specified for grade
3, but this has limited influence on the long-term fatigue behavior.
Such strength increases have practical consequences only over a small
number of loading cycles, and thus have little clinical significance.
The most effective way of increasing clinically relevant implant
strength, based on a grade 1 c.p. Ti implant, is therefore to increase
its diameter.1225
It may sound strange that different grades of c.p. Ti may be subject

to different fracture percentages, bearing in mind that all c.p. Ti
consists of about 99.7% of titanium. However, the fact is that the
remaining 0.3% of constituents is of clear importance for the strength
218
of the material, particularly if the iron contents increase which is the
case for higher grades of titanium. One of the major commercial
companies used only titanium grade 1 until the latter part of the
1990s when, finally, the change to grade 4 occurred with due higher
strength of their implants.
MBL and mechanical failure of the restorative components (i.e.,
frequent loosening and/or fracturing of prosthetic screws) should
be considered as warning signs.1214,1228 Several methods have been
reported to try to decrease the risk of implant failure1225,1228: reduction
of cantilever use, narrowing of buccolingual width/mesiodistal length
of the teeth, flattening the cuspal inclination, centering the occlusal
contacts, using additional implants with larger diameters, occlusal
guard treatment in patients with parafunctional habits, and insertion
of implants not in a straight line.
Different treatment alternatives have been suggested for implant
fractures. The least invasive approach is to leave the apical portion
embedded in bone either following the patient’s informed decision
or when retrieval of the implant may compromise the integrity
of adjacent vital structures (i.e., proximity to inferior alveolar
canal).1214 Another option is to flatten the head of the implant and
make it smooth to simulate the surface of the original implant face,
retapping the internal abutment screw thread and placing a longer
abutment connector, followed by the necessary modifications of the
prosthesis.1220,1250 The latter option should be considered only as an
emergency procedure in the transition to a more permanent solution,
since the crown-to–implant body ratio can be considerably altered,
offering a more complex biomechanical challenge; while creating
a butt joint repair between the fractured portion and the newly
connected abutment, microleakage and the lack of antirotational
features may further compromise the surrounding bone integrity.
The third and presumably the most common option would be the
removal of the fractured implant,226 using a trephine drill to core out
the bone to three quarters of the length of the implant. An elevator
is then used to fracture the most apical integration. A long healing
abutment is threaded in the remaining internal threads and lifted out
with forceps. The site may be tapped to receive a wider implant, or
following a suitable period of healing, usually 3 to 6 months, a new
implant can be placed.
219
CONTRAINDICATIONS
FOR IMPLANTS
It has been suggested that some local and systemic factors could
represent contraindications to dental implant treatment.1251-1254
Several factors have been implicated as contraindications of implant
surgery. Sugerman and Barber1251 suggested that conventional
dentures or fixed partial prostheses may be preferable to dental
implants in growing and epileptic patients and patients at risk of
oral carcinoma, anaphylaxis, severe hemorrhage, steroid crisis,
endocarditis, osteoradionecrosis, myocardial infarction, or peri-
implantitis. Hwang and Wang1253 suggested that the absolute
contraindications for dental implants include recent myocardial
infarction and cerebrovascular accident, transplant or valvular
prosthesis surgery, profound immunosuppression, severe bleeding
issues, active treatment of malignancy, drug abuse, psychiatric illness,
as well as intravenous bisphosphonate use. However, there is little or
no evidence to support most of these contentions.1255 Here follows
a discussion about some of these conditions that were suggested as
contraindications for treatment with oral implants.
(a) Bleeding disorders. In patients with bleeding disorders,

hemorrhage associated with implant surgery is more common and
may be prolonged,1256 particularly if the patient is taking warfarin
or acenocoumarol, both anticoagulants that function as vitamin
K antagonists. The treatment of a patient suffering from classical
hemophilia with repeated surgical session; for ankylosis of the right
temporomandibular joint, for bilateral sagittal split procedures,
for extraction of teeth, and for placement of implants1257 provides
220
some evidence to support the placement of implants in patients with
bleeding disorders. The important fact here to consider is that the
patient was prepared medically on each of the surgical occasions with
factor VIII replacement concentrate as well as oral antifibrinolytic
therapy (tranexamic acid). However, Gornitsky et al.1257 did not
provide information on the follow-up of the patients. Bacci et al.1258
evaluated the incidence of bleeding complications following surgical
implant therapy in a group of 50 consecutive patients receiving
oral anticoagulant therapy (warfarin) without interruption or
modifications of their therapy. The authors observed no statistically
significant difference in the bleeding risk between these patients and
109 other patients not taking anticoagulants. They concluded that
local hemostasis in dental implant surgery is capable of preventing
bleeding complications in patients on oral anticoagulants, allowing
these surgical procedures to be performed on an outpatient basis.
Again, the authors did not provide information on the follow-up of
the patients after the placement of the implant-supported prosthesis.
There is no evidence that bleeding disorders are an absolute
contraindication to oral implant surgery, although these patients
may be at risk of prolonged hemorrhage and blood loss.1255 In face
of the low number of publications focusing on this issue, with no
information on follow-up, the impact of bleeding disorders on the
long-term implant survival may be considered unknown.
(b) Bone diseases. There are only few reported cases of oral
implant placement in patients with osteogenesis imperfect,1259-1265
polyarthritis,1266-1268 or ankylosing spondylitis.1269 With only few cases
described in the literature, there is little evidence to suggest whether
these osseous diseases could affect implant survival or not. Thus,
there is no sufficient material to say whether these conditions would
be contraindication to oral implant surgery or not.
Two retrospective clinical trials1270,1271 assessed implant
outcomes in patients suffering from autoimmune rheumatoid
arthritis with or without concomitant connective tissue diseases.
A high implant survival rate was noted with follow-ups of 3 and
3.5 years, respectively. Patients with isolated rheumatoid arthritis
demonstrated acceptable marginal bone resorption and good soft
tissue conditions, while patients with rheumatoid arthritis and
concomitant connective tissue diseases showed increased bone
221
resorption. Although two clinical trials were published on the subject,
they are both from the same research group, and most of the patients
included in the studies are very probably the same ones.
Another bone condition to consider is osteoporosis. According
to a review, the evidence for an association between osteoporosis
and implant failure was low.1272 Several clinical trials in humans
have focused on the subject.810,1017,1273-1278 In general, results from
the studies led the authors to suggest that oral implant therapy in
patients suffering from osteoporosis is a reliable treatment option
with comparable integration rates as in healthy patients. Thus,
osteoporosis would not be considered as a contraindication for dental
implants. For more details on osteoporosis and the possible effect
on dental implants, see “Results and Discussion”, section “Health”,
sub-item “Patient’s sex” of the present thesis.
(c) Intravenous bisphosphonate (BP) use. The possible effects of the

use of bisphosphonates on the oral implant survival were already
discussed in the “Results and Discussion” of the present thesis. A
few number of patients rehabilitated with oral implants and being
under intravenous administration of BPs have been reported in the
literature,1279,1280 with no implant failures recorded. However, as the
cases consisted of only a couple of patients, there is no strong clinical
evidence to allege complete security of these medicaments under
parenteral administration. It has been observed that osteonecrosis
caused by intravenous BPs is more prevalent and more severe
than osteonecrosis induced by oral BPs.995 A higher prevalence of
osteonecrosis with the use of intravenous BPs could presumably
interfere with the healing process after implant placement, and
consequently increase the failure rates. Therefore, it is suggested
that the use of intravenous BPs might be a relative contraindication
for the placement of oral implants. For a deeper discussion on
the subject, see “Results and Discussion”, section “Health”, item
”Pharmaceutical reasons for implant problems”, sub-item “Effects
of bisphosphonates” of the present thesis.
(d) Corticosteroid therapy. Steroids, also called corticosteroids, are

anti-inflammatory medicines used to treat a range of conditions,
such as asthma, rheumatoid arthritis, inflammatory bowel disease
and autoimmune diseases.1281 Steroids do not tend to cause
222
significant side effects if they are taken for a short time or at low
doses. Long-term corticosteroid use may be associated with more
serious sequelae, which includes osteoporosis, increased epithelial
fragility and immunosuppression, among many other side effects.1282
As such, it has been suggested that the chronic use of systemic
glucocorticoids might compromise oral implant osseointegration
and peri-implant healing.1283 Therefore, corticosteroids have been
cited as a contraindication for placement of implants in the jaws.1284
However, only few studies have actually evaluated the association
between corticosteroid therapy and oral implants. Werner et al.1285
assessed the effect of dexamethasone on the first stages of the post-
implantation reparative process in rats. The extension of osteogenic
peri-implant response was greater in dexamethasone -treated animals
than in controls. Fujimoto et al.1284 evaluated the effects of steroid
administration on the osseointegration of c.p. Ti implants in an in vivo
study in rabbits. They observed no significant difference in removal
torque of the implants placed in the mandible between prednisolone-
treated group of rabbits and a control group, besides no significant
correlation between the bone density of the femur and the removal
torque of the implants placed in the mandible. Moy et al.950
retrospectively analyzed risk factors associated with the outcome of
4,680 implants placed in 1,140 patients. A logistic regression analysis
indicated that steroid therapy was not associated with a significant
increase in implant failure. Bencharit et al.1283 reported a case of a
patient with polymyalgia rheumatica, under chronic treatment with
systemic glucocorticoids and treated with oral implants. There were
no clinical problems after one year of follow-up. Shibuya et al.1286
retrospectively analyzed risk factors associated with the outcome of
619 TiUnite implants. A logistic regression analysis identified that
a history of steroid treatment, among other factors, was significant
predictors of implant failure. Due to the limited number of studies
on the subject, there is no clear evidence that corticosteroid therapy
is a contraindication to treatment with oral implants.
(e) Head and neck cancer patients. Radiotherapy can significantly

affect the dental implant failure rates.24 It is suggestive that
treatment with implants can be a contraindication in patients during
radiotherapy, just before or in the few months after it, in patients
who received or are planned to receive irradiation doses above 65 Gy,
223
and in patients showing sign and symptoms of osteoradionecrosis.
For a deeper discussion on the subject, see Chapter “Results and
Discussion”, section “Health”, sub-item “Irradiation” of the present
thesis.
(f) Alcoholism. Bone metabolism is affected by alcohol consumption

because alcohol inhibits osteoblast proliferation. However, there
is no clear evidence in the literature that alcoholism might be a
contraindication to the placement of oral implants, although the
literature is suggestive that alcoholic patients may be at increased
risk of complications. For a deeper discussion on the subject, see
Chapter “Results and Discussion”, section “Patient’s Habits”, sub-
item “Alcoholism” of the present thesis.
(g) Diabetes mellitus. Diabetes is a chronic disease that occurs when

the pancreas does not produce enough insulin, or when the body
cannot effectively use the insulin it produces. It has been suggested
that the relative contraindication for implant surgery is related to the
stability of the diabetic’s blood sugar level. However, there is still no
clear evidence that diabetes is a contraindication to treatment with
oral implants. For a deeper discussion on the subject, see Chapter
“Results and Discussion”, section “Health”, sub-item “Diabetes
mellitus” of the present thesis.
(h) Cardiovascular disease. Some forms of cardiovascular disease

(hypertension, atherosclerosis, vascular stenosis, coronary artery
disease, and congestive heart failure) may impair the healing process,
which depends on oxygen supply delivered by a normal blood flow.
However, several studies suggest that cardiovascular diseases may
not be a risk factor for dental implants. Khadivi et al.1287 conducted
a retrospective study including 246 patients, of which 39 patients had
some type of cardiovascular diseases, 109 patients had a history of
other systemic disease, and 98 patients were healthy. The study found
no statistically significant differences in implant failure rates between
the groups, and the authors concluded that cardiovascular diseases
may not be a risk factor for successful osseointegration. Several other
studies observed that the presence of cardiac problems and/or the
intake of antihypertensive drugs did not affect the implant failure
rates (Studies III, V and VIII included).161,191,193,942,944,945,950,965,1288 Wu
et al.159 observed a higher survival rate of dental implants among
224
users of antihypertensive drugs compared to nonusers. There is no
clear evidence in the literature that cardiovascular diseases or the
intake of antihypertensive drugs might be a contraindication to the
placement of oral implants. Patients with cardiac problems should,
however, receive careful supervision of bleeding time, as many of
these patients usually take blood thinners or antithrombotic agents
(antiplatelet drugs, anticoagulants, thrombolytic drugs). Moreover,
cardiovascular events such as recent myocardial infarction, stroke, and
cardiovascular surgery, might represent an absolute contraindication
to implant therapy.1253 Due to the high risk of complications following
a myocardial infarction or cerebrovascular accident, the surgeon
must wait until preliminary stabilization before the performance of
an elective oral implant surgery.1253
(i) Hyposalivation. Sjögren’s syndrome is probably the most common

cause of hyposalivation. Sjögren’s syndrome is a chronic autoimmune
disorder of the exocrine glands with associated lymphocytic
infiltrates in the affected glands. Involvement of the salivary glands
results in progressive dryness of the mouth, difficulties with chewing,
swallowing and speech, reduced oral clearance, and a shift in oral
flora.1289 As Sjögren’s syndrome is associated with several oral
problems,1290 one has raised the question whether patients with
this condition might be contraindicated to receive oral implants.
Nevertheless, several case reports and small case series reported
the use of dental implants in patients with the condition,1270,1291-1300
reporting excellent clinical results. Albrecht et al.1301 investigated
prevalence and patient-reported outcomes of dental implants in
patients with Sjögren’s syndrome. A total of 5 of 104 (4.8%) implants
in the patients with the syndrome and none of the 14 implants in
the controls had to be removed. A total of 75% of the patients were
highly satisfied with the implants and 97% would recommend them
to other patients with Sjögren’s syndrome. Korfage et al.1302 performed
a cohort study of well-classified patients with Sjögren’s syndrome
(n = 50) and its possible association to oral implants clinical outcomes.
The researchers observed that peri-implant health was reasonably
good in syndromic patients with minor MBL and a peri-implantitis
prevalence of 14%, comparable with healthy controls. Despite the
fact that a worse oral functioning was associated with more dryness
complaints, lower patient satisfaction, and worse subjective chewing
225
ability, the implant survival rate reached 97% (4 out of 142 implants
failed) after a median follow-up 46 months. All the studies support
the idea that the syndrome is no contraindication for the treatment
with oral implants.
(j) Immunocompromised patients. It has been suggested that

patients taking immunosuppressive drugs/agents might have some
impairment of bone metabolism, which in theory could have some
negative influence on osseointegration. For a deeper discussion on
the subject, see “Results and Discussion”, section “Health”, item
”Pharmaceutical reasons for implant problems”,sub-item “Effects
of immunosuppressives” of the present thesis.
There are few clinical studies evaluating oral implants outcomes
in patients who are immunocompromised. Most of them deal with
the acquired immune deficiency syndrome (AIDS), a spectrum of
conditions caused by the infection of components of the human immune
system such as CD4+ T cells, macrophages and dendritic cells by
the human immunodeficiency virus (HIV). Stevenson et al.1303
investigated the short-term clinical outcome of implant placement in
a group of HIV-positive and HIV-negative individuals who required
complete dentures, and the success rate was 100% for both groups.
There was also no difference in clinical outcome (presence of pain,
mobility, soft tissue status, and radiographic bone level) between
the groups. The limitation of this study is the short term follow-up,
of only 6 months. Oliveira et al.1304 evaluated the 12-month after
loading success rate of 59 dental implants placed in patients who
were HIV-positive and were receiving different regimens of highly
active anti-retroviral therapy, as the same time as comparing those
patients with a control group of other HIV-negative patients. The
study showed very similar results between the groups, regardless of
CD4+ cell count, viral load levels and type of antiretroviral therapy.
Once again, the limitation of this study was its short term follow-up.
Gay-Escoda et al.1305 retrospectively assessed 9 HIV-positive subjects
treated with 57 dental implants, with a mean follow-up time of 77.5
months. The implant survival was 98.3%, and the patients that
attended regular periodontal maintenance visits had significantly
less mean bone loss than non-compliant patients (1.3 mm and 3.9
mm respectively). Gherlone et al.1306,1307 examined the associations
between the success of implant-prosthetic treatment and systemic
226
CD4+ level, smoking habits, and oral hygiene. The authors concluded
that placement of dental implants in HIV-positive patients with stable
disease seems a reasonable treatment option, regardless of CD4+ cell
count, provided that they are in a normal range. The follow-up was
of only 12 months. May et al.1308 investigated the 5-year clinical
outcome of 33 oral implants in 16 patients diagnosed with AIDS.
The study found a slightly higher failure rate of 10% in patients
with AIDS than the previous clinical trials on the same subject,
probably due to a longer follow-up. There are in the literature other
reports of oral implant treatment in HIV-positive subjects, mostly
consisting of few or isolated case reports,1309-1317 all showing good
clinical outcomes. Thus, HIV-positive patients do not apparently
have any contraindication to receive oral implants, provided that
the disease is controlled. However, longer follow-up studies including
more patients are necessary to add more clinical evidence.
Another condition that causes immunodeficiency is Crohn’s
disease, a type of inflammatory bowel condition that may affect
any part of the gastrointestinal tract from mouth to anus. Crohn’s
disease is characterized by the presence of many antibody-antigen
complexes, leading to autoimmune inflammatory processes in
several parts of the body, which in theory could as well occur at the
interface with biocompatible implants, but which could in Crohn’s
patients be recognized as non-self, thus affecting the outcome of the
implant treatment.942 The study of van Steenberghe et al.,942 which
had three patients with Crohn’s disease, with two of them having
implant failure (3 out of 10 implants) and one patient having no
implant failure (0 out of 3 implants). However, both patients with
early failures, suffered from other medical conditions. Alsaadi et al.944
observed 11 of 12 oral implants placed in patients with Crohn’s
disease in their retrospective study integrated successfully. There is
low level of evidence to suggest any contraindication or not of the
use of oral implants in patients with Crohn’s disease.
There are some case reports of successful implant placement in
patients with Papillon-Lefèvre syndrome,1318-1324 a rare autosomal
recessive disorder, which oral manifestations include rapidly
progressive periodontal disease resulting in premature exfoliation of
primary and permanent dentitions. However, many of these patients
presented in these publications were followed up for only one year.
227
Only two cases1325 of oral rehabilitation using oral implants were
reported in patients presenting Chediak-Higashi syndrome, a rare
genetic immunodeficiency disorder that arises from a mutation of
a lysosomal trafficking regulator protein, which leads to a decrease
in phagocytosis. The decrease in phagocytosis results in recurrent
pyogenic infections. Most patients present severe periodontal disease
with an unfavorable prognosis. The two cases presented good clinical
results, but with only one year of follow up.
(k) Neuro-psychiatric disorders and disabilities. Case reports and

clinical series have shown good clinical outcomes with implant-
supported oral rehabilitations in patients with cerebral palsy,1295,1326-
1328
Down syndrome,1295,1327-1329 autism,1329 psychiatric disorders,1330
dementia,1327 intellectual disability,1331 mental retardation,1295,1328,1329
bulimia,1332 Parkinson disease,1333,1334 epilepsy,1328,1329,1335 and multiple
disabilities.1329,1335 However, it is important to stress that poor oral
hygiene, oral parafunction habits such as bruxism, harmful habits
such as repeated introduction of the fingers into the mouth and
behavioral problems are not uncommon in patients with neuro-
psychiatric diseases, and oral implants in such patients may lead
to complications.1255,1328 Therefore, patients with neuro-psychiatric
diseases might be relatively contraindicated to receive oral implants.
Medical advice is highly recommended in these cases,1330 and the
success of the oral rehabilitation in patients with neuro-psychiatric
diseases will depend fundamentally on the appropriate patient
selection.1331 The course of the disease, patient condition, quality
of life and life expectancy must be taken into consideration before
adopting a treatment with oral implants in this kind of patients.1336
Implants can be successful if these patients are given continuous
professional support.1295 There exist no apparent biological reasons
for patients with most of the above disorders to lose implants.1253
However, one state where implant placement is not recommended is
in a patient unable to comprehend and anticipate dental treatment
logically.1253
(l) Titanium allergy. Titanium allergy is an absolute contraindication

for implants manufactured with alloys containing this metal, provided
that is properly proven that a patient is allergic. Titanium allergy is
deeply discussed in the “Results and Discussion” of the present thesis,
section “Health”, sub-item “Titanium allergy”.
228
(m) Oral mucosal diseases. Several case reports and clinical series
evaluated the outcomes of oral implant treatment with four
mucosal diseases, namely ectodermal dysplasia, epidermolysis
bullosa, oral lichen planus, and Sjögren’s syndrome. They show
that implant survival rates in patients with these conditions are
comparable to those of patients without oral mucosal diseases.
Sjögren’s syndrome is discussed somewhere else in this chapter.
Ectodermal dysplasia is not a single disorder, but a group of
syndromes all deriving from abnormalities of the ectodermal structures.
It is a hereditary condition in which hypodontia is the second most
frequently occurring sign. Hypodontia is associated with lack of
development of the alveolar ridge and results in less volume of bone
for support of conventional prostheses. Minimal development of the
alveolar ridge can affect the bone volume available for the placement
of dental implants.1337 Several cases reports and clinical series of oral
rehabilitations with implants in patients with ectodermal dysplasia
have been reported,1333,1337-1352 usually with high survival rates. The
implant failure rates in children and adolescents, however, tend to be
worse than in adults.1342,1345
Epidermolysis bullosa represents a group of mainly hereditary skin
disorders, manifested by an exceptional tendency of the skin and
mucosa to form bullae and vesicles after minor friction and trauma.
Oral features include repeated blistering, scar formation, elimination
of buccal and vestibular sulci, and alveolar bone resorption.1353 There
are several case reports and clinical series of successful implant
placement in patients with epidermolysis bullosa.1353-1362 The main
reported complication during the implant surgical procedure was
the formation of bleeding blisters by minimal trauma. During the
follow-up period many patients also developed ulcers in the areas
of prosthesis contact, but these complications did not affect the
successful implant outcome.
Oral lichen planus is an inflammatory disease of the oral mucosa
with pathognomonic changes seen both in the epithelium and the
subepithelial layer of connective tissue. Implants penetrate the oral
mucosa into the alveolar bone to which they osseointegrate. The
epithelial attachment forms the barrier that separates the infected
oral environment from the internal tissues. It has been postulated that
oral lichen planus may directly alter the nature of the barrier affect,
229
jeopardizing the long-term success of the implants.1363 Moreover,
Langerhans cells and keratinocytes, in the oral lichen planus lesions
up-regulate the pro-inflammatory response by increasing interleukin-2
and interferon-ϒ secretion.1364,1365 These cytokines have an important
role in local bone resorption1366 and may lead to alveolar bone loss
around the implants. The studies evaluating oral implant outcomes in
patients with oral lichen planus1363,1367-1370 usually showed very high
implant survival rates.
Final remarks on contraindications. The impact of many oral and

systemic conditions on the outcome of implant therapy is still
unclear.1251,1255 Dental management of the medically compromised
patient requires acquisition of a complete health history of the
patient. This should include documentation via questionnaire as well
as a verbal history.1371 It seems like the medical control of the disease
is more important than the disease itself.1255 It is important that
the patient’s surgical risks should be weighed against the potential
benefits offered by the dental implant.1372
230
CONCLUSIONS
From the studies included in the present thesis, it can be concluded

that:
1. After a systematic review of the literature, it may be suggested

that the following situations may increase the implant failure
rate: a low insertion torque of implants that are planned to be
immediately or early loaded, inexperienced surgeons inserting the
implants, implant insertion in the maxilla, implant insertion in the
posterior region of the jaws, implants in heavy smokers, implant
insertion in bone qualities type III and IV, implant insertion in
places with small bone volumes, use of shorter length implants,
greater number of implants placed per patient, lack of initial
implant stability, use of cylindrical (non-threaded) implants and
prosthetic rehabilitation with implant-supported overdentures.
Moreover, it may be suggested that the following situations may
be correlated with an increase in the implant failure rate but with
a weaker association than the factors listed above: use of the
non-submerged technique, immediate loading, implant insertion
in fresh extraction sockets, smaller diameter implants. Some
recently published studies suggest that modern, moderately rough
implants may present with similar results irrespective if placed
in maxillae, in smoking patients or using only short implants
(Study I);
2. The systematic review of the literature with meta-analyses

suggested that the insertion of oral implants in smokers affects the
implant failure rates, the incidence of postoperative infections, as
well as the marginal bone loss (Study II);
231
3. Smoking and the intake of antidepressants are suggested to
be potentially influencing factors to the occurrence of implant
failures up to the second-stage surgery - abutment connection
(Study III);
4. Bruxism may significantly increase both the implant failure

rate and the rate of mechanical and technical complications of
implant-supported restorations (Study IV);
5. The intake of proton pump inhibitors may be associated with

an increased risk of oral implant failure (Study V), but not so
the intake of selective serotonin reuptake inhibitors (Study VI);
6. Different levels of failure incidence of oral implants could be

observed depending on the individual surgeons, occasionally
reaching significant levels. Although a direct causal relationship
could not be ascertained, it is suggested that the surgeons’
technique, skills, and/or judgment may influence the oral implant
survival rates (Study VII);
7. A cluster pattern among patients with implant failure is highly

probable. Shorter implants, turned implants, poor bone quality,
younger patients, the intake of antidepressants and of proton
pump inhibitors, smoking, and bruxism were identified as
suggested potential factors exerting a statistically significant
influence on the cluster behavior of dental implant failures (Study
VIII);
8. Most of the implant failures occur at the first years after

implantation, regardless of a very long follow-up. Implants in
different jaw locations, irradiation, and bruxism were the factors
suggested to affect the survival of implants. Marginal bone
loss can be insignificant in long term observations, but it may,
nevertheless, be the cause of secondary failure of oral implants
in some cases (Study IX).
232
ACKNOWLEDGEMENTS
I would like to express my sincere gratitude to everyone who

contributed in one way or another to the progress and completion
of this work. This thesis would not have been possible without all the
inspiring and generously supporting people around me. In particular
I wish to thank:
Professor Tomas Albrektsson, my main supervisor. There are not

enough words to express my deep and sincere gratitude for your
guidance, all the great scientific discussions, encouragement and your
invaluable endless support. Indeed, your commitment, supervision
and passion towards my PhD training are untold. Thank you very
much.
Professor Ann Wennerberg, my supervisor. Indeed there are not

enough words to express my deep and sincere gratitude for your
expertise guidance, remarkable and tireless support, encouragement
throughout my entire time as a doctoral student, and for always
believing in me. Thank you very much.
My profound appreciation goes to Övertandläkare Doctor Honoris

Causa Jenö Kisch, who I had the opportunity and pleasure to meet,
have some good laughs, and research with at the Specialisttandvård
Malmö, Folktandvården Skåne AB. Without you this work would
not have been accomplished. Thank you very much.
233
Professor Björn Klinge for the friendly atmosphere and your support
as a co-supervisor, as well as for the help in getting access to some
databases.
My colleagues PhD students, dentists and nurses of the Department of

Prosthodontics, Faculty of Odontology, Malmö University. And the
administrative and service staff of the Faculty of Odontology, Malmö
University. Thank you all for your invaluable support, comments,
encouragement and friendship.
VD Marika Qvist, Vice VD och Forsknings- och utvecklingschef Ewa

Ericsson, Enhetschef Kristoffer Alin, Övertandläkare Björn Gjelvold,
the dentists and nurses, and the administrative and service staff of the
Folktandvården Skåne AB, for their generous support and friendship.
Finally
My beloved wife Aleksandra and my precious son Nathan for your
love, understanding, support, encouragement and patience for my
work. I treasure your presence in my life.
And my parents for your endless love, care and support.
This work was supported by research funds from the Oral Health
Related Research by Region Skåne (Odontologisk Forskning i Region
Skåne, OFRS 414321), Sweden, and from the Scientific Research
Council of Sweden (Vetenskapsrådet, Dnr 2015-02971). This work
was supported by Folktandvården AB, Region Skåne, Sweden and
by CNPq, Conselho Nacional de Desenvolvimento Científico e
Tecnológico, Brazil.
234
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345
PAPERS I-IX
347
Journal of Oral Rehabilitation
Journal of Oral Rehabilitation 2014 41; 443--476
Review
Reasons for failures of oral implants
B. R. CHRCANOVIC*, T. ALBREKTSSON*† & A. WENNERBERG* *Department of
Prosthodontics, Faculty of Odontology, Malm€o University, Malm€o, and †Department of Biomaterials, G€oteborg University, G€oteborg,
Sweden
SUMMARY This study reviews the literature implant insertion in places with small bone
regarding the factors contributing to failures of volumes, use of shorter length implants, greater
dental implants. An electronic search was number of implants placed per patient, lack of
undertaken including papers from 2004 onwards. initial implant stability, use of cylindrical (non-
The titles and abstracts from these results were threaded) implants and prosthetic rehabilitation
read to identify studies within the selection with implant-supported overdentures. Moreover,
criteria. All reference lists of the selected studies it may be suggested that the following situations
were then hand-searched, this time without time may be correlated with an increase in the implant
restrictions. A narrative review discussed some failure rate: use of the non-submerged technique,
findings from the first two parts where separate immediate loading, implant insertion in fresh
data from non-comparative studies may have extraction sockets, smaller diameter implants.
indicated conclusions different from those possible Some recently published studies suggest that
to draw in the systematic analysis. It may be modern, moderately rough implants may present
suggested that the following situations are with similar results irrespective if placed in
correlated to increase the implant failure rate: a maxillas, in smoking patients or using only short
low insertion torque of implants that are planned implants.
to be immediately or early loaded, inexperienced KEYWORDS: dental implants, failure, associated
surgeons inserting the implants, implant insertion conditions, systematic review
in the maxilla, implant insertion in the posterior
region of the jaws, implants in heavy smokers, Accepted for publication 8 February 2014
implant insertion in bone qualities type III and IV,
ory of poor surgery would be that this is noted in the

Introduction
clinical records at the time of implant placement. This
Implant failure may be of a primary or secondary nat- is seldom the case. Instead, the poor surgery explana-
ure. In addition, marginal bone loss around oral tion is made retrospectively, perhaps in the lack of
implants may continue and create a secondary failure other evidence. In reality, we do not know why some
(Fig. 1). It is commonly difficult to assess the proper implants fail primarily but fortunately the frequency
reason for implant failure. For instance, in the case of of such failures is small, in the range of 1–2% in most
primary failures, that is, those implants that never os- clinical reports. Another substantial controversy
seointegrate, an alleged reason for the observed fail- relates to the reason for marginal bone loss, which
ure is overheating/poor surgery. However, from a may end in clinical failure. In the recent literature, it
strict scientific point of view, there is little evidence has been assumed that an alleged primary disease
incriminating poor surgery as the cause of primary entitled peri-implantitis is the original reason behind
failures. A minimal demand for believing in the the- marginal bone loss around oral implants (1, 2). Some
© 2014 John Wiley & Sons Ltd doi: 10.1111/joor.12157

444 B . R . C H R C A N O V I C et al.
failure under subheadings such as surgical, location,

patient, implant, prosthetic and other conditions. In
the major, systematic part of our review, we have
scrutinised comparative studies (with test and control
situations) to present an attempt to a deeper under-
standing of failure mechanisms. However, as the great
majority of clinical studies relate to turned, machined
implants, this approach presented with some limita-
tions with respect to understanding failure mecha-
Fig. 1. Failure of oral implants.
nisms of our present times when such implants have
been largely replaced by modern, moderately rough
devices. We have therefore added a narrative review
authors have even suggested that any marginal bone of the outcome of such modern implants alone. This
loss after the first year of clinical function must latter part of the paper is not based only on test and
depend on peri-implantitis (3). No <8 different defini- control situations as such an approach would have
tions exist of what is to be regarded as peri-implantitis resulted in the inclusion of too few studies. Even if
(4). In reality, the entire discussion about peri- the quality of the evidence in the first, systematic part
implantitis as a primary disease is probably miscon- of our review is greater than found in the latter nar-
ceived (5–7). The reason for onset of marginal bone rative review, we regarded the inclusion of some
loss around implants is in all probability dependent older papers of now withdrawn implant systems as
on a complication to treatment, not on disease phe- well as more recent publications on modern implants
nomenon. Infection and similar problems around oral to be important in our aim to present an as updated
implants is a secondary, not a primary phenomenon version of failure analyses as is possible.
(7). Marginal bone loss has been demonstrated to be
initiated by poor clinical handling, use of poor
Materials and methods
implant designs or by treating complicated patients.
At a later stage patient disease, rapidly changing load-
Objectives
ing situations or reactions to cement particles acciden-
tally embedded in the soft tissues represent other The purpose of this study is to review the literature
reasons for start of bone loss. Having said this, such regarding the factors contributing to failures of osseo-
conditions left untreated may secondarily result in integrated endosseous dental implants. The aetio-
aggravated bone resorption and peri-implantitis pathogenesis of failing/failed implants was evaluated
further complicating the clinical picture. Osseointegra- in relation to clinical findings. The following questions
tion is nothing but a foreign body response, and were raised and will be evaluated: What are the main
long-term clinical function is dependent on tissue factors that may exert influence on the failure of
equilibrium (7). endosseous dental implants? How these influences
Secondary failure of an oral implant is in the great possibly affect the osseointegration?
majority of cases preceded by marginal bone resorp-
tion, hence the importance of understanding the
Data source and search strategies
background to it. Chvartszaid et al. (8) assumed that if
small summed trauma to the tissues than minor bone An electronic search was undertaken in August 2013
resorption occurred, but if a summed large trauma in the PubMed website (U.S. National Library of Med-
prevailed, then implant failure would follow. Trauma icine, National Institutes of Health; Bethesda, Mary-
to the tissues that may disturb the maintained foreign land, USA). The last complementary check-up for
body equilibrium that we call osseointegration is newly published papers within the topic was per-
sometimes easy to understand such as inadequate sur- formed in October 2013. The following filters from
gery burning away the relevant cells needed for bone the referred website were selected: the item ‘Clinical
repair, but in other cases may be more difficult to Trial’ within ‘Article types’ and the item ‘English’
identify. In this paper we have subdivided reasons for within ‘Languages’. Only the papers from 2004
© 2014 John Wiley & Sons Ltd

REASONS FOR FAILURES OF ORAL IMPLANTS 445
onwards were included at the first part of the screen- publishing more than one paper but with different
ing process. The following terms were used in the follow-up periods, only the publication with the lon-
search strategy: gest (the last) follow-up period was considered. For
{Subject AND Adjective} this review, implant failure represents the complete
{Subject: (dental implant [text words]) loss of the implant.
AND
Adjective: (failure [text words])
NOT Exclusion criteria
(grafting OR irradiated OR sinus lift [text words])} Simple case reports, not controlled case series, and
Some procedures were a reason for exclusion of animal studies were not included. Comparisons of
studies because the influence of the irradiation of the failure rates between teeth and implants in studies
bone-grafting materials and the added surgical proce- performing the same prosthetic treatment were not
dure cannot be quantified or eliminated. considered, nor studies evaluating prostheses sup-
The publication had to be included in the electronic ported by the combination of teeth and implants.
database to be considered in the review. All reference Controlled studies not reporting implant failures rates
lists of the selected studies were then hand-searched were excluded. Studies reporting the use of implants
for additional papers that might meet the eligibility for anchorage of maxillofacial prostheses, use of zygo-
criteria for inclusion in this study. The titles and matic implants, transitional/provisional implants, zir-
abstracts (when available) from these results were conia implants, and/or orthodontic implants or any
read by the authors for identifying studies meeting other use were excluded. Studies performing grafting
the eligibility criteria. For studies appearing to meet procedures concomitantly or previously to implant
the inclusion criteria, or for which there were insuffi- insertion surgery were excluded. Studies evaluating
cient data in the title and abstract to make a clear the survival/failure rates of implants inserted in
decision, the full report was obtained and assessed. patients previously submitted to radiotherapy in the
In the second part of the screening process, a hand- head and neck region were excluded.
searching process called ‘snowballing’ included papers
that may have showed significant results implying
Data collection and synthesis
that certain factors may lead to implant failure, with
no restrictions concerning the year of publication. A sum-up of the clinical outcomes will be given in
In the third part of the screening process, literature most cases, usually without a detailed analysis of the
review papers about factors associated with implant individual papers.
failures were used to identify other possible factors We did another type of screening in the third part
that were not enumerated in the two previous screen- of the present paper. The first two parts of this contri-
ing processes. bution deal with comparative studies that have been
Contact with authors for possible missing data was selected and summarised in a systematic manner. In
not performed. Disagreement regarding the inclusion contrast, the third part represents a narrative review
or exclusion of the retrieved articles was resolved by a where other papers than comparative ones are
discussion between the three reviewers. included too. This third part will discuss some findings
from the first two parts where separate data from
non-comparative studies may have indicated conclu-
Inclusion criteria
sions different from those possible to draw in the sys-
Eligibility criteria included controlled clinical human tematic analysis. In addition, the third part of our
studies, either randomised or not. Regarding the type paper will discuss marginal bone loss which may lead
of intervention, endosseous root form titanium or to secondary failure of the implant. For example, data
titanium alloy implants to replace teeth were taken of a short-term nature (5 years follow-up or less) may
into consideration. All outcomes reporting on failure have indicated quite positive a clinical outcome of
of implants, including clinical, radiographic and some implant types such as IMZ or hydroxyapatite-
implant fracture, were considered. For the studies coated implants to mention but a few. In the first two

parts of this publication, known problems with such process added more 193 publications, totalling 311
systems may have passed unnoticed unless compara- publications.
tive studies indicated some problems. However, from
non-comparative studies of the same implant systems,
Surgical conditions
we have learned about severe problems in the form
of marginal bone loss with the same implants. This Prophylactic antibiotics versus placebo. Even though oral
will be reported in part 3 of this contribution. surgeons often prescribe antibiotics routinely follow-
ing implant surgery, the usefulness of pre- and post-
operative antibiotics in reducing the failure rates of
Results
endosseous implants remained unclear and unsub-
The study selection process is summarised in Fig. 2. stantiated for several years. Some studies tried to eval-
The first part of the search strategy resulted in 304 uate whether the use of antibiotics may or may not
papers from the period 2004 to 2013. The three influence the survival of dental implants.
reviewers independently screened the abstracts for Comparing the implant failure rates in patients
those articles related to the focus questions. Of the receiving pre-operative antibiotics versus in patients
304 studies found, 87 were excluded for not being who did not receive (or received a placebo), it was
controlled studies, 24 for performing graft procedures observed that antibiotics administered pre-operatively
in the implant site, 15 for using other types of statistically improved implant survival in some studies
implants (zygomatic, transitional, zirconia or ortho- (9, 10).
dontic), two for comparing failure rates between teeth However, it was observed for most of the studies
and implants in with the same prosthetic treatment or that there was no significant difference regarding the
prostheses supported by the combination of teeth and survival rate between the two groups (11–18), even
implants, 42 for not evaluating implant failure and 16 though in one of these studies (15), four times more
for being the same study but with earlier follow-up patients in the placebo group experienced implant
periods. Thus, the first part of the screening process failures than in the antibiotic group. Post-operative
resulted in 118 eligible publications. Additional hand- antibiotics did not influence the results of implant
searching of the reference lists of selected studies failure rates in one study (9). The drawback of these
yielded 67 additional papers from 2004 onwards, and studies is the fact that the regimens used by each
126 papers published before 2004 (already excluding study for each patient varied somewhat by antibiotic
12 papers for being the same study but with earlier type, dosage and time of administration.
follow-up periods). The second part of the screening From the results of these studies, it can be con-
cluded that there is some evidence suggesting that
pre-operative antibiotics significantly reduce failures
of dental implants placed in ordinary conditions, but
it is still unknown whether post-operative antibiotics
are beneficial. Although the exact mechanism by
which pre-operative antibiotics produce this effect is
not known, it may be that a more aseptic local envi-
ronment during the time of implant placement and in
the immediate perioperative period results in
improved healing and, ultimately, a better state of
osseointegration (10).
Different types/regimen of antibiotic therapy. Instead of

evaluating whether the use of antibiotics may or
may not influence the survival of dental implants,
some studies assessed whether the use of different
regimen of antibiotic therapy could affect the implant
Fig. 2. Study screening process. survival.

Lambert et al. (19) evaluated the influence of smok- peri-implant mucosa at the time of prosthetic rehabili-
ing on the survival of 2887 implants. At 36 months, tation (27). Several clinical studies were published
implants in smokers failed 149% of the time when comparing these two different surgical approaches.
pre-operative antibiotics were not given or given at Many studies observed that implant placement
an ineffective dosage. Non-smokers or those who according to single-stage surgery (non-submerged
have quit had a 75% failure rate when not given implant) has the same predictability as two-stage sur-
pre-operative antibiotics. Smokers not given pre-oper- gery (submerged implant), with a high survival rate
ative antibiotics were almost three times more likely (27–42). However, many other studies showed that
to have implant failures than those provided pre- there is a greater risk of implant failures with a non-
operative antibiotic coverage. When pre-operative submerged technique compared with a submerged
antibiotics were used, the failure rate for both smok- technique (43–50).
ers and non-smoker/quit subjects was the same,
decreasing to 47%. Flapless versus conventional flapped surgery. When plac-
Wagenberg and Froum (20) retrospectively evalu- ing dental implants, a flap is usually increased to
ated 1925 immediately placed implants. Patients better visualise the area. There is also the possibility
unable to utilise post-surgical amoxicillin were 334 to work blindly and insert implants without flap ele-
times as likely to experience implant failure as vation (flapless surgery). Currently, some software
patients who received amoxicillin. Patients with an systems using computed tomography scans have
allergy to penicillin (852% of failure) were 57 times been proposed to aid in planning surgery and to
more likely to experience implant failures due to produce surgical drilling guides to transfer the
infection than patients without allergy to penicillin planned position to the surgical field. These guides
(295% of failure). are manufactured in such a way that they match
However, it can be observed from the results of six the location, trajectory and depth of the planned
other studies that, in conjunction with routine oral implant with a high degree of precision. As the den-
implant surgery procedures, the adoption of different tal practitioner places the implants, the guides stabi-
antibiotic prophylaxis regimens does not affect the lise the drilling by restricting the degrees of freedom
implant failure rate. These different antibiotic pro- of the drill trajectory and depth (51). Some studies
phylaxis regimens could be a single pre-operative have compared the survival rate of implants using
dose versus 3 (21), 7 (22, 23) or 10 days of adminis- these two techniques.
tration (24), no antibiotic treatment versus a single By observing the results from the available con-
pre-operative dose versus a preoperative dose plus trolled studies on the subject, it can be stated that
post-operative antibiotic treatment for 7 days versus most studies reported that implant placement accord-
no pre-operative dose and post-operative antibiotic ing to flapless surgery has comparable results with the
treatment for 7 days (25), a single pre-operative dose conventional flapped surgery, with a high survival
versus a pre-operative dose plus post-operative antibi- rate (52–67). The one exception is the study of Senn-
otic treatment for 5 days versus no pre-operative erby et al. (68), which showed a higher failure proba-
dose and post-operative antibiotic treatment for bility for the implants inserted through the flapless
5 days (26). technique.
Submerged versus non-submerged implants. Two different Different insertion torques. Only two studies evaluating
methods of implant insertion have been developed: the survival rates of dental implants placed under dif-
the two-stage surgical technique (in which the ferent insertion torques were published, whereas one
implant is inserted in one session and the abutment is study (24) evaluated cutting torque measurements
connected in another surgical procedure (submerged during implant placement.
implant), and the one-stage surgery (non-submerged Friberg et al. (24) evaluated cutting torque measure-
implant). The use of one-stage surgery has gained ments during implant placement and correlated these
more and more interest as it reduces surgical inter- observations with implant failure. According to the
vention, thus reducing surgical time and patient technique, the consumed electric current during low-
discomfort, and produces healed and healthy speed threading of implant sites is registered and the

true cutting resistance of bone is calculated. The Standard drilling protocol versus adapted bone drilling
results of the study showed that the mean cutting tor- method in low-density bone. In the study of Alghamdi
que values for the 14 implants that failed and the 398 et al. (72), 26 implants were surgically placed accord-
successful implants were similar. ing to the standard drilling protocol (control group)
In the study of Ottoni et al. (69), implants were and 26 were placed in low-density bone using an
restored within a 24-h period after placement with a adapted bone drilling method (test group), which con-
provisional crown receiving occlusal load (test group), sisted of undersizing the bone drilling of the implant
and this situation was compared with implants bed. Widening of the implant bed with osteotomes or
restored after a healing of 3–6 months (control group; tapping was not used in any of the cases. None of the
23 implants for each group). The primary stability was implants failed at the end of 1 year. The results of this
standardised with a minimum insertion torque of study suggest that placement of implants by an
20 Ncm. Relative risk of implant failure was associ- adapted drilling technique in sites with poor bone
ated with insertion torque in the test group but not density does not increase/decrease the implant failure
so in the control group. To achieve osseointegration, rate.
it was found that an insertion torque above 32 Ncm
was necessary. It was observed that the insertion tor- Implants inserted with versus without piezoelectric surgery
que was associated with the risk potential, which can split crest. Piezoelectric surgery (PES) uses a modu-
be decreased by 20% per 98 Ncm added. The authors lated ultrasonic frequency that permits a highly pre-
suggested that, in cases of early loading, an appropri- cise and safe hard tissue-cutting technique allegedly
ate initial insertion torque must be applied to decrease avoiding nerve, vessel and soft tissue injuries, which
the implant failure rates. may result in a low bleeding tendency. Because of
Cannizzaro et al. (70) compared the outcome of this potential advantage, it was hypothesised by one
immediately loaded single implants inserted with study that the use of PES in surgical insertion of
medium (from 25 to 35 Ncm) or high insertion tor- implants would favour the survival outcome. Danza
ques (>80 Ncm), in a split-mouth design, 50 implants et al. (73) evaluated whether implants (N = 234, 86
in each group. The patients were followed for patients) inserted into crests split using PES (N = 21)
6 months after loading. Seven implants failed to have a comparable outcome to those inserted into
osseointegrate when inserted with a torque between unsplit bone. The patients were followed for a mean
25 and 35 Ncm versus none of the implants inserted of 13 months. Only nine of 234 implants were lost,
with a torque >35 Ncm. The authors concluded that it all from the unsplit group, but no statistical difference
is preferable to insert single implants with a high was demonstrated. Even though it was showed that
insertion torque in order to minimise early implant no implants inserted by PES were lost, the small sam-
failures, when loading them immediately. ple size of this group may be considered a limitation
By observing the results of these two last studies, it of this study.
can be suggested that a low insertion torque of
implants that are planned to be early or immediately Intra- or post-operative complications. In the study of
loaded increases the implant failure rate. Strietzel et al. (74), with 1554 implants followed for a
mean period of 62 years, a significant correlation
Bone condensing versus bone drilling. Markovic et al. between the occurrence of intra- or post-operative
(71) compared the stability of implants placed by complications (perforation of nasal floor or maxillary
bone condensing (implant sites were prepared by pilot sinus, suture spreading, oedema requiring therapy,
drill, followed by condensers of increasing diameter) sensation deficit and infection) and implant loss was
versus the standard drilling technique in the posterior established. The occurrence of complications increased
edentulous maxilla, in a split-mouth design, 24 the risk of implant loss 34 times (Pn = 1554 = 0001)
implants for each group. Patients were followed until and 48 times (Pn = 504 = 0011).
6 weeks after surgery, when the final prosthetic reha-
bilitation was performed. Even though no implants Two surgical guide systems. Abboud et al. (75) compared
were lost, the short period of follow-up is a consider- the survival rates of the immediately loaded dental
able limitation of this study. implants inserted with the help of two different

stereolithographic surgical guide systems, NobelGuide Ridge-expansion-with osteotome-only versus combined ridge
(41 implants) and SimPlant (34 implants). The split-and-osteotome procedure. In the study of Payne
patients received pre-fabricated provisional restora- et al. (105), 40 edentulous participants with mandibu-
tions. One of the NobelGuide-inserted implants failed, lar two-implant overdentures were allocated to two
with a cumulative survival rate (CSR) of 976% for groups, either a ridge-expansion-with osteotome-only
this group. No implant failures were observed in the (OO; N = 69) procedure or a combined ridge split-
other group. and-osteotome procedure (ORS; N = 48), depending
on ridge bucco-palatal width and the degree of ridge
Fresh extraction sockets versus healed sites. Alveolar ridge resorption detected radiographically. Of the 11
resorption after tooth extraction may considerably implant failures, 8 (167%) happened in the ORS
reduce the residual bone volume and affect the group (in type C/D bone quantity) and 3 (43%) in
favourable positioning of implants, which is required OO group, the difference being statistically significant
to produce optimal restoration. Thus, some authors (P = 003).
advocated immediate placement, which has some
advantages (76). Several studies have compared the Surgeon’s surgical experience. In the study of Adell et al.
clinical outcomes of implants placed in fresh extrac- (106), the material was divided into four groups
tion sockets versus in sites left to heal from few weeks (development group and routine groups I, II and III)
to several months. designated by time periods of fixture placement. Rou-
Some studies showed that there is a greater risk of tine group III represented those patients completed in
implant failures with insertion in fresh extraction sock- the most recent group, when providers had achieved
ets compared with placement in healed sites (77–82). the most experience. They reported 5-year CSR for
On the other side, few studies showed that there is a implants in the mandible for the developmental group
greater risk of implant failures with an early insertion to be 75%. However, routine groups I–III were 91%,
(within 6–8 weeks after tooth loss) (83) or late inser- 98% and 99%, respectively.
tion (more than 9 months after tooth loss) (84) com- Block and Kent (107) compared their CSR for
pared with an immediate insertion. However, most of hydroxyapatite (HA-coated) implants placed in two
the studies observed that the implants placed into fresh different periods. The first one, called ‘developmental
extraction sockets have similar failure rates as the period’ between 1985 and 1988 (4- to 8-year follow-
implants placed in healed sites (68, 85–103). up), was compared with the second one, called
‘recent period’ between 1989 and 1991 (1- to 4-year
Immediate placement in sockets with versus without periapi- follow-up). The CSR for the developmental period
cal pathology. Truninger et al. (104) compared the was 865%, improving to 976% for the recent period.
clinical outcomes of implants placed in fresh extrac- Minsk et al. (108), followed for 6 years 1263
tion sockets with (N = 17) or without (N = 17) peri- implants inserted by 80 different operators with a
apical pathology, patients in need of single-tooth wide range of clinical experience in 380 patients. The
replacement. Before the implant insertion, careful results indicated that the use of implants by operators
debridement of the extraction socket was performed. with different levels of experience did not affect the
Of the 34 patients, four test and one control patient implant survival rates.
had to be withdrawn from the study due to the Lambert et al. (109) evaluated the risk of an
inability to obtain primary implant stability. The resid- implant to fail according to the surgeons’ experience.
ual 29 implants revealed a survival rate of 100% Implants placed by inexperienced surgeons (<50
3 years after placement. implants; N = 1260; failure rate: 35%) failed twice as
often as those placed by experienced surgeons (≥50
Socket depth. Grunder et al. (87) assessed the clinical implants; N = 1381; failure rate: 18%; P < 005).
outcomes of 264 implants placed in fresh extraction Implants placed during the first 6, 8, 10, 12 and 16
sites, in healed sites and with membranes placed over cases were compared with all others. The greatest dif-
the extraction site. There was no clinical difference of ference was seen between the first nine cases and all
the implant failure rate when compared to the socket others (P = 0001), with later cases failing significantly
depth in which the implants had been placed. less often. Inexperienced surgeons had more failures

in the first nine cases (59%) than more experienced 172–175). Three studies compared the failure rates
surgeons (24%). within the posterior region, showing that the failure
Three of the four available studies evaluating the rate in the molar area was higher than that in the
influence of the surgeon’s surgical experience of the premolar area (176–178). One study (86) even
implant failure rates indicated that inexperienced sur- showed that implants placed in the anterior region of
geons tend to have more failures than more experi- the maxilla failed significantly more often than those
enced surgeons. placed in the posterior region; the same was not
observed for the mandible, but the investigated
implant was later withdrawn due to poor results.
Location conditions
Another study (170) showed the same, but in the
Maxilla versus mandible. Since the first studies evaluat- other jaw – implant failures in the mandible were
ing implant clinical outcomes have been published, more frequent in the anterior zone than in the poster-
most of the authors report the implant survival/failure ior region; in the maxilla, all failures occurred in the
rates relative to the jaw where the implants are posterior zone. Other few studies (136, 179, 180)
inserted. observed that a significantly higher early implant fail-
Most of the studies observed that implants fail more ure rate was found in the anterior regions of maxilla
when inserted in the maxilla in comparison with and mandible compared with the posterior regions.
implants inserted in the mandible, with statistically However, the majority of the studies observed that
significant difference in the implant failures rates (24, the greater failure rate is found in posterior regions
37, 74, 80, 81, 86, 90, 96, 110–141). Other studies (46, 74, 87, 88, 91, 113, 114, 117, 156, 157, 169,
presented similar findings, however, without demon- 181–187). This may be attributable to a combination
strating significant differences between the two jaws of the demanding pre-conditions often present in the
(19, 88, 106, 142–164). A smaller number of studies posterior maxilla, such as barely sufficient bone vol-
found the opposite that implants inserted in the man- ume, poor bone quality and high functional forces
dible tend to fail more (68, 165–172). One study (156). The cortical layer of both jaws tends to
showed the same implant failure rates for both jaws become thinner and more porous posteriorly. More-
(173). over, posterior implants have to withstand the heavi-
The opinion of the majority of the studies is that est loading and are in general short due to
the maxilla has a less favourable bone texture than insufficient quantity of available bone (the maxillary
mandibles, with low density of medullary bone and sinus and the inferior alveolar nerve are the main
thin cortical plates (80). Jaws with poor bone quality anatomical limitations). The high survival rates pre-
may be at risk of establishing initial instability of the sented in the canine and/or premolar maxillary area
implants and a lack of resistance to mechanical stres- in some studies (20, 113, 179, 186) could be attrib-
ses, thus also resulting in early implant failures (80, uted to favourable bone density and adequate bone
113). Failure could also be related to the fact that quantity due to relatively rare anatomical limitations.
short implants are more commonly placed in the pos- One study (20) found high failure rates in the
terior maxilla due to limited bone dimensions because mandibular anterior, which was suggested to be
of the pneumatisation of the maxillary sinus. caused by overheating of the bone when long
implants (15–18 mm) were placed (20). S anchez-
Region of the jaws. Several researchers tried to verify Garces et al. (188) followed for a mean of 81 months
whether there is a difference in the implant failure 273 implants ≤10 mm in length (from 5 to 10 mm),
rates depending on the region of the jaws where the placed in patients with severe alveolar bone resorp-
implants are inserted. tion. The relative percentage of failure in the upper
Based on the reviewed studies, it can be clearly sta- molar zone was slightly higher than in the mandibu-
ted that the implantation site influences implant fail- lar molar region (897% versus 798%). When the
ure rates. Several studies reported that there was no implants located in the position of the first upper
significant difference when the implant failure rates and lower molars were considered separately, the
in the maxilla and in the mandible were partitioned failure rate increased to 95%. The failure rate
by position (90, 116, 123, 132, 153, 154, 158, 168, recorded in the region of the lower premolars was

doubled compared with the region of the upper pre- able promise in improving the success rates of implant
molars. integration in previous smokers.
Periodontally compromised versus non-compromised situa-

Patient conditions
tions. Some evidence supports the concept that
Male versus female. Some studies showed that gender patients with a history of periodontal disease may
was a risk factor for failure where females had higher experience increased implant failure rates when
failure rates than males (74, 116, 189). In contrast, undergoing implant therapy. In many studies compar-
other studies reported higher failures rates for males ing the implant failure rates of implants inserted in
compared with females (20, 129, 136, 151). However, periodontally health patients and in periodontally
most of the studies did not find a significant effect of compromised patients, it was suggested that failed
patient’s sex on the failure of implants (19, 37, 46, implants were concentrated in patients with a rela-
47, 86, 115, 119, 120, 122, 138, 153, 156, 158, 170, tively high initial plaque index (151), in patients that
173, 179, 190). had their tooth (or teeth) extracted due to periodonti-
tis (20, 87, 88), in periodontally ‘maintained’ (168),
Age of the patient. The success of osseointegration ‘susceptible’ (201), ‘compromised’ (187) patients,
depends in part on the state of the host bone and its patients who had periodontal disease (89) and in
healing capacity. Osteoporosis, which is a disorder patients with aggressive periodontitis instead of in
characterised by a generalised diminution in bone patients with chronic periodontitis (131).
mass and bone density, may therefore represent a risk However, conclusions need to be interpreted with
factor for osseointegration (190). As the prevalence of caution, because some studies showed that a previous
osteoporosis rises with age, some researchers investi- history of periodontal disease (198, 202, 203) may not
gated whether the age of the patient may have some have a significant impact on implant failures. Further-
influence on the implant failure rates. more, a recent genetical study found clear differences
Few studies showed that there is an increase in between periodontitis and peri-implantitis (204).
implant failures with age (168, 191). On the other It might be difficult to assume a causal association
hand, most studies have shown that there is no corre- between implant failure and a previous history of
lation between implant failure and age of the patient periodontal disease (205). However, it can be specu-
(20, 46, 47, 86, 112, 115, 119, 120, 122, 129, 145, lated that periodontitis-affected tissues might have
158, 170, 190). had a negative local influence, also for the presence
of infrabony defects; this could increase the gap
Smokers versus non-smokers. As cigarette smoking has between bone and implant (206) or jeopardise the
been shown to adversely affect wound healing, it has achievement of primary stability (207) both at imme-
emerged as a factor that may affect the implant sur- diate and early implant placement.
vival outcomes (136). Several studies investigated
whether there is a greater incidence of implant failure Bone quality. Bone quality is believed to be one of the
in patients who smoke compared with non-smokers. most important aetiological factors for early implant
The review of these studies shows that cigarette failures. Bone quality is categorised into four groups,
smoking appears to have a statistically significant det- from type I to IV: (i) type I, homogeneous cortical
rimental effect on implant survival, even after bone; (ii) type II, thick cortical bone with marrow
accounting for some potentially confounding vari- cavity; (iii) type III, thin cortical bone with dense tra-
ables. Of the 27 studies reviewed, 22 showed that becular bone of good strength; and (iv) Type IV, very
smoking influences negatively the survival rate of the thin cortical bone with low-density trabecular bone of
implants (19, 46, 47, 49, 90, 117, 119, 128, 129, 133, poor strength. Several studies evaluated the influence
136, 164, 173, 192–200), and five studies showed that of bone quality on the implant failure rates.
smoking does not significantly influence the survival Receptor bone quality is a decisive factor for
rate of the implants (20, 36, 108, 132, 170). It has implant success. Analysis of the reviewed studies
been shown that a smoking cessation protocol showed that the outcome of implant treatment could
described in one study (193) demonstrated consider- be related to bone quality. It was observed by many

studies that there is an increased implant failure rate 191). For many others (145, 167, 178), there were no
when implants are inserted in bone qualities type III statistical significant differences.
and IV (126, 151, 154, 156, 184, 191, 197, 208) or Figure 3 shows implants inserted in a maxilla with
in bone quality type IV (90, 113, 114, 120, 135, small quantity of bone (courtesy of Dr. Anders
160). Few studies reported a higher implant failure €
Ortorp).
rate for implants inserted in bone quality type II (24)
or type III (87, 167). Some observed that insertion in Bruxism. Glauser et al. (156) evaluated 41 patients
bone type I (or ‘dense bone’) may also result in who received 127 immediately loaded implants. Their
increased implant failure rate (113, 160, 172). The results showed that implants in patients with a para-
bone quality type I is more commonly found in the functional habit (bruxers) were lost more frequently
anterior mandible, where usually there is more bone than those placed in patients with no parafunction
available to insert long implants. Thus, this may be (41% versus 12%).
related to overheating of the bone when long The higher failure rate among the bruxers is not so
implants are placed. Research has demonstrated that surprising because a high and unpredictable or
thermal damage at the drilling site inhibits the uncontrolled loading of the implant could lead to
regenerative response in bone healing, slowing the micromotions above the critical limit, resulting in
process of osseointegration and potentially resulting fibrous encapsulation of the implant instead of osseoin-
in implant mobility (209). Some studies (36, 145, tegration (156). It was suggested that early or immedi-
173, 176, 178) indicated that the bone quality did ate loading per se is not detrimental for osseointegration,
not significantly influence the failure rate of the unless excessive micromotions occur at the bone–
implants. implant interface during the healing phase (211).
The combination of poor bone quality and a shorter
implant length leads to diminished mechanical stabil- Number of present teeth/edentulism status. The implant
ity at the time of fixation and during the subsequent failure rate in the partially edentulous jaw was not
osseointegration period. significantly different from that in the totally edentu-
lous jaw in some studies (24, 116). It was also not sig-
Jaw bone volume/jaw bone resorption. Bone volume, nificantly different when comparing the failure rates
together with bone quality, is generally believed to be of implants placed to restore edentulous jaws versus
one of the most important aetiological factors for early posterior partial edentulism versus a single-tooth
implant failures. Several studies evaluated the influ- space versus an intermediate space (86). However,
ence of bone volume – or bone quantity, based on some observed that implants placed in completely
the Lekholm and Zarb (210) system of bone classifica- edentulous jaws demonstrated higher failure rates
tion – on the implant failure rates. than implants placed in partially edentulous jaws
Many studies found that there was a significant (128, 168). Kourtis et al. (90) observed in their study
higher implant failure rate when small bone volumes that that single-tooth implants showed statistically sig-
are present for implant insertion (111, 120, 126, 135, nificant lower failure rate and better survival rate
Fig. 3. Tilted implants inserted in a

maxilla with small quantity of bone
€
(courtesy of Dr. Anders Ortorp).

probability compared with implants used in partially (a)

or completely edentulous patients. The Cox propor-
tional hazard regression analyses performed in one
study (49) showed that implants inserted in subjects
with 20 or more teeth present were explanted at a
rate that was 38 times higher than in subjects with
fewer teeth present.
The observation that implants placed in completely
edentulous jaws demonstrated higher failure rates
than implants placed in partially edentulous jaws in
some studies may be related to the fact that the dental
status has a high influence on the jaw anatomy
(212). When there is insufficient bone volume and
grafting procedures are not performed, short implants (b)
are probably the only option, and shorter implants

usually have higher failure rates than longer ones
(consult subtopic ‘Implant length’).
Ethnicity. Lambert et al. (19) evaluated the influence

of smoking on the survival of 2887 implants, followed
for 3 years. When analysing ethnic groups, they
observed that implants in white smokers were 13
times more likely to fail, in Hispanics four times, in
blacks 24 times and in others 18 times more likely to
fail than in non-smoker/quit subjects.
Fig. 4. Dental implants in a patient with poor oral hygiene hab-
its (a). Despite poor oral hygiene, marginal bone levels were
Oral hygiene. Kourtis et al. (90) evaluated the clinical
maintained around the implants (b).
outcomes of 1692 implants. The oral hygiene was
evaluated subjectively as good, medium or insufficient
in all recall appointments. The failed implants in 18 patients diagnosed with oral lichen planus (OLP,
patients with good oral hygiene were 13 (176% of all 56 implants) and 18 control patients (62 implants). To
failures), in patients with a medium level of oral obtain a uniform sample, only patients with originally
hygiene 27 (365%), and in patients with insufficient erosive forms of OLP were included in the study and
oral hygiene, 34 failures (459%) were noticed. There the type, length and diameter of the implants were
was a statistically significant difference between fail- similar in both groups. The implant survival rate was
ures in good–medium and insufficient oral hygiene 100% for the OLP group and 968% in the control
groups compared with the chi-squared test group.
(P < 0001, v2 = 6155). The failure rate in good or The results of the only prospective controlled study
medium oral hygiene groups was 25% and 29%, on the subject seem to demonstrate that the presence
respectively, and in patients with insufficient oral of OLP is not associated with a higher prevalence of
hygiene, almost four times higher (138%). The sur- implant failure.
vival rate probability was also influenced accordingly.
Figure 4 shows mandibular dental implants in a Compromised medical status/systemic conditions. The
patient with poor oral hygiene habits (a). Despite influence of general health problems on the implant
poor oral hygiene, marginal bone levels were main- failure rates is still poorly documented, with only few
tained around the implants (b). controlled studies available.
Smith et al. (115) observed that the number of medi-
Patients with versus without oral lichen planus. Hern
an- cal problems (diabetes, oestrogen replacement and cor-
dez et al. (213) compared the implant survival rate in ticosteroid therapy) and the physical status of the

patient according to the American Society of Anaesthe- term resistance to bending moment forces, expedited
siologists classification system were not statistically healing and a decreased risk of movement at the
associated with an increased risk of implant failure. interface (216). A number of researchers evaluated
Wagenberg and Froum (20) also did not find significant whether the survival of the shorter implants was
difference in implant failure rate associated with any comparable with the longer implants.
medical condition (osteoporosis or taking bisphospho- From the review of these studies, it can be con-
nates) of the patients included in the study. cluded that is highly suggestive that implant length is
Morris et al. (214) attempted to determine whether a significant factor in implant survival. In most stud-
type 2 diabetes represents a significant risk factor to ies, there are significant findings of decreased survival
the long-term clinical performance of dental implants. with shorter length (<10 mm) implants compared
A model assuming independence showed that with their longer (≥10 mm) counterparts (47, 49, 81,
implants in type 2 patients have significantly more 86, 87, 90, 113, 116, 117, 122, 125, 126, 132, 133,
failures (P = 0020). 136, 149, 151, 154, 157, 158, 166–168, 170, 176, 178,
Kourtis et al. (90) evaluated the clinical outcomes 180, 182–185, 189, 191, 216–218). Some studies even
of 1692 implants. From this total, 56 (33%) were showed that there is a progressive increase in the
placed in patients with diabetes mellitus, 11 (07%) in implant failure rates as the implant length decreases
patients who had previously undergone chemother- (117, 122, 125, 146, 149, 157, 178, 183, 185, 216).
apy and 6 (04%) in patients who had metabolic dis- Two studies compared the implant failure rates
turbances. The failure rate was increased with between short implants [8 mm 9 10 mm by Levine
statistical significance among patients (P < 0001) with et al. (169); 7 mm 9 85 mm by Goen e et al. (160)],
metabolic diseases (e.g. thyroid gland dysfunction). and both studies showed increased implant failure
No statistical significance was noted among failures in rates for the shortest implants.
patients with diabetes. One interesting observation resulted from the study
Alsaadi et al. (215) assessed the influence of sys- of Naert et al. (158), saying that by decreasing the
temic and local bone and intra-oral factors on the implant length by 1 mm increases the hazard rate
occurrence of early 720 TiUnite implant failures. 016 times.
Between the systemic factors, the authors assessed Few studies observed that the implant length did
hypertension, cardiac problems, gastric problems, not appear to significantly affect the implant failure
osteoporosis, hypo- or hyperthyroid, hypercholestero- rate (36, 91, 123, 129, 130, 156, 171, 173, 174, 179,
laemia, asthma, diabetes types I or II, Crohn’s disease, 187, 188).
rheumatoid arthritis, chemotherapy, hysterectomy Figure 5 shows a bone resorption around a short
and intake of medication (antidepressants, steroids, turned surface implant (courtesy of Dr. Bj€orn Gjelvold).
hormone replacement). Owing to the very few fail-
ures (19%), no definitive conclusion concerning sta-
tistical significance can be achieved. However, a
tendency for more failures was noticed for hormone
replacement, gastric problems, Crohn’s disease, diabe-
tes I and radical hysterectomy.
Anner et al. (198) observed that diabetes was not
associated with long-term implant survival in a sam-
ple size of 1626 implants followed for an average of
30 months.
Implant conditions
Implant length. It has long been an axiom of implant

dentistry that as many implants as possible of maxi-
mum length should be used. Advantages of increased Fig. 5. Bone resorption around a short turned surface implant
implant length include increased initial stability, long- (courtesy of Dr. Bj€
orn Gjelvold).

Implant width/diameter. The clinical use of several Analysis on implant level did (222) or did not (156)
designs of oral implants has become highly predictable show significantly higher failure rates for implants
related to limitations of the geometry and volume of that had initial poor stability in comparison with
the alveolar bone. To reduce the risk of failure of implants that had good and very good initial stability.
endosseous implants used for posterior applications, Details from the other studies are important. In the
wide-diameter implants have been suggested. The use study of Friberg et al. (113), 69 (of 4641) implants
of a 50-mm-diameter implant that is 6 mm long failed, and in 22 of the failures (32%), the implants
increases the surface area available to contact the were placed in sites with extremely soft bone and/or
bone similar to that of a 375-mm-diameter implant where initial implant stability was not achieved.
that is 10 mm in length (216). Several studies Orenstein et al. (223) followed 2641 implants in
assessed whether the survival of the wider implants order to examine the likelihood for an implant that
was comparable with the narrower implants. was mobile at placement to osseointegrate, according
It can be concluded that is suggestive that implant to the surface modification of the implants. Seventy-
diameter is a significant factor in implant survival. six (938%) of the 81 mobile implants were integrated
Implants with wider diameter seemed to achieve bet- at uncovering compared with 975% for the 2560
ter results than standard ones of corresponding immobile implants. Of the 54 HA-coated implants that
lengths. In several studies, there are significant find- were mobile at placement, all (100%) integrated,
ings of increased failure with smaller diameter while only 17 (815%) of the 22 mobile non-
implants, either the comparison being between 33 HA-coated implants integrated (P = 0003).
versus 40 mm (86, 116), 375 versus 40 mm (151, One study (224) used resonance frequency analysis
154), ≤4 versus >4 mm (185), 33 versus 375 versus to verify whether the implant stability has some influ-
40 mm (182), 375 versus 40 versus 50 mm (178), ence on the possible differences between failing and
33 versus 40 versus 50 mm (180), 30–39 versus successful implants. It was observed that after
40–49 mm (216), from 33 to 65 mm (173), from 1 month, the resonance frequency analysis of failing
30 to 50 mm (219), or between implants from 325- implants was significantly lower than found with the
to 60-mm-diameter implants (132). successful ones. Nedir et al. (225) showed that after
On the other side, studies also showed a significant 1 year of loading, all implants loaded after 3 months
higher implant failure rate for wider diameter of healing with an initial of ISQ ≥ 49, and all implants
implants, either the comparison being between 375 immediately loaded with an initial ISQi ≥ 54 achieved
versus 40 versus 50 mm (167, 220, 221), 40 versus and maintained osseointegration (ISQ – implant sta-
50 mm (156), or between implants from 325- to 60- bility quotient).
mm-diameter implants (171). A reason for this may Rodrigo et al. (226) followed 4114 consecutive SLA
be, as observed by Shin et al. (221) in a multivariate Straumann implants to evaluate primary stability,
analysis, a predictive relationship between overall which was classified in four categories, depending on
CSR and the ratio of implant volume to remaining the degree of implant rotation when tightening the
bone volume. healing cap: A (no rotation at all), B (light rotation
Many showed no statistically significant difference with a feeling of resistance), C (rotation without resis-
in implant failure rates between narrow- and wide- tance) and D (rotation and lateral oscillation). A num-
diameter implants, either the comparison being ber of 3899 implants was classified as stable (A) and
between 33 versus 40 mm (86), from 325 to 5 mm 213 as unstable (B–D), showing survival rates of
(129, 179), 375 versus 40 (81), 375 versus 40 ver- 991% and 972%, respectively. In the case of the
sus 50 mm (187), from 35 to 6 mm (91), 40 versus unstable implants B (N = 158), C (N = 51) and D
50 versus 60 mm (36), or between 33- versus 41- (N = 4), they had a survival rate of 981%, 941%
versus 48-mm-diameter implants (170). and 100%, respectively. All these differences were
statistically significant (P < 0009). Using a resonance
Initial stability. The presence of implant mobility at frequency analysis device, a threshold value of
the initial stage of treatment is believed to represent a ISQ = 60 was used to stratify implants by stability
serious risk to its eventual integration and long-term (stable/non-stable), in both group 1 (resonance
survival. frequency analysis method used at the day of the sur-

gery) and group 2 (resonance frequency analysis ern (105), Frialit-2 and IMZ (173), cylindrical ITI and
method used at restoration placement) measurements. tapered ITI (235), and between ITI, SwissPlus and
At the group 1 measurement, there was no significant Astra (236).
association between primary stability and implant sur- A statistical significant difference was found in the
vival (P < 0753). However, in the group 2, the associ- comparison of implant failure rates between Steri-Oss
ation was significant (P < 0001). versus Southern implants (favouring Southern
Primary implant stability is determined by the bone implants) (237), Astra and ITI (favouring Astra
density, the implant design and the surgical tech- implants) (49), and between straight-walled and
nique. These studies show a correlation between tapered Osseotite (favouring straight-walled) (238).
implant stability and implant survival and probably It is important to stress that a comparison of results
reflect the importance of an undisturbed healing to between these studies is difficult to make, because
achieve adequate osseointegration. each study performed prosthetic rehabilitations on
these implants under several configurations, the load-
Threaded versus cylindrical implants. Four studies ing time after healing and the samples size varied, the
showed that there is a greater risk of implant failures bone quality in which these implants were inserted
with insertion of cylindrical implants when compared was different.
to threaded implants (123, 168, 227, 228). The statis-
tical analysis of four other studies indicated that the Number of implants placed per patient. Smith et al. (115)
type of implant (cylindrical versus threaded implant) studied 313 implants. The univariate analysis of risk
did not influence the failure rate of the implants (33, factors showed that the number of implants placed
36, 152, 229). per patient did correlate with implant failure. The
It is important to observe that we only report com- patients receiving from 41 implants had a greater
parative studies of implant failure under this heading, probability of having failures than the patients receiv-
that is, in this the systematic part of our review, we ing until 22 implants (P = 0016).
are not discussing potential problems with marginal Naert et al. (158) studied the outcome of 1956
bone loss that may occur to some implant systems. implants, and according to their results, the higher
However, early survival rates may be unaffected in the number of implants a patient has, the higher the
comparison with the ones where bone resorption has hazard rate (P = 0005). Increasing the number of
resulted in higher failure rates. implants by one increases the hazard rate 014 times.
According to Karoussis et al. (228), the possible rea- One may hypothesise that placing multiple implants
sons for inferior survival rates of cylindrical implants requires more mucoperiosteal stripping, compromising
in comparison with threaded implants are largely blood supply, more operating time and more contami-
unknown and may only be speculated upon. nation of the wound, all of which may contribute to
the increased complication rate (115).
Implant thread type/design. When standard and self-
tapping implants were compared, studies observed Implant surface. There have been constant efforts to
that the implant failure rate of standard implants was improve osseointegration by modifying the surface
higher than that of self-tapping implants (217, 230). properties of titanium, because this is where early
Others found that the difference in the implant failure interactions occur between the implant and the sur-
rate was not significant (82, 87, 158). rounding tissues following placement. Surface proper-
When a comparison of variable-thread design versus ties such as topography physics and chemistry may
standard tapered implants was made, no significant affect protein adsorption, cell–surface interaction and
difference in implant failure rates was observed (231). peri-implant tissue development, which are all relevant
A comparison of different implants showed no sta- to the functionality of the implant or device and may
tistical significant difference in implant failure rates have an influence on osseointegration, host response
between IMZ and Br anemark implants (232), Astra to the implant and subsequent treatment outcomes.
and ITI (124), IMZ, Br anemark and ITI (233), Br
ane- Titanium with different surface modifications shows
mark and ITI (30, 32, 34), titanium-blasted Astra Tech a wide range of chemical, physical properties, and
and turned Br anemark (234), Branemark and South- surface topographies or morphologies, depending on

how they are prepared and handled (239, 240). It is and two-piece (N = 380) implants, followed for at
not clear whether, in general, one surface modifica- least 1 year. Six (52%) and five (13%) implants
tion is better than another. failed in the one- and two-piece implants groups,
No statistically significant difference was observed respectively. The authors stated that factors such as
in comparisons of implant failure rates between implant design, insertion depth, rough surface
turned and HA-coated implants (174, 187), titanium towards the mucosa, in situ preparation and immedi-
plasma-sprayed (TPS) and HA-coated implants (122), ate loading may have an influence on the clinical out-
turned and grit-blasted (241, 242), turned and oxi- come.
dised (243–245), turned and ‘roughened’ (36), turned
and anodised (246–249), SLA and modSLA (250), Wide versus double implants. Bahat and Handelsman
grit-blasted and calcium-incorporated (251), and (263) compared the clinical outcomes of the place-
turned and acid-etched surfaces (252). ment of different combinations of implants at one site
Statistically significant difference was observed in in the posterior areas: (A) 59 single 5-mm implants,
comparisons of implant failure rates between (B) 20 pairs of 5-mm implants, (C) 34 5-mm implant
HA-coated and non-HA-coated implants (favouring paired with a 375- or 4-mm implant and (D) 162
HA-coated) (223), turned and TPS (favouring TPS) (253), double 375- or 4-mm implants. After a mean follow-
turned and anodised (favouring anodised) (37, 188, 254), up of 13–37 months (depending on the group), the
turned and ‘rough’ (favouring rough) (20, 184). number of failed implants was 2 (group A), 0 (group
One study did not inform whether there was statisti- B), 2 (group C) and 5 (group D). The failure rate for
cal significant difference in the implant failure rates all 5-mm implants was 23%, and that for all double
between turned and oxidised surfaces (162), but implants was 16%.
showed an implant failure rate of 9% for turned and
0% for oxidised implants. Another study showed Time since implant placement. Lemmerman and Lemm-
implant failure rates of 375% and 0% for turned and erman (36) evaluated the clinical outcomes of 1003
oxidised-surface implants (255), but also did not inform implants. The statistical analysis indicated that the
whether there was statistical significant difference in time since implant placement was the only variable
the implant failure rates. However, the authors (255) that influenced the success rate of the implants,
decided to abandon the use of turned implants, due to showing an increasing failure rate with time.
an unacceptably high failure rate, when correlated with
accepted criteria for assessment of implant performance.
Prosthetic conditions
Tilted versus axially placed implants. The technique of Occlusal versus non-occlusal loading. Most of the studies
tilting of posterior implants was developed for showed no statistically significant differences in
improving bone anchorage and prosthesis support and implant failure rates between functional (with occlu-
avoiding bone graft procedures. There was no signifi- sal contacts) immediate loading and non-functional
cant statistical difference in implant failure rates when (without occlusal contacts) immediate loading (186,
comparing implants placed in tilted positions with axi- 187, 264–267). One study (268) observed implant
ally placed implants in all available controlled studies failure rates of 0% and 67% for non-occlusal and
(140, 228, 256–260). A confounding factor can be the occlusal immediate loading, respectively, but there
fact that most of the studies splinted the tilted was no information whether the difference was statis-
implants with the axially placed implants to provide tically significant or not.
full-arch restorations in all (140, 258–261) or most The results of these studies tend to suggest that the
patients of the study (256). differences in immediate loading between occlusal
Figure 3 shows tilted implants inserted in a maxilla and non-occlusal loading may not have a detrimental
after partial maxillectomy (courtesy of Dr. Anders effect on the survival of dental implants.
€
Ortorp).
Cemented versus screw-retained implant. Three controlled
€
One-piece versus two-piece implants. Ostman et al. (262) studies (269–271) evaluated the differences in
compared the immediate loading of one- (N = 115) the clinical outcomes between cemented versus

screw-retained implant restorations, and all three supracrestal part of the implant bone reconstruction is
observed no statistically significant difference in often long in relation to the clinical crowns of the
implant failure rates between the two techniques. remaining dentition and to the supporting implant.
Cement remnants may indeed cause marginal bone Clinicians tend to insert the longest implants possible,
loss due to a foreign body on another foreign body presuming a higher success rate with increasing
reaction, but failure rates will increase first after many crown-to-implant length ratio (C/I ratio) (200). Three
years in situ. studies tested whether or not a higher C/I ratio is
associated with higher implant failure rates.
Type of prosthesis. Several studies observed statistically In the study of Blanes et al. (277), a total of 51
significant difference in the implant failure rates implants (265%) showed a clinical C/I ratio ≥ 2, and
between implants used to support different prosthetic three implants failed in this group, giving a CSR of
configurations, being overdentures versus fixed full- 941%. Schulte et al. (278) retrospectively evaluated
arch prostheses, favouring fixed prostheses (191), 889 single-tooth implants and observed that the mean
overdenture versus fixed partial prostheses, favouring C/I ratio of implants in function was 13:1, and the
fixed prostheses (122), overdentures versus all types mean C/I ratio of failed implants was 14:1. Schneider
of fixed prostheses (single-tooth, partial, full-arch), et al. (200) observed no statistically significant influ-
favouring fixed prostheses (46, 145, 182), overden- ence of the technical (the top of the implant shoulder
tures versus fixed full-arch bridges, favouring fixed was used as a transition between the crown and the
prostheses (but only in the maxilla) (157), overden- implant) and biological (the reference used for the
tures versus all types of fixed prostheses, favouring calculation was the initial peri-implant marginal bone
overdentures and full-arch fixed prostheses (173), and level) C/I ratio on the implant survival. Although Cox
single- versus multiple-implant-supported fixed pros- regression analysis revealed a higher biological C/I
theses, favouring single-tooth prostheses (68). ratio to negatively be associated with implant failure,
Many studies did not observe statistically significant this association was not statistically significant.
differences in the implant failure rates between From the results of the three published controlled
implants used to support different prosthetic configura- studies on the subject, it is suggested that implant res-
tions, being fixed prosthesis versus single-tooth restora- torations with high clinical or anatomical C/I ratios do
tions (272), single crowns versus fixed partial prosthesis not demonstrate lower survival or success rates as
(158), overdenture versus fixed full-arch prosthesis compared with implant restorations with low C/I
(273), single- versus multiple-implant-supported fixed ratios.
prosthesis (20) and all-ceramic versus metal-ceramic
implant-supported single-tooth restorations (274). Splinted versus unsplinted implants. Splinted implants
In one study (275), no comparisons were possible are usually indicated in clinical situations where there
between the groups (overdenture with a gold bar ver- is a risk of mechanical overloading to reduce the
sus CAD/CAM-fabricated implant overdenture with a forces on implants and surrounding tissues. It has
titanium bar versus CAD/CAM implant-supported been suggested that splinting implants helps to distrib-
fixed prosthesis) concerning implant failure rates, ute functional loads and therefore decrease the
because the only implant failure occurred before the implant failure rates. Some studies evaluated whether
loading of the implants. this is true or not.
Of the four studies comparing the splinting versus
All-on-2 versus all-on-4 implants mandibular cross-arch non-splinting of implants influence on implant failure
fixed prostheses. Cannizzaro et al. (276) followed 60 rates, one got no conclusive results (279), because the
patients who received mandibular cross-arch fixed implant failures happened at the stage-two surgery
prostheses immediately loaded supported by 2 (thus, before the prosthetic rehabilitation), one found
(N = 30) or 4 (N = 30) implants. One year after load- no difference between the approaches (280), one
ing, no implant failure had occurred. favoured unsplinted implants (158) and another
favoured the splinted implants (197). Due to the small
Different crown-to-implant ratio. Because of vertical loss number of controlled studies on the subject and to
of the alveolar bone after tooth extraction, the the divergent results, it is impossible to suggest that

one technique may cause higher implant failure rates gle implants immediately placed and restored
when compared to the other one. 4 months later either with Morse taper connection or
conventional abutments (20 implants each group). A
Number of implants for overdentures. It is generally provisional screw-retained crown was placed and
agreed that removable mandibular dentures retained adjusted for non-functional loading within 24 h. After
by some implants (overdentures) are more satisfactory 1 year, no implants were lost in the conventional
and functional than conventional dentures. Some abutments group, whereas one implant failed in the
researchers have been questioning whether the varia- Morse taper connection group.
tion in the number of implants used to support a
mandibular overdenture may influence the implant Immediate/early/delayed/late loading. In implantology,
failure rates. an undisturbed healing period was previously thought
There seems to be no statistically significant differ- needed to ensure osseointegration. A modified proto-
ence in implant failure rates between the use of one col with immediate or early loading has been tested,
or two implants (281), or two or four implants (282– in order to achieve a more rapid treatment and to
284) to support mandibular overdentures. In one reduce discomfort of wearing removable appliances
study, the implant failures occurred before the load- during the healing period.
ing, thus no comparisons were possible between the Some studies observed that failure rates for immedi-
groups concerning implant survival (285). It is impor- ately loaded implants were significantly higher than
tant to note that the attachment system used varied implants loaded after a healing period of 6 weeks
among studies, generally being ball-attachment in (294), 3 months (45), 4 months (295), 6 months (69,
studies comparing one and two implants, and bar-clip 296). The difference in implant failure rates was also
attachments in studies comparing two and four significant in comparison of loading of implants
implants. A study comparing mandibular overden- within 6 weeks versus loaded after 6 weeks (219).
tures being supported by one or four implants has not However, most of the studies showed no statistically
been performed so far. significant difference in comparison of implant failure
rates of implants loaded after several different healing
Type of overdenture attachment. Several studies observed periods, the comparisons being same day of surgery
no statistically significant difference in the implant versus next day (297), immediately versus 7 days
failure rates between implants used to support over- (298), immediately versus within 2 weeks (299),
dentures using different attachment systems, being immediately versus 1 month (300, 301), immediately
between gold-alloy bar without extension versus versus 6 weeks (302–305), immediately versus
gold-alloy bar with extension versus non-connected 2 months (306, 307), immediately versus 3–4 months
abutments with different attachments (111), bar with (55, 82, 103, 268, 308–316), immediately versus
clips versus ball attachments (126, 286), ball versus 6 months (187, 317), immediately versus after
magnet attachments (287), magnets versus ball 4–8 months (318), immediately versus 1 week versus
attachments versus straight bars (288), bar versus 3–4 months (319), within 9–18 days versus
telescopic crowns (289) and ball versus resilient tele- 25–5 months (320), 10 days versus 3 months (321),
scopic crown (290). Only one study (291) found sig- within 2 weeks versus 6 weeks–6 months (68),
nificant difference in implant failure rates between within 20 days versus after 4 months (31), within
standard ball attachments (25%), large ball attach- 3 weeks versus 3 months (48, 322), 6 versus
ments (0%) and Locator attachments (0%). In one 12 weeks (237, 323), 6 weeks versus 6 months (324).
study (292), the failure of implants occurred during
the healing period, and none after the prosthetic con- CNC (or laser-welded) titanium frameworks versus cast
structions and loading, which prevents any reliable gold-alloy frameworks. Titanium frameworks have for
comparison between the techniques concerning the more than 20 years been used as an option to gold-
implant survival. alloy castings to restore edentulous patients with
screw-retained implant-supported prostheses (164).
Morse taper connection versus conventional abutments. Pi- Few controlled clinical studies comparing the two
eri et al. (293) compared the clinical outcomes of sin- techniques were published.

One study showed that there is a greater risk of internal sinus lift and 2 (26%) in the native maxilla
implant failures with the implants supporting prosthe- group.
ses with laser-welded titanium frameworks compared
with implants supporting conventional gold-alloy Reason for tooth extraction. Grunder et al. (87) assessed
frameworks (325). Other studies did not show signifi- the clinical outcomes of 264 implants placed in fresh
cant difference in implant failure rates between the extraction sites, in healed sites, and with membranes
uses of these two frameworks (326, 327), or between placed over the extraction site. More implants were
computer numeric control-milled titanium frame- lost if the reason for tooth extraction was periodontitis
works versus conventional gold-alloy frameworks (102%) when compared with trauma (0%), root
(164). fracture (0%), periapical inflammation (0%) and car-
ies (50%). If teeth were extracted for a combination
of reasons, in four of six failures, periodontitis was
Other conditions
one of the reasons for tooth extraction. Only three of
Contamination with pre-fabricated stainless steel guide ver- the 14 patients having an implant failure had no his-
sus no guide. Jofr
e et al. (328) evaluated the 2-year sur- tory of periodontitis before tooth extraction.
vival rate of splinted mini-implants that came into
contact with stainless steel prior to their insertion into Narrow versus wide edentulous maxilla crest. Friberg and
the anterior mandible. A total of 46 implants were Jemt (218) compare the outcome of implants placed
inserted using a pre-fabricated stainless steel guide in edentulous maxillae with either wide (226
(group 1), whereas 44 implants were placed without a implants) or narrow (279 implants) jaw shapes and
guide (group 2). One implant failed (978% survival followed clinically up to 7 years. The implant CSR at
rate) in group 1, and four failed in group 2 (909% sur- 7 years was of 946% and 936% for wide and narrow
vival rate). Energy dispersive X-ray spectroscopy analy- crests, respectively.
sis revealed carbon and oxygen on all implants. On the
implants that were in contact with stainless steel, addi-
Narrative review with focus on oral
tional elements were identified, including silica, cal-
implant failures and marginal bone
cium, iron and chromium. The authors concluded that
resorption in relation to some findings in
contact between mini-implants and stainless steel sur-
the systematic review
gical guides does not seem to generate contamination
that compromises the survival of mini-implants. The previous part of this paper represents a systematic
screening process review on reasons for implant fail-
Control versus immediate orthodontic loading. Palagi et al. ure. We have added this narrative review on implant
(329) evaluated 20 implants under immediate pros- failures and bone resorption to ensure that our paper
thetic and orthodontic forces after a follow-up period is to date and that we will not miss any important
of at least 2 years. All implants received screwed pro- reasons for implant problems. This narrative part is of
visional crowns immediately after surgery. The a lower level of evidence than found in the first part.
implants were randomly divided into two groups: the We will start by commenting on some findings rela-
control group (nine implants), with a healing period tive to the systematic review of the present paper
of 4 months, and the immediate orthodontic loading where non-comparative data are available, at times
group (11 implants), and the survival rates were pointing in a different direction than described in the
889% and 909%, respectively. systematic review. We will then comment on mar-
ginal bone resorption that, if unstoppable, certainly
Internal sinus lift without graft material versus implants in may result in secondary failures of implants.
native posterior maxilla. In the study of Gabbert et al. The most commonly used material for oral implants
(330), 36 patients received 92 screw-shaped implants is commercially pure (c.p.) titanium found in more
in combination with an internal sinus lift without than 95% of all annually placed implants. C.p. tita-
graft material, while 44 patients received 77 implants nium is an excellent implant material where a dense
in the native posterior maxilla. After a mean follow- oxide layer will make it biocompatible (331). How-
up was 12 years, four implants (43%) failed in the ever, recently there have been reports of a possible

allergy to titanium (332). Titanium allergy cannot be limited to compromised situations such as patient
excluded as a reason for implant loss (333), but a smoking, implant placement in irradiated areas and
number of reports including the so-called Melisa test applied direct loading in addition to benefits with
for evaluating allergies (334) have been criticised for maxillary and short implants.
lack of scientific correlates. In the past, aluminium Focusing on implant designs, we have solid informa-
oxides were used as implant materials too (335). tion that cylindrical implants without threads do not
However, ceramic materials share the shortcoming of work well in the long run. With the possible exception
ageing in the body with due possible subsequent of one porous-coated oral implant system, such
implant fractures, a known fact for aluminium oxides unthreaded designs have been more or less withdrawn
and a clear long-term risk with zirconium materials from clinical usage due to marginal bone resorption
too (6). In fact, implant fractures with titanium (338–340). The precise reason for clinical failure with
implants were not uncommon in the infancy of osseo- unthreaded oral implant systems is difficult to assess.
integration (110), but are much more uncommon Is the reported high marginal bone loss related to the
today when we use titanium grade 3 or 4 materials cylindrical shape of the implant per se or to the rela-
instead of c.p. titanium grade 1 originally preferred by tively rough plasma-sprayed surface typical for such
Branemark et al. (336). implant designs or even a combination of these two
In the systematic review, an obvious conclusion is characteristics? We have now come over to the second
that maxillary implants perform less well than man- part of this narrative review; marginal bone resorption
dibular ones. This statement is based on machined and have already learnt that the type of implant is
and other old implant surfaces and has been thor- indeed important for bone maintenance but only as
oughly documented. However, with modern moder- one factor. In fact, there are other factors behind mar-
ately rough surfaces, the situation may have changed. ginal bone loss, such as clinical handling and state of
In one study from the Br anemark clinic based on the patient, as described by Albrektsson et al. (341).
thousands of implants, it was clearly indicated that Some clinicians have simply more marginal bone loss
early maxillary failures dropped rapidly with the and higher failure rates than others. Albrektsson (342)
introduction of modern moderately rough surfaces investigated the clinical outcome of all implants placed
(337). The drop in maxillary failures was so substan- at the Branemark clinic in 1986 and found that one
tial that there seemed to be no differences in clinical surgeon (who was not inexperienced) was alone
outcome between mandibular and maxillary implants responsible for the majority of failures with the
with the more modern implants. A recent overview implants and also responsible for the majority of those
displayed similar findings; different types of modern implants that demonstrated undue marginal bone
implant brands characterised by a moderately rough resorption. The old machined Br anemark implant was
surface had significantly improved clinical outcome in the only one used in this study as well as in a study by
the maxilla compared with the situation when older Bryant (343) who reported of a correlation between
implants types were preferred, R. Jimbo, T. Albrekts- implant outcome/marginal bone resorption and the
son, unpublished data. A very similar observation was individual surgeon who had placed the implants as
made with short implants where the systematic well as the initial prosthodontist who had taken care
review of the present paper pointed to increased fail- of the patients. Everyone is not a good surgeon even if
ure rates of short implants, a finding that may be dis- he or she has had proper training and experience. Sim-
puted with the use of modern implants. It seems ilar viewpoints of the close correlation between
indeed to be the case that the modern surfaces, implant problems and the involved clinician were dis-
known to display a stronger bone to implant contact cussed in a recent book pointing to the human factor
than found with the old standard of machined being of main importance for failure (344). The com-
implants, compensate for the minimal osseointegrated bined findings in these reports point to the importance
area of the short implants. However, modern implants of proper clinical handling to avoid implant failure and
seem to have a very similar clinical outcome as older that poor clinical techniques may be behind a large
types of implants in uncompromised situations such number of implant failures and cases that later develop
as placement between the mental foraminae of the peri-implantitis (342–344). Another example of the
mandible. The advantage of the modern implants is importance of clinical handling for avoidance of mar-

ginal bone loss and failure emanate from experience patients with poor bone quality/quantity) but do also
with the Nobel Direct system (219). This implant sys- include cement remnants in the soft tissues, suddenly
tem showed either failure or rapid marginal bone loss changed loading patterns or certain types of patient
in about one-third of placed implants. However, the disease (6, 7).
problem seemed not to have to do with the implant The end result of marginal bone loss may indeed be
design per se but with the clinical procedures; clinicians peri-implantitis that may threaten implant survival,
were recommended to grind down the implant in situ but the start of the problem has nothing to do with
(which of course caused severe bone vibrations and periodontitis, at least we lack any evidence of this as of
due destruction) and then load the implants immedi- today. To maintain oral implants in the body, we have
ately. This is a vicious combination of drastic clinical to have a foreign body equilibrium without or with
handling after placement with a direct loading proce- only very little marginal bone resorption. More severe
dure that in itself presents a threat to implant survival marginal bone resorption will lead to peri-implantitis
(68, 219). Another threat to implant survival related that may start as an aggravation of the inflammatory
to clinical handling may come from inexperienced cli- response inevitable to any foreign body such as an oral
nicians (6). It is also important that the whole team implant. However, as demonstrated by pioneers
could plan and design a prosthetic suprastructure in a behind reactions to foreign bodies (346–348), the pres-
way that it will be possible for the patient to perform ence of a foreign body may render the tissues to react
an adequate routine oral hygiene. For example, non- with a much lowered resistance to infection. Foreign
connected implants are generally considered to facili- bodies in form of sutures were combined with bacterial
tate optimal oral hygiene by the patients because of exposition and resulted in severe infections, whereas
superior accessibility. the same amount of injected bacteria caused no visible
All these examples of increased failure rates and/or harm if no foreign body was present (346–348). Future
increased marginal bone resorption point to the need research will be guided by injecting a defined amount
for a shift of focus away from assumed similarities of bacteria in animals with or without an oral implant
between teeth and implants as the background for to find out whether Koch’s postulates (349) apply to
implant problems. There are, in fact, very little if any oral implants or not.
evidence of a true connection between periodontitis Understanding the mechanisms behind marginal
and the start of marginal bone loss around oral bone resorption will help in minimising the problem
implants. Furthermore, such a connection is most in the future. The proper therapy to established
unlikely in the light of the very different interfacial peri-implantitis may be difficult to identify, but the
situations between the tooth and the implant. The clinician may act rapidly when pre-stages to peri-
former is anchored in a periodontal ligament that implantitis is evidenced by an onset of bone resorp-
allows movement and is characterised by a rich vascu- tion. Take, for example, the case of cement remnants
larisation and innervation. This stands in stark con- that really represent a foreign body on another for-
trast to the implant that is clinically stable and has an eign body. In case such cement particles are carefully
interfacial low blood circulation and an almost total removed from the soft tissues, we may establish a sec-
lack of interfacial nerves. In recent studies, distinctly ondary foreign body equilibrium if with some bone
different genetical patterns were observed between resorption. With other words, we act before a perma-
periodontitis and peri-implantitis (204), and the nent state of peri-implantitis has been established.
implant was found representative of a foreign body Another situation may be the patient who rapidly
reaction (7). The successful implant is one that main- loses teeth around a single implant; if the body has
tains osseointegration, a typical foreign body response no time to adapt to the new loading situation mar-
to the hardware that is shielded off from the tissues ginal bone resorption may follow, and in this situa-
by embedment in bone. We see a similar foreign body tion, it may prove needed to temporarily unload the
reaction to Bioss particles, likewise separated from the implant to give bone tissue time to gradually adapt to
tissues by bony encapsulation (345). What may dis- the new situation. These two examples point to the
turb the foreign body equilibrium leading to marginal necessity to be clinically active in cases of early bone
bone loss has to part already been mentioned (unsuit- resorption instead of falsely believing that we have a
able implant designs, poor clinical handling and situation beyond clinical control.

limit and implants that are unaccounted for in dropout

Concluding remarks
patients. There is a risk that the latter category of unac-
Implant therapy is, today, a routinely used treatment counted for implants may present with higher failure
option, frequently used even for young individuals. rates than those implants that are yet not followed up
The implants must therefore ideally function for dec- for a specific time but still remain in the study.
ades. Ten years or more clinical outcomes with mod- Some of the factors compared in the present review
ern, moderately rough implants point to a summed were only covered in a couple of papers, and hence,
frequency of implant failure and peri-implantitis to be findings from such comparative studies would present
within 5% of all placed implants (5). Thus, one short- only weak evidence for the preference of one particu-
coming of studies on implant failures is related to lar approach.
time – 5-year survival rates of a particular implant Considering these limitations and according to the
system may be quite acceptable, but ongoing bone findings of the present study, it may be suggested that
resorption may nevertheless present with poor long- the following situations are correlated to increase the
term results of the same design. implant failure rate: a low insertion torque of implants
There are other limitations of clinical studies such that are planned to be immediately or early loaded,
as (i) study conducted in a single centre; (ii) con- inexperienced surgeons inserting the implants, implant
trolled studies but not randomised; (iii) the lack of insertion in the maxilla, implant insertion in the pos-
double blindness; (iv) limited number of patients/ terior region of the jaws, implants in heavy smokers,
sample size, which may be too low to detect a statisti- implant insertion in bone qualities type III and IV,
cally significant difference in implant failures between implant insertion in places with small bone volumes,
the different procedures/conditions being compared use of shorter length implants, greater number of
and may not have been scientifically sound. The small implants placed per patient, lack of initial implant sta-
sample size limited the power of the tests; therefore, bility, use of cylindrical (non-threaded) implants and
the lack of statistical significance taken alone is not prosthetic rehabilitation with implant-supported over-
strong evidence of similarity between the groups; and dentures. Moreover, it may be suggested that the fol-
(v) statistical method used for evaluation of implant lowing situations may be correlated with an increase in
failure/survival rates. the implant failure rate: use of the non-submerged
Concerning the statistical method, the typical technique, immediate loading, implant insertion in
method of calculating survival in most studies is a sim- fresh extraction sockets, smaller diameter implants.
ple ratio of the number of implants removed to the The higher failure rate documented for shorter
total number of implants placed, which is misleading implants compared with longer ones may be related
because it does not take into consideration the effects to compromised placement in restricted anatomical
of time. The life-table analysis would be a more appro- sites and to the reduced surface area available to con-
priate method (122). This method calculates the num- tact the bone. The combination of poor bone quality
ber of failures in a defined interval versus the number and shorter implant length has been recognised as
of implants at risk during that interval, and this ratio is providing less mechanical stability at the time of
then cumulated over the study period. At each suc- implant placement and during the osseointegration
ceeding interval, the number of failed implants and the period. This emphasises the rather deleterious combi-
number of implants lost to follow-up are subtracted nation of a small bone volume and a soft bone tex-
from the number of implants at risk from the preceding ture, when using short implants.
interval. A characteristic feature of this progression is Some recently published studies of the narrative
that the number of implants at risk decreases with time. part of our review suggest that modern, moderately
Therefore, the confidence interval for the mean sur- rough implants may present with similar results irre-
vival increases as a function of time. As a consequence, spective if placed in maxillas, in smoking patients or
similar absolute differences between two populations using only short implants.
may be statistically significant at an early interval but
not significant at later intervals (122). However, one
Ethical approval
shortcoming of the CSR table is the lack of separation
between implants yet not followed up for a given time Not applicable.

Source of funding the survival of a new implant design. J Oral Implantol.

2004;30:144–151.
This work was supported by CNPq, Conselho Nacional 13. Abu-Ta’a M, Quirynen M, Teughels W, van Steenberghe
ogico – Brazil.
de Desenvolvimento Cientıfico e Tecnol D. Asepsis during periodontal surgery involving oral
implants and the usefulness of peri-operative antibiotics: a
prospective, randomized, controlled clinical trial. J Clin
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14. Anitua E, Aguirre JJ, Gorosabel A, Barrio P, Errazquin
There is no conflict of interest. JM, Roman P et al. A multicentre placebo-controlled
randomised clinical trial of antibiotic prophylaxis for
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journal of dentistry 43 (2015) 487–498
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.intl.elsevierhealth.com/journals/jden
Review
Smoking and dental implants: A systematic review

and meta-analysis
Bruno Ramos Chrcanovic a,*, Tomas Albrektsson a,b, Ann Wennerberg a

a
Department of Prosthodontics, Faculty of Odontology, Malmö University, Malmö, Sweden
b
Department of Biomaterials, Göteborg University, Göteborg, Sweden
article info abstract
Article history: Objective: Recent studies implicate smoking as a significant factor in the failure of dental
Received 31 October 2014 implants. This review aims to test the null hypothesis of no difference in the implant failure
Received in revised form rates, risk of postoperative infection, and marginal bone loss for smokers versus non-
3 March 2015 smokers, against the alternative hypothesis of a difference.
Accepted 5 March 2015 Data: Main search terms used in combination: dental implant, oral implant, smoking,
tobacco, nicotine, smoker, and non-smoker.
Sources: An electronic search was undertaken in September/2014 in PubMed/Medline, Web
Keywords: of Science, Cochrane Oral Health Group Trials Register plus hand-searching.
Dental implants Study selection: Eligibility criteria included clinical human studies, either randomized or not.
Smoking The search strategy resulted in 1432 publications, of which 107 were eligible, with 19,836
Implant failure rate implants placed in smokers, with 1259 failures (6.35%), and 60,464 implants placed in non-
Postoperative infection smokers, with 1923 failures (3.18%).
Marginal bone loss Conclusions: The insertion of implants in smokers significantly affected the failure rates, the
Meta-analysis risk of postoperative infections as well as the marginal bone loss. The results should be
interpreted with caution due to the presence of uncontrolled confounding factors in the
included studies.
Clinical significance: Smoking is a factor that has the potential to negatively affect healing and
the outcome of implant treatment. It is important to perform an updated periodic review to
synthesize the clinical research evidence relevant to the matter.
# 2015 Elsevier Ltd. All rights reserved.
diseases.1 Studies have also demonstrated the detrimental

1. Introduction effects of smoking on oral health. A clinical study2 observed
that smokers had a higher prevalence of moderate and severe
Nicotine is the most important constituent among more than periodontitis and higher prevalence and extent of attachment
4000 potentially toxic substances in tobacco products. It is the loss and gingival recession than non-smokers, suggesting
main chemical component responsible for tobacco addiction, poorer periodontal health in smokers. In addition, smokers
appears to mediate the haemodynamic effects of smoking, had a higher number of missing teeth than non-smokers.
and has been implicated in the pathogenesis of numerous Concerning the bone-implant interface, the deleterious effects
* Corresponding author. Tel.: +46 725 541 545; fax: +46 40 6658503.
E-mail addresses: [email protected], [email protected] (B.R. Chrcanovic).
http://dx.doi.org/10.1016/j.jdent.2015.03.003
0300-5712/# 2015 Elsevier Ltd. All rights reserved.
488 journal of dentistry 43 (2015) 487–498
of tobacco smoke reflects a series of direct and indirect reports, technical reports, biomechanical studies, finite ele-
systemic and local effects on bone metabolism.3 It has been ment analysis (FEA) studies, animal studies, in vitro studies,
strongly suggested that local exposure of the peri-implant and review papers.
tissues to tobacco products is the main factor leading to an
overall increase in implant failure rate in smokers.4 A recent 2.4. Study Selection
meta-analysis on the subject5 observed that smoking was
associated with a higher risk of dental implant failure. The titles and abstracts of all reports identified through the
However, the review was only able to include 33 studies, electronic searches were read independently by three authors.
even though observational retrospective studies were eligible, For studies appearing to meet the inclusion criteria, or for
according to the inclusion criteria. Moreover, the study did not which there were insufficient data in the title and abstract to
evaluate the effects of smoking on marginal bone loss (MBL) make a clear decision, the full report was obtained. Disagree-
around implants. ments were resolved by discussion between the authors.
The ability to anticipate outcomes is an essential part of
risk management in an implant practice. Recognizing condi- 2.5. Quality Assessment
tions that place the patient at a higher risk of failure will allow
the surgeon to make informed decisions and refine the Quality assessment of the studies was executed according to
treatment plan to optimize the outcome.6 The use of implant the Newcastle–Ottawa scale (NOS), which is a quality assess-
therapy in special populations requires consideration of ment tool to use when observational studies are also included
potential benefits to be gained from the therapy. To better in systematic reviews.8 The NOS calculates the study quality
appreciate this potential, we conducted a systematic review on the basis of three major components: selection, compara-
and meta-analysis of both prospective and retrospective bility, and outcome for cohort studies. It assigns a maximum
studies to compare the survival rate of dental implants, of four stars for selection, a maximum of two stars for
postoperative infection, and MBL between smokers and non- comparability, and a maximum of three stars for outcome.
smokers. The present meta-analysis included non-random- According to that quality scale, a maximum of nine stars/
ized studies and performed several sensitivity analyses, in points can be given to a study, and this score represents the
order to verify whether the results were sensitive to restric- highest quality, where six or more points were considered of
tions on the data included. high quality.
2.6. Data Extraction and Meta-analysis

2. Materials and Methods
From the studies included in the final analysis, the following
This study followed the PRISMA statement guidelines.7 A data was extracted (when available): year of publication, study
review protocol does not exist. design, unicenter or multicenter study, country, setting
(academic, institutional, industry, etc.), number of patients,
2.1. Objective type of smokers included in the study, patients’ age, follow-up,
days of antibiotic prophylaxis, mouth rinse, implant healing
The purpose of the present review was to test the null period, failed and placed implants, postoperative infection,
hypothesis of no difference in the implant failure rates, marginal bone loss, implant surface modification, jaws
postoperative infection, and MBL for smokers or non-smokers, receiving implants (maxilla and/or mandible), type of pros-
against the alternative hypothesis of a difference. The focused thetic rehabilitation, and opposing dentition. Only one
question was elaborated by using the PICO format (partici- reviewer performed the data extraction. Authors were con-
pants, interventions, comparisons, and outcomes): in patients tacted for possible missing data.
undergoing implant placement, are patients who smoke Implant failure and postoperative infection were the
versus those who do not at higher risk for implant failure, dichotomous outcomes measures evaluated. Weighted mean
postoperative infection, and greater MBL? differences were used to construct forest plots of marginal
bone loss, a continuous outcome. The statistical unit for all
2.2. Search Strategies outcomes (‘implant failure’, ‘marginal bone loss’, and ‘post-
operative infection’) was the implant. Whenever outcomes of
See appendix-supplementary data. interest were not clearly stated, the data were not used for
analysis. The I2 statistic was used to express the percentage of
2.3. Inclusion and Exclusion Criteria the total variation across studies due to heterogeneity, with
25% corresponding to low heterogeneity, 50% to moderate, and
Eligibility criteria included clinical human studies, either 75% to high. The inverse variance method was used for
randomized or not, providing outcome data for dental implant random-effects or fixed-effects model. Where statistically
failure in smokers and non-smokers, in any group of patients significant (P < 0.10) heterogeneity is detected, a random-
(of any age, race, or sex), with no follow-up restrictions There effects model was used to assess the significance of treatment
were no time or language restrictions for the publications. For effects. Where no statistically significant heterogeneity was
this review, patients smoking a minimum of one cigarette per found, analysis was performed using a fixed-effects model.9
day were classified as smokers, and implant failure represents The estimates of relative effect for dichotomous outcomes
the complete loss of the implant. Exclusion criteria were case were expressed in risk ratio (RR) and in mean difference (MD)
journal of dentistry 43 (2015) 487–498 489
in millimetres for continuous outcomes, both with a 95% (duplicates). The three reviewers independently screened the
confidence interval (CI). Only if there were studies with similar abstracts for those articles related to the focus question. Of the
comparisons reporting the same outcome measures was resulted 968 studies, 754 were excluded for not being related to
meta-analysis to be attempted. In the case where no events the topic. Additional hand-searching of the reference lists of
(or all events) are observed in both groups, the study provides selected studies yielded 32 additional papers. The full-text
no information about relative probability of the event and is reports of the remaining 246 articles led to the exclusion of 139
automatically omitted from the meta-analysis. In this (these) because they did not meet the inclusion criteria (80 papers did
case(s), the term ‘not estimable’ is shown under the column of not inform the number of implants and/or failures in each
RR of the forest plot table. group, 32 review papers, 20 papers not evaluating failures, two
Sensitivity analysis tests were performed when possible, in same studies published in a different journal, two histologic
order to verify whether the results were sensitive to restric- studies, one earlier follow-up, one gene expression profile
tions on the data included. A funnel plot (plot of effect size study, and one case report paper). Thus, a total of 107
versus standard error) was drawn. Asymmetry of the funnel publications were included in the review.
plot may indicate publication bias and other biases related to
sample size, although the asymmetry may also represent a 3.2. Description of the Studies
true relationship between trial size and effect size.10
The data were analyzed using the statistical software Detailed data of the 107 included studies are listed in Table 1 and
Review Manager (version 5.3.3, The Nordic Cochrane Centre, 2 (appendix-supplementary data). Four randomized clinical
The Cochrane Collaboration, Copenhagen, Denmark, 2014). trials (RCT),11–14 16 controlled clinical trials (CCT),15–30 16
prospective studies,31–46 and 71 retrospective analyses47–117
were included in the meta-analysis. Seven CCTs15–17,22,27,29,30
3. Results were controlled for the patients’ smoking habit. Four RCTs and
nine of the CCTs included here were not controlled for the
3.1. Literature Search smoking habit.
In total, 39 publications16,19,24,25,27–30,32,33,35–37,41,44,45,51,54,
59,61,62,64,65,68,70,73–77,82,85,94,99,103,104,111,112,117
The study selection process is summarized in Fig. 1. The clearly defined what
search strategy resulted in 1432 papers. A number of 464 kind of smoking patients were included in their studies based
articles were cited in more than one research of terms on how many cigarettes the patients used to smoke per day.
Fig. 1 – Study screening process.

Three studies13,21,66 included light or heavy smokers ‘without

distinction’, or the patients were classified as non-smokers,
former smokers, and current smokers in two studies.55,67 Only
15 studies11,13,18,22,29,45,46,55,63,71,81,83,89,107,111 provided informa-
tion about postoperative infection, with 65 occurrences in a
total of 2580 patients receiving 7745 implants. In total, 18
studies12,14,29,30,39,44,65,74,75,78,91,99,103–106,113,115 provided infor-
mation about the marginal bone loss separated by groups
and with mean values and standard deviation.
From the 107 included studies, three studies12,14,104 did not
provide information about the implant failure rates separately
between smokers and non-smokers, reporting information
only about the marginal bone loss. From the 104 studies
comparing the implant failure rates, a total of 19,836 dental
implants were placed in smokers, with 1259 failures (6.35%),
and 60,464 implants were placed in non-smokers, with 1923
failures (3.18%). There were no implant failures in five
studies.24,28,94,95,105 In total, 44 studies11,15,17,20,22,26,30,34,37–39,
43,45,47,48,51,57,61,65,67,69,73,74,77,80,81,83,84,87,88,90,93,96,99–103,106,107,110,
112,116,117
informed whether there was a statistically significant
difference or not between the implant failure rates between
smokers and non-smokers, and
1720,22,26,30,34,39,61,69,73,81,83,88,90,99–101,110 of these studies did
not find a statistically significant difference favouring smokers
or non-smokers, one65 found a statistically higher implants
failure rate in non-smokers, while the other 26 studies found a
statistically higher implants failure rate in smokers.
3.3. Quality Assessment
In total, 85 studies were of high quality and 22 were of

moderate quality. The scores are summarized in Table 3
(appendix-supplementary data). The moderate quality of
some studies is due to four main reasons: (a) the fact that
the individuals were not representative from the general
population seeking dental implant treatment, (b) the ascer-
tainment of exposure is an issue in retrospective analyses
given that this data is collected using questionnaires, (c) short
follow-ups, and (d) a considerable number subjects lost to
follow-up.
3.4. Meta-analysis
In this study, a random-effects model was used to evaluate the

implant failure in the comparison between the procedures,
since statistically heterogeneity was found (P < 0.00001;
I2 = 51%). The insertion of dental implants in smokers
statistically affected the implant failure rates (P < 0.00001; Fig. 2 – Forest plot for the event ‘implant failure’.
Fig. 2). A RR of 2.23 (95% CI 1.96–2.53) implies that failures of
implants inserted in smokers are 2.23 times likely to happen
than failures of implants inserted in non-smokers; i.e. the analysis was performed. When only the studies inserting
insertion of implants in smokers increases the risk of implant implants in maxillae were pooled, a RR of 2.22 resulted (95% CI
failure by 123%. The insertion of dental implants in smokers 1.63–3.01; heterogeneity: P = 0.005; I2 = 49%, random-effects
statistically affected the incidence of postoperative infections model; and Fig. 5—appendix-supplementary data), also
(RR 2.01, 95% CI 1.09–3.72; P = 0.03; heterogeneity: P = 0.63; statistically affecting the implant failure rates (P < 0.00001).
I2 = 0%, fixed-effects model; and Fig. 3), as well as the marginal When only the studies inserting implants in mandibles were
bone loss (MD 0.32, 95% CI 0.21–0.43; P < 0.00001; heterogene- pooled, a RR of 2.61 resulted (95% CI 0.92–7.39; heterogeneity:
ity: P < 0.00001; I2 = 95%, random-effects model; and Fig. 4). P = 0.09; I2 = 48%, random-effects model; and Fig. 6—appendix-
Since the effect size could differ depending on the insertion supplementary data), not statistically affecting the implant
of implants in bone areas of different quality, a sensitivity failure rates (P = 0.07).
Fig. 3 – Forest plot for the event ‘postoperative infection’.
Fig. 4 – Forest plot for the event ‘marginal bone loss’.
Other sensitivity analyses were also performed, pooling model; and Fig. 10—appendix-supplementary data), and
studies evaluating different implant surface modification oxidized surface implants (RR 5.07, 95% CI 2.76–9.30,
processes, there was a statistically significant difference P < 0.00001; heterogeneity: P = 0.35; I2 = 10%, fixed-effects
between smokers and non-smokers when the only studies model; and Fig. 11—appendix-supplementary data).
making use of turned implants were pooled (RR 2.17, 95% CI
1.53–3.06, P < 0.0001; heterogeneity: P = 0.001; I2 = 64%, ran- 3.5. Publication Bias
dom-effects model; and Fig. 7—appendix-supplementary
data), acid-etched surface implants (RR 2.07, 95% CI 1.20– The funnel plot for the studies reporting the outcome ‘implant
3.58, and P = 0.009; heterogeneity: P = 0.50; I2 = 0%, fixed- failure’ did not show a clear asymmetry (Fig. 12), indicating
effects model; and Fig. 8—appendix-supplementary data), possible absence of publication bias.
the same happening to sandblasted and acid-etched surface
implants (RR 2.92, 95% CI 1.60–5.34, and P = 0.0005; heteroge-
neity: P = 0.02; I2 = 50%, random-effects model; and Fig. 9— 4. Discussion
appendix-supplementary data), sandblasted and fluoride-
modified surface implants (RR 4.18, 95% CI 2.06–8.50, and In a meta-analysis, homogeneity implies a mathematical
P < 0.0001; heterogeneity: P = 0.22; I2 = 32%, fixed-effects compatibility between the results of each individual trial.
Fig. 12 – Funnel plot for the studies reporting the outcome event ‘implant failure’.
Potential biases are likely to be greater for non-randomized Furthermore, sensitivity analysis suggests that smoking
studies compared with RCTs, so results should always be significantly affects the survival of implants inserted only in
interpreted with caution when they are included in reviews the maxilla. The lack of statistical significance for the
and meta-analyses.10 However, narrowing the inclusion mandible is surprising but is most likely explained by the
criteria increases homogeneity but also excludes the results limited number of studies16,24,28,34,35 reporting implant sur-
of more trials, and thus risks the exclusion of significant vival for smokers and non-smokers exclusively in the inferior
data.118 This was the reason to include non-randomized jaw. A previous review125 on the subject suggested that
studies in the present meta-analysis. The issue is important smoking may be a significant risk factor with an adverse effect
because meta-analyses are frequently conducted on a limited on implant survival and success in areas of loose trabecular
number of RCTs. In meta-analyses, such as these, adding more bone, but may not be as significant for good bone sites. It is
information from observational studies may aid in clinical important to stress that caution is required when sensitivity
reasoning and establish a more solid foundation for causal analyses are performed, because both type I and type II errors
inferences.118 are likely given the multiple testing and the subgrouping.
In the present meta-analysis, the statistical unit of analysis Moreover, these studies were never designed for showing
for ‘implant failure’ was the implant. It would be technically these effects, and thus all the findings are presumably heavily
more correct to adjust for the effect of clustered, correlated biased.
observations; however, it is a challenging analytic method and Concerning the subgroup analyses for the different
the implant survival is so high that failing to adjust for surfaces, sensitivity analyses suggest that smoking signifi-
clustered, correlated observations would have little effect on cantly affects the survival of implants submitted to any
the estimate and deviation of survival.119 surface modification here reviewed (turned, acid-etched,
The results of the present study suggest that the insertion of sandblasted and acid-etched, sandblasted and fluoride-modi-
dental implants in smokers affects implant failure rates, the risk fied, and oxidized). The fact is that titanium with different
of postoperative infection, and the MBL. The increase of implant surface modifications shows a wide range of chemical and
failure rates due to smoking is hypothesized to be related mainly physical properties, and surface topographies or morpholo-
to the effect of smoking in osteogenesis and angiogenesis. It was gies, depending on how they are prepared and handled.126–128
shown120 that nicotine inhibited the gene expression of several It is known that the surface properties of dental implants, such
enzymes that play an important role in the regulation of as topography and chemistry are relevant for the osseointe-
osteoblast proliferation, differentiation, and apoptosis, with gration process and may influence the results.129 It seems
subsequent important effects on bone formation and remodel- evident from our results (Figs. 7–11) that smoking is associated
ling.121 Moreover, it was demonstrated122 that nicotine exposure with increased number of failures irrespective of the type of
has direct effects on blood vessels, producing vasoconstriction implant surface being investigated. Moreover, a higher risk
and systemic venoconstriction, which decreases blood perfusion ratio was observed for implants with roughened surfaces in
and causes low oxygen and ischaemia.123 Besides carrying comparison with turned implants in smokers. Having said
oxygen and nutrients to bone tissue, blood flow plays an active this, there is some contradictory evidence published that
role in bone formation and remodelling by mediating the smoking mainly is associated with older turned implant
interactions among osteoblasts, osteocytes, osteoclasts, and surfaces but not with more modern ones. Balshe et al.130
vascular cells at a variety of levels.124 observed that smoking was not identified as significantly
associated with implant failure among the moderately rough together may be more detrimental than the individual risk
surface (anodized) implants, while it was associated with factors alone.125 The lack of control of the confounding factors
implant failure among the group with minimally rough limited the potential to draw robust conclusions. Second, most
surface implants. Even though Balshe et al.’s paper130 of the included studies had a retrospective design, and the
presented a great number of implants in their study nature of a retrospective study inherently results in flaws.
(n = 4607), the results were not included in the present These problems were manifested by the gaps in information
meta-analysis because the number of implants placed and and incomplete records. Furthermore, all data rely on the
the number of failures were not reported separately between accuracy of the original examination and documentation.
smokers and non-smokers. The evidence presented by Balshe Items may have been excluded in the initial examination or
et al.130 did not fulfil all requirements to be included in the not recorded in the medical chart.139–141 In a retrospective
meta-analysis, but is nevertheless an important contribution study, it is difficult to assess the adverse effects of smoking on
since a great number of implants are being investigated. More the prognosis of implants purely on the basis of implant failure
recently, Sayardoust et al.103 showed that turned implants because of the multifactorial genesis of implant failure.6 Third,
failed more frequently and lost more marginal bone in much of the research in the field is limited by small cohort size
smokers, and that oxidized implants showed similar failure and short follow-up periods. It is important to stress that some
rates and bone loss in smokers and never-smokers. These publications included in this review have a short-term follow-
contrasting results between the present meta-analysis and up period, of up to 3 years. In a 12-month follow-up study, Kan
previous studies indicate that controversy still exists and that et al.51 reported a 93.04% success for non-smokers and an
there is a need for more studies to evaluate the long-term 82.82% success for smokers. In a second study by the
outcome of implants with altered surface characteristics in authors,142 but now with a 60-month follow-up, the success
smokers.125 The studies included here made use of implants rate for the non-smokers was 82.7% and for smokers was
with several different brands and surface treatments. 65.3%. Thus, if one considers the difference in success rates for
The results of the present study have to be interpreted with smokers and non-smokers with implants placed in loose
caution because of its limitations. First of all, all confounding trabecular bone sites that are followed over a longer period of
factors may have affected the long-term outcomes and not time, the adverse effect of smoking may be more evident. A
just the fact that implants were placed in smokers or non- longer follow-up period can lead to an increase in the failure
smokers, and the impact of these variables on the implant rate, especially if it extended beyond functional loading,
survival rate, postoperative infection, and marginal bone because other prosthetic factors can influence implant failure
loss131–138 is difficult to estimate if these confounding factors from that point onward. This might have led to an underesti-
are not identified separately between the two different mation of actual failures in some studies. However, it is hard to
procedures in order to perform a meta-regression analysis. define what it would be considered as a short follow-up period
The studies included here have a considerable number of to evaluate implant failures in smokers. Fourth, the criteria for
confounding factors, and most of the studies, if not all, did not the classification of patients as ‘smokers’ and ‘non-smokers’
inform how many implant were inserted and survived/lost in were not always reported by the included studies, which
several different conditions. The use of grafting in some probably resulted in a poor homogeneity of the study group.
studies is a confounding risk factor, as well as the insertion of Fifth, most included studies are characterized by a low level of
some or all implants in fresh extraction sockets, the insertion specificity, where the assessment of smoking as a complicat-
of implants in different locations, different healing periods, ing factor for dental implants was seldom the main focus of
different prosthetic configurations, type of opposing dentition, the investigation.
different implant angulation ranges, splinting of the implants,
and the presence of bruxers, or diabetics patients. The dose
effect of smoking is another important consideration. There is 5. Conclusion
evidence to suggest that smoking may have a dose-related
effect on osseointegration.70 Unfortunately, not all studies The results of the present review should be interpreted with
included here reported the quantity of cigarettes smoked per caution due to the presence of uncontrolled confounding
day, and almost none reported the number of years those factors in the included studies. Within the limitations of the
patients have smoked. The real fact is that individual patients existing investigations, the results of the present study
sometimes present with more than one risk factor, and groups suggest that the insertion of dental implants in smokers
of patients are typically heterogeneous with respect to risk affects the implant failure rates, the incidence of postopera-
factors and susceptibilities so the specific effect of an tive infections, as well as the marginal bone loss.
individual risk factor could be isolated neither for individual
studies nor for the present review. This is understandable and
expected because study populations are typically representa- Acknowledgements
tive of normal populations with various risk factors.125 To
precisely assess the effect of a risk factor on implant This work was supported by CNPq, Conselho Nacional de
outcomes, it would be ideal to eliminate all other risk factors Desenvolvimento Cientı́fico e Tecnológico–Brazil. The authors
from the study population. Not only does the coexistence of would like to thank Dr. Rodolfo Gianserra, for having sent us
multiple risk factors within a study population create an his article, Mrs. Angela Ruban, who provided us some missing
inability to assess the specific effect of one individual risk information about Dr. Devorah Schwartz-Arad’s article, Dr.
factor, but there is a possibility that certain risk factors Derk Siebers, Dr. James S. Hodges, Dr. Ronen Ofec, Dr. David
Schneider, and Dr. Swati Ahuja, who provided us some 13. Cannizzaro G, Felice P, Leone M, Ferri V, Viola P, Esposito
missing information about their studies, and Dr. Torsten Jemt, M. Immediate versus early loading of 6.5 mm-long flapless-
placed single implants: a 4-year after loading report of a
Dr. Miguel de Araújo Nobre, and Dr. Francesco Guido
split-mouth randomised controlled trial. European Journal of
Mangano, who replied our e-mail, even though it was not
Oral Implantology 2012;5:111–21.
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646098
research-article2016
JDRXXX10.1177/0022034516646098Journal of Dental ResearchEarly Dental Implant Failures
Research Reports: Clinical

Journal of Dental Research
2016, Vol. 95(9) 995–1002
Factors Influencing Early Dental © International & American Associations
for Dental Research 2016
Implant Failures Reprints and permissions:

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DOI: 10.1177/0022034516646098
jdr.sagepub.com
B.R. Chrcanovic1, J. Kisch2, T. Albrektsson1,3,

and A. Wennerberg1
Abstract
The purpose of the present study was to assess the influence of local and systemic factors on the occurrence of dental implant failures
up to the second-stage surgery (abutment connection). This retrospective study is based on 2,670 patients who received 10,096 implants
and were consecutively treated with implant-supported prostheses between 1980 and 2014 at 1 specialist clinic. Several anatomic-,
patient-, health-, and implant-related factors were collected. Descriptive statistics were used to describe the patients and implants.
Univariate and multivariate logistic regression models were used at the patient level as well as the implant level to evaluate the effect of
explanatory variables on the failure of implants up to abutment connection. A generalized estimating equation method was used for the
implant-level analysis to account for the fact that repeated observations (several implants) were available for a single patient. Overall,
642 implants (6.36%) failed, of which 176 (1.74%) in 139 patients were lost up to second-stage surgery. The distribution of implants in
sites of different bone quantities and qualities was quite similar between implants lost up to and after abutment connection. Smoking and
the intake of antidepressants were the statistically significant predictors in the multivariate model (ClinicalTrials.gov NCT02369562).
Keywords: endosseous dental implantation, osseointegration, treatment outcome, adverse effects, survival rate, multivariate analysis
Introduction Materials and Methods

Nowadays dental implant placement is an effective and pre- Materials
dictable treatment modality for replacing missing teeth in fully
and partially edentulous patients. Nevertheless, failures still This retrospective study is based on all 2,670 patients who
happen despite high implant survival and success rates received 10,096 implants and were consecutively treated with
(Chrcanovic et al. 2014). Failures of dental implants can be implant-supported prostheses between 1980 and 2014 at 1 spe-
subdivided into early and late failures, depending on whether cialist clinic (Clinic for Prosthodontics, Centre of Dental
they occur before or at abutment connection surgery (early) or Specialist Care, Malmö, Sweden). The study was approved by
after occlusal loading by a prosthetic restoration (late). This the Regional Ethical Review Board in Lund (Dnr 2014/598,
subdivision is relevant because it suggests that failures in these Dnr 2015/72). This study is in concordance with the STROBE
2 distinct periods may be associated with different factors. An (Strengthening the Reporting of Observational Studies in
early failure of an implant results from an inability to establish Epidemiology) guidelines for observational studies.
an intimate bone-to-implant contact. In this case, bone healing
after implant insertion is impaired and may be influenced by Inclusion and Exclusion Criteria
local and systemic factors (Alsaadi et al. 2007). Systemic dis-
eases and compromising risky habits may affect oral tissues by All implants that had failed up to second-stage surgery (abut-
increasing their susceptibility to other diseases or by interfer- ment connection) were included. Therefore, there is a mini-
ing with wound healing. Surgical conditions, submission to mum risk of selection bias, since all implants with early failure
radiotherapy, and the intake of medications by the patient may were selected from all implants ever inserted in this clinic.
play a role on the outcome of implants. When it comes to late
implant failures, oral microbial environment, parafunctional 1
Department of Prosthodontics, Faculty of Odontology, Malmö
habits, and prosthetic rehabilitation variables are also taken
University, Malmö, Sweden
into account. Although many studies have shown the influence 2
Clinic for Prosthodontics, Centre of Dental Specialist Care, Malmö,
of local and systemic factors in the long-term outcome of den- Sweden
tal implants (Chrcanovic et al. 2014), less is known concerning 3
Department of Biomaterials, Göteborg University, Göteborg, Sweden
the factors affecting the initial phases of osseointegration. The
Corresponding Author:
aim of the present study was to assess the influence of local B.R. Chrcanovic, Department of Prosthodontics, Faculty of Odontology,
and systemic factors on the occurrence of implant failures up to Malmö University, Carl Gustafs väg 34, SE-214 21, Malmö, Sweden.
second-stage surgery (abutment connection). Emails: [email protected]; [email protected]
Downloaded from jdr.sagepub.com at Malm? University on August 8, 2016 For personal use only. No other uses without permission.
© International & American Associations for Dental Research 2016

996 Journal of Dental Research 95(9)
Only modern endosseous dental implants with cylindrical or of explanatory health variables on the failure of implants up to
conical design were considered. Zygomatic implants were not abutment connection—that is, health factors that are inherently
included in the study, as well as implants that were detected in associated to the patient, not to the implant. First, a univariate
radiographies, but that did not have basic information about effect of each health factor on the implant failure was evalu-
them in the patients’ files. ated. Odds ratios and their 95% confidence intervals were
computed. The Wald test based on robust standard errors was
used to assess the significance of each factor. A factor was
Definitions excluded from further multivariate analysis if the univariate
An implant was considered a failure if presenting signs and logistic regression resulted in a clearly nonsignificant odds
symptoms led to implant removal. Thus, a failed implant in our ratio (P > 0.1). In the second step, a multivariate logistic
study is equal to a lost implant. regression gave the effects on different risk factors when con-
trolling for other factors. The results of the final model were
presented as an estimated odds ratio of each significant prog-
Data Collection nostic variable (P < 0.05).
The following data were collected: implant surface (turned/ An implant-level model having the implant as the statistical
machined or enlarged surfaces, the latter including sandblasted, unit was performed to assess the effects of the implant-related
acid-etched, sandblasted + acid-etched, anodized, hydroxyapatite- and local bone factors on the failure of implants up to abutment
coated surfaces), implant system (Nobel turned, Nobel TiUnite, connection, also including the health variables. A generalized
Astra TiOblast, Astra Osseospeed, Straumann SLA/SLActive/ estimating equation (GEE) method was used to account for the
Roxlid, XIVE/Frialit-2, other), implant length and diameter, fact that repeated observations (several implants) were avail-
implant design (cylindrical or conical), prescription of antibi- able for a single patient. Because the outcomes relating to
otics (the prophylactic antibiotic regimen usually started 1 to implants within a single patient must be more closely corre-
2 h before surgery and went from 5 to 7 d postoperatively), lated to each other than the outcomes of implants in separate
bone graft procedures, reason for tooth extraction (periodontal patients, ignoring these correlations could result in a bias in P
disease, fracture/trauma, advanced caries, agenesia, other), value computations (Shintani 2014). All models were adjusted
implant jaw location (maxilla or mandible), number of implants for clustering of subject and implants in a binary logistic
in maxilla or mandible, anterior or posterior location of the regression model through GEE with a binomial distribution
implant (locations between 13 and 23 and between 33 and 43 and a logit link function, while assuming an exchangeable
were considered anterior location), patient’s sex, age of the working correlation structure to assess the relationship between
patient at the implant insertion surgery, number of days until implant failure up to abutment connection (dependent vari-
failure, time between loss of an implant and replacement by able) and the risk factors (independent variables). Initially, a
another one, and follow-up time. Bone quantity and quality of univariate GEE on each variable was performed. To verify
the treated jaws were classified at the time of surgery accord- multicollinearity, a correlation matrix of all predictor variables
ing to the Lekholm and Zarb (1985) classification. with a significant odds ratio (P value cutoff point of 0.1) identi-
General health and behavioral history were collected from the fied in the univariate GEE was scanned to see whether there
patients’ files. The presence of a medicament list in the patients’ were some high correlations among the predictors. Collinearity
records was used to correlate the use of certain drugs to specific statistics obtaining variance inflation factor and tolerance sta-
health conditions. The following health factors were assessed: tistic were also performed to detect more subtle forms of mul-
diabetes type I or II, hypertension, hypercholesterolemia, hypo- ticollinearity. Then, a multivariable model with a forced entry
thyroidism, asthma, psoriasis, chemotherapy, and irradiation of method was used to evaluate the effect of the factors that were
the head-neck region. The patients were also classified according univariately significant (P < 0.1) and did not present multicol-
to the intake of the following medication types: antidepressants, linearity. A Wald chi-square test was used to analyze the statis-
immunosuppressive drugs, bisphosphonates, antithrombotic tical significance of each parameter within the model. The
agents (antiplatelet, anticoagulant, thrombolytic drugs), hormone results of the final model were presented as an estimated odds
replacement therapy in women, and medicaments to reduce gas- ratio of each significant prognostic variable (P < 0.05).
tric acid production. The following behavioral factors were All data were statistically analyzed with SPSS 22 (SPSS
assessed: smoking habits, use of snuff, bruxism. Inc.).
Statistical Analyses Results

The mean, standard deviation, and percentages were presented Overall, 642 of 10,096 implants (6.36%) failed. From this total
as descriptive statistics. Logistic regression models were used of 642 lost implants, 176 implants in 139 patients were lost up
at the patient level as well as the implant level. The patient- to the second-stage surgery (65 men and 74 women; mean age
level analysis considered the patient as the statistical unit, with at the time of implant surgery, 54.1 ± 16.3 y; minimum, 17.7 y;
patients presenting or not presenting implant failures. maximum, 90.1 y). This corresponds to a failure rate up to
Regression at the patient level was used to evaluate the effect abutment connection of 1.74% at the implant level and 5.21%

Early Dental Implant Failures 997
Table 1. Comparison of Implants That Failed up to and after Abutment Connection.
A B C D E Total %
Up to Abutment Connectiona
1 0 0 1 6 1 8 4.8
2 4 30 10 3 2 49 29.7
3 6 29 26 12 1 74 44.9
4 0 4 12 10 8 34 20.6
Total 10 63 49 31 12 165 100
% 6.0 38.2 29.7 18.8 7.3 100
After Abutment Connectionb
1 0 1 5 0 1 7 1.5
2 7 67 37 12 3 126 27.8
3 9 72 85 51 7 224 49.3
4 0 16 24 32 25 97 21.4
Total 16 156 151 95 36 454 100
% 3.5 34.4 33.3 20.9 7.9 100
According to the Lekholm and Zarb (1985) classification, bone quality is broken into 4 groups per the proportion and structure of compact and
trabecular bone tissue: type 1, large homogeneous cortical/compact bone; type 2, thick layer of compact bone surrounding a dense trabecular bone;
type 3, thin cortical layer surrounding a dense trabecular bone; type 4, thin cortical layer surrounding a core of low-density trabecular bone. The
quantity of jawbone is broken into 5 groups (A–E) based on the residual jaw shape following tooth extraction: bone classified as A presents the largest
amount of bone among all classes, whereas bone classified as E presents the lowest volume of bone.
a
Missing information of bone quantity and quality: 11 implants.
b
Missing information of bone quantity and quality: 12 implants.
at the patient level. The location of the implants was as fol- with a statistically significant odds ratio were included in the
lows: 73 in the anterior maxilla, 36 in the anterior mandible, 44 multivariate GEE model (Table 5), only smoking (P = 0.022)
in the posterior maxilla, and 23 in the posterior mandible. Only continued to present a statistically significant odds ratio.
4 of the 176 failures up to the abutment connection occurred in As none of the patients who presented a failure before abut-
nonsubmerged implants with a delayed loading protocol. ment connection were taking bisphosphonates, this variable
Table 1 shows a comparison of groups of implants failed up was not included in any statistical model.
to and after abutment connection according to the distribution
of implants with regard to the Lekholm and Zarb (1985) clas-
sification of bone quantity and quality. Note that the distribu-
Discussion
tion of implants in sites of different bone quantities and The aim of the present study was to assess the influence of
qualities was quite similar between the groups. local and systemic factors on the occurrence of implant failures
The univariate binary logistic regression showed that the up to second-stage surgery. As the study of failures only before
following predictors had a statistically significant odds ratio at the abutment connection limits the observation to the stage
the patient level (Table 2): smoking (P < 0.001), number of before the prosthetic treatment, confounding factors are elimi-
cigarettes per day (P = 0.002), the intake of antidepressants (P = nated. The regression analyses performed in this study tried to
0.002), and age of the patient at the time of the surgery (P = identify the factors that were possibly related to implant fail-
0.001). After only the variables with a statistically significant ure. The univariate regression assessed the relationship
odds ratio were included in the multivariate binary logistic between each independent variable and implant failure sepa-
regression model (Table 3), smoking (P = 0.003) and the intake rately, and the multivariate regression assessed the relationship
of antidepressants (P = 0.009) continued to present a statisti- of the variables that were univariately significant to implant
cally significant odds ratio. failure, controlling for one another. In the multivariate model,
The univariate GEE model showed that the following pre- only 2 variables were shown to exert some significant effect on
dictors had a statistically significant odds ratio at the implant the failures up to abutment connection: the intake of antide-
level (Table 4): smoking (P < 0.001), number of cigarettes per pressant drugs at the patient-level analysis and smoking at both
day (P = 0.040), hypothyroidism (P = 0.065), the intake of the implant- and patient-level analyses.
antidepressants (P = 0.046), implant jaw location (P = 0.064), Regarding the intake of antidepressants, there is biochemi-
bone quantity (quantity A as the reference category; quantity C, cal and clinical evidence suggesting a relationship between the
P = 0.039; quantity D, P < 0.001; quantity E, P < 0.001), bone intake of such medicaments and the impairment of bone
quality (quality 1 as the reference category; quality 4, P = metabolism, which in theory could interfere with the osseointe-
0.034), implant surface (P < 0.001), implant system (Nobel gration process. From the biochemical point of view, it is pos-
turned as the reference category; Nobel TiUnite, P = 0.002), sible that neuroendocrine mechanisms related to the serotonin
and bone graft procedures (P = 0.009). After only the variables system could regulate osteoclast differentiation/activation

Table 2. Univariate Binary Logistic Regression for Implant Failure up to Table 3. Multivariate Logistic Regression Model for Implant Failure up
Abutment Connection: Sex and Health Factors at the Patient Level. to Abutment Connection at the Patient Level.
Factor OR (95% CI) P Value Factor OR (95% CI) P Value
Smoking Smoking
No 1 No 1
Yes 3.065 (1.965 to 4.779) <0.001 Yes 3.265 (1.486 to 7.173) 0.003
Former smoker 1.359 (0.318 to 5.799) 0.679 Former smoker 1.430 (0.332 to 6.156) 0.631
Cigarettes/day: increase by 1 1.043 (1.015 to 1.071) 0.002 Cigarettes/day: increase by 1 0.990 (0.943 to 1.039) 0.676
Snuff Intake of antidepressants
No 1 No 1
Yes 1.363 (0.578 to 3.212) 0.479 Yes 2.438 (1.251 to 4.751) 0.009
Bruxism Age: increase by 1 1.005 (0.992 to 1.018) 0.451
No 1
Yes 1.567 (0.705 to 3.485) 0.270 Only the patient and health factors that were considered statistically
Diabetes significant (P < 0.1) in the univariate model and did not present
No 1 multicollinearity were included in the multivariate model.
95% CI, 95% confidence interval; OR, odds ratio.
Type I 0.775 (0.104 to 5.775) 0.804
Type II 1.576 (0.708 to 3.507) 0.265
High blood pressure
system in osteoblasts and osteoclasts (Bliziotes et al. 2001;
No 1
Yes 0.948 (0.580 to 1.551) 0.832 Westbroek et al. 2001; Battaglino et al. 2004) in which the
High cholesterol serotonin transporter and several receptors are expressed in
No 1 osteoblasts as well as osteoclasts (Bliziotes et al. 2001;
Yes 0.893 (0.442 to 1.807) 0.754 Westbroek et al. 2001). The presence of serotonin receptors
Hypothyroidism and the serotonin transporter in bone raises the question
No 1 whether medications that antagonize serotonin reuptake could
Yes 0.429 (0.104 to 1.768) 0.241
influence bone metabolism. Peripheral serotonin signaling
Asthma
No 1 directly activates osteoblastic serotonin receptors to inhibit
Yes 1.471 (0.722 to 2.997) 0.288 bone formation. Central serotonin signaling inhibits the sym-
Intake of antidepressants pathetic nervous system, thus alleviating the negative adrener-
No 1 gic tone on osteoblasts. In the situation of elevated serotonin
Yes 2.477 (1.385 to 4.429) 0.002 levels that result from treatment with SSRIs (i.e., selective
Irradiation
serotonin reuptake inhibitors—a class of antidepressant drugs),
No 1
Yes 1.076 (0.255 to 4.534) 0.920
the negative skeletal effects of peripheral serotonin may out-
Hormone replacement therapy weigh the positive skeletal benefits resulting from the enhanced
No 1 central serotonin antidepressant and antisympathetic activity
Yes 1.452 (0.516 to 4.086) 0.480 (Ducy and Karsenty 2010).
Gastric In vitro studies have shown that activity of the serotonin
No 1 transporter is required for osteoclast differentiation. While
Yes 1.569 (0.739 to 3.330) 0.241
blockage of the serotonin transporter reduced osteoclast dif-
Antithrombotics
No 1 ferentiation when fluoxetine, an antidepressant, was adminis-
Yes 1.476 (0.875 to 2.489) 0.145 tered to produce micromolar (μM) concentrations (Battaglino
Immunosuppressive et al. 2004; Gustafsson et al. 2006), there was an increase in
No 1 osteoclast differentiation for the same medicament in the nano-
Yes 0.845 (0.113 to 6.321) 0.870 molar (nM) concentrations (Gustafsson et al. 2006). In vivo
Psoriasis studies demonstrated detrimental effects of fluoxetine on tra-
No 1
becular architecture (Warden et al. 2008) and bone mineral
Yes 2.719 (0.612 to 12.076) 0.189
Sex density (Warden et al. 2005; Warden et al. 2008) in mice.
Male 1 Another in vivo study showed that serotonin acts on osteo-
Female 0.980 (0.696 to 1.380) 0.909 blasts, inhibiting their proliferation (Yadav et al. 2008). These
Age: increase by 1 1.014 (1.006 to 1.023) 0.001 studies in animal models indicate a negative effect of SSRIs on
bone mass and suggest that these antidepressants may possess
direct antianabolic skeletal effects through the pharmacologic
inhibition of the serotonin transporter.
because osteoclasts derive from hematopoietic cell precursors From the clinical point of view, an association between
and a relationship between bone and the immune system has antidepressants and decreased bone mineral density in humans
been established (Gruber 1991; Bab and Einhorn 1993; Ershler has been suggested (Cauley et al. 2005; Richards et al. 2007;
et al. 1997). Studies have identified a functional serotonin Williams et al. 2008). Moreover, bone mass has been shown to

Table 4. Risk Factor Analysis for Implant Failure up to Abutment Connection with a Univariate Generalized Estimating Equations Logistic Regression
Model at the Implant Level.
Factor Failure: Survivala OR (95% CI) P Value
Smoking
No 232: 4,125 1
Yes 180: 1,838 2.709 (1.737 to 4.226) <0.001
Former smoker 14: 186 2.159 (0.463 to 10.070) 0.327
Cigarettes/day: increase by 1 1.024 (1.001 to 1.048) 0.040
Snuff
No 380: 5,824 1
Yes 27: 247 2.063 (0.829 to 5.139) 0.120
Bruxism
No 361: 6,320 1
Yes 85: 342 1.386 (0.611 to 3.142) 0.434
Sex
Male 289: 4,471 1
Female 353: 4,983 1.034 (0.716 to 1.494) 0.857
Diabetes
No 404: 6,037 1
Type I 7: 110 0.585 (0.085 to 4.051) 0.588
Type II 33: 477 1.574 (0.669 to 3.703) 0.298
High blood pressure
No 295: 4,498 1
Yes 147: 2,101 0.857 (0.508 to 1.445) 0.563
High cholesterol
No 365: 5,652 1
Yes 76: 910 0.806 (0.362 to 1.793) 0.596
Hypothyroidism
No 419: 6,210 1
Yes 24: 358 0.274 (0.069 to 1.086) 0.065
Asthma
No 412: 6,056 1
Yes 35: 527 1.559 (0.751 to 3.237) 0.233
Intake of antidepressants
No 358: 5,991 1
Yes 94: 584 1.735 (1.010 to 2.980) 0.046
Irradiation
No 434: 6,443 1
Yes 12: 172 0.760 (0.188 to 3.080) 0.701
Hormone replacement therapy
No 508: 7,750 1
Yes 20: 227 1.472 (0.478 to 4.540) 0.501
Gastric
No 368: 5,990 1
Yes 58: 475 1.059 (0.510 to 2.199) 0.877
Antithrombotics
No 304: 5,224 1
Yes 128: 1,322 1.276 (0.729 to 2.233) 0.394
Immunosuppressive
No 422: 6,428 1
Yes 8: 87 0.614 (0.092 to 4.097) 0.615
Psoriasis
No 428: 6,448 1
Yes 3: 72 1.974 (0.500 to 7.796) 0.332
Age: increase by 1 0.997 (0.989 to 1.005) 0.463
Implant diameter: increase by 1 0.982 (0.455 to 2.118) 0.963
Implant length: increase by 1 0.945 (0.862 to 1.036) 0.230
Implant design
Cylindrical 631: 9,018 1
Conical 11: 436 0.798 (0.357 to 1.787) 0.584
Location
Maxilla 473: 5,303 1
Mandible 169: 4,151 0.701 (0.481 to 1.021) 0.064
Anterior 390: 5,702 1
Posterior 252: 3,752 1.001 (0.708 to 1.414) 0.997
(continued)

Table 4. (continued)
Factor Failure: Survivala OR (95% CI) P Value
Bone quantity
A 26: 1,247 1
B 219: 4,482 1.730 (0.803 to 3.730) 0.162
C 200: 2,619 2.255 (1.042 to 4.879) 0.039
D 126: 735 4.714 (2.050 to 10.840) <0.001
E 48: 122 10.777 (4.221 to 27.518) <0.001
Bone quality
1 15: 371 1
2 175: 4,089 0.674 (0.213 to 2.139) 0.504
3 298: 4,234 0.952 (0.317 to 2.861) 0.930
4 131: 511 3.399 (1.097 to 10.537) 0.034
Reoperation
No 596: 9,326 1
Yes 46: 128 0.824 (0.084 to 8.071) 0.868
Implant surface
Turned 493: 5,255 1
Enlarged 149: 4,199 0.494 (0.341 to 0.716) <0.001
Implant system
Nobel turned 493: 5,255 1
Nobel TiUnite 102: 2,818 0.501 (0.326 to 0.768) 0.002
Astra TiOblast 24: 367 0.752 (0.314 to 1.798) 0.522
Astra Osseospeed 4: 204 0.266 (0.041 to 1.749) 0.168
Straumann 9: 325 0.324 (0.084 to 1.248) 0.101
XIVE/Frialit-2 6: 260 0.579 (0.185 to 1.813) 0.348
Other 4: 226 0.373 (0.094 to 1.417) 0.159
Antibiotics
No 47: 574 1
Yes 242: 4,309 0.773 (0.410 to 1.458) 0.427
Bone grafting
No 550: 8,980 1
Yes 91: 473 2.274 (1.226 to 4.216) 0.009
Reason for tooth extraction
Periodontal disease 52: 892 1
Fracture/trauma 27: 558 1.006 (0.331 to 3.060) 0.991
Advanced caries 9: 236 1.453 (0.389 to 5.424) 0.579
Agenesia 25: 791 2.152 (0.888 to 5.216) 0.102
Other 6: 199 1.129 (0.245 to 5.206) 0.876

a
The information for some conditions is unknown for a variable number of implants.
remain negatively associated with not only clinical depression VEGF in osteoblasts. BMP-2 is the most potent osteogenic
but also depressive symptoms (Robbins et al. 2001; Williams induction factor regulating osteoblast differentiation, ALP
et al. 2011). Bone quality has also been shown to be reduced expression, and subsequent mineralization (Rawadi et al.
among men and younger women with a history of mood disor- 2003). TGF-b1 is produced by osteoblasts and incorporated
ders (Williams et al. 2013). into the bone matrix. During bone remodeling, TGF-b1 plays
In some studies, smoking has been associated with depres- an important role in the regulation of osteoblast proliferation,
sion (Escobedo et al. 1998; Hall et al. 1993). In the present differentiation, and apoptosis, with subsequent important
study, smoking was identified as the other predictor to exert effects on bone formation and remodeling (Deng et al. 2008).
some statistically significant effect on the failures up to abut- PDGF and VEGF have angiogenic effects during bone healing
ment connection. A recent meta-analysis analyzing >100 stud- (De la Riva et al. 2010). Whereas their expression can be
ies has shown that failures of implants inserted into smokers detected in osteoblasts, they are considered to be able to regu-
are 2.23 times more likely to happen than failures of implants late osteoblast activity as well. VEGF can interact synergisti-
inserted into nonsmokers (Chrcanovic et al. 2015). The cally with bone morphogenetic protein to promote skeletal
increase of implant failure rates due to smoking is hypothe- development and bone healing by enhancing cell recruitment,
sized to be related mainly to the effect of smoking in osteogen- prolonging cell survival, and increasing angiogenesis (Patel
esis and angiogenesis (Ma et al. 2010). Concerning the effects et al. 2008). Bone morphogenetic protein acts as an important
on osteogenesis, Ma et al. (2011) showed that nicotine inhib- regulator that stimulates production of VEGF in osteoblasts
ited the gene expression of BMP-2, TGF-b1, PDGF-AA, and (Samee et al. 2008). Therefore, the inhibitive effect of nicotine

on osteoblastic activity may contribute to the failure of dental Table 5. Multivariate Generalized Estimating Equations Logistic
implant osseointegration (Ma et al. 2011). Regression Model at the Implant Level.
In addition, some studies showed that osteogenesis and Factor OR (95% CI) P Value
angiogenesis are tightly coupled during bone formation and
Smoking
that angiogenesis plays a pivotal role in skeletal development
No 1
and bone repair (Fang et al. 2005). Besides carrying oxygen Yes 2.120 (1.113 to 4.037) 0.022
and nutrients to bone tissue, blood flow plays an active role in Former smoker 2.129 (0.338 to 13.411) 0.421
bone formation and remodeling by mediating the interactions Cigarettes/day: increase by 1 0.987 (0.952 to 1.023) 0.463
among osteoblasts, osteocytes, osteoclasts, and vascular cells Hypothyroidism
at a variety of levels (Fleming et al. 2001). The deleterious No 1
effects of smoking have been shown on not only osteoblasts Yes 0.508 (0.131 to 1.966) 0.327
but also microcirculation—including morphologic aspects, No 1
particularly vessel wall injury and capillary loss, as well as Yes 1.742 (0.856 to 3.542) 0.126
functional aspects, predominantly changes in tissue perfusion Location
and its regulatory mechanisms, notable reactive hyperemia, Maxilla 1
and sequestration of blood cells in the microcirculation (Lehr Mandible 0.805 (0.421 to 1.537) 0.510
2000). Studies (Ma et al. 2007; Ma et al. 2010) demonstrated Bone quantity
A 1
that nicotine exposure has direct effects on blood vessels, pro-
B 2.838 (0.779 to 10.343) 0.114
ducing vasoconstriction and systemic venoconstriction, which C 2.538 (0.670 to 9.621) 0.171
decrease blood perfusion and cause low oxygen and isch- D 3.621 (0.804 to 16.308) 0.094
emia—the major stimulus for initiating the angiogenic cascade E 2.197 (0.267 to 18.052) 0.464
(Wang et al. 2007). Hypoxia and ischemia owing to nicotine Bone quality
exposure could stimulate HIF-1α expression, leading to an 1 1
increased expression of VEGF, which in turn stimulates angio- 2 1.176 (0.168 to 8.233) 0.870
3 1.471 (0.202 to 10.696) 0.703
genesis. However, the enhanced vessel formation is incapable
4 4.679 (0.591 to 37.050) 0.144
of compensating for the adverse effect of the reduced blood Implant surface
flow possibly caused by nicotine-induced vasoconstriction Turned 1
(Ma et al. 2010). Even though the increased expression of Enlarged 0.642 (0.339 to 1.213) 0.172
VEGF caused by hypoxia and ischemia may stimulate angio- Implant system
genesis, it may also contribute to compromised bone healing Nobel turned 1
Nobel TiUnite 0.642 (0.339 to 1.213) 0.172
because excessive VEGF may lead to impairment in bone for-
Astra TiOblast 0.602 (0.152 to 2.380) 0.469
mation—possibly by promoting mesenchymal stem cell differ- Astra Osseospeed 0.515 (0.065 to 4.098) 0.530
entiation toward an endothelial lineage (Kon et al. 2001), Straumann 0.311 (0.040 to 2.397) 0.262
consequently reducing the availability of mesenchymal stem XIVE/Frialit-2 1.339 (0.264 to 6.800) 0.725
cells for osteogenic differentiation (Keramaris et al. 2008). Others 0.316 (0.048 to 2.094) 0.232
Alternatively, excessive VEGF may increase recruitment of Bone grafting
osteoclasts into the bone regeneration sites and lead to an No 1
Yes 1.680 (0.805 to 3.507) 0.167
excessive bone resorption (Keramaris et al. 2008). Another fact
that should be taken into consideration is that the inflammatory Only the factors that were considered statistically significant (P < 0.1) in
response to bone trauma plays an important role in initiating the univariate model and did not present multicollinearity were included
the repair cascade. The trauma activates downstream factors in the multivariate model.
(e.g., cytokines and growth factors) that recruit osteoprogeni-
tor and mesenchymal cells to the injury site (Kon et al. 2001;
Mountziaris and Mikos 2008). The problem is that nicotine is the statuses of the patients’ systemic conditions and the dos-
an anti-inflammatory agent (Geng et al. 1996). ages of their medications is a limitation also connected to the
Concerning the bone quantity and quality of the implant retrospective nature of this study. It is also important to stress
site, as the distribution of implants that failed up to abutment that the different classes of antidepressants were prescribed to
connection was similar to the implants failing after this proce- patients of the present study. Antidepressants are a large family
dure, poor bone was not likely a determinant factor to influ- of drugs, which have different biological properties and mech-
ence an early failure for the patients of the present study. anisms of action that might have differently affected the bone
The limitations of the present study include that it is a retro- metabolism and, consequently, the failures of dental implants.
spective study, which inherently results in flaws. These prob- The present results might be applicable to the general popula-
lems were manifested by the gaps in information and tion, since all patients ever treated with dental implants in the
incomplete records. As all data rely on the accuracy of the clinic were included in the database from which the implants
original examination and documentation, items may have been with early failures were analyzed. No patient was excluded,
excluded in the initial examination or not recorded in the dental/ regardless of any health or other condition. For that reason,
medical chart. The lack of specific information characterizing selection bias was also minimized.

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Author Contributions Keramaris NC, Calori GM, Nikolaou VS, Schemitsch EH, Giannoudis PV.
2008. Fracture vascularity and bone healing: a systematic review of the role
B.R. Chrcanovic, contributed to conception and design, data of VEGF. Injury. 39 Suppl 2:S45–S57.
acquisition, analysis, and interpretation, drafted and critically Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D, Gerstenfeld LC,
revised the manuscript; J. Kisch, T. Albrektsson, and A. Wennerberg, Einhorn TA. 2001. Expression of osteoprotegerin, receptor activator of
NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory
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This work was supported by research funds from the Oral Health Ma L, Zheng LW, Cheung LK. 2007. Inhibitory effect of nicotine on bone
Related Research by Region Skåne (Odontologisk Forskning i Region regeneration in mandibular distraction osteogenesis. Front Biosci.
Skåne; OFRS 414321), Sweden, and from the Scientific Research 12:3256–3262.
Ma L, Zheng LW, Sham MH, Cheung LK. 2010. Uncoupled angiogenesis and
Council of Sweden (Vetenskapsrådet; Dnr 2015-02971). This work osteogenesis in nicotine-compromised bone healing. J Bone Miner Res.
was supported by Folktandvården AB, Region Skåne, Sweden, and by 25(6):1305–1313.
CNPq, Conselho Nacional de Desenvolvimento Científico e Ma L, Zwahlen RA, Zheng LW, Sham MH. 2011. Influence of nicotine on the bio-
logical activity of rabbit osteoblasts. Clin Oral Implants Res. 22(3):338–342.
Tecnológico, Brazil. The authors declare no potential conflicts of inter- Mountziaris PM, Mikos AG. 2008. Modulation of the inflammatory response for
est with respect to the authorship and/or publication of this article. enhanced bone tissue regeneration. Tissue Eng Part B Rev. 14(2):179–186.
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Bruno Ramos Chrcanovic Bruxism and dental implant treatment
Jen€
o Kisch
Tomas Albrektsson
complications: a retrospective
Ann Wennerberg comparative study of 98 bruxer
patients and a matched group
Authors’ affiliations: Key words: bruxism, dental implant, implant failure, mechanical complications, risk factor
Bruno Ramos Chrcanovic, Tomas Albrektsson,
Ann Wennerberg, Department of Prosthodontics,
Faculty of Odontology, Malm€ o University, Malm€o, Abstract
Sweden Objectives: To analyze the complications of dental implant treatment in a group of patients with
o Kisch, Clinic for Prosthodontics, Centre of
Jen€
bruxism in comparison with a matched group of non-bruxers.
Dental Specialist Care, Malm€ o, Sweden
Tomas Albrektsson, Department of Biomaterials, Material and methods: Patients being diagnosed as bruxers were identified within a group of
G€oteborg University, G€oteborg, Sweden patients consecutively treated with implant-supported prostheses at one specialist clinic, based on
Corresponding author:
the most recent listed sign and symptoms of bruxism according to the International Classification
Bruno Ramos Chrcanovic, DDS, MSc of Sleep Disorders. A diagnostic grading system of “possible,” “probable,” and “definite” sleep or
Department of Prosthodontics, Faculty of awake bruxism was used, according to a recent published international consensus. A case–control
Odontology
Malm€ o University matching model was used to match the bruxers with a group of non-bruxers, based on five
Carl Gustafs v€ag 34, SE-214 21, Malm€
o, Sweden variables. Implant-, prosthetic-, and patient-related data were collected, as well as 14 mechanical
Tel.: +46 725 541 545 complications, and compared between groups.
Fax: +46 40 6658503
e-mails: [email protected]; Results: Ninety-eight of 2670 patients were identified as bruxers. The odds ratio of implant failure
[email protected] in bruxers in relation to non-bruxers was 2.71 (95% CI 1.25, 5.88). Considering the same number of
patients with the same total number of implants equally distributed between groups, the bruxers
group had a higher prevalence of mechanical complications in comparison with the non-bruxers
group.
Conclusions: This study suggests that bruxism may significantly increase both the implant failure
rate and the rate of mechanical and technical complications of implant-supported restorations.
Other risk factors may also have influenced the results.
Bruxism is a repetitive jaw-muscle activity that the insertion of dental implants in

that is mainly characterized by teeth grinding patients being diagnosed with bruxism nega-
and clenching, during sleep as well as during tively affected the implant failure rates. How-
wakefulness (Lobbezoo et al. 2013, AASM ever, the authors stressed that the effect size
2014). It is reported that its prevalence could observed was not reliable due to a limited
reach 20% among the adult population (Glaros number of published studies, all character-
1981). Bruxism has been generally considered ized by a low level of specificity, and most of
a clinical problem with possible detrimental them dealing with a limited number of cases.
consequences for dental, periodontal, and Therefore, the real effect of bruxism on the
musculoskeletal tissues (Lobbezoo et al. survival of dental implants is still not well
2006b). These possible consequences made established.
bruxism to be considered a contraindication The ability to anticipate outcomes is an
for dental implant treatment, even though the essential part of risk management in an
evidence for this is usually based on clinical implant practice. Recognizing conditions that
experience only (Lobbezoo et al. 2006a, b). place the patient at a higher risk of failure
Date:
Bruxism is suggested to cause excessive load will allow the surgeon to make informed
Accepted 6 March 2016 of implant-supported rehabilitations, which decisions and refine the treatment plan to
To cite this article: may cause an implant fracture or may result optimize the outcomes (Chrcanovic et al.
Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A. in bone loss around the implants and subse- 2014). Having said this and considering that
Bruxism and dental implant treatment complications: a
retrospective comparative study of 98 bruxer patients and a quent implant failure. several publications refer to bruxism as a risk
matched group. The results of a recent meta-analysis on factor capable of exerting a negative effect on
Clin. Oral Impl. Res. 00, 2016, 1–9
doi: 10.1111/clr.12844 the subject (Chrcanovic et al. 2015a) found the successful outcome of the long-term
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 1
Chrcanovic et al Bruxism and dental implant complications
osseointegration of implants and on the out- report, by means of questionnaires and/or the et al. 2013). The clinical condition was
come of implant-supported rehabilitations, anamnestic part of a clinical examination. re-evaluated to assess possible bruxism-
the aim of this retrospective clinical study “Probable” sleep or awake bruxism should be related signs and symptoms. The sign and
was to analyze the complications of dental based on self-report plus the inspection part symptoms of bruxism were listed according
implant treatment in a group of patients with of a clinical examination. “Definite” sleep to the International Classification of Sleep
bruxism in comparison with a matched group bruxism should be based on self-report, a Disorders (AASM 2014): (i) presence of regu-
of non-bruxers. clinical examination, and a polysomno- lar or frequent tooth grinding sounds occur-
graphic recording, preferably along with ring during sleep, (ii) abnormal tooth wear
audio/video recordings. As electromyography consistent with above reports of tooth grind-
Material and methods and/or polysomnography were not used due ing during sleep, (iii) transient morning jaw
to high cost and limited availability, the muscle pain or fatigue; and/or temporal head-
Aim of the study patients of this study would only fall into the ache; and/or jaw locking on awakening con-
The aim of this retrospective study was to
categories “possible” or “probable”. Thus, a sistent with above reports of tooth grinding
analyze the complications of dental implant
patient was considered as presenting bruxism during sleep. Moreover, clenching or grinding
treatment in a group of patients presenting
based on self-report of clenching/grinding of the teeth and/or by bracing or thrusting of
bruxism in comparison with a matched group
during sleep or during wakefulness, plus the the mandible during wakefulness was also
of non-bruxers. The focused question was
inspection part of a clinical examination. considered, according to a recent interna-
elaborated using the PICO format (Partici-
tional consensus (Lobbezoo et al. 2013). The
pants, Interventions, Comparisons, Outcomes):
Patients clinical examination was carried out by the
“Do bruxers undergoing implant-prosthetic This retrospective study is based on all 2670 same trained operator.
rehabilitation present a higher risk for implant patients (1434 women, 1236 men) consecu-
failure and mechanical complications in tively treated with implant-supported pros- Patients not willing to attend a follow-up visit
comparison with patients not presenting theses between 1980 and 2014 at one The patients who were not willing to attend
bruxism?” specialist clinic (Clinic for Prosthodontics, an additional visit were asked permission for
Centre of Dental Specialist Care, Malm€ o, the use of the information present in their
Definitions Sweden). The study was approved by the records and were asked the same questions
Late biological complications were defined as Regional Ethical Review Board in Lund (Dnr listed above. The answers were correlated
pathological bone loss after osseointegration 2014/598; Dnr 2015/72). with the clinical notes/findings registered in
was obtained at an earlier stage, with possi- First, the patients’ records were scrutinized the patients’ records.
ble subsequent implant failure. Implant fail- looking for clinical notes and photographs
ure represents the complete loss of the that would suggest the possible/probable Deceased patients
implant. Mechanical complications were diagnosis of bruxism. All patients who were The diagnosis of bruxism in patients who
defined as failure of one or more components still alive and were diagnosed in the records were already deceased was based on notes of
of an implant system: fracture of an implant as bruxers were considered for a clinical clinical assessment and photographs, present
itself, loosening, loss or fracture of connect- re-evaluation. The patients were contacted in the patients’ records. Only patients with
ing screws or abutment screws, loosening, through a telephone call and were asked to records showing a strong correlation between
excessive wear or fracture of structural com- attend a follow-up appointment. these two items were considered as possibly/
ponents in overdentures, excessive wear or probably having the diagnosis of bruxism.
fracture of suprastructural porcelain or Patients willing to attend a follow-up visit Access to the patients’ information was
acrylic teeth (Gothberg et al. 2003), hard The patients willing to come back signed an granted and approved by the Ethical Commit-
splint fracture, and loss of implant’s hole informed and written consent form approving tee, provided that would not represent a
composite sealing. the participation in the study and were clini- threat to the patients’ confidentiality.
For this study, the authors followed the cally re-assessed. The self-conscience of the The patients were not identifiable in any
definition of bruxism proposed by Lobbezoo condition was evaluated with some ques- way, and a decoding list linking patient
et al. (2013): “Bruxism is a repetitive jaw- tions, according to suggestions of a previous names and numbers was used and stored by
muscle activity characterized by clenching or study (Paesani et al. 2013), questions like the the principal investigator, which was
grinding of the teeth and/or by bracing or following were asked: (i) Are you aware of destroyed after completion of the study.
thrusting of the mandible. Bruxism has two the fact that you grind your teeth during
distinct circadian manifestations: it can sleep? (ii) Did anyone tell you that you grind Data collection
occur during sleep (indicated as sleep brux- your teeth during sleep? (iii) On morning Information on mechanical complications
ism) or during wakefulness (indicated as awakening or on awakenings during the was collected for the implant restorations
awake bruxism).” As reliable and valid diag- night, do you have your jaws thrust or only, even though the patients may have had
nostic tools for bruxism are scarce (Lobbezoo braced? (iv) Do you clench your teeth while mechanical complications on prostheses
et al. 2013), a diagnostic grading system of awake? (v) Do you grind your teeth while made on natural teeth.
“possible,” “probable,” and “definite” sleep awake? All questions could be answered with The following data were collected: implant
or awake bruxism was used, as suggested for either “yes” or “no”. The patients were surface (turned/machined or roughened sur-
clinical and research purposes (Treede et al. instructed to answer “yes” if considered their faces, the latter including sandblasted, acid-
2008). According to an international consen- habit to be frequent enough to be clinically etched, sandblasted + acid-etched, anodized,
sus (Lobbezoo et al. 2013), “possible” sleep or relevant (e.g. frequency of more than thrice a hydroxyapatite-coated surfaces), implant
awake bruxism should be based on self- week and/or several hours per day) (Paesani length and diameter, implant jaw location
2 | Clin. Oral Impl. Res. 0, 2016 / 1–9 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
(maxilla/mandible), anterior or posterior loca- in the maxilla, and (v) number of implants in the study and were re-examined at the clinic
tion of the implant (locations between 13–23 the mandible. As there were no perfect during the year of 2015. There were 49 men
and 33–43 were considered anterior location), matches in a first matching attempt consid- (mean age SD, 51.1 18.2 years; median
patient’s sex, age of the patient at the ering all five variables, some tolerance was 56.0, minimum 16.9, maximum 79.2) and 49
implant insertion surgery, number of days set for four predictors: 7 years for the women (48.6 17.7 years; median 50.7,
until failure, follow-up time, prosthetic com- patients’ age, 500 days for the total follow- minimum 16.7, maximum 77.3) in the
plications of mechanical nature, type of up time, and 2 implants in maxilla and bruxer group. After matching, the non-bruxer
implant-supported prosthetic restoration (sin- mandible. Thus, a little variance of these pre- group was also comprised of 49 men
gle crown, partial bridge with 2–6 prosthetic dictors between the groups was expected. In (52.8 17.8 years; median 54.8, minimum
units, partial bridge with 7–10 prosthetic the case of the patients’ gender, the number 17.6, maximum 79.0) and 49 women
units, full-arch, overdenture), and the number of males and females in each group was set (48.1 17.6 years; median 49.8, minimum
of bruxers with a hard stabilization splint for to be equal. 17.3, maximum 73.4). Bruxers were followed
nightly use. Bone quantity and quality of the up for a mean (SD) of 3459 2464 days
treated jaws were classified at the time of Statistical analyses (median 2916, minimum 245, maximum
surgery according to Lekholm & Zarb (1985) The mean, standard deviation, and percent- 9619), and non-bruxers for 3428 2471 days
classification. ages were presented as descriptive statistics. (median 2627, minimum 358, maximum
The general health and the behavioral his- Kolmogorov–Smirnov test was performed to 10,099) (P = 0.925, Wilcoxon signed–rank
tory of the patients were collected from the evaluate the normal distribution of the vari- test). Of the 98 bruxer patients, 59 had hard
patients’ files. The presence of a medicament ables, and Levene’s test evaluated stabilization splint for nightly use. However,
list in the patients’ records was also use to homoscedasticity. The performed tests for the patients’ assiduity to the use of the night-
correlate the use of certain drugs to specific two independent groups were Student’s t-test guards appeared to be completely erratic.
health conditions. The following health fac- or Mann–Whitney test, and paired-samples All implants in the included patients had
tors were assessed: diabetes types I or II, t-test or Wilcoxon signed–rank test for two been inserted with open-flap surgery. The
hypertension, hypercholesterolemia, hypothy- dependent groups, depending on the normal- abutment connection surgery was performed
roidism, asthma, psoriasis, chemotherapy, ity. Pearson’s chi-square test or Fisher’s exact after a mean (SD) healing time of
and irradiation of the head–neck region. The test was used in the analysis of contingency 159 53 days (median 167) for bruxers and
patients were also classified according to the tables of categorical data of independent 156 59 days (median 162) for non-bruxers
intake of the following medication types: groups, and McNemar’s test for dependent (P = 0.292; Wilcoxon signed–rank test).
antidepressants, immunosuppressive drugs, groups. The degree of statistical significance Thirty-one (7.3%) implants had been non-
bisphosphonates, antithrombotic agents (an- was considered P < 0.05. All data were statis- submerged in the bruxers group and 9
tiplatelet, anticoagulant, thrombolytic drugs), tically analyzed using the Statistical Package (2.1%) in the non-bruxers group. The group
hormone replacement therapy in women, and for the Social Sciences (SPSS) version 22 soft- of bruxing patients had a total of 227
medicaments to reduce the acid gastric pro- ware (SPSS Inc., Chicago, IL, USA). implants (53.2%) with turned surfaces,
duction. The following behavioral factors whereas in the non-bruxers group 173
were assessed: smoking habits and the use of Results turned-surface implants (40.5%) were
snuff. counted (P = 0.236; McNemar’s test). The
Ninety-nine patients were initially identified rest of the implants had various types of
Formation of a matched group with the condition. As one patient diagnosed roughened surfaces. The number of implants
As the division of all initial patients into once as bruxer did not fulfill what we estab- placed in each region is presented in
groups would generate extremely unbalanced lished as a person with the habit, 98 of the Table 1. The mean diameter and length for
groups and the variance was not homogenous 2670 patients were identified as bruxers. The implants placed in bruxers and non-bruxers
between them, the two groups were therefore information of being a bruxers or non-bruxer is presented in Table 2.
not expected to be comparable with respect was ultimately available for 1915 patients, Table 3 shows a comparison of the number
to important covariates (D’Agostino 1998), which represents 5.12% of this population. of implant-supported prosthetic restorations
and then methods were used to match All patients diagnosed with bruxism reported performed between the 98 bruxers and 98
patients and implants between bruxers to that they already had the habit prior to non-bruxers. The difference of the number of
non-bruxers patients. Matching ensures that implant treatment. Eleven (75 implants) of partial fixed restorations with 2 to 6 pros-
any differences between the study and the the 98 patients were no longer alive at the thetic units and full-arch fixed restorations
control groups are not a result of differences time of the study data collection, and three between the groups varied. This was related
on the matching variables, thus reducing patients had moved out of the country. The to the fact that, for example, some partial
selection bias. remaining 84 patients agreed to participate in fixed restorations were supported by the
From the group of patients not presenting
bruxism, a control group was included with
the same number of patients as in the study Table 1. Number of implants placed in each region, in bruxers and non-bruxers
group. The matching was performed using Region Bruxers n (%) Non-bruxers n (%) Total n (%)
the “case control matching” function in Anterior maxilla 168 (39.4) 148 (34.7) 316 (37.0)
SPSS, and the matches were selected on the Anterior mandible 41 (9.6) 102 (23.9) 143 (16.7)
basis of similarities in (i) patients’ gender, (ii) Posterior maxilla 118 (27.6) 96 (22.5) 214 (25.1)
Posterior mandible 100 (23.4) 81 (18.9) 181 (21.2)
patients’ age at the time of the surgery, (iii)
Total 427 (100) 427 (100) 854 (100)
total follow-up time, (iv) number of implants
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 3 | Clin. Oral Impl. Res. 0, 2016 / 1–9
Table 2. Implant diameter and length in bruxers and non-bruxers 6048), against 2197 1491 days (median
Bruxers Non-bruxers 1792) for the group of implants with a rough-
mean SD (median, min, max) mean SD (median, min, max) ened surface (P < 0.001; Mann–Whitney test).
Implant (mm) (mm) P-value* Table 7 shows a comparison of groups
Diameter 3.79 0.23 (3.75, 3.0, 5.0) 3.75 0.15 (3.75, 3.3, 5.0) 0.001 according to the distribution of implants
Length 12.53 2.14 (13.0, 7.0, 18.0) 13.20 2.14 (13.0, 7.0, 20.0) <0.001
with regard to the classification of bone
SD, standard deviation; min, minimum; max, maximum. quantity and quality (Lekholm & Zarb 1985).
*Wilcoxon signed–rank test. It can be observed that a greater percentage
of implants were placed in bone sites with
quantities D and E (P < 0.001; McNemar’s
Table 3. Comparison of the number of implant-supported prosthetic restorations performed
between bruxers and non-bruxers test) and qualities 3 and 4 (P = 0.052; McNe-
Bruxers Non-bruxers mar’s test) in the bruxers patients group, in
comparison with the non-bruxers group.
Prosthetic However, the difference was shown to not be
elements
Number of Prosthetic elements Number of (teeth) significant for bone quality.
Prosthetic restorations (teeth) Acrylic/ restorations Acrylic/ There was a statistically significantly
restoration (n) porcelain* (n) (n) porcelain* (n) unbalanced distribution of the systemic con-
Single crown 69 0/69 55 0/55 ditions and habits for the patients between
Partial fixed, 2–6 53 11/173 38 11/104 the two groups (bruxers vs. non-bruxers)
prosthetic units
(Table 8). Other conditions did not include
Partial fixed, 7–10 3 9/16 3 17/7
prosthetic units enough cases to perform a direct compar-
Full-arch fixed 26 254/30 45 436/73 ison, such as irradiation of the head–neck
Overdenture 1 12/0 3 36/0 region (two patients with four implants in
Total 152 286/288 144 500/239
non-bruxers group), chemotherapy (one
*Acrylic teeth in metallo-acrylic restorations; porcelain teeth in metalloceramic or pure ceramic patient with four implants in bruxers group),
restorations.
intake of bisphosphonates (one patient with
six implants in bruxers group), intake of
hormone replacement therapy in women
Table 4. Comparison of survival and failure of implants between bruxers and non-bruxers at the
patient level, based on all patients of the database (four patients with 20 implants in bruxers
Implants Bruxers n (%) Non-bruxers n (%) P-value Unknown* Total group), intake of immunosuppressive medi-
No implant failures 73 (74.5) 1618 (89.0) 653 (86.5) 2344 (87.8)
cation (one patient with two implants in
At least one implant failure 25 (25.5) 199 (11.0) <0.001** 102 (13.5) 326 (12.2) bruxers and one patient with five implants
Odds ratio (95% CI)*** 2.78 (1.73, 4.49) <0.001 in non-bruxers group), and psoriasis (one
Total 98 (100) 1817 (100) 755 (100) 2670 (100)
patient with two implants in bruxers and
Bruxers, 427 implants in total (342 survived, 69 failed due to lose/lack of osseointegration, 16 one patient with four implant in non-
implants fractured). bruxers group).
Non-bruxers, 6681 implants in total (6320 survived, 347 failed due to lose/lack of osseointegration,
Considering the same number of patients
14 implants fractured).
Unknown for the condition, 2988 implants in total (2792 survived, 186 failed due to lose/lack of with the same total number of implants
osseointegration, 10 implants fractured). equally distributed between groups, the brux-
*Unknown for the condition of bruxism.
ers group had a higher prevalence of mechan-
**Pearson’s chi-square test.
***The odds ratio considered all failures (lost/lack of osseointegration + fractures) into account. ical complications in comparison with the
non-bruxers group (Table 9). The odds ratio
was calculated for the complications with
same number of implants as in some full- implant failures between bruxers and non-
known total number of units in each group,
arch fixed rehabilitations. bruxers, according to different implant
that is, number of acrylic/porcelain teeth,
Table 4 shows a comparison of the sur- lengths, diameters, and surfaces. A higher
number of fixed prostheses, and the number
vival/failure rates in the group of bruxers and failure rate of short implants in bruxers in
of screws. The calculated odds ratios showed
non-bruxers before matching the groups, and comparison with longer implants was
a higher statistically significant probability
Table 5 shows the same comparison after observed. The difference in implant failure
(P < 0.001) of these five complications to
matching. The odds ratios of implant failure rates between the groups tended to decrease
happen in bruxers.
in bruxers in relation to non-bruxers before as the implant length increased, that is,
and after the group matching were 2.78 and 25.7% vs. 2.8% (7–10 mm long implants),
2.71, respectively. Implants in bruxers pre- 18.4% vs. 3.3% (11–13 mm long implants), Discussion
sented a statistically significantly (P = 0.001, and 17.3% vs. 4.2% (15–20 mm long
Wilcoxon signed–rank test) longer mean time implants), in bruxers vs. non-bruxers, respec- The aim of this retrospective clinical study
from insertion to failure (1840 2009 days, tively. Moreover, a lower failure rate of was to analyze the complications of dental
median 1123, minimum 84, maximum 8840) rough-surface implants in comparison with implant treatment in a group of patients pre-
in comparison with non-bruxers (634 turned-surface implants was found. However, senting bruxism in comparison with a
757 days, median 186, minimum 24, maxi- the group of turned-surface implants had a matched group of non-bruxers, and the
mum 2295). Table 6 shows a comparison of mean follow-up of 6134 2224 days (median results showed a statistically higher implant
Table 5. Comparison of survival and failure rates of implants inserted in bruxers and a matched back mechanisms to the jaw-closing muscles
group of non-bruxers
are limited as well. It is therefore not unli-
Implants Bruxers n (%) Non-bruxers n (%) P-value Total kely that forces that are applied to implants
No implant failures 73 (74.5) 87 (88.8) 160 (81.6) during bruxism are even larger than those
At least one implant failure 25 (25.5) 11 (11.2) <0.001* 36 (18.4) exerted during mastication (Lobbezoo et al.
Odds ratio (95% CI)** 2.71 (1.25, 5.88) 0.01
Total 98 (100) 98 (100) 196 (100) 2006a), making them more prone to occlusal
overload and possible subsequent failure
Bruxers – 427 implants in total (342 survived, 69 failed due to lose/lack of osseointegration, 16
(Meyer et al. 2012), as well as more subject
implants fractured).
Non-bruxers – 427 implants in total (412 survived, 15 failed due to lose/lack of osseointegration, no to mechanical complications.
implants fractured). When it comes to fracture of implants and
*McNemar’s test. their components, it has been suggested that
**The odds ratio considered all failures (lost/lack of osseointegration + fractures) into account.
these are associated with overloads created by
a combination of parafunctional stresses, can-
tilevers, posterior implant location and diam-
Table 6. Comparison of implant failures between bruxers and non-bruxers, according to different
implant lengths, diameters, and surfaces eter, bone resorption, and possible misfit in
Bruxers failure/ Non-bruxers superstructures (Balshi 1996). A superstruc-
Implants total (%) failure/total (%) P-value* ture with non-passive entry creates undesir-
7–10 mm long 27/105 (25.7) 2/71 (2.8) <0.001 able stress, which has often been linked to
11–13 mm long 38/207 (18.4) 7/212 (3.3) <0.001 implant fractures (Adell et al. 1981). Thus,
15–20 mm long 19/110 (17.3) 6/142 (4.2) <0.001 bruxism may have not been the only factor
3.00–3.50 mm wide 9/37 (24.3) 0/29 (0) 0.002
3.75–4.30 mm wide 74/381 (19.4) 14/394 (3.6) <0.001
involved in the fractures. Two studies
4.50–5.00 mm wide 2/9 (22.2) 1/4 (25) 1.000 reported the absence of relationship between
Turned-surface 57/173 (32.9) 12/227 (5.3) <0.001 bruxism and mechanical complications
Roughened-surface 28/254 (11) <0.001** 3/200 (1.5) 0.037*** <0.001
(Tawil et al. 2006; Schneider et al. 2012), and
*McNemar’s test. one investigation reported uncertain findings
**Pearson’s chi-square test. Comparison of failures between turned- and roughened-surface implants (Wahlstr€ om et al. 2010). However, some stud-
in bruxers.
ies suggested that bruxism may be a risk fac-
***Fischer’s exact test. Comparison of failures between turned- and roughened-surface implants in
non-bruxers. tor for fractures of ceramics (Kinsel & Lin
2009) and, in general, for the need for techni-
Table 7. Comparison of groups according to the distribution of implants with regard to Lekholm cal interventions on implant-supported
& Zarb (1985) classification of bone quantity and quality. restorations (Br€agger et al. 2001; De Boever
A B C D E Total et al. 2006; Mal o et al. 2011). The results of
Implants in bruxers patients the present study add evidence to suggest that
1 0 5 7 0 0 12 bruxism may be an important contributor to
2 35 (3) 103 (8) 30 (11) 1 0 169 (22)
the rate of mechanical complications in
3 10 78 (11) 76 (11) 28 (15) 4 (1) 196 (38)
4 0 3 22 (12) 16 (8) 8 (5) 49 (25) implant-supported restorations, as well as for
Total 45 (3) 189 (19) 135 (34) 45 (23) 12 (6) 426 (85) a higher prevalence of implant fracture.
Missing information: one implant Considering the whole population treated
Implants in non-bruxers patients
1 3 6 5 0 0 14
in the present study’s clinic, there was a
2 21 106 (4) 57 8 0 192 (4) lower percentage of women presenting with
3 25 (3) 131 (3) 43 (3) 11 (1) 0 210 (10) bruxism (49 of 1433, 3.42%) than men (49 of
4 0 2 7 (1) 2 0 11 (1)
1236, 3.96%). This is in contrast to Manfre-
Total 49 (3) 245 (7) 112 (4) 21 (1) 0 427
No missing information dini et al. (2004), who observed a strong dif-
ference in the prevalence of bruxism between
The number between parentheses represents failures.
female (57.8%) and male (25.5%) patients,
who attended a neuroscience clinic. This
female predilection was also observed in a
failure rate in the group of bruxers. Although 1 year, as well as Ji et al. (Ji et al. 2012), with study adopting clinical and/or interview-
a recent review (Manfredini et al. 2014) has a mean follow-up of 42.1 months. based diagnosis of bruxism (Jensen et al.
concluded that is unlikely that bruxism These results are believed to be partly 1993). On the other hand, there was no gen-
would be considered a risk factor for a higher related to the decreased proprioception of der predilection found in a study of poli-
implant failure, based on the identified stud- implants in comparison with teeth. The peri- somnographically diagnosed sleep bruxism
ies that considered bruxism as presenting no odontal ligament of natural teeth provides (Lavigne et al. 1996). Thus, it can be seen
or uncertain risk factor for biological compli- the central nerve system with feedback for that the difference in prevalence in the pre-
cations in implant-supported restorations, sensory perception and motor control (Meyer sent study is opposite to what has been usu-
there are some studies that corroborate our et al. 2012), whereas the proprioception ally observed in the literature. This may be
results. Wannfors et al. (2000) and Glauser around dental implants is limited because of explained by the fact that the present study
et al. (2001) reported a significant relation- the absence of a periodontal ligament, caus- population may not be representative of the
ship between bruxism and implant failure ing lower tactile sensitivity (H€ammerle et al. general population, comprising only patients
after the implants have been functional for 1995). Consequently, the proprioceptive feed- being treated with dental implants.
Table 8. Comparison of survival and failure of dental implants between bruxers and non-bruxers, according to health condition and patients’ habits –
“n” represents the number of patients, and the number between parentheses represents the number of implants
Bruxer patients Non-bruxer patients
At least one
No implant failures At least one implant Total n No implant implant failure Total n
n (implants) failure n (implants) (implants) failures n (implants) n (implants) (implants) P-value*
High blood pressure
No 48 (209) 15 (58) 63 (267) 63 (291) 6 (7) 69 (298)
Yes 21 (97) 5 (14) 26 (111) 20 (98) 5 (8) 25 (106)
Total** 69 (306) 20 (72) 89 (378) 83 (389) 11 (15) 94 (404)
Unknown 4 (36) 5 (13) 9 (49) 4 (23) 0 (0) 4 (23)
Patients/Group High blood pressure – 26. Normal – 63 High blood pressure – 25. Normal – 69 <0.001
Diabetes
No 60 (260) 15 (58) 75 (318) 81 (385) 11 (15) 92 (400)
Type 1 1 (4) 2 (5) 3 (9) 1 (2) 0 (0) 1 (2)
Type 2 8 (42) 3 (9) 11 (51) 2 (13) 0 (0) 2 (13)
Total** 69 (310) 20 (72) 89 (382) 84 (400) 11 (15) 95 (415)
Unknown 4 (36) 5 (13) 9 (49) 3 (12) 0 (0) 3 (12)
Patients/Group Diabetes – 14. Normal – 75 Diabetes – 3. Normal – 92 <0.001
High cholesterol
No 54 (235) 16 (54) 70 (289) 78 (360) 9 (13) 87 (373)
Yes 15 (71) 4 (18) 19 (89) 5 (29) 2 (2) 7 (31)
Total** 69 (306) 20 (72) 89 (378) 83 (389) 11 (15) 94 (404)
Unknown 4 (36) 5 (13) 9 (49) 4 (23) 0 (0) 4 (23)
Patients/Group High cholesterol – 19. Normal – 70 High cholesterol – 7. Normal – 87 <0.001
Hypothyroidism
No 63 (281) 18 (66) 81 (347) 79 (369) 11 (15) 90 (384)
Yes 6 (27) 3 (8) 9 (35) 4 (20) 0 (0) 4 (20)
Total** 69 (308) 21 (74) 8 (382) 83 (389) 11 (15) 94 (404)
Unknown 4 (34) 4 (11) 8 (45) 4 (23) 0 (0) 4 (23)
Patients/Group Hypothyroidism – 9. No – 81 Hypothyroidism – 4. No – 90 <0.001
Asthma
No 60 (274) 19 (66) 79 (340) 79 (356) 9 (10) 88 (366)
Yes 9 (41) 2 (12) 11 (53) 4 (33) 2 (5) 6 (38)
Total** 69 (315) 21 (78) 90 (393) 83 (389) 11 (15) 94 (404)
Unknown 4 (27) 4 (7) 8 (34) 4 (23) 0 (0) 4 (23)
Patients/Group Asthma – 11. No – 79 Asthma – 6. No – 88 <0.001
Intake of medicaments for depression
No 57 (238) 16 (43) 73 (281) 80 (375) 10 (11) 90 (386)
Yes 12 (77) 5 (35) 17 (112) 3 (14) 1 (4) 4 (18)
Total** 69 (315) 21 (78) 90 (393) 83 (389) 11 (15) 94 (404)
Unknown 4 (27) 4 (7) 8 (34) 4 (23) 0 (0) 4 (23)
Patients/Group Depression – 17. No – 73 Depression – 4. No – 90 <0.001
Intake of medicaments to reduce the acid gastric production
No 63 (269) 16 (57) 79 (326) 80 (376) 9 (13) 89 (389)
Yes 6 (37) 4 (15) 10 (52) 3 (13) 2 (2) 5 (15)
Total** 69 (306) 20 (72) 89 (378) 83 (389) 11 (15) 94 (404)
Unknown 4 (36) 5 (13) 9 (49) 4 (23) 0 (0) 4 (23)
Patients/Group Intake – 10. No – 79 Intake – 5. No – 89 <0.001
Intake of antithrombotic agents
No 59 (237) 15 (54) 74 (291) 78 (340) 7 (8) 85 (348)
Yes 10 (69) 5 (18) 15 (87) 5 (49) 4 (7) 9 (56)
Total** 69 (306) 20 (72) 89 (378) 83 (389) 11 (15) 94 (404)
Unknown 4 (36) 5 (13) 9 (49) 4 (23) 0 (0) 4 (23)
Patients/Group Intake – 15. No – 74 Intake – 9. No – 85 <0.001
Smoking
No 42 (189) 12 (43) 54 (232) 63 (273) 7 (8) 70 (281)
Yes 19 (76) 7 (32) 26 (108) 19 (117) 4 (7) 23 (124)
Former smoker 4 (37) 1 (2) 5 (39) 0 (0) 0 (0) 0 (0)
Total** 65 (302) 20 (77) 85 (379) 82 (390) 11 (15) 93 (405)
Unknown 8 (40) 5 (8) 13 (48) 5 (22) 0 (0) 5 (22)
Patients/Group Smoker – 26. No smoker – 54 Smoker – 23. No smoker – 70 0.001
Snuff
No 62 (274) 16 (59) 78 (333) 75 (367) 10 (14) 85 (381)
Yes 3 (19) 3 (12) 6 (31) 7 (23) 1 (1) 8 (24)
Total** 65 (293) 19 (71) 84 (364) 82 (390) 11 (15) 93 (405)
Unknown 8 (49) 6 (14) 14 (63) 5 (22) 0 (0) 5 (22)
Patients/Group Snuff – 6. No – 78 Snuff – 8. No – 85 <0.001
*McNemar’s test.
**Total of patients (implants) for patients to which the information of the habit or medical-related condition is known.
Table 9. Comparison of the number of mechanical complications between bruxers and non-bruxers Wennerberg 2004; Chrcanovic et al. 2015b).
patients groups in the implant-supported prosthetic restorations (possible complications in teeth-
supported prosthetic restorations are not included) There is supportive evidence for a positive
relationship between an improved bone heal-
Complication Bruxers Non-bruxers Odds ratio (95% CI) P-value
ing around implants and its surface rough-
Acrylic teeth fractured/lost (n) 154 44 12.091 (8.211, 17.805)† <0.001
ness (Shalabi et al. 2006), which enhances
Segment of prosthesis’ acrylic 15 5
fractured (n) the process of osseointegration. However, it
Implant’s hole sealing lost (n) 43 21 is also important to note that the group of
Porcelain fracture (n) 50 4 12.342 (4.388, 34.719)† <0.001 turned-surface implants had statistically sig-
Prosthesis fractured* (n) 17 1
Prosthesis loose (n) 73 15 7.862 (4.215, 14.662)‡ <0.001 nificantly longer mean follow-up time than
Fixed prosthesis fell out/came off (n) 2 0 the group of enlarged surface implants, which
Screw fractured (n) 96 (61/35)¶ 3 (2/1)¶ 40.991 (12.875, 130.509)§ <0.001 can lead to an increase in the failure rate.
Screw loose (n) 54 11 5.475 (2.821, 10.627)§ <0.001
The nightly use of a hard acrylic occlusal
Screw lost (n) 8 0
Fractured implant 16 0 guard by the present sample of bruxers was
Abutment deformed (n) 16 0 found to be erratic in this study. Thus, a
Overdenture component fractured (n) 7 6 proper evaluation of the effect of nightguard
Hard splint fractured (n) 2 –
use on implant failure and/or mechanical
*Prosthesis with complete transversal (buccal–lingual) fracture. complication rates was not possible. It is
†The total number of acrylic/porcelain teeth was considered for the calculation of the odds ratio.
important to note that there are conflicting
‡The total number of fixed prostheses (excluding overdentures) was considered for the calculation of
the odds ratio. results regarding the clinical efficacy of
§The total number of screws was considered for the calculation of the odds ratio. occlusal splints (Dao & Lavigne 1998; List &
¶(n1/n2) – the first number between parenthesis (n1) represents the number of fractures of prosthetic Axelsson 2010) and a lack of knowledge
screws, and the second number (n2) represents the number of fractures of abutment screws.
about the potential mechanisms that explain
their success in the treatment of bruxism.
It was suggested that one of the most mine agonists, such as amphetamine, which This has led to the understanding that these
important factors responsible for implant fail- can induce manic symptoms (Sokoloff et al. devices represent a nonspecific therapy (Dao
ures is probably the local anatomic structure 1990) and tooth grinding may also play a & Lavigne 1998), being restricted to the pre-
regarding bone quality and quantity, or rather possible role (Milosevic et al. 1999). Alonso- vention and/or limitation of dental wear
the lack thereof (Ekfeldt et al. 2001). The pre- Navarro et al. (2009) reported a case of a potentially induced by bruxism (Dao & Lavi-
sent study observed that a greater percentage 62-year-old man who developed severe brux- gne 1998; Ommerborn et al. 2011).
of implants were placed in bone sites having ism that began 2 weeks after starting a ther- Although associated with a number of clin-
been classified as quantities D and E in the apy with venlafaxine because of depression ical problems, including orofacial pain, tooth
bruxer patients group, in comparison with and anxiety. After venlafaxine withdrawal, wear, and failing dental restorative treat-
the non-bruxer group, with the difference bruxism improved gradually and disappeared ments, bruxism remains difficult to manage
showing to be statistically significant. This 2 months later. in effective and safe ways (Lobbezoo et al.
fact may also have exerted some influence on The present results documented a higher 2006b). Unfortunately, there is a scarcity of
the difference in implant failure rates. failure rate of short implants in bruxers in reliable and valid diagnostic tools for the con-
It was also observed that the patients’ med- comparison with longer implants, which dition (Lobbezoo et al. 2013). Without a “def-
ically related conditions and habits had sta- tended to decrease as the implant length inite” diagnosis of bruxism been established
tistically significantly different numbers of increased. Implants with regular diameter in the present study, it is acknowledged that
patients included in the two groups (bruxers (3.75–4.30 mm) had a lower failure rate than some of the outcomes illustrated in some of
vs. non-bruxers), which may also have influ- narrow diameter implants (3.00–3.50 mm) in the clinical cases may be due to such load-
enced the implant failure rates. Depression is bruxers. The total number of implants of increasing or material-related factors, rather
a condition of great interest, due to its sug- wide diameter (4.50–5.00 mm) was consid- than to bruxism per se (Johansson et al.
gested strong association with bruxism. A ered too low to possibly draw any conclusion 2011). Some of the assessment procedures
study by Manfredini et al. (2004) found sig- concerning this group. The diameter and here performed may also have some
nificant differences between bruxers and con- length of an implant (Himmlova et al. 2004), limitations, as for example, difficulties in
trols regarding the presence of depressive as well as thread pitch, shape, and surface distinguishing between functional and non-
symptoms, such as manic symptoms, stress treatment (Abuhussein et al. 2010), are modi- functional tooth wear during a clinical
sensitivity, and anxious expectation. This fiers that affect load transfer characteristics evaluation (Manfredini et al. 2004). Another
may be related to the fact that disturbances between implant and bone. Longer implants limitation of the present study is its retro-
in the central neurotransmitter system may with a larger diameter help to keep the stres-
spective nature, which inherently results in
be involved in the etiology of bruxism ses in the bone as low as possible (el Askary
flaws. These problems were manifested by
(Lobbezoo et al. 1997; Lavigne et al. 2003). In et al. 1999). Moreover, implants classified as
the gaps in information and incomplete
addition, results from pharmacological stud- having roughened surfaces had a statistically
records.
ies suggest a possible role for selective sero- significantly lower probability to fail in com-
tonin reuptake inhibitors, a class of parison with turned implants, in both bruxers
antidepressants, which can exacerbate manic and non-bruxers. It has been shown that the Conclusions
symptoms in bipolar individuals (Craddock osseointegration process is influenced by sev-
et al. 2001) and can also cause bruxism after eral factors (Chrcanovic et al. 2014), among The present study suggests that bruxism may
long-term usage (Lobbezoo et al. 2001). Dopa- them the surface texture (Albrektsson & significantly increase both the implant
failure rate and the rate of mechanical and Related Research by Region Sk ane US National Institutes of Health
technical complications of implant-supported (Odontologisk Forskning Sk ane), Sweden, (clinicaltrials.gov): NCT02369562.
restorations. Other risk factors may also have and from the Scientific Research Council
influenced the results. of Sweden (Vetenskapsr adet, Dnr
2015-02971). This work was supported
Declaration of conflicting interests
by Folktandv arden AB, Region Sk ane,
Acknowledgements: Funding and Sweden and by CNPq, Conselho
There are no conflict of interests to declare.
support: This work was supported by Nacional de Desenvolvimento Cientıfico e
research funds from the Oral Health Tecnologico, Brazil. Trial registration at the
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V

The intake of proton pump inhibitors is associated with an increased risk of dental implant failure
Bruno Ramos Chrcanovic 1*
Jenö Kisch 2
Tomas Albrektsson 3
Ann Wennerberg 4
1
DDS, MSc, PhD student; Department of Prosthodontics, Faculty of Odontology, Malmö University,
Malmö, Sweden
2
DDS; Clinic for Prosthodontics, Centre of Dental Specialist Care, Malmö, Sweden
3
MD, PhD; Retired Professor and Former Head, Department of Biomaterials, Göteborg University,
Göteborg, Sweden; Guest Professor, Department of Prosthodontics, Faculty of Odontology, Malmö
4
DDS, PhD; Professor and Head, Department of Prosthodontics, Faculty of Odontology, Malmö
* Corresponding author:
Bruno Ramos Chrcanovic, Department of Prosthodontics, Faculty of Odontology, Malmö University,
Carl Gustafs väg 34, SE-‐214 21, Malmö, Sweden. [email protected];
[email protected] Mobile: +46 725 541 545 Fax: +46 40 6658503

Abstract
Purpose. To investigate the association between the intake of pump proton inhibitors (PPIs) and the
risk of dental implant failure.
Materials and Methods. The present retrospective cohort study is based on the patients
consecutively treated with implant-‐supported/retained prostheses at one specialist clinic. Modern
endosseous dental implants with cylindrical or conical design were included. Only complete cases
were considered, i.e. only those implants with information available for all variables were included in
the regression model analysis. Zygomatic implants and Implants detected in radiographies, but
without basic information about them in the patients’ files were excluded from the study. Implant-‐
and patient-‐related data were collected. Multilevel mixed effects parametric survival analysis was
used to test the association between PPIs exposure (predictor variable) and risk of implant failure
(outcome variable) adjusting for several potential confounders (other variables).
Results. A total of 3,559 implants were placed in 999 patients, with 178 implants reported as
failures. The implant failure rates were 12.0% (30/250) for PPIs users and 4.5% (148/3309) for
nonusers. Forty-‐five (25.3%) out of 178 failed implants were lost up to the abutment connection (6
in PPIs users, 39 in nonusers), with an early:late failure ratio of 0.34:1. The intake of PPIs has shown
to be statistically significantly for implant survival rate (HR 2.811; 95%CI 1.139, 6.937; P=0.025).
Bruxism, smoking, implant length, prophylactic antibiotic regimen, and implant location were also
identified as factors that statistically significantly affected the implant survival rate.
Conclusion. This study suggests that the intake of PPIs may be associated with an increased risk of
dental implant failure.
Keywords
Dental implant; failure; risk factors; proton pump inhibitors; multivariate analysis; multilevel mixed
effects parametric survival analysis

Introduction
Dental implants are an effective and predictable treatment modality for replacing missing
teeth in both fully and partially edentulous patients. However, failures can occur.1 Several risk
factors have been suggested to influence the failure of implants. Surgical conditions, submission to
radiotherapy, the oral microbial environment, parafunctional habits, and prosthetic variables are
some of these factors. Systemic diseases and habits such as smoking may affect oral tissues by
increasing their susceptibility to other diseases or by interfering with wound healing. The intake by
the patient of medications that directly or indirectly affect the bone metabolism may also play a role
on the outcome of implants.2 Among the drugs commonly prescribed nowadays, we find the proton
pump inhibitors (PPIs).
Proton pump inhibitors (PPIs) are commonly used for the treatment of acid-‐related
disorders, such as gastroesophageal reflux disease or gastric ulcer disease, by inhibiting the acid
output of the stomach. The higher probability of losing an implant in patients taking medicaments to
reduce the acid gastric production has been suggested to be related to observations indicating that a
reduction of gastric acidity may impair effective calcium uptake through the intestines.3 As the
calcium balance is essential for the maintenance of bone health, it seems reasonable to believe that
the unbalance of calcium may to some degree affect osseointegration.
There is still no consensus on the influence of PPIs on the risk of dental implant failure. The
aim of this retrospective study was to investigate the association between the intake of PPIs and the
risk of dental implant failure, and to describe and compare the group of patients taking PPIs with the
one not taking this class of drugs. In this study, it was hypothesized that the intake of PPIs might be
associated with an increased risk of dental implant failure.

Study design/sample
This study was designed as a retrospective cohort study, and is based on 10,096 implants
placed in all 2,670 patients consecutively treated with implant-‐supported prostheses between 1980
and 2014 at one specialist clinic (Clinic for Prosthodontics, Centre of Dental Specialist Care, Malmö,
Sweden).
Inclusion criteria:
• All modern endosseous dental implants with cylindrical or conical design;
• Complete cases only, i.e. only those implants with information available for all variables
here included (see Variables below) were included in the regression model analysis.
Exclusion criteria:
• Zygomatic implants;
• Implants detected in radiographies, but without basic information about them in the
patients’ files.
Each patient received oral prophylaxis by a dental hygienist within 6 months after the final
implant-‐supported/retained restoration and enrolled in a prophylaxis schedule based on their
individual needs.
Variables
For this study, the PPIs status was the predictor variable. Patients who reported to be taking
this type of medication during the presurgery appointment (1 to 2 weeks prior to implant
placement) were defined as PPIs users. The PPIs verified included omeprazole, lansoprazole,
dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole.
The outcome variable was implant failure. An implant was considered a failure if presenting
signs and symptoms that led to implant removal. Thus, a failed implant in our study is equal to a lost
implant.

Other variables included: implant surface (machined or rough surfaces, specifically
sandblasted, acid-‐etched, sandblasted + acid-‐etched, anodized, hydroxyapatite-‐coated surfaces),
implant system (Nobel machined, Nobel TiUnite [Nobel Biocare, Göteborg, Sweden], Astra TiOblast,
Astra Osseospeed, XIVE/Frialit-‐2 [Dentsply, Mölndal, Sweden], Straumann SLA/SLActive/Roxlid
[Straumann, Basel, Switzerland], other), implant length (three categories: 6.0-‐10.0, 10.5-‐14.0, 15.0-‐
20.0 mm), implant diameter (three categories: 3.00-‐3.50, 3.70-‐4.10, 4.20-‐5.00 mm), prescription of
prophylactic antibiotics (starting 1-‐2 hours before surgery and continuing for 5-‐7 days), bone graft
procedures, implant jaw location (maxilla or mandible, anterior or posterior; region from a canine
tooth to the contralateral canine tooth was considered anterior location), patient’s gender, age of
the patient at the implant insertion surgery (three categories: ≤30, 30<x≤60, >60 years), time period
until failure, and follow-‐up time (baseline = day of implant installation). Health factors, medical
disorders, and patients’ habits known or suspected to substantially affect bone metabolism were
evaluated: smoking, bruxism, and the intake of PPIs, antidepressants, immunosuppressives,
bisphosphonates, antihypertensive drugs, and antithrombotic agents (antiplatelet, anticoagulant,
thrombolytic drugs).
Data collection methods
The dental records of all patients ever treated with implants in the aforementioned clinic
were read in order to collect the data. The data were directly entered into a SPSS file (SPSS software,
version 23, SPSS Inc., Chicago, IL, USA) as the files were being read. The general health and the
behavioral history of the patients and correlation of drugs to specific health conditions were
collected from the patients’ files.
Data analyses
Descriptive statistics were used to describe the basic features of the data. Differences
between implants of PPIs users and nonusers were compared with the student’s t-‐test or Mann-‐

Whitney test for continuous variables, depending on the normality, and the Pearson’s chi-‐squared or
Fisher’s exact tests for categorical variables, depending on the expected count of events in a 2x2
contingency table. Comparison between PPI drugs users and nonusers in terms of demographic
systemic conditions and other factors were done; odds ratios (OR) and their 95% confidence
intervals (CI) were computed.
Multilevel mixed effects parametric survival analysis4, 5 was performed to assess the
association between PPIs intake (predictor variable) and dental implant failure (outcome variable),
accounting for the fact that repeated observations (several implants) were available for a single
patient (cluster effect). Because there was little prior knowledge about the appropriate shape of
survival probability, parametric frailty models were extended including five different parametric
models (Weibull, Exponential, Log logistic, Log Normal, and Gamma) to allow any number of
normally distributed random effects. Akaike information criteria (AIC) were used to choose the best
fit survival model.6 The intake of PPIs was the exposure variable, and all analyses were adjusted for
the following potential confounders (other variables): patient’s gender and age, implant surface,
implant type, implant length, implant diameter, implant location, bone augmentation, smoking
habits, bruxism, and the intake of prophylactic antibiotics, antidepressants, immunosuppressives,
bisphosphonates, antihypertensive drugs, and antithrombotic agents. In order to verify
multicollinearity, a correlation matrix of all of the predictor variables with a significant odds ratio (P-‐
value cut-‐off point of 0.1) was scanned, to see whether there were some high correlations among
the predictors. Collinearity statistics obtaining variance inflation factor (VIF) and tolerance statistic
were also performed to detect more subtle forms of multicollinearity. The results of the final model
were presented as an estimated hazard ratio (HR) of each significant prognostic variable.
A P-‐value of P<0.05 was considered statistically significant. All data were statistically
analyzed using the software Stata version 14 (StataCorp LP, College Station, TX, USA) and SPSS
version 23 (SPSS Inc., Chicago, IL, USA). The study was approved by the Regional Ethical Review

Board in Lund (Dnr 2014/598; Dnr 2015/72), and is in concordance with the STROBE guidelines for
observational studies.
Results
The number of implants with information available for all variables totaled 3,559, placed in
999 patients, with 178 implants reported as failures and removed. There were 1,773 implants in 479
men (mean age±SD 60.4±15.9, min-‐max 15.9-‐90.2) and 1786 implants in 520 women (mean age±SD
59.6±15.0, min-‐max 14.9-‐90.8). Sixty-‐seven PPIs users received a total of 250 implants whereas 932
nonusers received 3,309 implants. The number of implants per patient ranged from 1 to 20
(mean±SD 3.46±2.64). The mean±SD follow-‐up time was 94.8±78.7 months [median 71.4, 25th
percentile 30.4, 75th percentile 138.9] (PPIs users: 88.8±80.5 months, median 52.3, 25th percentile
26.9, 75th percentile 115.3, nonusers: 95.2±78.6 months, median 72.2, 25th percentile 31.2, 75th
percentile 139.2; P = 0.072; Mann-‐Whitney test). The implant failure rates were 12.0% (30/250) for
people taking PPIs and 4.5% (148/3309) for people not taking these drugs (P < 0.001; Pearson’s chi-‐
squared test). The 178 failed implants were lost at a mean±SD of 37.6±53.8 months (min-‐max, 0.8-‐
316.4). Forty-‐five (25.3%) out of 178 failed implants were lost up to the abutment connection
procedure or 2nd stage surgery (6 in PPIs users, 39 in nonusers). Eighty-‐five out of 178 (47.8%) failed
implants were lost until 1 year after surgery. All implants were inserted with open flapped surgery.
Twenty implants were immediately loaded (1 in PPIs users, 19 in nonusers). Eleven implants were
placed in fresh extraction sockets, all in nonusers of PPIs. A number of 113 implants were non-‐
submerged (13 in PPIs users, 100 in nonusers). The abutment connection surgery was performed
after a mean±SD healing time of 5.2±1.8 and 5.2±2.1 months for the PPIs users and nonusers,
respectively (P = 0.588; Mann-‐Whitney test).
The comparison between patients taking and not taking PPIs (Table 1) showed that people
from the age range 30<x≤60 and older than 60 years were more likely to take PPIs than younger
patients (≤30). Moreover, shorter implants were more common in PPIs users than in nonusers. There

were more bruxers, and people taking antihypertensive, antidepressants, and antithrombotic drugs
among the PPIs users. The two groups of patients were comparable in terms of the factors gender,
implant diameter, implant surface, implant location, smoking habits, bone augmentation
procedures, prophylactic antibiotic regimen, and intake of bisphosphonates and
immunosuppressives, and for most of the different implant types (Table 1).
The multilevel mixed effects parametric survival analysis adjusted for the aforementioned
confounders using Weibull model (Table 2) based on AIC selection showed that the intake of PPIs
statistically significantly affected the implant survival rate. Bruxism, smoking, implant length,
prophylactic antibiotic regimen, and implant location were also identified as factors that statistically
significantly affected the implant survival rate. Age, gender, implant diameter, implant surface,
implant type, bone augmentation, former smokers, and the intake of antihypertensive,
antidepressants, antithrombotic, and immunosuppressive drugs did not statistically significantly
affect the implant survival rate (Table 2). Multicollinearity was not detected.
Discussion
The results of the present study suggested that the intake of PPIs might be associated with
an increased risk of dental implant failure. Moreover, the statistical model also suggested bruxism,
smoking, implant length, prophylactic antibiotic regimen, and implant location as potential factors
exerting a statistically significant influence on dental implant failures.
Some reasons could theoretically account for the suggested association between PPIs intake
and the increased likelihood of dental implant failures. The most prominent hypothesis assumes that
the reduced acidity in the stomach impairs the intestinal absorption of dietary calcium. Thus, there
7-‐9
can be a decreased calcium absorption under PPI therapy . Graziani et al.7 observed that
postprandial calcium concentrations did not increase in subjects on a PPI regime (omeprazole 20 mg
3x daily), whereas control subjects demonstrated a clear spike in serum calcium levels. They as well
observed that the urine calcium excretion in the PPI group was also reduced in comparison to the

control group. O’Connell et al.8 measured the intestinal calcium absorption and observed that 7 days
of PPI (omeprazole 20 mg once a day) intake significantly reduced calcium absorption in elderly
women under fasting conditions compared with the placebo group. Schinke et al.9 showed that
genetically manipulated mice to be achlorhydric (with absence of hydrochloric acid from gastric
juice) presented decreased serum calcium levels and developed osteoporosis and secondary
hyperparathyroidism in an effort to maintain calcium balance. As the calcium balance is essential for
the maintenance of bone health, it seems reasonable to believe that the unbalance of calcium may
to some degree affect osseointegration.
Bruxism was shown to significantly affect the implant failure rates negatively, agreeing with
the results of a recent meta-‐analysis 10 and two clinical trials 11, 12 on the subject. This is due to the
fact that bruxism is suggested to cause excessive load of implant-‐supported rehabilitations, which
may cause an implant fracture or may result in bone loss around the implants and subsequent
implant failure.13 Smoking was also shown as a factor affecting negatively the failure rates. A meta-‐
analysis analyzing more than 100 studies has shown that failures of implants inserted in smokers are
2.23 times likely to happen than failures of implants inserted in non-‐smokers.14 The increase of
implant failure rates due to smoking is hypothesized to be related mainly to the effect of smoking in
osteogenesis and angiogenesis.15 Moreover, smokers’ health behavior and attitudes appear to be
less favorable to oral health than those of non-‐smokers.16 Studies have shown that smokers brush
and floss their teeth less frequently than non-‐smokers 17 and have dental visits less frequently than
do non-‐smokers.18 With regard to lower hazard ratios for longer implants, although some good
results can be obtained with the use of shorter implants, they seem to fail more often than longer
ones.19 Increased initial stability, long-‐term resistance to bending moment forces, expedited healing,
and a decreased risk of movement at the interface are listed as advantages of increased implant
length.20 When it comes to the statistically reduced failures rates when a prophylactic antibiotic
regimen was prescribed for the surgery, it has been suggested that the use of antibiotics in healthy
patients significantly decreases implant failures.21 Implants inserted in the anterior mandible

presented a statistically lower risk of failure when compared to those inserted in the anterior
maxilla. The maxilla has a less favorable bone texture than mandibles, with low density of medullary
bone and thin cortical plates.22 The region of the anterior mandible is usually considered as having
an osseous structure more propitious to achieve primary instability of implants. Jaws with poor bone
quality may be at risk of establishing initial instability of the implants and a lack of resistance to
mechanical stresses, thus also resulting in early implant failures.22, 23
The limitations of the present study include the fact that this is a retrospective study, which
inherently results in flaws, manifested by the gaps in information and incomplete records. The lack
of specific information characterizing the some patients’ systemic conditions status and the
medications dosage are limitations also connected to the retrospective nature of this study.
Conclusions
It is suggested that the intake of PPIs may be associated with an increased risk of dental
implant failure.

Acknowledgements
Funding and support: This work was supported by research funds from the Oral Health Related
Research by Region Skåne (Odontologisk Forskning i Region Skåne, OFRS 414321), Sweden, and from
the Scientific Research Council of Sweden (Vetenskapsrådet, Dnr 2015-‐02971). This work was
supported by Folktandvården AB, Region Skåne, Sweden and by CNPq, Conselho Nacional de
Desenvolvimento Científico e Tecnológico, Brazil.
Trial registration at the U.S. National Institutes of Health (clinicaltrials.gov): NCT02369562
Declaration of conflicting interests: There are no conflicts of interest to declare.
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Tables
Table 1. Description of the cohort by patients (n=999) between proton pump inhibitors (PPIs) users
and nonusers. The number between parentheses represents the number of implants.
Variables Proton pump inhibitors -‐ patients Odds Ratio (95% CI) p value
(implants)
Users Nonusers
Age (years)
≤30 1 (6) 159 (248) 1
30 < x ≤ 60 24 (95) 361 (1163) 10.571 (1.418, 78.818) 0.021
>60 42 (149) 412 (1898) 16.209 (2.212, 118.764) 0.006
Gender
Male 28 (113) 451 (1660) 1
Female 39 (137) 481 (1649) 1.306 (0.790, 2.158) 0.297
Implant length (mm)*
6.0-‐10.0 29 (73) 306 (644) 1
10.5-‐14.0 52 (128) 677 (1621) 0.810 (0.505, 1.302) 0.385
15.0-‐20.0 19 (49) 430 (1044) 0.466 (0.257, 0.847) 0.012
Implant diameter
(mm)*
3.00-‐3.50 6 (16) 129 (290) 1
3.70-‐4.10 61 (228) 806 (2951) 1.627 (0.689, 3.841) 0.267
4.20-‐5.00 5 (6) 54 (68) 1.991 (0.583, 6.801) 0.272
Implant surface*
Machined 16 (90) 333 (1523) 1
Rough 51 (160) 622 (1786) 1.706 (0.958, 3.039) 0.070
Implant type*
Nobel Machined 16 (90) 333 (1523) 1
Nobel TiUnite 34 (114) 466 (1300) 1.519 (0.825, 2.796) 0.180
Astra TiOblast 2 (3) 38 (158) 1.095 (0.243, 4.948) 0.906
Astra Osseospeed 3 (6) 19 (56) 3.286 (0.881, 12.264) 0.077
Straumann 5 (13) 27 (73) 3.854 (1.311, 11.327) 0.014
XiVE/Frialit-‐2 0 (0) 9 (33) -‐ -‐
Other 9 (24) 77 (166) 2.433 (1.036, 5.711) 0.041
Implant location*
Anterior maxilla 31 (85) 458 (1129) 1
Posterior maxilla 32 (51) 360 (653) 1.313 (0.786, 2.193) 0.298
Anterior mandible 20 (62) 235 (888) 1.257 (0.701, 2.254) 0.442
Posterior mandible 24 (52) 302 (639) 1.174 (0.676, 2.040) 0.569
Bone augmentation*
No 64 (221) 900 (3201) 1
Yes 7 (29) 62 (108) 1.588 (0.698, 3.611) 0.270
Prophylactic
antibiotics*
No 7 (20) 112 (323) 1
Yes 60 (230) 838 (2986) 1.146 (0.511, 2.568) 0.741
Smoking
No 47 (147) 666 (2236) 1
Yes 16 (90) 247 (991) 0.918 (0.511, 1.649) 0.774

Former smoker 4 (13) 19 (82) 2.983 (0.975, 9.125) 0.055

Bruxism
No 59 (219) 884 (3156) 1
Yes 8 (31) 48 (153) 2.497 (1.129, 5.522) 0.024
Antihypertensive drugs
No 33 (116) 683 (2291) 1
Yes 34 (134) 249 (1018) 2.826 (1.713, 4.662) <0.001
Antidepressants
No 48 (165) 858 (3050) 1
Yes 19 (85) 74 (259) 4.590 (2.565, 8.213) <0.001
Bisphosphonates
No 66 (246) 914 (3257) 1
Yes 1 (4) 18 (52) 0.769 (0.101, 5.853) 0.800
Antithrombotic drugs
No 43 (166) 793 (2736) 1
Yes 24 (84) 139 (573) 3.184 (1.873, 5.415) <0.001
Immunosuppressives
No 65 (238) 923 (3269) 1
Yes 2 (12) 9 (40) 3.156 (0.668, 14.907) 0.147
CI – confidence interval
* Since a single patient may have received several implants with different characteristics, or implants
placed in different locations, a patient may have entered in more than one category for this factor

Table 2. Multilevel survival analysis for dental implant failure in terms of different factors (total
number of implants=3,559). Hazard ratios (HR) were performed using multilevel mixed effects
parametric survival analysis.
Factor Number of Number of Failure (%) p HR (95% CI)

failed survived value
implants (%) implants (%)
Proton pump
inhibitors
No 148 (83.1) 3161 (93.5) 4.5 1
Yes 30 (16.9) 220 (6.5) 12.0 0.025 2.811 (1.139, 6.937)
Age (years)
≤30 10 (5.6) 244 (7.2) 3.9 1
30 < x ≤ 60 101 (56.7) 1157 (34.2) 8.0 0.876 0.925 (0.346, 2.474)
>60 67 (37.6) 1980 (58.6) 3.3 0.099 0.418 (0.148, 1.179)
Gender
Male 78 (43.8) 1695 (50.1) 4.4 1
Female 100 (56.2) 1686 (49.9) 5.6 0.940 1.022 (0.582, 1.793)
Implant length (mm)
6.0-‐10.0 75 (42.1) 642 (19.0) 10.5 1
10.5-‐14.0 67 (37.7) 1682 (49.7) 3.8 <0.001 0.394 (0.254, 0.611)
15.0-‐20.0 36 (20.2) 1057 (31.3) 3.3 <0.001 0.298 (0.172, 0.515)
Implant diameter

(mm)
3.00-‐3.50 19 (10.7) 287 (8.5) 6.2 1
3.70-‐4.10 157 (88.2) 3022 (89.4) 4.9 0.171 0.546 (0.229, 1.298)
4.20-‐5.00 2 (1.1) 72 (2.1) 2.7 0.520 0.546 (0.087, 3.448)
Implant surface
Machined 122 (68.5) 1491 (44.1) 7.6 1
Rough 56 (31.5) 1890 (55.9) 2.9 0.114 0.300 (0.068, 1.333)
Implant type
Nobel Machined 122 (68.5) 1491 (44.1) 7.6 1
Nobel TiUnite 35 (19.7) 1379 (40.8) 2.5 0.871 1.132 (0.254, 5.037)
Astra TiOblast 12 (6.8) 149 (4.4) 7.5 0.579 1.733 (0.249, 12.070)
Astra Osseospeed 1 (0.6) 61 (1.8) 1.6 0.584 0.447 (0.025, 7.991)
Straumann 4 (2.2) 82 (2.4) 4.7 0.792 0.746 (0.085, 6.549)
XiVE/Frialit-‐2 0 (0) 33 (1.0) 0 -‐ -‐
Other 4 (2.2) 186 (5.5) 2.1 -‐ -‐
Implant location
Anterior maxilla 73 (41.0) 1141 (33.7) 6.0 1
Posterior maxilla 41 (23.0) 663 (19.6) 5.8 0.530 0.864 (0.550, 1.361)
Anterior mandible 25 (14.1) 925 (27.4) 2.6 0.049 0.537 (0.288, 0.999)
Posterior mandible 39 (21.9) 652 (19.3) 5.6 0.418 0.788 (0.443, 1.402)
Bone augmentation
No 163 (91.6) 3259 (96.4) 4.8 1
Yes 15 (8.4) 122 (3.6) 10.9 0.398 1.478 (0.597, 3.655)
Prophylactic
antibiotics
No 24 (13.5) 319 (9.4) 7.0 1
Yes 154 (86.5) 3062 (90.6) 4.8 0.046 0.496 (0.249, 0.987)
Smoking
No 85 (47.7) 2298 (68.0) 1
Yes 82 (46.1) 999 (29.5) 7.6 0.003 2.363 (1.336, 4.180)
Former smoker 11 (6.2) 84 (2.5) 11.6 0.276 2.302 (0.514, 10.306)
Bruxism
No 155 (87.1) 3220 (95.2) 4.6 1
Yes 23 (12.9) 161 (4.8) 12.5 0.032 2.892 (1.098, 7.618)
Antihypertensive
drugs
No 127 (71.3) 2280 (67.4) 5.3 1
Yes 51 (28.7) 1101 (32.6) 4.4 0.662 0.855 (0.423, 1.727)
Antidepressants
No 146 (82.0) 3069 (90.8) 4.5 1
Yes 32 (18.0) 312 (9.2) 9.3 0.711 1.178 (0.495, 2.804)
Bisphosphonates
No 178 (100) 3325 (98.3) 5.1 1
Yes 0 (0) 56 (1.7) 0 -‐ -‐
Antithrombotic drugs
No 140 (78.7) 2762 (81.7) 4.8 1
Yes 38 (21.3) 619 (18.3) 5.8 0.625 1.223 (0.546, 2.740)
Immunosuppressives
No 171 (96.1) 3336 (98.7) 4.9 1
Yes 7 (3.9) 45 (1.3) 13.5 0.706 1.491 (0.187, 11.875)
CI – confidence interval
VI
Int. J. Oral Maxillofac. Surg. 2017; 46: 782–788
http://dx.doi.org/10.1016/j.ijom.2017.01.016, available online at http://www.sciencedirect.com
Clinical Paper
Dental Implants
Is the intake of selective B. R. Chrcanovic1, J. Kisch2,

T. Albrektsson1,3, A. Wennerberg1
1
Department of Prosthodontics, Faculty of
serotonin reuptake inhibitors Odontology, Malmö University, Malmö,

Sweden; 2Clinic for Prosthodontics, Centre of
Dental Specialist Care, Malmö, Sweden;
3
Department of Biomaterials, Gothenburg
associated with an increased University, Göteborg, Sweden
risk of dental implant failure?

B.R. Chrcanovic, J. Kisch, T. Albrektsson, A. Wennerberg: Is the intake of selective
serotonin reuptake inhibitors associated with an increased risk of dental implant
failure?. Int. J. Oral Maxillofac. Surg. 2017; 46: 782–788. ã 2017 International
Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights
reserved.
Abstract. The aim of this retrospective study was to investigate the association
between the intake of selective serotonin reuptake inhibitors (SSRIs) and the risk of
dental implant failure. Patients were included if they were taking SSRIs only and no
other medication, did not present any other systemic condition or compromising
habits (bruxism, smoking, snuff), and complied with the use of prophylactic
antibiotics for implant surgery. The multivariate generalized estimating equation
(GEE) method and multilevel mixed-effects parametric survival analysis were used
to test the association between SSRI exposure (predictor variable) and the risk of
implant failure (outcome variable), adjusting for several potential confounders
(other variables). The total number of implants with information available and
meeting the necessary eligibility criteria was 931 (35 failures). These were placed in
300 patients. The implant failure rate was 12.5% for SSRI users and 3.3% for non- Key words: dental implant; implant failure;
users (P = 0.007). Kaplan–Meier analysis showed a statistically significant selective serotonin reuptake inhibitors; multi-
difference in the cumulative survival rate (P < 0.001). The multivariate GEE model variate generalized estimating equation analy-
sis; multilevel mixed-effects parametric survival
did not show a statistically significant association between SSRI intake and implant analysis.
failure (P = 0.530), nor did the multilevel model (P = 0.125). It is suggested that the
intake of SSRIs may not be associated with an increased risk of dental implant Accepted for publication 26 January 2017
failure. Available online 20 February 2017
Nowadays dental implant placement is an implant survival and success rates.1 Sev- and prosthetic variables are some of these
effective and predictable treatment modal- eral risk factors have been suggested to factors. Systemic diseases and
ity for replacing missing teeth in both fully influence the failure of implants. Surgical compromising risky habits may affect
and partially edentulous patients. Never- conditions, radiotherapy, the oral micro- the oral tissues by increasing their suscep-
theless, failures still happen despite high bial environment, parafunctional habits, tibility to other diseases or by interfering
0901-5027/060782 + 07 ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
SSRIs and dental implants 783
with wound healing. The patient’s intake influence of antidepressants on the risk immunosuppressive drugs, antithrombotic
of medications that directly or indirectly of dental implant failure. agents (antiplatelet, anticoagulant, throm-
affect bone metabolism may also play a As the recognition of conditions that bolytic drugs), antiepileptic drugs, proton
role in the outcome of implants.2 place the patient at a higher risk of failure pump inhibitors, bisphosphonates, medi-
Among the drugs commonly pre- will allow the surgeon to make informed cations for asthma, or medications to de-
scribed today are the selective serotonin decisions and refine the treatment plan to crease high levels of cholesterol. Thus, the
reuptake inhibitors (SSRIs). SSRIs are a optimize the clinical outcome, the purpose status ‘taking SSRIs’ was isolated as much
class of drugs typically used as antide- of this study was to investigate the associ- as possible from the influence of other
pressants in the treatment of major de- ation between the intake of SSRIs and the systemic conditions or medications. Zygo-
pressive and anxiety disorders. Studies risk of dental implant failure. It was hy- matic implants were not included in the
have shown that the use of antidepres- pothesized that patients taking SSRIs study, nor were implants detected in radio-
sants predicts decreased bone mineral would have a higher implant failure rate graphs but without basic information
density in women,3 and both depression than patients not taking this class of drugs. about them in the patient’s files.
and the use of antidepressants are sug- The specific aims of the study were to In accordance with the standard proto-
gested to be possible risk factors for compare the implant failure rates between col at the study clinic, the patients’ dental
osteoporosis in men.4 It is possible that users and non-users of SSRIs, and to esti- hygiene was followed up by a dental
neuroendocrine mechanisms related to mate the influence of several variables on hygienist within 6 months after the final
the serotonin system could regulate oste- the prevalence of implant failure in regres- implant-supported/retained restoration.
oclast differentiation/activation, because sion models, with the intake of these med- Each patient then attended a dental hy-
osteoclasts derive from haematopoietic ications as the predictor variable. giene recall programme based on individ-
cell precursors and a relationship between ual needs.
bone and the immune system has been The trial from which data in this study
established.5–7 Studies have identified a Materials and methods were derived is registered with the US
functional serotonin system in osteoblasts National Institutes of Health
Study design/sample
and osteoclasts,8–10 in which the seroto- (clinicaltrials.gov, NCT02369562).
nin transporter and several receptors are A retrospective cohort study was designed
expressed in osteoblasts as well as in and implemented to address the research
Variables
osteoclasts.9,10 The presence of serotonin purposes. The study population comprised
receptors and the serotonin transporter in all patients treated consecutively with im- In this study, the patient’s SSRI status was
bone raises the question whether medica- plant-supported prostheses between 1980 the predictor variable. SSRI users were
tions that antagonize serotonin reuptake and 2014 at one specialist clinic (Clinic for defined as patients who reported taking
could influence bone metabolism. Prosthodontics, Centre of Dental Special- this type of medication during the pre-
It has been shown in in vitro studies that ist Care, Malmö, Sweden). surgery appointment that was scheduled
activity of the serotonin transporter is To be included in the study sample, the 1 to 2 weeks prior to implant placement.
required for osteoclast differentiation. patient had to be taking only SSRIs and no The SSRIs verified included citalopram,
While blockage of the serotonin transport- other medication and not present any other dapoxetine, escitalopram, fluoxetine, flu-
er was found to reduce osteoclast differ- systemic condition. The analysis was voxamine, indalpine, paroxetine, sertra-
entiation when fluoxetine, an based on complete cases only; i.e. only line, venlafaxine, and zimelidine.
antidepressant, was administered to pro- those implants with information available The outcome variable was implant fail-
duce micromolar concentrations,8,11 there for all variables investigated here (see ure. An implant was considered a failure in
was an increase in osteoclast differentia- section on Data collection below) were the presence of signs and symptoms that
tion for the same medication in the nano- included in the analysis. As it has been led to implant removal, including lack or
molar concentrations.11 In vivo studies suggested that the use of antibiotics in loss of osseointegration, implant mobility,
have demonstrated detrimental effects of healthy patients significantly decreases continuous pain, advanced marginal bone
fluoxetine on the trabecular architecture12 early implant failure,19 all patients had loss, and refractory infection.
and on bone mineral density12,13 in mice. to have taken prophylactic antibiotics The following factors were the other
Another in vivo study showed that seroto- for implant surgery in order to be included. variables investigated: implant surface
nin acts on osteoblasts, inhibiting their All modern endosseous dental implants (turned/machined or enlarged surfaces,
proliferation.14 These animal studies indi- with a cylindrical or conical design were the latter including sandblasted, acid-
cate a negative effect of SSRIs on bone included. etched, sandblasted + acid-etched, anod-
mass and suggest that these antidepres- Patients were excluded as study subjects ized), implant length (three categories:
sants may possess direct anti-anabolic if they presented a severe systemic disease 6.0–10.0, 10.5–14.0, 15.0–20.0 mm), im-
skeletal effects through the pharmacolog- (American Society of Anesthesiologists plant diameter (three categories: 3.00–
ical inhibition of the serotonin transporter. physical status III or IV) or had been 3.50, 3.70–4.10, 4.20–5.00 mm), prescrip-
Therefore, the intake of SSRIs could in subjected to irradiation of the head and tion of antibiotics (the prophylactic anti-
theory interfere with the osseointegration neck region, were pregnant, alcoholic, biotic regimen was usually started 1–2 h
process. In the case of dental implants in bruxers, or smokers, presented a medical before surgery and continued for 5–7 days
particular, the findings of recent studies disorder known to substantially affect postoperatively), bone graft procedures,
suggest that treatment with antidepres- bone metabolism (such as hyperthyroid- implant jaw location (maxilla/mandible),
sants is associated with an increased risk ism, hypothyroidism, vitamin D deficien- anterior or posterior location of the im-
of failure of osseointegrated implants,2,15 cy, osteomalacia, osteoporosis, Paget’s plant (locations 13–23 and 33–43 were
while others have not found a relationship disease, cancer (excluding non-melanoma considered anterior), patient sex, patient
between these two factors.16–18 Thus, skin cancer), diabetes), or were taking age at implant insertion surgery (three
there is still no clear consensus on the corticosteroids, antihypertensive drugs, categories: 30, >30 to 60, >60 years),
784 Chrcanovic et al.
number of days until failure, and the du- assess the association between SSRI in- (mean age 56.0 17.8, range 14.9–90.8
ration of follow-up. take and dental implant failure, accounting years; P = 0.665, Mann–Whitney test). A
for the fact that repeated observations total of 48 implants were placed in
(several implants) were available for a 18 SSRI users, whereas 883 implants were
Data collection methods
single patient (cluster effect). Because placed in 282 non-users. The number
The dental records of all patients ever there was little prior knowledge about of implants per patient ranged from 1 to
treated with implants at the study clinic the appropriate shape of survival proba- 15 (mean 3.10 2.49). The mean
were read in order to collect the data. The bility, parametric frailty models including follow-up time was 2741 2258
data were entered directly into an SPSS five different parametric models (Weibull, days (1578 1717 days for SSRI
file as the files were being read (IBM SPSS exponential, log-logistic, log-normal, and users, 2804 2267 days for non-users;
Statistics version 23; IBM Corp., Armonk, gamma) were extended to allow any num- P < 0.000, Mann–Whitney test).
NY, USA). In order to identify patients ber of normally distributed random The implant failure rate was 12.5% (6/
with the systemic conditions that would effects. The Akaike information criterion 48) for SSRI users and 3.3% (29/883) for
exclude them from the analysis, the gen- (AIC) was used to choose the best fit non-users (P = 0.007, Fisher’s exact test).
eral health and behavioural history of each survival model.22 The intake of SSRIs The 35 failed implants were lost at a
patient was collected from the patient files. was the exposure variable, and all analyses mean of 756 958 days (range 24–
The presence of a medication list in the were adjusted for the following potential 3980 days). Eleven of the 35 failed
patient records was also used to correlate confounders: age, sex, implant length, im- implants (31.4%) were lost prior to the
the use of certain drugs to specific health plant diameter, implant surface, implant abutment connection procedure or second
conditions. location, and bone augmentation. stage surgery (one in SSRI users, 10 in
In order to verify multicollinearity, a non-users). Eighteen of the 35 failed
correlation matrix of all of the predictor implants (51.4%) were lost up to 1 year
Data analyses
variables with a significant OR (P-value after surgery.
With regard to descriptive statistics, the cut-off point of 0.1) was scanned to deter- All implants were inserted with open
mean standard deviation or number and mine whether there were some high cor- flap surgery. Nine implants were immedi-
percentage were recorded. Differences be- relations among the predictors. ately loaded and three implants were
tween implants placed in SSRI users and Collinearity statistics obtaining the vari- placed in fresh extraction sockets, all in
SSRI non-users were compared with the ance inflation factor (VIF) and tolerance SSRI non-users. Thirty-five implants were
Student t-test or Mann–Whitney test for statistics were also performed to detect non-submerged (five in SSRI users, 30 in
continuous variables, depending on the more subtle forms of multicollinearity. non-users). The abutment connection sur-
normality of the data, and with the Pearson The results of the final multivariate GEE gery was performed after a mean healing
x2 test or Fisher’s exact test for categori- model were presented as the estimated time of 159 63 days for the SSRI users
cal variables, depending on the expected OR, and the results of the multilevel and 150 59 days for the non-users
count of events in a 2 2 contingency mixed-effects parametric survival analysis (P = 0.012, Mann–Whitney test). All
table. Comparisons were made between were presented as the estimated hazard 469 ‘turned/machined’ implants were Brå-
SSRI users and SSRI non-users in terms of ratio (HR) of each significant prognostic nemark implants (Nobel Biocare AB,
demographic systemic conditions and oth- variable (P < 0.05). Göteborg, Sweden). The ‘enlarged-
er factors; odds ratios (OR) and their 95% Kaplan–Meier survival curves were surface’ implants were mostly Brånemark
confidence intervals (CI) were computed. plotted to describe the cumulative propor- MKIII implants with a TiUnite surface
An implant-level model with the im- tion of dental implant failure stratified by (n = 386); the rest (n = 76) were Astra
plant as the statistical unit was performed use of SSRIs (yes/no), and a comparison TiOblast, OsseoSpeed, XiVE, Frialit-2
in order to assess the effects of age, sex, among groups was analyzed by log-rank (Dentsply Implants, Mölndal, Sweden)
implant length, implant diameter, implant test. and Straumann SLA (Straumann, Basel,
surface, implant location, and bone aug- The level of statistical significance was Switzerland) implants. There were no hy-
mentation on the failure of implants in set at P < 0.05. All data were analyzed droxyapatite-coated surface implants in
patients taking SSRIs. A multivariate gen- statistically using the software Stata ver- this group.
eralized estimating equation (GEE) meth- sion 14 (StataCorp LP, College Station, Comparisons between users and non-
od was used to account for the fact that TX, USA) and IBM SPSS Statistics ver- users of SSRIs in terms of demographic
repeated observations (several implants) sion 23 (IBM Corp., Armonk, NY, USA). systemic conditions and other factors (Ta-
were available for a single patient. All The study was approved by the Regional ble 1) showed that people from the age
models were adjusted for clustering of Ethics Review Board in Lund and was range >30 to 60 years and those
subject and implants in a binary logistic performed in accordance with the >60 years were more likely to be taking
regression model using GEE with a bino- STROBE guidelines for observational SSRIs than younger patients (30 years),
mial distribution and a logit link function, studies. although this did not reach statistical sig-
while assuming an exchangeable working nificance. More women were taking SSRIs
correlation structure, to assess the rela- than men. Furthermore, fewer implants
Results
tionship between implant failure (depen- were placed in the mandible in relation
dent variable) and the risk factors Following the application of the eligibility to the anterior maxilla, and fewer patients
(independent variables). A Wald x2 test criteria, a total of 931 implants placed in were followed up for longer periods in the
was used to analyze the statistical signifi- 300 patients were included in the study; 35 SSRI user group than in the non-user
cance of each parameter within the model. implant failures were reported. Of these group, and these differences were statisti-
Furthermore, a multilevel mixed-effects 931 implants, 460 were placed in 145 men cally significant. The groups of SSRI users
parametric survival analysis was used20,21 (mean age 55.9 18.5, range 15.9–82.6 and non-users were comparable in terms
– a patient-based multilevel analysis – to years) and 471 were placed in 155 women of the other factors.
Table 1. Description of the cohort by implants (n = 931) between users and non-users of SSRIs. or maxilla. Furthermore, implants failed
SSRIs less in those with longer follow-ups in
Variables OR (95% CI) P-value comparison to shorter periods of observa-
Users, n (%) Non-users, n (%) tion.
Age (years) The multilevel mixed-effects paramet-
30 3 (6.3) 127 (14.4) 1 ric survival analysis (Table 3) adjusted for
>30 to 60 21 (43.8) 311 (35.2) 2.859 (0.838–9.752) 0.093 the aforementioned confounders using a
>60 24 (50.0) 445 (50.4) 2.283 (0.677–7.705) 0.183 Weibull model based on the AIC selec-
Sex
tion, showed that the intake of SSRIs did
Male 3 (6.3) 457 (51.8) 1
Female 45 (93.8) 426 (48.2) 16.092 (4.964–52.166) <0.001 not significantly affect the implant surviv-
Implant length (mm) al rate, and nor did age, sex, implant
6.0–10.0 11 (22.9) 179 (20.3) 1 diameter, implant surface, and implant
10.5–14.0 27 (56.3) 425 (48.1) 1.034 (0.502–2.129) 0.928 location. Longer implants had a statisti-
15.0–20.0 10 (20.8) 279 (31.6) 0.583 (0.243–1.402) 0.228 cally significant HR, as did bone augmen-
Implant diameter (mm) tation procedures.
3.00–3.50 6 (12.5) 85 (9.6) 1 Figure 1 shows a comparison of the
3.70–4.10 42 (87.5) 774 (87.7) 0.769 (0.318–1.861) 0.560 Kaplan–Meier curves between the users
4.20–5.00 0 (0) 24 (2.7) – – and non-users of SSRIs (log-rank test); a
Implant surface
Turned 22 (45.8) 447 (50.6) 1
statistically significant difference in the
Enlarged 26 (54.2) 436 (49.4) 1.212 (0.676–2.170) 0.519 cumulative implant survival was found
Implant location between the groups (P < 0.001).
Anterior maxilla 27 (56.3) 308 (34.9) 1
Posterior maxilla 9 (18.8) 158 (17.9) 0.650 (0.298–1.415) 0.278
Discussion
Anterior mandible 6 (12.5) 235 (26.6) 0.291 (0.118–0.717) 0.007
Posterior mandible 6 (12.5) 182 (20.6) 0.376 (0.152–0.928) 0.034 The purpose of this study was to investi-
Bone augmentation gate the association between the intake of
No 48 (100) 852 (96.5) 1 SSRIs and the risk of dental implant fail-
Yes 0 (0) 31 (3.5) – –
ure. It was hypothesized that patients tak-
Follow-up time (years)
1 7 (14.6) 91 (10.3) 1 ing SSRIs would have a higher implant
>1 to 5 32 (66.7) 307 (34.8) 1.355 (0.579–3.172) 0.484 failure rate than patients not taking this
>5 to 10 4 (8.3) 207 (23.4) 0.251 (0.072–0.879) 0.031 class of drugs. A comparison of the im-
>10 5 (10.4) 278 (31.5) 0.234 (0.072–0.755) 0.015 plant failure rates between SSRI users and
SSRIs, selective serotonin reuptake inhibitors; OR, odds ratio; CI, confidence interval. non-users was performed, as well as an
estimation of the influence of several vari-
ables on the prevalence of implant failure
in regression models, with the intake of
The multivariate GEE model (Table 2) er, longer implants failed less in compari- these medications as the predictor vari-
showed that the intake of SSRIs did not son to shorter ones, as did enlarged- able.
exert a statistically significant influence on surface implants in relation to turned Four different statistical methods were
implant failure, nor did age, sex, implant implants and implants placed in the used to assess this relationship, with two
diameter, or bone augmentation. Howev- anterior mandible in relation to the anteri- analyses identifying an association and the
other two not finding such an association.
A statistically significant association be-
tween the intake of SSRIs and an in-
creased risk of implant failure was
found using Fisher’s exact test. However,
this test does not take into consideration
the other confounders, the factor time, and
the cluster effect, i.e. the fact that several
implants were available for a single pa-
tient. The Kaplan–Meier analysis showed
a statistically significant difference in the
cumulative survival rate between SSRI
users and non-users. Although this test
considers the factor time, it does not con-
sider the influence of the other variables
and the cluster effect. The multivariate
GEE method did not find a statistically
significant association, but although ana-
lyzing the influence of the other confoun-
ders on implant failure, the model takes
the factor time as a simple confounder.
Fig. 1. Kaplan–Meier curves comparing the cumulative survival between implants placed in The multilevel mixed-effects parametric
users and non-users of selective serotonin reuptake inhibitors (SSRIs). survival analysis could represent the best
Table 2. Multivariate generalized estimating equation (GEE) logistic regression model (total need for augmentation arises as a result of
implants, n = 931). bone loss due to periodontal disease, in-
Variables Failed/survived, n/n OR (95% CI) P-value fection, or osteoporosis, it is possible that
SSRIs these conditions will affect the successful
No 29/854 1 integration of the graft.33
Yes 6/42 2.316 (0.168–31.932) 0.530 The influence of the follow-up time on
Age (years) the failure rate, with a lower risk of failure
30 4/126 1 with a longer follow-up, may be connected
>30 to 60 23/309 1.936 (0.318–11.781) 0.474 to the fact that 31.4% of the implants were
>60 8/461 0.224 (0.026–1.916) 0.172 lost prior to the abutment connection pro-
Sex cedure and 51.4% up to 1 year after sur-
Male 10/450 1
gery.
Female 25/446 1.846 (0.655–5.203) 0.246
Implant length (mm) Studies in the field of dentistry have
6.0–10.0 18/172 1 already assessed whether the intake of
10.5–14.0 12/440 0.203 (0.077–0.536) 0.001 antidepressants might be associated with
15.0–20.0 5/284 0.172 (0.036–0.827) 0.028 an increased risk of implant failure.
Implant diameter (mm) Alsaadi et al. evaluated the impact of local
3.00–3.50 3/88 1 and systemic factors on the incidence of
3.70–4.10 31/785 0.880 (0.124–6.222) 0.898 oral implant failure up to abutment con-
4.20–5.00 1/23 1.665 (0.113–24.545) 0.710 nection, finding no relationship between
Implant surface these two factors.16,18 The same group of
Turned 21/448 1
researchers also evaluated the impact of
Enlarged 14/448 0.085 (0.015–0.495) 0.006
Implant location the same factors on the incidence of late
Anterior maxilla 15/320 1 oral implant failure, again finding no rela-
Posterior maxilla 6/161 0.341 (0.097–1.197) 0.093 tionship.17 However, these three studies
Anterior mandible 3/238 0.124 (0.019–0.805) 0.029 did not specify whether the medications
Posterior mandible 11/177 0.490 (0.101–2.386) 0.377 used were SSRIs only or included other
Bone augmentation classes of antidepressant. A very recent
No 32/868 1 cohort study evaluated the same condi-
Yes 3/28 3.220 (0.698–14.847) 0.134 tions as these two previous studies, i.e.
Follow-up time (years)
failure up to abutment connection, with
1 18/80 1
>1 to 5 11/328 0.088 (0.026–0.295) <0.001 several implant- and health-related factors
>5 to 10 5/206 0.069 (0.012–0.415) 0.004 as confounders and not limiting antide-
>10 1/282 0.002 (0.000–0.047) <0.001 pressants to the SSRI class.2 In contrast to
Alsaadi et al.,16–18 an increased risk of
SSRIs, selective serotonin reuptake inhibitors; OR, odds ratio; CI, confidence interval.
implant failure was observed with the
use of these medications.2
A study by Wu et al. is the only one
among those previously published that has
analysis; it showed no statistically signifi- such as their topography and chemistry, are evaluated SSRIs only, excluding the other
cant association between the intake of relevant for the osseointegration process, classes of antidepressant, and a statisti-
SSRIs and a higher risk of dental implant influencing ionic interactions, protein ad- cally significant association was found.15
failure. sorption, and cellular activity at the However, it is important to take into ac-
The statistical models identified implant surface.26–28 count certain aspects of the study by Wu
length, implant surface, implant location, Regarding the implant location, the et al.15 A table in that publication included
bone augmentation, and the duration of maxilla has a less favourable bone texture nine factors other than the intake of SSRIs,
follow-up as potential factors exerting a than the mandible, with low density med- which was presented alone in a different
statistically significant influence on dental ullary bone and thin cortical Plates.29 The table. It is not entirely clear from the
implant failure. Increased initial stability, anterior mandible region is usually con- publication whether they included the in-
long-term resistance to bending moment sidered to have an osseous structure more take of SSRIs in this final model or wheth-
forces, expedited healing, and a decreased favourable to achieving primary stability er they analyzed the factor SSRIs alone in
risk of movement at the interface are listed of implants. Jaws with poor bone quality a crude model. If they did not analyze the
as advantages of increased implant length, may be at risk of establishing initial insta- factor SSRIs in the model with the other
which could increase the chance of a better bility of the implants and a lack of resis- nine factors, this could have generated a
implant clinical outcome.23 Implants clas- tance to mechanical stresses, thus misspecified model, i.e. one that is not
sified as having an enlarged surface showed resulting in early implant failure.29,30 complete and is missing key/important
a significantly lower probability of failing in The greater risk of implant failure at explanatory variables and so does not
comparison to turned implants. There is sites submitted to bone augmentation pro- adequately represent what one is trying
supportive evidence for a positive relation- cedures may be related to the fact that to model or trying to predict. Supposing
ship between improved bone healing these implants were placed in areas of that the variable SSRIs was not included in
around implants and the roughness of the insufficient bone volume and/or remaining the model together with the other con-
implant surface,24,25 which enhances the defects, which could indicate a more chal- founders, and if it were, the interaction
process of osseointegration. It is known that lenging healing situation in comparison to of other confounders of strong effect on
the surface properties of dental implants, implants placed in healed sites.31,32 If the the outcome (implant diameter and smok-
Table 3. Multilevel survival analysis for dental implant failure in terms of different factors (total implants, n = 931). Hazard ratios (HR) were
determined using multilevel mixed-effects parametric survival analysis.
Implants, n (%)
Factor Failure (%) P-value HR (95% CI)
Failed Survived
SSRIs
No 29 (82.9) 854 (95.3) 3.4 1
Yes 6 (17.1) 42 (4.7) 14.3 0.125 4.108 (0.676–24.963)
Age (years)
30 4 (11.4) 126 (14.1) 3.2 1
>30 to 60 23 (65.7) 309 (34.5) 7.4 0.662 1.426 (0.290–7.008)
>60 8 (22.9) 461 (51.5) 1.7 0.160 0.258 (0.039–1.710)
Sex
Male 10 (28.6) 450 (50.2) 2.2 1
Female 25 (71.4) 446 (49.8) 5.6 0.404 1.641 (0.513–5.250)
Implant length (mm)
6.0–10.0 18 (51.4) 172 (19.2) 10.5 1
10.5–14.0 12 (34.3) 440 (49.1) 2.7 0.074 0.426 (0.167–1.088)
15.0–20.0 5 (14.3) 284 (31.7) 1.8 0.040 0.249 (0.066–0.940)
Implant diameter (mm)
3.00–3.50 3 (8.6) 88 (9.8) 3.4 1
3.70–4.10 31 (88.5) 785 (87.6) 3.9 0.816 0.812 (0.141–4.697)
4.20–5.00 1 (2.9) 23 (2.6) 4.3 0.945 0.900 (0.045–18.139)
Implant surface
Turned 21 (60.0) 448 (50.0) 4.7 1
Enlarged 14 (40.0) 448 (50.0) 3.1 0.132 0.383 (0.110–1.335)
Implant location
Anterior maxilla 15 (42.9) 320 (35.7) 4.7 1
Posterior maxilla 6 (17.1) 161 (18.0) 3.7 0.831 0.890 (0.306–2.587)
Anterior mandible 3 (8.6) 238 (26.6) 1.3 0.167 0.307 (0.058–1.637)
Posterior mandible 11 (31.4) 177 (19.8) 6.2 0.329 1.885 (0.528–6.729)
Bone augmentation
No 32 (91.4) 868 (96.9) 3.7 1
Yes 3 (8.6) 28 (3.1) 10.7 0.036 8.538 (1.154–63.170)
HR, hazard ratio; CI, confidence interval; SSRIs, selective serotonin reuptake inhibitors.
ing, in this case in particular) could have be similar around implants (peri-implan- duration of follow-up as potential factors
influenced the significance of the factor titis). exerting a statistically significant influ-
SSRIs. It might happen that when there is The limitations of the present study ence on dental implant failure. New re-
the inclusion of a new variable in a model, include the retrospective design, with gaps search efforts on the subject should be
something that was previously statistically in information and incomplete records. As concentrated in prospective studies with
significant becomes non-significant.34 all data rely on the accuracy of the original a larger cohort size presenting more bal-
Thus, the results of the study by Wu examination and documentation, items anced study groups.
et al. must be analyzed carefully.15 may have been excluded in the initial
It is important to take into consideration examination or not recorded in the den-
Funding
that the alleged higher risk of dental im- tal/medical charts. The lack of specific
plant failure could be associated with the information characterizing the systemic This work was supported by research
patient’s mental condition rather than by conditions status and the medication funds from the Oral Health Related Re-
the intake of antidepressants per se. Some dosages of some patients represents a search by Region Skåne, Sweden (Odon-
studies have demonstrated that psychoso- limitation also connected to the retrospec- tologisk Forskning i Region Skåne, OFRS
cial stress may induce neglect of oral tive nature of this study. Moreover, as the 414321), and from the Scientific Research
hygiene,35,36 and that people suffering status ‘taking SSRIs’ was completely iso- Council of Sweden (Vetenskapsrådet, Dnr
from psychosocial stress may show resis- lated from the influence of other systemic 2015-02971). This work was supported by
tance to periodontal therapies.37 Thus, it is conditions, medications, or compromising Folktandvården AB, Region Skåne,
suggested that psychosocial stress may be habits (bruxism, smoking, snuff) that Sweden, and by CNPq, Conselho Nacio-
an important risk factor in defining the could somehow have affected the bone nal de Desenvolvimento Cientı́fico e Tec-
progression of periodontitis, even if the metabolism and/or osseointegration, the nológico, Brazil.
patient is undergoing therapy.38 More- group investigated in this study is, itself,
over, another study showed depression not representative of the general popula-
Competing interests
to be associated with more extensive peri- tion.
odontitis, with continuous periodontal In conclusion, it is suggested that the None declared.
breakdown, and with differences in serum intake of SSRIs may not be associated
antibody titres to pathogens associated with an increased risk of dental implant
Ethical approval
with periodontitis.39 It is a matter of de- failure. The statistical models also identi-
bate whether the results relating depres- fied implant length, implant surface, im- Regional Ethics Review Board, Lund,
sion to periodontitis (around teeth) could plant location, bone augmentation, and the Sweden (Dnr 2014/598; Dnr 2015/72).
Patient consent Ducy P, Karsenty G. Lrp5 controls bone 29. Horwitz J, Zuabi O, Peled M, Machtei EE.
formation by inhibiting serotonin synthesis Immediate and delayed restoration of dental
Not required. in the duodenum. Cell 2008;135:825–37. implants in periodontally susceptible
15. Wu X, Al-Abedalla K, Rastikerdar E, Abi patients: 1-year results. Int J Oral Maxillofac
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Tommeras K, Westbroek I, Waldum HL, 25. Shalabi MM, Gortemaker A, Van’t Hof MA, Machtei EE, Tedesco LA. Exploratory case–
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JE, Syversen U. Serotonin and fluoxetine roughness and bone healing: a systematic adult periodontitis. J Periodontol
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Biochem 2006;98:139–51. 26. Chrcanovic BR, Leão NL, Martins MD.
12. Warden SJ, Nelson IR, Fuchs RK, Bliziotes Influence of different acid etchings on the Address:
MM, Turner CH. Serotonin (5-hydroxytryp- superficial characteristics of Ti sandblasted Bruno Ramos Chrcanovic
tamine) transporter inhibition causes bone Department of Prosthodontics
with Al2O3. Materials Research
loss in adult mice independently of estrogen Faculty of Odontology
2013;16:1006–14.
deficiency. Menopause 2008;15:1176–83. Malmö University
27. Chrcanovic BR, Martins MD. Study of the
13. Warden SJ, Robling AG, Sanders MS, Bli- Carl Gustafs väg 34
influence of acid etching treatments on the Malmö
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serotonin (5-hydroxytryptamine) transporter Research 2014;17:373–80. Sweden
reduces bone accrual during growth. Endo- 28. Chrcanovic BR, Wennerberg A, Martins Tel: +46 725 541 545; Fax: +46 40 6658503
crinology 2005;146:685–93. MD. Influence of temperature and acid etch- E-mails: [email protected],
14. Yadav VK, Ryu JH, Suda N, Tanaka KF, ing time on the superficial characteristics of [email protected]
Gingrich JA, Schütz G, Glorieux FH, Chiang Ti. Materials Research 2015;18:963–70.
CY, Zajac JD, Insogna KL, Mann JJ, Hen R,
VII
Impact of different surgeons on dental implant failure
Bruno Ramos Chrcanovic 1*
Jenö Kisch 2
Tomas Albrektsson 1,3
Ann Wennerberg 1
1
Department of Prosthodontics, Faculty of Odontology, Malmö University, Malmö, Sweden
2
Clinic for Prosthodontics, Centre of Dental Specialist Care, Malmö, Sweden
3
Department of Biomaterials, Gothenburg University, Göteborg, Sweden
Bruno Ramos Chrcanovic, Department of Prosthodontics, Faculty of Odontology, Malmö University,
Carl Gustafs väg 34, SE-‐214 21, Malmö, Sweden. [email protected];

Abstract
Aims. To assess the influence of several factors on dental implant failure prevalence, with special
consideration on the placement of implants by different dental surgeons.
Methods. This retrospective study is based on 2,670 patients who received 10,096 implants at one
specialist clinic. Only the data of patients and implants treated by surgeons who had inserted a
minimum of 200 Implants at the clinic were included. Kaplan-‐Meier curves were stratified with
respect to the individual surgeon. A generalized estimating equation (GEE) method was used, to
account for the fact that repeated observations (several implants) were placed in a single patient.
The factors bone quantity/quality, implant location, implant surface, and implant system were
analyzed with descriptive statistics separately for each individual surgeon.
Results. Ten surgeons were eligible. The differences between the survival curves of each individual
were statistically significant. The multivariate GEE model showed the following variables to be
statistically significant: surgeon, bruxism, intake of antidepressants, location, implant length, and
implant system. The surgeon with the highest absolute number of failures was also the one who
inserted most implants in sites of poor bone and used turned implants in most cases, whereas the
surgeon with the lowest absolute number of failures used mainly modern implants. Separate survival
analyses of turned and modern implants stratified for the individual surgeon showed statistically
significant differences in cumulative survival.
Conclusion. Different levels of failure incidence could be observed between the surgeons,
occasionally reaching significant levels. Although a direct causal relationship could not be
ascertained, the results of the present study suggest that the surgeons’ technique, skills, and/or
judgment may negatively influence the implant survival rates.
Keywords
Dental implants; osseointegration; surgeons; predictors; survival rate

Introduction
Some studies have assumed that the operator skill and/or experience is of importance for
achieving high implant success rates and that a learning curve does exist for dental implant therapy.1-‐
4
However, this subject is not without controversy, and a significant association of ‘experienced
surgeon-‐less implant failures’ has not been verified by all studies. Melo et al.5 found no statistically
significant difference in implant survival rates among oral and maxillofacial residents of different
levels of training. However, the authors stressed that this observation may be due to the fact that
more complicated cases were assigned to surgeons with more experience in implant surgery.
Another study6 observed that clinical experience had no significant impact on implant survival, at
least not on the basis of multivariate analyses. The authors suggested that a significant difference in
favor of inexperienced surgeons based on univariate methods could be explained by the fact that the
more challenging cases with poor bone quality and/or quantity had been treated by the academic
staff; whereas, standard cases had been usually treated by clinicians-‐in-‐training.
Since studies of clinical experience may be skewed by the fact that difficult patients are
selected for the experienced clinician, another potential clinician–related factor would be the skill of
the surgeon, that may depend on other reasons than mere experience. Having this in mind, the aim
of the present retrospective study was to assess, among other factors, the influence of the
placement of dental implants by different dental surgeons on the implant failure prevalence.
Objective. The purpose of the present study was to assess the influence of several factors on
dental implant failure prevalence, with special consideration on the placement of implants by
different dental surgeons. The main aim was to test the null hypothesis of a difference in the implant
failure rates for different surgeons, against the alternative hypothesis of no difference.
Materials. This retrospective study is based on all 2,670 patients who received 10,096
implants, and were consecutively treated with implant-‐supported prostheses between 1980 and
2014 at one specialist clinic (Clinic for Prosthodontics, Centre of Dental Specialist Care, Malmö,
Sweden). The study was approved by the Regional Ethical Review Board in Lund (Dnr 2014/598; Dnr
2015/72).
Inclusion and exclusion criteria. To be included in the study, a surgeon needed to have
inserted a minimum of 200 Implants in the clinic. Only modern endosseous dental implants with
cylindrical or conical design were considered. Zygomatic implants were not included in the study, as
well as implants detected in radiographies, but without basic information about them in the patients’
files.
Definitions. An implant was considered a failure if presenting signs and symptoms that led to
implant removal, including lack or loss of osseointegration, implant mobility, continuous pain,
advanced marginal bone loss, refractory infection, and implant fracture.
Data collection. The dental records of all patients ever treated with implants in the
aforementioned clinic were read in order to collect the data. The data were directly entered into a
SPSS file (SPSS software, version 23, SPSS Inc., Chicago, IL, USA) as the files were being read.
The following data were collected: implant surface (turned/machined or enlarged surfaces,
the latter including sandblasted, acid-‐etched, sandblasted + acid-‐etched, anodized or
hydroxyapatite-‐coated surfaces), implant system (Nobel turned, Nobel TiUnite, Astra
TiOblast/Osseospeed, Straumann SLA/SLActive/Roxlid, XIVE/Frialit-‐2, others), implant length and
diameter, implant design (cylindrical or conical), prescription of antibiotics (the prophylactic
antibiotic regimen was usually starting 1-‐2 hours before surgery and lasting for 5-‐7 days
postoperatively), bone graft procedures, reason for tooth extraction (periodontal disease,
fracture/trauma, advanced caries, tooth agenesis, others), implant jaw location (maxilla or
mandible), anterior or posterior location of the implant (locations between 13-‐23 and between 33-‐43
were considered anterior location), patient’s sex, age of the patient at the time for implant surgery,
number of days until failure, and follow-‐up time. Periapical radiographic images were used to classify
the bone sites at the time of surgery according to the Lekholm and Zarb7 classification. According to
this classification, bone quality is broken down into four groups according to the proportion and
structure of compact and trabecular bone tissue: type 1 = large homogenous cortical/compact bone;
type 2 = thick layer of compact bone surrounding a dense trabecular bone; type 3 = thin cortical layer
surrounding a dense trabecular bone; type 4 = thin cortical layer surrounding a core of low-‐density
trabecular bone. The quantity of jawbone is broken down into five groups (A, B, C, D, and E), based
on the residual jaw shape following tooth extraction. Bone classified as ‘A’ presents the largest
amount of bone among all classes, whereas bone classified as ‘E’ presents the lowest volume of
bone. The classification was performed based on the radiograms available for each and every implant
included in the study, and was performed case by case at the same time by two researchers who
were calibrated previously. Disagreements were resolved by discussion between them, until there
was an agreement about the classification of each case.
The general health and the behavioral history of the patients were collected from the
patients’ files. The presence of a medicament list in the patients’ records was used to correlate the
use of certain drugs to specific health conditions. The following health factors were assessed:
diabetes types I or II, hypertension, hypercholesterolemia, hypothyroidism, asthma, psoriasis, and
irradiation of the head-‐neck region. The patients were also classified according to the intake of the
following medication types: antidepressants, immunosuppressive drugs, antithrombotic agents
(antiplatelet, anticoagulant, thrombolytic drugs), hormone replacement therapy (HRT) in women,
and medicaments to reduce the acid gastric production (proton pump inhibitors -‐ PPI). The following
behavioral factors were assessed: smoking habits, use of snuff, bruxism.
Statistical analyses. The mean, standard deviation, and percentages were presented as
descriptive statistics. Survival analysis stratified in relation to the surgeon was performed using the
Kaplan-‐Meier analysis, and a comparison among groups was analyzed using the log-‐rank test. Survival
analyses stratified in relation to each surgeon were also performed for turned and enlarged-‐surface
implant groups. Logistic regression models were used and a generalized estimating equation (GEE)
method was performed to account for the fact that repeated observations (several implants) were
available for a single patient. All models were adjusted for clustering of subject and implants in a
binary logistic regression model using GEE with a binomial distribution and a logit link function, while
assuming an exchangeable working correlation structure to assess the relationship between implant
failure (dependent variable) and the risk factors (independent variables). Initially a univariate GEE on
each of the variables was performed. In order to verify multicollinearity, a correlation matrix of all of
the predictor variables with a significant odds ratio (OR; P-‐value cut-‐off point of 0.1) identified in the
univariate GEE was scanned, to see whether there were some high correlations among the
predictors. Collinearity statistics obtaining variance inflation factor (VIF) and tolerance statistic were
also performed to detect more subtle forms of multicollinearity. Then a multivariable model with a
forced entry method was used to evaluate the effect of the factors that were univariately significant
(P<0.1) and did not present multicollinearity. A Wald chi-‐square test was used to analyze the
statistical significance of each parameter within the model. The results of the final model were
presented as an estimated OR of each significant prognostic variable (P<0.05). The factors bone
quantity/quality, implant location, and implant surface, and implant system were analyzed separately
for each individual surgeon, with descriptive statistics. All data were statistically analyzed using the
SPSS version 23 software (SPSS Inc., Chicago, IL, USA).
Results
Ten surgeons were identified as having inserted a minimum of 200 Implants in the clinic,
totaling 8930 implants in 2340 patients. Figure 1 shows a comparison of the Kaplan-‐Meier curves
between the surgeons (P<0.001, log-‐rank test). Table 1 shows detailed implant information for the
surgeons, including the crude GEE analysis with a statistically significant difference for some surgeons
in comparison to surgeon 1, which was the category reference. The univariate GEE model showed
that the other variables (Table 2) also had a statistically significant OR: smoking, bruxism, intake of
antidepressants, Intake of PPIs, implant diameter, implant length, location (anterior maxilla as the
reference category), bone quantity (quantity A as the reference category), bone quality (quality 1 as
the reference category), implant system (Nobel turned as the reference category), antibiotics, and
bone grafting. Only the variables with a statistically significant odds ratio were included in the
multivariate GEE model (Table 3). The following variables continued to be statistically significant:
surgeon 3 in relation to surgeon 1, smoking, bruxism, intake of antidepressants, anterior mandible in
relation to anterior maxilla, implants placed in bone quantity D in relation to bone quantity A,
implant length, and implant system (Nobel turned as the reference category; Nobel TiUnite, P<0.001;
Astra TiOblast/Osseospeed, P=0.035; Straumann, P=0.030; other, P=0.001). Only 129 implants (1.44%
of 8,930) were installed before 1985 (before the Lekholm and Zarb classification), of which only 6
(4.65% of 129) were considered as failures.
The separate descriptive analysis of the variables for each surgeon (Table 4) showed an
unequal distribution of implants placed in sites of poor bone (bone quantity D/E, bone quality 4)
among the surgeons, as well as for implant location and use of turned and enlarged-‐surface implants.
From this point of view it can be seen, for example, that the surgeon with the highest absolute
number of failures (surgeon 4 – 12.20%) was also the one who mostly inserted implants in sites of
poor bone and virtually used only turned implants (99.9%). On the other hand, the surgeon with the
lowest absolute number of failures (surgeon 10 – 1.79%) mainly used modern implants (99.1%).
Moreover, surgeon 4 had the highest percentage of implants placed in poor bone in comparison to
any other surgeon. Table 5 shows the failure and survival distribution of implants according to region
and bone quality. Implants placed in poor bone quality in the maxilla had the highest failure rates.
In order to verify the survival of different implant types separately for each surgeon, survival
analysis for turned (Figure 2) and enlarged-‐surface implants (Figure 3) were also performed (P<0.001
for both analyses, log-‐rank test). Due to an extremely reduced number of turned implants placed by
surgeon ‘10’, he was not included in the survival analysis of turned implants (Figure 2), the same
happening to surgeons ‘4’, ‘6’, ‘7’, and ‘9’ when it comes to the enlarged-‐surface implants survival
analysis (Figure 3).

Discussion
The aim of the present study was to assess the influence of the placement of dental implants
by different dental surgeons on the implants failure prevalence. We found clear differences in clinical
outcome that were coupled to the responsible surgeon. Different levels of failure prevalence could
be observed between the surgeons, occasionally reaching significant levels.
Besides the surgeon, the multivariate GEE model showed a statistically significant influence
of bruxism, intake of antidepressants, implant system, implant length, and implant location on the
implant failure prevalence. Bruxism was shown to significantly affect the implant failure prevalence
negatively, agreeing with the results of the only meta-‐analysis on the subject8 and recent clinical
trials.9, 10 This is due to the fact that bruxism is suggested to cause excessive load of implant-‐
supported rehabilitations, which may cause an implant fracture or may result in bone loss around the
implants and subsequent implant failure.11 A meta-‐analysis including more than 100 studies has
shown that failures of implants inserted in smokers are 2.23 times likely to happen than failures of
implants inserted in non-‐smokers.12 The increase of implant failure rates due to smoking is
hypothesized to be related mainly to the effect of smoking in osteogenesis and angiogenesis.13 There
are biochemical14, 15 and clinical16, 17 evidence suggesting a relationship between the intake of
antidepressants and the impairment of bone metabolism, which in theory could interfere with the
osseointegration process.
Concerning implant length, there was a decrease in the failure probability with the increase
of the implant length. Although some good results can be obtained with the use of shorter implants,
they seem to fail more often than longer ones,18 at least for the turned implants, which presented
the majority of implants in the present study. Increased initial stability, long-‐term resistance to
bending moment forces, expedited healing and a decreased risk of movement at the interface are
listed as advantages of increased implant length.19 The fact that implants in the anterior mandible
presented a lower risk of failure than those inserted in the anterior maxilla may also be associated
with the implant length. Longer implants are placed in regions that usually provide more bone
height, i.e. the anterior mandible.20
Although a direct causal relationship could not be ascertained, the results of the present
study put some light into the matter of to what point the surgeons’ technique, skills, and/or
judgment may negatively influence the implant survival rates and prevalence.
A study1 comparing treatment outcomes in implant therapy between surgeons with a
minimum of 2 years implant experience and surgeons just beginning involvement in implant
techniques observed that the surgeon's experience had a major impact on the failure probability of
unloaded implants. Lambert et al.2 observed that implants placed by inexperienced surgeons (who
had placed < 50 implants) failed twice as often as those placed by experienced surgeons (who had
placed 50 or more implants). The results of Morris et al.3 showed that the percentage of failure for
the less experienced surgeons was nearly twice that seen with the more experienced surgeons. Ji et
al.4 reported in their study that the implant failure rate for 2 surgeons with >5 years of surgical
experience was 2.4% (2 of 85 implants), whereas the remaining 18 surgeons, i.e. those with ≤5 years
of surgical experience, incurred an implant failure rate of 12.2% (26 of 212 implants). On the other
hand, Morris et al. 21 noticed an only slightly greater survival for implants placed by the more
experienced dentists in their study, evaluating more than 2600 implants followed up for 3 years. Two
other studies5, 6 also observed that clinical experience had no significant impact on implant survival,
but in these studies only experienced surgeons treated the complicates patients.
There is also a relationship between the quantity of surgical procedures performed and
clinical outcomes. Although surgical volume is less important for simple procedures, it might be so
for complex procedures. Procedure volume may be linked to other delivery factors associated with
surgical outcomes, but it has been assumed that volume is important in large part because it serves
as a proxy for operative proficiency.22
Besides the procedure volume and experience of the surgeon, the skill is another important
factor to take into consideration. A considerable body of research suggests that some surgeons have
better results than others, with some studies showing wide variation in risk-‐adjusted patient
mortality across surgeons, as observed in studies on bariatric and open heart surgeries.22-‐24 Another
example comes from the Swedish Hip Arthroplasty Register where about 13,000 hips placed in the
country annually are followed up. Year after year some surgeons show less good clinical results than
their peers, despite them using the same hip design.25
In many procedures, the technical skill of the operating surgeon may be an important
determinant of the outcomes. Analyzing the outcome of about 1000 implants placed at the
University Clinic of Göteborg in 1986, a particular surgeon with more than 3 years of clinical
experience was found responsible for 40% of all failures as well as for a majority of the implants that
showed marginal bone resorption.26 Bryant27 likewise found a correlation between some surgeons
and implant outcome and marginal bone loss. These data support the theory that implant bone loss
may depend on minor trauma whereas implant failure may depend on a greater level of trauma.28
However, in the present study we did not investigate marginal bone resorption; survival of the
implants was our key parameter. A high level of surgical skill may be essential in preventing
intraoperative problems, such as failure to properly maintain or use equipment and instruments that
may compromise drilling precision. If an imprecise implant site is prepared or if tapping procedures
are excessive, initial implant stability and subsequent osseointegration may be compromised. A bony
dehiscence or defect may occur as a result of incorrect implant placement. Moreover, an excessive
countersinking may result in the loss of a superior cortical bone plate to stabilize the implant. The
failure to preserve keratinized gingiva was even mentioned as a problem, as it may compromise
maintenance of peri-‐implant tissue health in the long-‐term.29 Because failure to osseointegrate can,
in part, be related to imprecise surgical technique, it follows that these complications are more likely
to occur after operations performed by less skilled surgeons.
It is important to note some facts concerning the observed statistically significant difference
in implant failure rates between some surgeons in the present study. The success of a technique
depends on careful and scrupulous adherence to the prescribed clinical protocol by the combined
surgical-‐prosthodontic team. Theoretically, oral implants may display marginal bone loss or fail due
to different clinical skills or clinical judgement.30 The present authors observed that clinical judgment
may be an important reason behind oral implant problems. Generally, clinical judgment may be
defined as the application of information based on actual observation of a patient combined with
subjective and objective data that lead to a conclusion.31 Everyone working in the health disciplines
must realize the importance of clinical judgment, since not doing so may result in unnecessary
implant failures. However, there is an obvious problem in measuring the level of clinical judgment.
Judgment with due problems afterwards is certainly not limited to the clinical situation. What we call
human error, for instance in a flight catastrophy32 is in many cases dependent more on judgment
than on lack of particular skills. Skills can always be trained to an increased level of skill whereas our
level of judgment is dependent on the individual human being and may be very hard to improve. In
clinical dentistry, the success of a technique depends on careful and scrupulous adherence to the
prescribed clinical protocol by the combined surgical/prosthodontic team. Failure in so doing may
result in clinical problems due to either lacking skills about the clinical protocol or violations of it due
to clinical judgment. The surgeon might display habits and choices that would, as for example, risk
too much in inserting implants in sites with poor bone quantity/quality. The level of complexity of
cases treated by different dentists may vary, and some professionals may be more willing to take
more risky cases. The surgeons may overestimate their ability to execute a complex or high-‐risk
procedure.27, 33 There are some categories of behavior that are frequently cited to increase the
likelihood of one or more complications occurring during the implementation of a procedure, and
such behaviors are also relevant in the dental/medical field and may make the surgeon less careful.32
The present study observed that the surgeon with the highest absolute number of failures was also
the one who inserted most implants in sites of poor bone. Some surgeons might have had
considerable experience with some implant systems but not with other systems. Moreover, some
surgeons used old implants more often than other surgeons, but this is also related to the fact that
some surgeons inserted more implants in the 1980’s and 1990’s. Modern implants having an
enlarged surface had a statistically significant lower probability to fail in comparison to turned
implants. It has been shown that the osseointegration process is influenced by several factors,
among them the surface texture.34-‐36 There is supportive evidence for a positive relationship between
an improved bone healing around implants and its surface roughness,37 which enhances the process
of osseointegration. However, it is also important to note that the group of turned implants had
statistically significant longer mean follow-‐up time than the group of enlarged surface implants,
which can lead to an increase in the failure rate due to longer time at risk.
A separate analysis showed a far unequal distribution of implants placed in sites of poor bone
(bone quantity D/E, bone quality 4) among the surgeons. The surgeon with the highest absolute
number of failures was also the one who inserted most implants in sites of poor bone. It was
suggested that one of the most important factors responsible for implant failures is probably the
local anatomic structure regarding bone quality and quantity, or rather the lack thereof.38 Even if the
Lekholm and Zarb7 paper was published first in 1985, the general knowledge that implants fared less
well in poor bone was discussed among the few implant users of those days prior to 1985.
Furthermore, in the material of the present paper only 1.44% (129 of 8,930 implants) were actually
placed before 1985 and only 6 of those implants failed.
Unfortunately, it was not always possible in the present study to assess implant survival
based on dentist experience in implant surgery, as this information was not found in the records.
Dentists at the specialist clinic of the present study had a diverse background; some entered the
specialist training program after only 2 years of working in general practice after leaving the dental
school (minimum requirement to enter a specialist program in the country), whereas others had
substantial experience from a private dental practice. It is important to remember that the present
study includes implants placed as long ago as 1980, and some of the surgeons are already retired. We
have lacked information of the particular previous experience of some surgeons. Other important
issues include the fact that the experience of the surgeon may be masked by that of the restorative
dentist, which was found to influence marginal bone loss and implant outcome in one study.27 With
the existing data forms, the particular experience of each surgeon was difficult to ascertain, and any
conclusions regarding experience drawn from these data must be considered with caution in mind.
However, if one hypothetically assumes that the surgeons analyzed in the present study would have
the same level of experience, and assuming all other factors equal, the variations in the failure rates
could be, in part, explained by the surgeons’ skill and/or judgment.
Another limitation of the present study is its retrospective nature, which inherently results in
flaws. These problems were manifested by the gaps in information and incomplete records. As all
data rely on the accuracy of the original examination and documentation, items may have been
excluded in the initial examination or nor recorded in the dental/medical chart.
Conclusions
Different levels of dental implants failure prevalence could be observed between the
surgeons, occasionally reaching significant levels. Although a direct causal relationship could not be
ascertained, the results of the present study put some light into the matter of to what point the
surgeons’ poor technique, poor skills, and/or poor judgment may negatively influence the implant
survival rates.

Acknowledgements
Funding and support: This work was supported by research funds from the Oral Health Related
Research by Region Skåne (Odontologisk Forskning i Region Skåne, OFRS 414321), Sweden, and from
the Scientific Research Council of Sweden (Vetenskapsrådet, Dnr 2015-‐02971). This work was
supported by Folktandvården AB, Region Skåne, Sweden and by CNPq, Conselho Nacional de
Desenvolvimento Científico e Tecnológico, Brazil.
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Tables
Table 1. Univariate generalized estimating equations (GEE) logistic regression model for implant
failure: different surgeons (OR – odds ratio).
Surgeon Failure/survival (% failure) OR (95% CI) P-‐value
1 134/3418 (3.77)
2 140/1413 (9.01) 2.477 (1.655, 3.707) <0.001
3 40/824 (4.63) 1.030 (0.582, 1.825) 0.918
4 85/612 (12.20) 3.301 (1.923, 5.665) <0.001
5 28/477 (5.54) 0.939 (0.278, 3.174) 0.919
6 35/412 (7.83) 2.112 (1.010, 4.414) 0.047
7 33/387 (7.86) 2.122 (0.926, 4.865) 0.075
8 25/368 (6.36) 1.617 (0.718, 3.638) 0.246
9 29/247 (10.51) 5.150 (2.637, 10.057) <0.001
10 4/219 (1.79) 0.248 (0.009, 6.654) 0.406
TOTAL 553/8377 (6.19)

Table 2. Risk factor analysis for implant failure including implants of the 10 surgeons, using a
univariate generalized estimating equations (GEE) logistic regression model, at the implant-‐level (OR
– odds ratio).
Factor Failure/survival* OR (95% CI) P-‐value
Smoking
No 204/3695 1
Yes 155/1663 1.903 (1.322, 2.738) 0.001
Former smoker 7/152 1.661 (0.632, 4.366) 0.304
Snuff
No 334/5207 1
Yes 19/235 0.884 (0.386, 2.024) 0.770
Bruxism
No 310/5624 1
Yes 72/318 3.594 (2.152, 6.003) <0.001
Gender
Male 246/3975 1
Female 307/4402 1.190 (0.894, 1.584) 0.233
Diabetes
No 352/5387 1
Type I 7/105 1.473 (0.426, 5.092) 0.541
Type II 25/443 0.857 (0.477, 1.541) 0.607
High blood pressure
No 262/3975 1
Yes 121/1944 0.916 (0.636, 1.319) 0.636
High cholesterol
No 325/5046 1
Yes 57/848 0.819 (0.487, 1.377) 0.451
Hypothyroidism
No 360/5582 1
Yes 24/318 1.344 (0.669, 2.700) 0.406
Asthma
No 360/5431 1
Yes 24/469 1.008 (0.574, 1.771) 0.977
No 307/5361 1
Yes 79/529 2.366 (1.433, 3.908) 0.001
Irradiation
No 375/5754 1
Yes 11/160 1.196 (0.431, 3.322) 0.731
No 445/6886 1
Yes 10/207 0.690 (0.339, 1.403) 0.306
Proton pump inhibitors
No 321/5375 1
Yes 46/428 2.156 (1.256, 3.703) 0.005
Antithrombotics
No 262/4655 1
Yes 107/1195 1.273 (0.836, 1.939) 0.261
Immunosuppressive
No 359/5744 1
Yes 8/79 1.110 (0.326, 3.781) 0.868
Psoriasis
No 365/5760 1
Yes 3/68 1.217 (0.375, 3.944) 0.744
Age
Increase by 1 0.997 (0.989, 1.004) 0.360
Implant diameter
Increase by 1 2.284 (1.142, 4.567) 0.019
Implant length
Increase by 1 0.885 (0.824, 0.951) 0.001
Implant design
Cylindrical 544/7970 1
Conical 9/407 0.238 (0.057, 0.997) 0.050
Location
Anterior maxilla 263/2989 1
Anterior mandible 65/2097 0.468 (0.283, 0.774) 0.003
Posterior maxilla 137/1611 1.331 (0.998, 1.776) 0.052
Posterior mandible 88/1680 0.697 (0.457, 1.062) 0.093
Bone quantity
A 23/1032 1
B 182/4112 1.646 (0.892, 3.039) 0.111
C 172/2252 2.949 (1.586, 5.482) 0.001
D 113/652 7.386 (3.876, 14.075) <0.001
E 42/115 11.735 (4.911, 28.040) <0.001
Bone quality
1 14/343 1
2 145/3719 1.167 (0.390, 3.493) 0.782
3 251/3615 1.539 (0.507, 4.669) 0.446
4 122/486 6.464 (2.015, 20.735) 0.002
Implant system
Nobel turned 440/4871 1
Nobel TiUnite 84/2492 0.301 (0.183, 0.497) <0.001
Astra 14/379 0.324 (0.088, 1.190) 0.090
TiOblast/Osseospeed**
Straumann 6/179 0.141 (0.011, 1.809) 0.132
XIVE/Frialit-‐2 5/232 0.092 (0.002, 4.755) 0.236
Other 4/224 0.145 (0.042, 0.495) 0.002
Antibiotics
No 46/548 1
Yes 218/4081 0.590 (0.386, 0.903) 0.015
Bone grafting
No 474/7978 1
Yes 79/388 2.184 (1.235, 3.862) 0.007
Periodontal disease 44/766 1
Fracture/trauma 24/489 1.072 (0.583, 1.969) 0.823
Advanced caries 7/231 0.827 (0.366, 1.867) 0.647
Tooth agenesis 19/595 0.508 (0.234, 1.106) 0.088
Other 6/180 0.680 (0.273, 1.695) 0.408
* The information for some conditions is unknown for a variable number of implants
** Unfortunately, it was not possible to run the regression having Astra TiOblast and Astra
Osseospeed as different categories within the parameter ‘Implant system’, even knowing that they
are implants of different designs and surface treatments, although of the same manufacturer. The
reason was because of the problem of quasi-‐complete separation, since there were no events of
failure for Astra Osseospeed. The numbers were (failure/survival): Astra TiOblast (14/288) and Astra
Osseospeed (0/91)

Table 3. Multivariate generalized estimating equations (GEE) logistic regression model at the implant-‐
level. Only the factors that were considered statistically significant (P < 0.1) in the univariate model
and didn’t present multicollinearity were included in the multivariate model (OR – odds ratio).
Factor OR (95% CI) P-‐value
Surgeon
1 1
2 1.148 (0.693, 1.902) 0.593
3 2.834 (1.394, 5.764) 0.004
4 1.180 (0.584, 2.385) 0.645
5 0.795 (0.233, 2.712) 0.713
6 1.243 (0.518, 2.982) 0.627
7 1.566 (0.769, 3.189) 0.216
8 1.153 (0.277, 4.801) 0.845
9 1.377 (0.549, 3.452) 0.495
10 0.583 (0.076, 4.471) 0.604
Smoking
No 1
Yes 1.875 (1.273, 2.763) 0.001
Former smoker 1.239 (0.397, 3.869) 0.712
Bruxism
No 1
Yes 3.165 (1.740, 5.758) <0.001
No 1
Yes 2.174 (1.150, 4.106) 0.017
Proton pump inhibitors
No 1
Yes 1.831 (0.911, 3.680) 0.089
Location
Anterior maxilla 1
Anterior mandible 0.588 (0.362, 0.956) 0.032
Posterior maxilla 0.910 (0.666, 1.243) 0.554
Posterior mandible 0.844 (0.545, 1.307) 0.448
Bone quantity
A 1
B 1.398 (0.703, 2.780) 0.339
C 1.544 (0.773, 3.083) 0.218
D 2.278 (1.036, 5.007) 0.041
E 1.845 (0.431, 7.900) 0.409
Bone quality
1 1
2 1.012 (0.349, 2.934) 0.983
3 0.958 (0.325, 2.823) 0.938
4 2.419 (0.756, 7.734) 0.136
Implant diameter
Increase by 1 1.816 (0.466, 7.077) 0.390
Implant length
Increase by 1 0.903 (0.839, 0.971) 0.006
Implant design
Cylindrical 1
Conical 1.036 (0.365, 2.943) 0.947
Implant system
Nobel turned 1
Nobel TiUnite 0.307 (0.176, 0.535) <0.001
Astra TiOblast/Osseospeed** 0.226 (0.057, 0.898) 0.035
Straumann 0.087 (0.009, 0.789) 0.030
XIVE/Frialit-‐2 0.111 (0.005, 2.736) 0.179
Other 0.087 (0.020, 0.369) 0.001
Bone grafting
No 1
Yes 1.651 (0.904, 3.015) 0.103
The predictor ‘Antibiotics’ was shown to present multicollinearity and was excluded from this
multivariate model
** Unfortunately, it was not possible to run the regression having Astra TiOblast and Astra
Osseospeed as different categories within the parameter ‘Implant system’, even knowing that they
are implants of different designs and surface treatments, although of the same manufacturer. The
reason was because of the problem of quasi-‐complete separation, since there were no events of
failure for Astra Osseospeed. The numbers were (failure/survival): Astra TiOblast (14/288) and Astra
Osseospeed (0/91)

Table 4. Distribution of the factors for each surgeon. The total number of implants might not add to
8,930 due to missing information. n (%); n – implants.
Surgeon 1 2 3 4 5
Bone quantity
A/B/C 3473 (97.9) 1144 (77.2) 765 (95.5) 470 (70.5) 441 (89.8)
D/E 74 (2.1) 337 (22.8) 36 (4.5) 197 (29.5) 50 (10.2)
Total 3547 (100) 1481 (100) 801 (100) 667 (100) 491 (100)
Bone quality
1/2/3 3441 (97.0) 1283 (86.6) 780 (97.4) 498 (74.7) 481 (98.0)
4 106 (3.0) 198 (13.4) 21 (2.6) 169 (25.3) 10 (2.0)
Total 3547 (100) 1481 (100) 801 (100) 667 (100) 491 (100)
Implant location
Anterior maxilla 1181 (33.2) 572 (36.8) 429 (49.6) 303 (43.5) 240 (47.5)
Anterior mandible 1005 (28.3) 377 (24.3) 101 (11.7) 151 (21.7) 44 (8.7)
Posterior maxilla 681 (19.2) 300 (19.3) 195 (22.6) 144 (20.6) 139 (27.5)
Posterior mandible 685 (19.3) 304 (19.6) 139 (16.1) 99 (14.2) 82 (16.3)
Total 3552 (100) 1553 (100) 864 (100) 697 (100) 505 (100)
Implant surface
Turned 1441 (40.6) 1497 (96.4) 60 (6.9) 696 (99.9) 151 (29.9)
Enlarged 2111 (59.4) 56 (3.6) 804 (93.1) 1 (0.1) 354 (70.1)
Total 3552 (100) 1553 (100) 864 (100) 697 (100) 505 (100)
Implant system
Nobel turned 1441 (40.6) 1497 (96.4) 60 (6.9) 696 (99.9) 151 (29.9)
Nobel TiUnite 1644 (46.3) 45 (2.9) 504 (58.4) 1 (0.1) 170 (33.7)
Astra 195 (5.5) 5 (0.3) 37 (4.3) 0 (0) 117 (23.2)
Straumann 41 (1.1) 6 (0.4) 84 (9.7) 0 (0) 36 (7.1)
XiVE/Frialit-‐2 21 (0.6) 0 (0) 177 (20.5) 0 (0) 31 (6.1)
Others 210 (5.9) 0 (0) 2 (0.2) 0 (0) 0 (0)
Total 3552 (100) 1553 (100) 864 (100) 697 (100) 505 (100)

Table 4. (continued)
Surgeon 6 7 8 9 10
Bone quantity
A/B/C 368 (85.0) 393 (93.6) 329 (86.8) 214 (80.8) 176 (83.4)
D/E 65 (15.0) 27 (6.4) 50 (13.2) 51 (19.2) 35 (16.6)
Total 433 (100) 420 (100) 379 (100) 265 (100) 211 (100)
Bone quality
1/2/3 422 (97.5) 379 (90.2) 350 (92.3) 243 (91.7) 210 (99.5)
4 11 (2.5) 41 (9.8) 29 (7.7) 22 (8.3) 1 (0.5)
Total 433 (100) 420 (100) 379 (100) 265 (100) 211 (100)
Implant location
Anterior maxilla 179 (40.0) 99 (23.6) 106 (27.0) 73 (26.5) 70 (31.4)
Anterior mandible 78 (17.5) 143 (34.0) 127 (32.3) 88 (31.9) 48 (21.5)
Posterior maxilla 110 (24.6) 39 (9.3) 58 (14.8) 36 (13.0) 46 (20.6)
Posterior mandible 80 (17.9) 139 (33.1) 102 (25.9) 79 (28.6) 59 (26.5)
Total 447 (100) 420 (100) 393 (100) 276 (100) 223 (100)
Implant surface
Turned 442 (98.9) 415 (98.8) 334 (85.0) 273 (98.9) 2 (0.9)
Enlarged 5 (1.1) 5 (1.2) 59 (15.0) 3 (1.1) 221 (99.1)
Total 447 (100) 420 (100) 393 (100) 276 (100) 223 (100)
Implant system
Nobel turned 442 (98.9) 415 (98.8) 334 (85.0) 273 (98.9) 2 (0.9)
Nobel TiUnite 0 (0) 0 (0) 50 (12.7) 2 (0.7) 160 (71.7)
Astra 5 (1.1) 5 (1.2) 7 (1.8) 1 (0.4) 21 (9.4)
Straumann 0 (0) 0 (0) 2 (0.5) 0 (0) 16 (7.2)
XiVE/Frialit-‐2 0 (0) 0 (0) 0 (0) 0 (0) 8 (3.6)
Others 0 (0) 0 (0) 0 (0) 0 (0) 16 (7.2)
Total 447 (100) 420 (100) 393 (100) 276 (100) 223 (100)

Table 5. Failure/survival distribution of implants according to region and bone quality*.
Implant failure/survival – n (% failure)
Bone quality
1 2 3 4 Total
Anterior maxilla 0/14 (0) 53/1184 (4.3) 118/1497 74/204 (26.6) 245/2899
(7.3) (7.8)
Anterior 9/234 (3.7) 33/1248 (2.6) 18/507 (3.4) 5/58 (7.9) 65/2047 (3.1)
mandible
Posterior maxilla 0/6 (0) 11/291 (3.6) 81/1096 (6.9) 42/164 (20.4) 134/1557
(7.9)
Posterior 5/85 (5.6) 48/988 (4.6) 34/510 (6.2) 1/60 (1.6) 88/1643 (5.1)
mandible
Total 14/339 (4.0) 145/3711 251/3610 122/486 (20.1) 532/8146
(3.8) (6.5) (6.1)
* The information of bone quality is unknown for a variable number of implants

Figures
Figure 1. Kaplan-‐Meier curves comparing the survival of implants placed by different surgeons.

Figure 2. Kaplan-‐Meier curves comparing the survival of turned implants placed by different
surgeons.
Figure 3. Kaplan-‐Meier curves comparing the survival of enlarged-‐surface implants placed by
different surgeons.

VIII
Received: 6 December 2016 | Revised: 4 February 2017 | Accepted: 6 March 2017
DOI: 10.1111/cid.12485
ORIGINAL ARTICLE
Analysis of risk factors for cluster behavior of dental implant

failures
€ Kisch, DDS2 |
Bruno Ramos Chrcanovic, DDS, MSc, PhD student1 | Jeno
Tomas Albrektsson, MD, PhD3,4 | Ann Wennerberg, DDS, PhD4
1
Odontology, Malm€o University, Malm€
o,
Abstract
Sweden
Background: Some studies indicated that implant failures are commonly concentrated in few
2
Clinic for Prosthodontics, Centre of Dental
patients.
Specialist Care, Malm€
o, Sweden
3
Department of Biomaterials, G€
oteborg Purpose: To identify and analyze cluster behavior of dental implant failures among subjects of a
University, G€
oteborg, Sweden retrospective study.
4
Odontology, Malm€o University, Malm€
o,
Materials and Methods: This retrospective study included patients receiving at least three
Sweden implants only. Patients presenting at least three implant failures were classified as presenting a
cluster behavior. Univariate and multivariate logistic regression models and generalized estimating
Correspondence
equations analysis evaluated the effect of explanatory variables on the cluster behavior.
Bruno Ramos Chrcanovic, Department of
Prosthodontics, Faculty of Odontology, Results: There were 1406 patients with three or more implants (8337 implants, 592 failures).
Malm€o University, Carl Gustafs väg 34,
Sixty-seven (4.77%) patients presented cluster behavior, with 56.8% of all implant failures. The
SE-214 21, Malm€ o, Sweden.
Email: [email protected]; intake of antidepressants and bruxism were identified as potential negative factors exerting a stat-
[email protected] istically significant influence on a cluster behavior at the patient-level. The negative factors at the
implant-level were turned implants, short implants, poor bone quality, age of the patient, the
Funding information
intake of medicaments to reduce the acid gastric production, smoking, and bruxism.
Oral Health Related Research by Region
Skåne (Odontologisk Forskning i Region
Conclusions: A cluster pattern among patients with implant failure is highly probable. Factors of
Skåne, Grant/Award Number: OFRS
interest as predictors for implant failures could be a number of systemic and local factors, although
414321; Scientific Research Council of
Sweden, Vetenskapsrådet, Grant/Award a direct causal relationship cannot be ascertained.
Number: Dnr 2015-02971; Folktandvården
AB, Region Skåne, Sweden; CNPq, Con- KEYWORDS
selho Nacional de Desenvolvimento Cientí-
cluster phenomenon, dental implant, implant failure, logistic models, multivariate analysis, risk
fico e Tecnol
ogico, Grant/Award Number:
201318/2012-1 factors
1 | INTRODUCTION these implant loss clusters happen in specific high-risk groups and
individuals.7
Results of some studies indicated that implant failures are commonly Common risk factors for implant failures are poor bone quantity
concentrated in few patients, rather than to be evenly distributed and quality, implant insertion in the maxilla and in the posterior
among all treated patients.1–6 Implant failures are not randomly distrib- region of the jaws, heavy smoking, use of shorter length implants,
uted in all patients and a cluster behavior can occur.4 Cluster was once untreated chronic periodontitis, irradiation of the head and neck
defined as more than one implant failure per patient, not necessarily in region, lack of initial implant stability, a low insertion torque of
the same area or quadrant.5 As such, these failing patients have been implants that are planned to be immediately or early loaded, use of
described as “cluster patients,” and even though they have seemingly cylindrical (nonthreaded) implants, inexperienced surgeons conduct-
been observed in a randomized pattern, it is reasonable to assume that ing the surgery, greater number of implants placed per patient,
the patient with failing implant has certain individual characteristics implant insertion in fresh extraction sockets, and prosthetic rehabili-
that separate them from the more successful implant patients,4 that is, tation with implant-supported overdentures.8,9 However, there is
Clin Implant Dent Relat Res. 2017;1–11. wileyonlinelibrary.com/journal/cid V

C 2017 Wiley Periodicals, Inc. | 1
2 | CHRCANOVIC ET AL.
still no consensus on or scientific evidence for the etiology of clus- 2. Site-related factors: implant jaw location (maxilla/mandible), ante-
tering failure phenomena.6 rior or posterior location of the implant (sites from right canine to
The aim of this study was to retrospectively analyze cluster behav- left canine teeth were considered anterior location), bone quantity
ior of dental implant failures among patients, to assess the possible risk and quality of the implant sites, which were classified at the time
factors influencing this phenomenon, and to describe and compare this of surgery according to the Lekholm and Zarb13 classification, and
group of patients with one not presenting this behavior. implant sites with previous implant failures (reoperation).
3. Patient-related factors: patient’s sex, age of the patient at the

2 | MATERIALS AND METHODS implant insertion surgery, general health, and behavioral history.
The presence of a medicament list in the patients’ records was
2.1 | Materials also use to correlate the use of certain drugs to specific health
conditions. Health factors assessed: diabetes types I or II, hyper-
This retrospective study was based on all 2670 patients provided with
tension, hypercholesterolemia, hypothyroidism, asthma, psoriasis,
implants, consecutively treated on a routine basis at one specialist clinic
chemotherapy, and irradiation of the head-neck region. The
(Clinic for Prosthodontics, Centre of Dental Specialist Care, Malm€
o,
patients were also classified according to the intake of the follow-
Sweden) during the period from 1980 to 2014. The study protocol was
ing medication types: antidepressants, immunosuppressives,
approved by the regional Ethical Committee, Lund, Sweden (Dnr 2014/
bisphosphonates, antithrombotic agents (antiplatelet, anticoagu-
598; Dnr 2015/72).
lant, thrombolytic drugs), hormone replacement therapy in
women, and medicaments to reduce the acid gastric production.
2.2 | Definitions Behavioral factors assessed: smoking habits, use of snuff, bruxism.
An implant was considered a failure if presenting signs and symptoms 4. Other factors: prescription of antibiotics (the prophylactic antibiotic
that led to implant removal. Thus, a failed implant in our study is equal regimen was usually starting 1-2 hours before surgery and going
to a lost implant. The failures were classified into two types: (1) from 5 to 7 days postoperatively), bone graft procedures, reason for
implants lost due to lack/loss of osseointegration and (2) fractured tooth extraction (periodontal disease, fracture/trauma, advanced
implants. Primary failures were the failures occurring until/at the day of caries, agenesia, other), type of implant-supported prosthetic restora-
8
the 2 stage surgery (abutment connection). A patient was considered tion (single crown, partial bridge with 2-6 prosthetic elements, partial
as presenting a cluster behavior of failures when having at least three bridge with 7-10 prosthetic elements, full-arch, overdenture), number
dental implant failures. In order to diagnose patients as bruxers, the of days until failure, and follow-up time (1 year, 1 year< x 5
authors followed the definition of bruxism proposed by Lobbezoo years, 5 years< x 10 years, 10 years< x 20 years, >20 years).
et al.,10 and the sign and symptoms of bruxism were listed according to
11 As the standard protocol in the clinic, the patients’ dental hygiene was
the International Classification of Sleep Disorders, following the
followed up by a dental hygienist within 6 months after the final
same guidelines used in a recent study.12
implant-supported/retained restoration. Each patient then attended a
dental hygiene recall program based on individual needs.
2.3 | Inclusion and exclusion criteria
Only patients receiving at least three implants were included. Patients 2.5 | Statistical analyses
with all modern types of implants with cylindrical or conical design
The mean, standard deviation (SD), and percentage were calculated for
were included. Zygomatic implants were not included in the study, as
several variables. Differences between implants of cluster and nonclus-
well as implants detected in radiographies, but without basic informa-
ter patients were compared with the student’s t-test or Mann-Whitney
tion about them in the patients’ files.
test for continuous variables, depending on the normality and, the Pear-
son’s chi-squared or Fisher’s exact tests for categorical variables,
2.4 | Data collection depending on the number of samples in a 2 3 2 contingency table. Sta-
The dental records of all patients ever treated with implants in the tistical significance was set at P < .05. Logistic regression models were
aforementioned clinic were read in order to collect the data. The data used at the patient-level as well as at the implant-level. The patient-level
were directly entered into a SPSS file (SPSS software, version 23, SPSS analysis considered the patient as the statistical unit, with patients pre-
Inc., Chicago, IL) as the files were being read. The following data were senting or not presenting implant failures. Regression at the patient-level
collected: was used to evaluate the effect of explanatory health variables on the
cluster behavior of implant failures, that is, health factors there are inher-
1. Implant-related factors: implant surface (turned/machined or ently associated to the patient, not to the implant. First, a univariate
enhanced surfaces, the latter including sandblasted, acid-etched, effect of each health factor on the implant failure was evaluated. Odds
sandblasted 1 acid-etched, anodized, hydroxyapatite-coated surfa- ratios (OR) and their 95% confidence intervals (CI) were computed. The
ces), implant diameter and length, and implant design (cylindrical Wald test based on robust standard errors was used to assess the signif-
or conical); icance of each factor. A factor was excluded from further multivariate
CHRCANOVIC ET AL. | 3
analysis if the univariate logistic regression resulted in a clearly nonsigni- together (lack/loss of osseointegration 1 fracture of implants). Sixty-
ficant odds ratio (P > .1). In the second step, a multivariate logistic one (19.4%) of the 315 implants with osseointegration failure in cluster
regression gave the effects on different risk factors when controlling for patients were lost until or at the day of the second-stage surgery (pri-
other factors. The results of the final model were presented as an esti- mary failures), and 80.6% after loading. The 67 cluster patients had a
mated OR of each significant prognostic variable (P < .05). mean implant failure rate of 53.4% (range 20-100%). Twelve patients
An implant-level model was performed in order to assess the lost all their implants. One-hundred-and-thirty-three implants (40.2%)
effects of the implant-related and local bone factor on the implant fail- were lost (lack/loss of osseointegration 1 fracture) until 1 year after
ures, also including the health variables. A generalized estimating equa- surgery, 192 (58.0%) later than 1 year of surgery, and there was no
tions (GEE) method was used to account for the fact that repeated information for six implants (1.8%).
observations (several implants) were available for a single patient. All A total of 1339 patients did not present a cluster behavior, and
models were adjusted for clustering of subject and implants in a binary they received 7717 implants, of which 261 failed (3.38%; 241 lack/loss
logistic regression model using GEE with a binomial distribution and a of osseointegration, 20 fractured implants). In this group, 41.5% of the
logit link function, while assuming an exchangeable working correlation failures (100 out of 241 implant failures) occurred until/at the abut-
structure to assess the relationship between patients with cluster ment connection (primary failures).
behavior and the risk factors. Initially, a univariate GEE on each of the All implants were inserted with open flapped surgery. Only three
variables was performed. In order to verify multicollinearity, a correla- implants were immediately loaded, all in noncluster patients, with no
tion matrix of all of the predictor variables with a significant odds ratio failures. The abutment connection surgery was performed after a
(P-value cut-off point of .1) identified in the univariate GEE was mean 6 SD healing time of 184 6 66 and 162 6 128 days for the clus-
ter and noncluster groups, respectively (P < .001; Mann-Whitney test).
scanned, to see whether there were some high correlations among the
The number of nonsubmerged implants for the respective groups was
predictors. Collinearity statistics obtaining variance inflation factor and
7 (out of 620; 1.13%) and 289 (out of 7717; 3.74%), and the number
tolerance statistic were also performed to detect more subtle forms of
of implants placed in fresh extraction sockets was 6 (out of 620;
multicollinearity. Then, a multivariable model with a forced entry
0.97%) and 15 (out of 7717; 0.19%). The cluster group presented 479
method was used to evaluate the effect of the factors that were uni-
implants (77.3%) with turned surfaces, whereas there were 4785
variately significant (P < .1) and did not present multicollinearity. A
turned-surface implants (62.0%) in the noncluster group (P < .001;
Wald chi-square test was used to analyze the statistical significance of
Pearson’s chi-squared test). The rest of the implants had some kind of
each parameter within the model. The results of the final model were
enhanced surface. The group of turned-surface implants had a mean
presented as an estimated OR of each significant prognostic variable
follow-up of 4678 6 2612 days, against 2215 6 1474 days for the
(P < .05).
group of enhanced-surface implants (P < .001; Mann-Whitney test).
SPSS software version 23 (SPSS Inc., Chicago, IL) was used for the
The mean length of the inserted implants was 12.5 6 2.7 mm for the
statistical analyses.
cluster group and 12.9 6 2.4 mm for the noncluster group (P 5 .008;
Mann-Whitney test). The mean diameter for cluster and noncluster
3 | RESULTS groups were 3.76 6 0.16 and 3.75 6 0.15, respectively (P 5 .042;
Mann-Whitney test).
A number of 766 patients (390 men, 376 women) received only one Table 1 shows a comparison of groups according to the distribu-
implant, and presented 17 implant failures (2.22%; 15 lack/loss of tion of implants with regard to Lekholm and Zarb (1985) classification
osseointegration, 2 fractured implants), and 498 patients (221 men, of bone quantity and quality. It can be observed that a greater percent-
277 women) received two implants, and presented 37 implant failures age of implants were placed in bone sites having been classified as
(out of 996, 3.71%; 35 lack/loss of osseointegration, 2 fractured quantities D and E (P < .001; Pearson’s chi-squared test) and qualities 3
implants). These patients with only one or two implants were not eligi- and 4 (P < .001; Pearson’s chi-squared test) in the cluster patients
ble for the analysis. group, in comparison to the noncluster group. Table 2 shows a compar-
There were 1406 patients with three or more implants, totaling ison of the difference in failure rates between implants groups of dif-
8337 implants, with 592 implant failures (7.10%; 556 lack/loss of ferent surfaces, for cluster and noncluster patients, in relation to bone
osseointegration, 36 fractured implants). Sixty-seven (4.77%) patients sites of different quantities/qualities, according to the Lekholm and
were identified as presenting cluster behavior, who received 620 Zarb (1985) classification.
implants, of which 331 failed (3.37%; 315 lack/loss of osseointegration, The univariate binary logistic regression at the patient-level
16 fractured implants). Thirty-two of these 67 patients were already showed that the following predictors had a statistically significant odds
deceased when the data collection was performed. There were 328 ratio at the patient-level (Table 3): the intake of antidepressants, the
implants in 33 men (mean age 6 SD 62.1 6 10.3, min–max 36.9-83.3) intake of medicaments to reduce the acid gastric production, the intake
and 292 implants in 34 women (mean age 6 SD 59.5 6 9.2, min–max of antithrombotic agents, smoking, number of cigarettes per day, and
39.7-79.6). These 4.75% of the patients had 56.8% of all implant fail- bruxism. Only the intake of antidepressants and bruxism continued to
ures, when only the failures due to lack/loss of osseointegration were present a statistically significant odds ratio in the multivariate binary
considered. The percentage is 56.0% when all failures are considered logistic regression model (Table 4).
TA BL E 1 Comparison of cluster and noncluster groups according to the distribution of implants with regard to Lekholm and Zarb classifica-
tion of bone quantity and qualitya
Cluster group
A B C D E Total % Groupb % Failedc
1 0 1(1) 4 6(3) 0 11(4) 1.8 36.4
2 7 80(33) 47(19) 13(7) 7(4) 154(63) 25.6 40.9
3 7(3) 102(48) 114(59) 64(40) 6(6) 293(156) 48.7 53.2
4 0 21(16) 24(15) 47(32) 52(30) 144(93) 23.9 64.6
Total 14(3) 204(98) 189(93) 130(82) 65(40) 602(316) 100 52.5
% Groupb 2.3 33.9 31.4 21.6 10.8 100
% Failedc 21.4 48.0 49.2 63.1 61.5 52.5
Missing information of bone quantity/quality: 18 implants, 15 failures

Noncluster group
A B C D E Total % Groupb % Failedc
1 19 56 90(6) 141(3) 41(2) 347(11) 4.6 3.2
2 317(6) 1858(50) 814(27) 147(8) 26(1) 3162(92) 42.1 2.9
3 344(9) 1621(44) 1266(45) 308(20) 10(2) 3549(120) 47.3 3.4
4 19 106(3) 193(18) 104(9) 28(3) 450(33) 6.0 7.3
Total 699(15) 3641(97) 2363(96) 700(40) 105(8) 7508(256) 100 3.4
% Groupb 9.3 48.5 31.5 9.3 1.4 100
% Failedc 2.1 2.7 4.1 5.7 7.6 3.4
The number between parentheses represents failures.

a
According to the Lekholm and Zarb classification, bone quality is broken down into four groups according to the proportion and structure of com-
pact and trabecular bone tissue: type 1 5 large homogenous cortical/compact bone; type 2 5 thick layer of compact bone surrounding a dense tra-
becular bone; type 3 5 thin cortical layer surrounding a dense trabecular bone; type 4 5 thin cortical layer surrounding a core of low-density
trabecular bone. The quantity of jawbone is broken down into five groups (A, B, C, D, and E), based on the residual jaw shape following tooth
extraction. Bone classified as “A” presents the largest amount of bone among all classes, whereas bone classified as “E” presents the lowest volume
of bone.
b
Percentage of implants in each bone quantity/quality class, considering all implants in cluster or noncluster group as 100%.
c
Percentage of failed implants for each bone quantity/quality class.
TA BL E 2 Comparison of the difference in failure rates (Pearson’s chi-squared test) between implants groups of different surfaces, for cluster
and noncluster patients, in relation to bone sites of different quantities/qualities, according to the Lekholm and Zarb classification
Implant
failure/total (% failed)
Bone Group Turned Enhanced P value*
Quantity A/B/C Cluster 145/285 (50.9%) 49/122 (40.2%) .047

Noncluster 154/4010 (3.8%) 54/2693 (2.0%) <.001
Quantity D/E Cluster 114/176 (64.8%) 8/19 (42.1%) .052

Noncluster 36/655 (5.5%) 12/150 (8.0%) .243
Quality 1/2 Cluster 52/115 (45.3%) 15/50 (30%) .067

Noncluster 75/2129 (3.5%) 28/1380 (2.0%) .010
Quality 3/4 Cluster 207/346 (59.8%) 42/91 (46.2%) .019

Noncluster 115/2536 (4.5%) 38/1463 (2.6%) .002
*Pearson’s chi-squared test.

TA BL E 3 Univariate binary logistic regression for cluster behavior: TA BL E 3 (continued)

gender and health factors at the patient-level (OR—odds ratio)
Patients
Patients with 3
with 3 failures/0-2
failures/0-2 Factor failuresa OR (95% CI) P-value
Factor failuresa OR (95% CI) P-value
Smoking
Gender No 22/588 1
Male 33/592 1 Yes 26/259 2.683 (1.493, 4.822) .001
Female 34/747 0.817 (0.500, 1.334) .418 Former smoker 1/32 0.835 (0.109, 6.394) .862
Age Cigarettes/day
Increase by 1 – 1.011 (0.994, 1.028) .196 Increase by 1 – 1.034 (0.998, 1.072) .068
Diabetes Snuff
No 44/850 1 No 43/839 1
Type I 1/18 1.073 (0.140, 8.224) .946 Yes 3/28 2.091 (0.611, 7.148) .240
Type II 4/72 1.073 (0.375, 3.071) .895
Bruxism
High blood pressure No 38/901 1
No 29/608 1 Yes 11/43 6.065 (2.901, 12.681) <.001
Yes 20/331 1.267 (0.706, 2.274) .428
a
The information for some conditions is unknown for a variable number
High cholesterol of patients.
No 39/795 1
Yes 10/138 1.477 (0.721, 3.028) .287
The univariate GEE model at the implant-level showed that the fol-
Hypothyroidism lowing predictors had a statistically significant odds ratio at the
No 45/881 1
implant-level (Table 5): implant surface, implant length, implant loca-
Yes 4/54 1.450 (0.503, 4.181) .491
tion, bone quantity and quality, reoperation, age of the patient at the
Asthma time of the surgery, the intake of antidepressants, the intake of medi-
No 46/854 1
caments to reduce the acid gastric production, smoking, bruxism, the
Yes 4/81 0.917 (0.322, 2.612) .871
use of prophylactic antibiotics, bone grafting, and follow-up time. The
Intake of antidepressants following factors remained statistically significant in the multivariate
No 38/853 1
Yes 13/79 3.694 (1.889, 7.223) <.001
Irradiation TA BL E 4 Multivariate logistic regression model for cluster behavior

No 48/911 1 at the patient-level
Yes 2/30 1.265 (0.294, 5.451) .752
Factor OR (95% CI) P-value
No 56/1080 1
No 1
Yes 2/37 1.042 (0.245, 4.435) .955
Yes 2.473 (1.026, 5.958) .044
Gastric
Gastric
No 39/850 1
No 1
Yes 8/71 2.456 (1.105, 5.456) .027
Yes 2.182 (0.829, 5.744) .114
Antithrombotics
Antithrombotics
No 32/723 1
No 1
Yes 16/209 1.730 (0.931, 3.214) .083
Yes 1.247 (0.552, 2.813) .596
Immunosuppressive
Smoking
No 46/915 1
No 1
Yes 2/11 3.617 (0.779, 16.794) .101 Yes 2.170 (0.629, 7.483) .220
Former smoker 0.658 (0.079, 5.481) .699
Psoriasis
No 48/915 1 Cigarettes/day
Yes 0/12 0.000 (0.000) 1.000 Increase by 1 1.003 (0.934, 1.078) .932
Bisphosphonates Bruxism
No 47/907 1 No 1
Yes 0/18 0.000 (0.000) 1.000 Yes 6.376 (2.567, 15.834) <.001
(continues) Only the patient and health factors that were considered statistically sig-
nificant (P < .1) in the univariate model and did not present multicolli-
nearity were included in the multivariate model (OR—odds ratio).
TA BL E 5 Risk factor analysis using a univariate generalized estimating equations logistic regression model, at the implant-level (OR—odds
ratio)
Failure/survival in Failure/survival in
Factor cluster patientsa noncluster patientsa OR (95% CI) P-value
Implant-related factors
Implant surfaceb
Turned 274/205 194/4591 1
Enhanced 57/84 67/2865 0.286 (0.190, 0.430) <.001
Implant diameter
Increase by 1 – – 1.656 (0.783, 3.502) .187
Implant length
Increase by 1 – – 0.904 (0.849, 0.962) .002
Implant design
Cylindrical 330/281 257/7297 1
Conical 1/8 4/159 0.174 (0.008, 3.767) .265
Site-related factors
Location
Maxilla 277/175 160/3795 1
Mandible 54/114 101/3661 0.454 (0.334, 0.617) <.001
Anterior 231/183 121/4469 1
Posterior 100/106 140/2987 1.233 (1.007, 1.510) .043
Bone quantity
A 3/11 15/684 1
B 98/106 97/3544 1.529 (0.777, 3.011) .219
C 93/96 96/2267 2.398 (1.204, 4.778) .013
D 82/48 40/660 4.913 (2.346, 10.289) <.001
E 40/25 8/97 9.251 (3.892, 21.988) <.001
Bone quality
1 4/7 11/336 1
2 63/91 92/3070 1.193 (0.439, 3.243) .730
3 156/137 120/3429 1.640 (0.610, 4.413) .327
4 93/51 33/417 5.282 (1.793, 15.565) .003
Reoperation
No 228/240 260/7392 1
Yes 43/49 1/64 5.423 (3.358, 8.758) <.001
Patient-related factors
Gender
Male 160/168 108/3494 1
Female 171/121 153/3962 1.052 (0.784, 1.411) .735
Age
Increase by 1 – – 0.981 (0.972, 0.990) <.001
Diabetes
No 226/174 143/4701 1
Type I 3/0 4/97 1.461 (0.420, 5.086) .551
Type II 15/21 17/419 0.968 (0.558, 1.679) .908
High blood pressure

No 162/96 104/3394 1
Yes 82/99 59/1813 0.899 (0.625, 1.293) .567
High cholesterol
No 198/152 132/4382 1
Yes 46/43 30/789 1.124 (0.714, 1.771) .614
(continues)
TA BL E 5 (continued)
Hypothyroidism
No 231/179 156/4893 1
Yes 13/16 8/286 1.034 (0.478, 2.235) .932
Asthma
No 231/179 151/4746 1
Yes 19/25 11/438 0.799 (0.427, 1.493) .481
No 180/150 145/4737 1
Yes 77/65 15/432 2.523 (1.527, 4.167) <.001
Irradiation
No 241/190 157/5062 1
Yes 7/6 5/151 1.105 (0.430, 2.828) .836

No 13/9 8/190 1
Yes 273/250 192/6076 1.130 (0.505, 2.531) .766
Gastric
No 195/157 143/4705 1
Yes 36/33 17/395 1.890 (1.105, 3.233) .020
Antithrombotics
No 151/127 119/4007 1
Yes 83/71 43/1151 1.289 (0.862, 1.928) .217
Immunosuppressive
No 227/188 159/5071 1
Yes 7/10 1/59 1.310 (0.388, 4.422) .663
Psoriasis
No 234/234 159/5072 1
Yes 0/0 2/63 0.000 (0.000) 1.000
Bisphosphonates
No 232/190 159/5044 1
Yes 0/0 1/80 0.000 (0.000) 1.000
Smoking
No 119/95 96/3179 1
Yes 115/102 51/1495 1.747 (1.202, 2.541) .003
Former smoker 7/5 7/159 1.312 (0.555, 3.106) .536
Cigarettes/day
Increase by 1 – – 1.014 (0.990, 1.038) .262
Snuff
No 206/173 145/4620 1
Yes 20/13 5/152 1.713 (0.745, 3.937) .205
Bruxism
No 177/155 150/5001 1
Yes 63/49 20/242 4.449 (2.691, 7.357) <.001
Other factors
Antibiotics
No 20/20 25/457 1
Yes 130/117 92/3505 0.641 (0.401, 1.025) .063
Bone grafting
No 267/253 239/7155 1
Yes 64/36 22/301 2.139 (1.083, 4.226) .029
(continues)
TA BL E 5 (continued)

Periodontal disease 24/34 28/791 1
Fracture/trauma 1/0 9/140 1.633 (0.809, 3.297) .171
Advanced caries 6/4 2/188 0.878 (0.381, 2.020) .759
Agenesia 0/0 17/361 0.821 (0.366, 1.843) .633
Other 1/2 3/52 1.443 (0.490, 4.250) .506
Prosthetic restoration
Single crown 2/0 22/414 1
Partial fixed, 2-6 units 50/46 68/1986 0.872 (0.539, 1.410) .575
Partial fixed, 7-10 units 17/16 9/328 1.115 (0.457, 2.722) .810
Full-arch fixed 220/198 134/4502 1.031 (0.626, 1.696) .905
Overdenture 33/25 15/169 1.807 (0.500, 6.533) .367
Time of follow-up
1 year 6/4 5/327 1
1 year< x 5 years 49/55 50/1742 1.709 (0.328, 8.875) .524
5 years< x 10 years 69/69 59/1916 2.301 (0.469, 11.298) .305
10 years< x 20 years 123/106 106/2686 3.777 (0.791, 18.041) .096
>20 years 84/55 42/784 8.658 (1.801, 41.613) .007
a
The information for some conditions is unknown for a variable number of implants.
b
The turned implants group was comprised by Nobel turned implants only. The numbers (failure/survival) for the enhanced surface implants in cluster
and noncluster patients were, respectively: Nobel TiUnite, 42/56 and 41/1989; Astra TiOblast, 12/12 and 11/285; Astra Osseospeed, 0/0 and 4/139;
Straumann, 0/2 and 8/232; XIVE/Frialit-2, 0/6 and 2/89; other, 3/8 and 1/131.
GEE model (Table 6): turned implants, short implants, poor bone qual- attenders. Monteiro da Silva et al.17 found significantly increased
ity, age of the patient, the intake of medicaments to reduce the acid depression and loneliness in patients with rapidly progressive adult-
gastric production, smoking, and bruxism. onset periodontitis compared with a group with regular chronic adult
periodontitis and a control group. Among the risk factors associated
4 | DISCUSSION with periodontal disease and ultimate tooth loss, smoking is the best
documented one.18 In some studies, smoking has also been associated
The results of the present study showed profound differences of with depression.19,20
implant survival rate in different individuals, that is, less than 5% of Some reasons could theoretically account for the suggested associ-
patients showed about 56% of all implant failures, and this suggests a ation between PPIs intake and the increased likelihood of dental
cluster behavior with regard to implant failures, most likely with multi- implant failures. The most prominent hypothesis assumes that the
factorial causes.8 The regression analyses performed in this study tried reduced acidity in the stomach impairs the intestinal absorption of die-
to identify the factors that could possibly be related to implant failure. tary calcium. Thus, there can be a decreased calcium absorption under
The univariate regression assessed the relationship between each inde- PPI therapy.21–23 As the calcium balance is essential for the mainte-
pendent variable and implant failure separately, and the multivariate nance of bone health, it seems reasonable to believe that the unbal-
regression assessed the relationship of the variables that were univari- ance of calcium may to some degree affect osseointegration.
ately significant to implant failure, controlling for each other. At the Concerning the patients’ habits, bruxism was shown to significantly
patient-level, the multivariate regression model identified the intake of affect the implant failure rates negatively, agreeing with the results of
antidepressants and bruxism as potential negative factors exerting a the two very recent clinical trials assessing the effect of bruxism on
statistically significant influence on the high failure rates in cluster dental implants.12,24 This gives a new perspective on the condition,
patients. At the implant-level, the negative factors identified by the which was, until very recently, considered to be not related with
multivariate GEE model were turned implants, shorter implants, poor implant failures.25,26 Bruxism is suggested to generate overload of
bone quality, younger patients, the intake of medicaments to reduce prosthetic rehabilitations on implants, which could possibly cause
the acid gastric production, smoking, and bruxism. implant fracture or peri-implant marginal bone loss, ultimately resulting
Two health-related variables were shown to exert some significant in implant failure.27 Implant failure may result in a “domino” effect that
effect on the cluster behavior. The first one was depression. Knowing could lead to further implant failures in the same individual.5 This kind
that a loss of motivation is one of the volitional symptoms of depres- of effect was noticed in one study,4 where an observed pattern in the
sion,14 one may presume that depression could have a negative impact study group was that implant failures started in some patients predomi-
on oral hygiene.15 Kurer et al.16 found an association between mean nantly in one quadrant, causing an unfavorable distribution of the
depression scores and oral hygiene in a group of 51 regular dental remaining implants. Even if adjustments with shortening of the fixed
TA BL E 6 Multivariate generalized estimating equations logistic implant-supported prostheses were made, these situations indicate
regression model at the implant-level that an overload could be a contributing factor of importance for some
Factor OR (95% CI) P-value of the cluster failures.
Other patients’ habits such as smoking and the use of smokeless
Implant surface
Turned 1 tobacco (snuff) were also analyzed. The results of the multivariate GEE
Enhanced 0.311 (0.127, 0.762) .011 logistic regression model suggest a statistically significant influence of
Implant length smoking on the cluster behavior. A recent meta-analysis analyzing

Increase by 1 0.863 (0.773, 0.964) .009 more than 100 studies has shown that failures of implants inserted in
smokers are 2.23 times likely to happen than failures of implants
Location
Maxilla 1 inserted in nonsmokers.28 The increase of implant failure rates due to
Mandible 0.789 (0.452, 1.375) .403 smoking is hypothesized to be related mainly to the effect of smoking
Anterior 1
Posterior 1.122 (0.770, 1.636) .548 in osteogenesis and angiogenesis.29 Moreover, smokers’ health behav-
ior and attitudes appear to be less favorable to oral health than those
Bone quantity
of nonsmokers.30 Studies have shown that smokers brush and floss
A 1
B 1.658 (0.476, 5.779) .427 their teeth less frequently than nonsmokers31 and have dental visits
C 1.136 (0.297, 4.341) .852 less frequently than do nonsmokers.32
D 2.790 (0.616, 12.636) .183
E 4.330 (0.547, 34.291) .165 With regard to the age of the patient, the results of the multivari-
ate GEE model suggest that the odds of implant failure decrease by
Bone quality
3.3% for every 1 year increase in the patient’s age. This could be
1 1
2 1.094 (0.387, 3.088) .866 related to the lower prevalence of bruxism among the elderly in rela-
3 1.066 (0.374, 3.041) .905
tion to younger adult,33 to the ageing effect in oral physiology, result-
4 4.023 (1.133, 14.286) .031
ing in less muscular strength and weaker mastication forces,34 and to a
Reoperation high prevalence of removable prosthesis opposing implant-supported
No 1
Yes 0.470 (0.037, 6.021) .562 restorations.35
The patients of the cluster group presented, in comparison to the
Age
patients of the noncluster group, a statistically significant greater per-
Increase by 1 0.973 (0.954, 0.992) .005
centage of implants placed in sites of poor bone, that is, bone quanti-
ties D and E, and bone qualities 3 and 4. The multivariate GEE model
No 1
Yes 1.077 (0.423, 2.747) .876 showed a statistically significant negative influence of poor bone on
the cluster behavior of implant failures. Poor bone site has been con-
Gastric
sidered an important factor to influence implant survival negatively.3
No 1
Yes 2.135 (1.001, 4.064) .049 Concerning the different implant surfaces, the higher failure rate
of turned implants is hypothesized to be related to the small differen-
Smoking
No 1 ces in the osseointegration process in relation to the enhanced-surface
Yes 1.975 (1.137, 3.429) .016 implants. The enhanced surfaces are designed to allow greater bone-
Former smoker 1.908 (0.693, 5.254) .211
to-implant contact, and provide better possibilities for microbiome-
Bruxism chanical retention due to larger surface and thus more retention for
No 1 proteins to attach and new bone formation.36 The longer mean follow-
Yes 5.200 (2.235, 12.097) <.001
up of the turned implants in comparison to the enhanced-surface
Antibiotics implants group may also have some influence on these results, as a lon-
No 1
Yes 0.658 (0.354, 1.222) .185
ger period of follow-up can result in an increased failure rate, especially
if it extended beyond functional loading, because other prosthetic fac-
Bone grafting
tors can influence implant failure from that point onward.
No 1
Yes 2.082 (0.425, 10.207) .366 With regard to lower hazard ratios for longer implants, although
some good results can be obtained with the use of shorter implants,
Time of follow-up
1 year 1
they seem to fail more often than longer ones.37 Increased initial stabil-
1 year< x 5 years 4.356 (0.290, 65.416) .287 ity, long-term resistance to bending moment forces, expedited healing,
5 years< x 10 years 3.814 (0.275, 52.982) .319
and a decreased risk of movement at the interface are listed as advan-
10 years< x 20 years 3.075 (0.230, 41.066) .396
>20 years 7.289 (0.541, 98.232) .134 tages of increased implant length.38
The lack of specific information characterizing the patients’ sys-
Only the factors that were considered statistically significant (P < .1) in
the univariate model and did not present multicollinearity were included temic conditions status and the medications dosage, as well as gaps in
in the multivariate model (OR—odds ratio). information in the dental records are limitations also connected to the
retrospective nature of this study. Moreover, the implant primary sta- [3] Ekfeldt A, Christiansson U, Eriksson T, et al. A retrospective analysis
bility was not analyzed, as well as the possible influence of the place- of factors associated with multiple implant failures in maxillae. Clin
Oral Implants Res. 2001;12:462–467.
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In the clear advantage of hindsight, it may be said that some
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IX

A retrospective study on clinical and radiological outcomes of oral implants in patients

followed up for a minimum of 20 years

Bruno Ramos Chrcanovic 1*,
Jenö Kisch 2
Tomas Albrektsson 3
Ann Wennerberg 4

1
DDS, MSc, PhD student; Department of Prosthodontics, Faculty of Odontology, Malmö
2
DDS, OD. h.c.; Clinic for Prosthodontics, Centre of Dental Specialist Care, Malmö, Sweden
3
MD, PhD, RCPSG; Department of Biomaterials, Göteborg University, Göteborg, Sweden;
Department of Prosthodontics, Faculty of Odontology, Malmö University, Malmö, Sweden
4 DDS, PhD; Department of Prosthodontics, Faculty of Odontology, Malmö University,
Malmö, Sweden

Bruno Ramos Chrcanovic, Department of Prosthodontics, Faculty of Odontology, Malmö
University, Carl Gustafs väg 34, SE-‐214 21, Malmö, Sweden. [email protected];

Abstract
Purpose. To assess dental implant failure rates and marginal bone loss (MBL) of patients
followed up for a minimum of 20 years.
Materials and Methods. This retrospective study is based on 2,670 patients who received
10,096 implants and were consecutively treated with implant-‐supported prostheses at one
specialist clinic. Only implants placed in patients followed up for at least 20 years were
included. Several anatomical-‐, patient-‐, health-‐, and implant-‐related factors were collected.
Descriptive statistics and survival analyses were performed. Generalized estimating
equations (GEE) analysis evaluated the effect of explanatory variables on implant failure. A
number of 300 implants were randomly selected for MBL.
Results. A total of 1,045 implants placed in 227 patients were included. Implant location,
irradiation, and bruxism were identified as the factors that statistically significantly affected
the implant survival rate. Thirty-‐five percent of the implant failures occurred within the first
year after implantation, and another 26.8% of the failures occurred in the second and third
year. There was a CSR of 87.8% after 36 years of follow-‐up. In the last radiological follow-‐up,
35 implants (11.7%) had bone gain, and 35 implants (11.7%) presented at least 3 mm of
MBL. Twenty-‐six out of 86 failed implants with available radiograms presented severe MBL
in the last radiological register before implant failure.
Conclusions. Most of the implant failures occurred at the first few years after implantation,
regardless of a very long follow-‐up. MBL can be insignificant in long term observations, but it
may, nevertheless, be the cause of secondary failure of oral implants in some cases.

Keywords
Dental implants; implant failure; risk factors; marginal bone loss, long-‐term follow-‐up,
multivariate analysis

Introduction
Brånemark discovered the process of osseointegration in the 1960s and placed the
first dental implant about 50 years ago.1 Since then dental implants supported by evidence-‐
based data became an increasingly viable alternative to conventional prosthodontic
treatment options. Thousands of clinical studies on dental implants have been carried out
and published. Most studies present data on implant and prosthesis survival, as well as on
bone response adjacent to the implants. However, many of the studies are on a relatively
short-‐ or medium-‐term basis.2 There is an increase in the volume of dental implants being
placed and follow-‐up is essential to determine and predict a future clinical course. The
patients receiving implants expect to keep them for years ever, and therefore it is more
reliable to have a basis for dental implants prognosis with long follow-‐up studies.
During the first decades of osseointegration, the most commonly used implant in the
world was the turned (“machined”) Brånemark implant. This implant design showed quite
good long term data with survival rates in the mandible above 90% and in the maxilla above
80% for a follow up time of 5 years or more.3-‐5 Having said this, there were some problems
reported in soft maxillary bone6, 7 and the old Brånemark implants showed less good clinical
results if loaded prematurely or used in form of short implants.8 Another problem was
reported with Brånemark implants; that of substantial marginal bone loss allegedly leading
to disease entitled “Peri-‐implantitis”. Roos-‐Jansåker et al.9 initially defined disease around
oral implants based on bleeding on probing and >1.8 mm of marginal bone loss at 9-‐14 years
of follow up; they reported 6.6% of their Brånemark implants with disease. Fransson et al.10
saw any bone loss after the first year if combined with bleeding on probing and pus to be
synonymous to implant disease and reported 12.4% of their 5-‐20 years followed up
Brånemark implants with such problems.
These early reports of disease may not have survived the scrutiny of time,11 but
previous reports have focused on the importance of careful monitoring of implant marginal
bone loss as one way of documenting their long term performance.3, 12 The latter authors
reported that a successful implant would maximally lose 1 mm of bone during the implant´s
first year in function and less than 0.2 mm annually thereafter. Implants losing more bone
would not be successful, but may certainly survive and function in the bone of the patient.
The purpose of the present study was to assess the dental implant failure rates and
marginal bone loss (MBL) of patients followed up for a minimum of 20 years. By selecting

such a long follow up time of implants placed at one specialist clinic in Malmö, the included
implants are indeed old turned Brånemark ones (n=1025) and a very small number of turned
Astra implants (n=20).

Materials. This retrospective study was based on all 2,670 patients provided with
implants, consecutively treated on a routine basis at one specialist clinic (Clinic for
Prosthodontics, Centre of Dental Specialist Care, Malmö, Sweden) during the period from
1980 to 2014. The study protocol was approved by the regional Ethical Committee, Lund,
Sweden (Dnr 2014/598; Dnr 2015/72).
Definitions. An implant was considered a failure if presenting signs and symptoms
that led to implant removal. Thus, a failed implant in our study is equal to a lost implant. The
failures were classified into two types: (1) implants lost due to lack/loss of osseointegration
and (2) fractured implants. Primary failures were those occurring until/at the day of the 2o
stage surgery (abutment connection).
We considered as severe MBL at least 1.0 mm of bone loss per year or a minimum
bone loss of 1/3 of the implant’s full length in the last radiological register before implant
failure.
Inclusion and exclusion criteria. Only implants placed in patients followed up for at
least 20 years were included. Patients with all modern types of threaded implants with
cylindrical or conical design were included. Zygomatic implants were not included in the
study, as well as implants detected in radiographies, but without basic information about
them in the patients’ files.
A number of 300 implants were randomly selected for MBL. Only implants not lost
and with baseline radiographs taken within 12 months after implant placement and with a
minimum of 10 years of radiological follow-‐up were considered for MBL. Negative values
correspond to bone loss. The marginal bone around the failed implants was also assessed.
Data collection. The dental records of all patients ever treated with implants in the
aforementioned clinic were read in order to collect the data. The data were directly entered
into a SPSS file (SPSS software, version 23, SPSS Inc., Chicago, IL, USA) as the files were being
read. The following data were collected:
(a) Implant-‐related factors: implant diameter and length;

(b) Site-‐related factors: implant jaw location (maxilla/mandible), anterior or posterior
location of the implant (sites from right canine to left canine teeth were considered anterior
location), and bone quantity and quality of the implant sites, which were classified at the
time of surgery according to the Lekholm and Zarb13 classification;
(c) Patient-‐related factors: patient’s sex, age of the patient at the implant insertion
surgery, general health, and behavioral history. The presence of a medicament list in the
patients’ records was also use to correlate the use of certain drugs to specific health
conditions. Health factors assessed: diabetes types I or II, hypertension,
hypercholesterolemia, hypothyroidism, asthma, chemotherapy, and irradiation of the head-‐
neck region. The patients were also classified according to the intake of the following
medication types: antidepressants, immunosuppressives, bisphosphonates, antithrombotic
agents (antiplatelet, anticoagulant, thrombolytic drugs), hormone replacement therapy in
women, and medicaments to reduce the acid gastric production. Behavioral factors
assessed: smoking habits, use of snuff, bruxism;
(d) Other factors: prescription of antibiotics (the prophylactic antibiotic regimen was
usually starting 1-‐2 hours before surgery and going from 5-‐7 days postoperatively), bone
graft procedures, type of implant-‐supported prosthetic restoration (single crown, partial
bridge with 2-‐6 prosthetic elements, partial bridge with 7-‐10 prosthetic elements, full-‐arch,
overdenture), number of days until failure, and follow-‐up time.
As the standard protocol in the clinic, the patients’ dental hygiene was followed up
by a dental hygienist within 6 months after the final implant-‐supported/retained restoration.
Each patient then attended a dental hygiene recall program based on individual needs.
Marginal bone level evaluation. Reproducible intra-‐oral radiographs were used.
When there were no available digital radiographies from the baseline appointment, the
analogue periapical radiographies were scanned at 1200 dpi (Epson Perfection V800 Photo
Color Scanner; Nagano, Japan). Marginal bone level (MBL) was measured after calibration
based on the inter-‐thread distance of the Nobel implants (0.60 mm). Measurements were
taken from the implant-‐abutment junction to the marginal bone level, at both mesial and
distal sides of each implant, and then the mean value of these two measurements was
considered. MBL was calculated by comparing bone-‐to-‐implant contact levels to the
radiographic baseline examination. The Image J software (National Institute of Health,
Bethesda, USA) was used for all measurements.

Statistical analyses. The mean, standard deviation (SD), and percentage were
calculated for several variables. The Kolmogorov–Smirnov test was performed to evaluate
the normal distribution of the variables, and Levene’s test evaluated homoscedasticity.
Differences between groups were compared with the student’s t-‐test or Mann-‐Whitney test
for continuous variables, depending on the normality. Survival analyses were performed. A
life table was presented with cumulative survival rate (CSR), besides Kaplan-‐Meier analysis.
Correlation and linear regression were performed to check the relationship between MBL
and time of follow-‐up. An implant-‐level model was performed in order to assess the effects
of the implant-‐related and local bone factors on the implant failures, also including health
variables. A generalized estimating equations (GEE) method was used to account for the fact
that repeated observations (several implants) were available for a single patient. All models
were adjusted for clustering of subject and implants in a binary logistic regression model
using GEE with a binomial distribution and a logit link function, while assuming an
exchangeable working correlation structure. Initially a univariate GEE on each of the
variables was performed. In order to verify multicollinearity, a correlation matrix of all of the
predictor variables with a significant odds ratio (P-‐value cut-‐off point of 0.1) identified in the
univariate GEE was scanned, to see whether there were some high correlations among the
predictors. Collinearity statistics obtaining variance inflation factor (VIF) and tolerance
statistic were also performed to detect more subtle forms of multicollinearity. Then a
multivariable model with a forced entry method was used to evaluate the effect of the
factors that were univariately significant (P<0.1) and didn’t present multicollinearity. A Wald
chi-‐square test was used to analyze the statistical significance of each parameter within the
model. The results of the final model were presented as an estimated OR of each significant
prognostic variable (P<0.05). SPSS software version 23 (SPSS Inc., Chicago, IL, USA) was used
for the statistical analyses.

Results
Overall, 642 of 10,096 implants (6.36%) failed. A number of 95 men (405 implants)
and 132 women (640 implants) were followed up for at least 20 years and were included for
analysis in the present study. The patients were followed-‐up for a mean±SD of 291.0±33.7
months (min-‐max, 244.4-‐437.5). These patients received 1,045 threaded implants with a
cylindrical design -‐ 1025 Nobel turned and 20 Astra turned implants. Fifty-‐eight patients

presented 131 implants failures, 116 due to loss/lack of osseointegration and 15 failed
fixtures due to implant fracture. There was a mean of 2.26 failures per patient (min-‐max, 1-‐
9). Failures were recorded for 130 Nobel implants and 1 Astra implant. The failures
happened at a mean±SD of 54.3±67.0 months (min-‐max, 1.2-‐294.7) after implant insertion.
The exact date of failure of 8 implants was not known; these failures were confirmed when
these implants were no longer in place in subsequent radiograms. Nineteen failures
happened before the abutment connection. 499 implants were installed in maxillae, of
which 92 (18.4%) failed (82 due to loss/lack of osseointegration, 10 fractured implants), and
546 implants were placed in mandibles, of which 39 (7.1%) failed (34 due to loss/lack of
osseointegration, 5 fractured implants).
Table 1 shows a comparison of groups according to the distribution of implants with
regard to Lekholm and Zarb13 classification of bone quantity and quality. A greater
percentage of failed implants were placed in bone sites having been classified as quantities D
and E and bone quality 4. Table 2 shows the life table for implant fracture. Thirty-‐five
percent of the occurrences of failed implants occurred within the first year after
implantation. Another 26.8% of the failures occurred in the second and third year after
implant insertion. Thus, 59.3% of all failures occurred at the first three years after
implantation. There was a CSR of 87.8% after 36 years of follow-‐up. Figure 1 shows the
Kaplan-‐Meier analysis. No censored cases were observed before 20 years of follow-‐up, as
only these cases were included in the present study.
All implants were inserted with open flapped surgery and had a delayed loading. Only
5 implants were inserted in fresh extraction sockets. The abutment connection surgery was
performed after a mean±SD healing time of 167±56 days. The mean length of the inserted
implants was 12.4±2.7 mm and the mean diameter for was 3.74±0.09 mm.
Seventy-‐four implants were used for single-‐crown restorations (3 failed due to
loss/lack of osseointegration, 5 fractured implants), 242 implants for fixed partial prostheses
of 2-‐6 prosthetic elements (23 failed due to loss/lack of osseointegration, 4 fractured
implants), 25 implants fixed partial prostheses of 7-‐10 prosthetic elements (7 failed due to
loss/lack of osseointegration, no fractured implants), 666 implants for full-‐arch fixed
prostheses (69 failed due to loss/lack of osseointegration, 6 fractured implants), and 33
implants to support overdentures (9 failed due to loss/lack of osseointegration, no fractured

implants). There was no information for 5 implants concerning the type of prosthodontic
restoration performed.
The univariate GEE model at the implant-‐level showed that the following predictors
had a statistically significant odds ratio at the implant-‐level (Table 3): location, bone quantity
and quality, the intake of antidepressants, irradiation, the intake of medicaments to reduce
the acid gastric production, bruxism, and the type of implant-‐supported prosthetic
restoration. The following factors remained statistically significant in the multivariate GEE
model (Table 4): location, irradiation, and bruxism.
Of the 4,691 implants that were placed until December 31st 1996, and then could
theoretically reach the minimum of 20 years in the year of 2017, 2,762 implants (58.88%)
were placed in patients that were deceased by the first day of the year of 2017. Of these
2,762 implants, 2,402 (86.97%) were placed in patients who died before a hypothetical 20-‐
year follow-‐up. Patient referral to other clinics and other reasons accounted for 884 of the
unaccounted for implants.
With regard to the MBL around the 300 randomly selected implants, all Nobel turned
implants, 1948 measurements were performed, considering the several radiological follow-‐
ups for each implant. This resulted in a mean of 6.5 MBL measurements per implant. Each
MBL measurement consisted of a mean value of mesial + distal measurements. A number of
1032 MBL measurements were performed for the 152 implants in the maxilla and 916 MBL
measurements for the 148 implants in the mandible. The baseline radiograms were taken at
a mean±SD of 7.0±2.4 months (min-‐max, 0-‐12) after implant placement. The implants were
radiologically followed up for mean±SD of 244.8±54.8 months (min-‐max, 127.2-‐350.2). At
the last follow-‐up, there was a mean±SD MBL of -‐1.405±1.504 mm (min, max; -‐7.955, 1.442)
for all implants (n=300). These values at the last follow-‐up were -‐1.391±1.691 mm (min, max;
-‐7.955, 1.442) for implants placed in maxillae (n=152), and -‐1.419±1.289 mm (min, max; -‐
7.128, 0.858) for implants placed in mandibles (n=148). The difference in MBL between
implants placed in different jaws was not statistically significant at the last radiological
follow-‐up (p = 0.176, Mann-‐Whitney test). The last radiological follow-‐up was performed at a
mean±SD of 258.9±54.0 months (min-‐max, 123.1-‐350.2) for implants placed in maxillae and
229.4±52.7 months (min-‐max. 127.2-‐336.8) for implants in mandibles. This difference in the
mean last follow-‐up between different jaws was statistically significant (p < 0.001, Mann-‐
Whitney test).

In the last radiological follow-‐up (Table 5), it was observed that 35 implants (11.7%)
had bone gain (min-‐max 0.010-‐1.442 mm), 109 implants (36.3%) displayed up to 1 mm of
MBL, 84 implants (28%) showed a MBL between 1 and 2 mm, 37 implants (12.3%) a MBL
between 2 and 3 mm, and 35 implants (11.7%) with at least 3 mm of MBL, of which 7
implants (2.3%) presented MBL of more than 6 mm. It is important to stress that these 300
implants randomly selected for MBL measurements were among the implants that were not
lost.
Figure 2 shows a scatter plot of all 1948 MBL measurements, showing that there is an
estimated trend to loss bone with time, reaching 1.98 mm of bone loss 30 years after
implant installation. The linear regression equation (y = -‐0.35 – 0.00453x) estimated a loss of
0.00453 mm of bone for every additional month of follow-‐up. MBL was moderately
associated to the follow-‐up time (R = -‐0.358, R2 = 0.128, p < 0.001, Pearson correlation).
The marginal bone around the 131 failed implants was also assessed. The radiological
follow-‐up protocol at the clinic did not include the register of a radiogram at the implant
placement day, beginning at the abutment connection day only. Thus, it was not able to
evaluate the marginal bone condition around some implants, due to lack of radiograms,
because they failed before the abutment connection (primary failures). In other cases, some
patients received several implants, but the first radiological register of the implants was
carried out only after abutment connection. These cases that presented no radiological
register of the failed fixtures accounted for 37 implants. Then, of the 131 lost implants, 86
implants had available radiograms: 131 total implants – 8 implants with unknown date of
failure – 37 implants without radiograms = 86 implants with radiograms. Twenty-‐six out of
these 86 implants with radiograms presented severe MBL. Figure 3 shows radiograms of
some examples of implants with advanced MBL found in the present study.

Discussion
The results of the present study showed that most of the implant failures occurred at
the first few years after implantation, regardless of a very long follow-‐up. The regression
analysis performed in this study tried to identify the factors that could possibly be related to
implant failure. The univariate regression assessed the relationship between each
independent variable and implant failure separately, and the multivariate regression
assessed the relationship of the variables that were univariately significant to implant

failure, controlling for each other. The negative factors identified by the multivariate GEE
model were implant location, irradiation, and bruxism. The improved survival rate of
implants placed in the anterior mandible in relation to the anterior maxilla may be related to
the usually improved bone quality and greater bone volume found in the anterior mandible,
even years after teeth extraction in this region.14 When it comes to irradiation, it has been
shown that it negatively affects the survival of implants,15 which is mostly related to the
deleterious long-‐term effects of irradiation on the bone vascularization16 and bone-‐healing
capacity,17 compromising the implantation site. Concerning the patients’ habits, bruxism was
shown to significantly affect the implant failure rates negatively, agreeing with the results of
the two very recent clinical trials assessing the effect of bruxism on dental implants.18, 19
Bruxism is suggested to generate overload of prosthetic rehabilitations on implants, which
could possibly cause implant fracture or peri-‐implant marginal bone loss, ultimately resulting
in implant failure.20 Implant fractures noticed in the present study may further be related to
the use of grade 1 titanium which is a less strong material than presently used grade 3-‐4
titanium.
About 12% of the implants in this study displayed more than 3 mm of marginal bone
loss. However, this observation must be balanced against the observation that hexed
Brånemark implants display an average of 1 mm of marginal bone loss already at 1 year of
follow up, although the five year bone loss figures of the same implants indicated a relative
steady state with respect to further bone loss.4 In contrast, implants with internal couplings
instead of hexes only demonstrated an average 5-‐year bone loss of about 0.2 mm.4
Furthermore, an average marginal bone loss of more than 3 mm need not represent disease
or other clinical problems as indicated by Jemt et al.21 These authors followed up what
happened to the allegedly sick implants of the study by Fransson et al.22 who saw 12.4% of
their implants with >2.4 mm of marginal bone loss coupled with bleeding on probing and
increased pocket depths. Fransson´s et al.22 implants were followed up for a median of 12.5
years. Jemt et al.21 reported that 91.3% of the allegedly sick implants of Fransson´s et al.
study22 saw no significant further bone loss another 9.1 years (average) of follow-‐up, i.e. a
total follow-‐up in the 20-‐year range. A total of 95.4% of the implants with progressive bone
loss were still functioning as part of support for dental bridges at 20+ years of follow-‐up.
Based on these figures, it is obvious that one cannot judge disease on a millimeter report of

bone loss. In addition, Coli et al.23 have recently questioned the relevance of using probes as
criteria for disease around oral implants.
Therefore, we have to analyze other reasons than only disease for marginal bone
loss. In a recent paper11 some cases with bone loss were reported to most likely be
dependent on an age-‐related bone loss that may happen around implants as well as teeth.
The number of unaccounted for implants was quite high in the present report.
However, when patients who died or were just referred to other clinics are concerned, these
reasons for drop out are unlikely to skew the present analysis. It must be remembered that
the Malmö clinic originally was the only implant active unit in the region, therefore when
new clinics started with implants at a later time, it was quite natural that those clinics took
over the controls of some patients.
The total failure rate of the Malmö material has been reported to 6.36%. However,
this failure rate is presumably greater in reality since some implants controlled at other
clinics may have failed too. However, overall oral implants fare quite well, despite some of
them seeing marginal bone loss of 3 mm of more. The term peri-‐implantitis indicative of
disease of all implants with marginal bone loss has, to the knowledge of the present authors
not been verified in clinical studies and it seems likely that the future will see improved ways
of looking at the implants with bone loss. Physiological causes have been overlooked as one
reason for bone loss and, furthermore, as described by orthopedic surgeons, some implants
may display stress shielding; i.e. only the amount of bone needed for implant anchorage
remains after long time.

Conclusions
Most of the implant failures occurred at the first few years after implantation,
regardless of a very long follow-‐up. Implants in different jaw locations, irradiation, and
bruxism were the factors suggested to affect the long-‐term survival of implants. Marginal
bone loss can be insignificant in long term observations, but it may, nevertheless, be the
cause of secondary failure of oral implants in some cases.

Acknowledgements
Funding and support: This work was supported by research funds from the Oral Health
Related Research by Region Skåne (Odontologisk Forskning i Region Skåne, OFRS 414321),
Sweden, and from the Scientific Research Council of Sweden (Vetenskapsrådet, Dnr 2015-‐
02971). This work was supported by Folktandvården AB, Region Skåne, Sweden and by
CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil.

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Tables
Table 1. Distribution of implants with regard to Lekholm and Zarb (1985) classification of bone
quantity and quality. The number between parentheses represents failures.

A B C D E Total % %
Group** Failed†
1 8 10 15(2) 60(1) 16(2) 109(5) 10.5 4.6
2 51(5) 162(21) 147(13) 19 19(4) 398(43) 38.1 10.8
3 21 158(18) 185(11) 46(15) 6(2) 416(46) 39.9 11.1
4 2 19(6) 37(7) 35(10) 27(14) 120(37) 11.5 30.8
Total 82(5) 349(45) 384(33) 160(26) 68(22) 1043(131) 100 12.6
% 7.9 33.5 36.8 15.3 6.5 100
Group**
% Failed† 6.1 12.9 8.6 16.3 32.4 12.6
* According to the Lekholm and Zarb (1985) classification, bone quality is broken down into four
groups according to the proportion and structure of compact and trabecular bone tissue: type 1 =
large homogenous cortical/compact bone; type 2 = thick layer of compact bone surrounding a dense
trabecular bone; type 3 = thin cortical layer surrounding a dense trabecular bone; type 4 = thin
cortical layer surrounding a core of low-‐density trabecular bone. The quantity of jawbone is broken
down into five groups (A, B, C, D, and E), based on the residual jaw shape following tooth extraction.
Bone classified as ‘A’ presents the largest amount of bone among all classes, whereas bone classified
as ‘E’ presents the lowest volume of bone.
** Percentage of implants in each bone quantity/quality class, considering all implants as 100%
† Percentage of failed implants for each bone quantity/quality class

Table 2. Life table for implant failure.

Interval Number Number Number Number Proportion Proportion Cumulative
start entering withdrawing exposed of terminating surviving proportion
time interval during to risk* terminal surviving
(years) interval events at end of
(failures) interval
0 1037 0 1037.0 43 .041 .959 .959
1 994 0 994.0 17 .017 .983 .942
2 977 0 977.0 16 .016 .984 .927
3 961 0 961.0 8 .008 .992 .919
4 953 0 953.0 3 .003 .997 .916
5 950 0 950.0 5 .005 .995 .911
6 945 0 945.0 5 .005 .995 .906
7 940 0 940.0 2 .002 .998 .905
8 938 0 938.0 1 .001 .999 .904
9 937 0 937.0 2 .002 .998 .902
10 935 0 935.0 4 .004 .996 .898
11 931 0 931.0 2 .002 .998 .896
12 929 0 929.0 2 .002 .998 .894
13 927 0 927.0 2 .002 .998 .892
14 925 0 925.0 0 0.000 1.000 .892
15 925 0 925.0 3 .003 .997 .889
16 922 0 922.0 4 .004 .996 .885
17 918 0 918.0 0 0.000 1.000 .885
18 918 0 918.0 0 0.000 1.000 .885
19 918 5 915.5 1 .001 .999 .884
20 912 140 842.0 0 0.000 1.000 .884
21 772 112 716.0 1 .001 .999 .883
22 659 137 590.5 0 0.000 1.000 .883
23 522 129 457.5 0 0.000 1.000 .883
24 393 113 336.5 2 .006 .994 .878
25 278 84 236.0 0 0.000 1.000 .878
26 194 48 170.0 0 0.000 1.000 .878
27 146 46 123.0 0 0.000 1.000 .878
28 100 59 70.5 0 0.000 1.000 .878
29 41 23 29.5 0 0.000 1.000 .878
30 18 10 13.0 0 0.000 1.000 .878
31 8 0 8.0 0 0.000 1.000 .878
32 8 3 6.5 0 0.000 1.000 .878
33 5 0 5.0 0 0.000 1.000 .878
34 5 0 5.0 0 0.000 1.000 .878
35 5 5 2.5 0 0.000 1.000 .878
* The exact date of failure was unknown for 8 implants. Therefore, they were not considered here. If
these 8 lost implants were included in the present life table, the CSR would be lower

Table 3. Risk factor analysis using a univariate generalized estimating equations (GEE) logistic
regression model, at the implant-‐level (OR – odds ratio).

Factor Failure/survival* OR (95% CI) P-‐value
IMPLANT-‐RELATED FACTORS
Implant diameter
Increase by 1 -‐ 1.134 (0.045, 28.288) 0.939
Implant length
Increase by 1 -‐ 0.930 (0.835, 1.035) 0.183
SITE-‐RELATED FACTORS
Location
Anterior Maxilla 58/280 1
Posterior Maxilla 34/127 1.546 (0.945, 2.530) 0.083
Anterior Mandible 13/283 0.302 (0.141, 0.647) 0.002
Posterior Mandible 26/224 0.579 (0.306, 1.096) 0.093
Bone quantity
A 5/77 1
B 45/304 1.564 (0.315, 7.758) 0.584
C 33/351 1.743 (0.367, 8.269) 0.484
D 26/134 2.788 (0.567, 13.714) 0.207
E 22/46 8.079 (1.624, 40.194) 0.011
Bone quality
1 5/104 1
2 43/355 2.369 (0.556, 10.097) 0.244
3 46/370 1.805 (0.445, 7.319) 0.409
4 37/83 7.048 (1.690, 29.387) 0.007
PATIENT-‐RELATED FACTORS
Gender
Male 62/343 1
Female 69/571 0.672 (0.359, 1.258) 0.214
Age
Increase by 1 -‐ 0.998 (0.980, 1.015) 0.781
Diabetes
No 102/568 1
Type I 0/0 -‐
Type II 12/64 1.080 (0.393, 2.970) 0.882
High blood pressure
No 83/418 1
Yes 31/228 0.734 (0.363, 1.484) 0.390
High cholesterol
No 93/512 1
Yes 21/114 1.196 (0.514, 2.780) 0.678
Hypothyroidism
No 109/580 1
Yes 5/46 0.605 (0.153, 2.391) 0.474
Asthma
No 101/577 1
Yes 13/61 1.339 (0.452, 3.965) 0.598
No 79/570 1
Yes 35/58 3.874 (1.381, 10.866) 0.010

Irradiation
No 112/625 1
Yes 2/3 4.255 (2.996, 6.043) <0.001
No 117/744 1
Yes 9/22 2.111 (0.641, 6.956) 0.219
Gastric
No 90/556 1
Yes 24/62 2.917 (1.161, 7.324) 0.023
Antithrombotics
No 77/461 1
Yes 38/169 1.499 (0.743, 3.025) 0.258
Immunosuppressive
No 111/612 1
Yes 3/10 1.513 (0.277, 8.246) 0.632
Bisphosphonates
No 113/610 1
Yes 1/18 0.283 (0.048, 1.676) 0.164
Smoking
No 65/405 1
Yes 42/164 1.397 (0.630, 3.096) 0.411
Former smoker 3/11 3.616 (0.618, 21.152) 0.154
Cigarettes/day
Increase by 1 -‐ 1.028 (0.983, 1.074) 0.229
Snuff
No 106/567 1
Yes 4/13 1.356 (0.309, 5.953) 0.687
Bruxism
No 79/583 1
Yes 37/50 4.414 (1.840, 10.590) 0.001
OTHER FACTORS
Antibiotics
No 12/87 1
Yes 51/358 0.754 (0.298, 1.908) 0.551
Bone grafting
No 100/864 1
Yes 31/50 2.753 (0.753, 10.062) 0.126
Single crown 8/66 1
Partial fixed, 2-‐6 27/215 1.007 (0.347, 2.921) 0.990
units
Partial fixed, 7-‐10 7/18 2.192 (0.371, 12.966) 0.387
units
Full-‐arch fixed 75/591 1.033 (0.387, 2.755) 0.948
Overdenture 9/24 4.686 (1.185, 18.528) 0.028
* The information for some conditions is unknown for a variable number of implants

Table 4. Multivariate generalized estimating equations (GEE) logistic regression model at the implant-‐
level. Only the factors that were considered statistically significant (P < 0.1) in the univariate model
and didn’t present multicollinearity were included in the multivariate model (OR – odds ratio).

Factor OR (95% CI) P-‐value
Location
Anterior Maxilla 1
Posterior Maxilla 1.388 (0.784, 2.458) 0.260
Anterior Mandible 0.264 (0.109, 0.643) 0.003
Posterior Mandible 0.488 (0.232, 1.030) 0.060
Bone quantity
A 1
B 1.455 (0.392, 5.407) 0.575
C 1.078 (0.281, 4.142) 0.913
D 1.828 (0.435, 7.677) 0.410
E 3.412 (0.605, 19.241) 0.164
Bone quality
1 1
2 1.228 (0.318, 4.744) 0.766
3 0.713 (0.177, 2.878) 0.635
4 1.335 (0.285, 6.267) 0.714
No 1
Yes 2.578 (0.813, 8.175) 0.108
Irradiation
No 1
Yes 13.560 (6.058, 30.354) <0.001
Gastric
No 1
Yes 2.097 (0.685, 6.416) 0.194
Bruxism
No 1
Yes 2.800 (1.012, 7.748) 0.047
Single crown 1
Partial fixed, 2-‐6 1.592 (0.448, 5.660) 0.473
units
Partial fixed, 7-‐10 0.520 (0.051, 5.315) 0.582
units
Full-‐arch fixed 1.788 (0.456, 7.016) 0.405
Overdenture 1.631 (0.314, 8.467) 0.561

Table 5. Marginal bone condition around 300 non-‐failed implants at the last radiological follow-‐up
(mean of 244.8 months).

Marginal bone condition Number of implants (%)
Bone gain (0.010 – 1.442 mm) 35 (11.7%)
Bone loss up to 1 mm 109 (36.3%)
Bone loss between 1 and 2 mm 84 (28.0%)
Bone loss between 2 and 3 mm 37 (12.3%)
More than 3 mm of bone loss 35* (11.7%)
* Seven (2.3% of the total number of implants) out of these 35 implants
presented MBL of more than 6 mm

Figures

Figure 1. Kaplan-‐Meier curve.

Figure 2. Scatter plot of 1948 marginal bone loss (MBL) measurements of 300 implants. The line
represents the estimated MBL along the years of observation, according to the linear regression.

Figure 3. Examples of cases of severe MBL around implants that were eventually lost or fractured.

isbn 978-91-7104-766-3 (print)
isbn 978-91-7104-767-0 (pdf)
MALMÖ UNIVERSITY
205 06 MALMÖ, SWEDEN
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BRUNO CHRCANOVIC

DOCTOR AL DISSERTATION IN ODONTOLOGY

© Bruno Chrcanovic 2017

Malmö University, 2017

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31. Pia Bolind DDS, 2004. On 606 retrieved oral and

32. Patricia Miranda Burgos DDS, 2006. On the influence of

33. Jonas P. Becktor DDS, 2006. On factors influencing the

34. Anna Göransson DDS, 2006. On Possibly Bioactive CP

35. Andreas Thor DDS, 2006. On platelet-rich plasma in

37. Pär-Olov Östman DDS, 2007. On various protocols for direct

38. Kerstin Fischer DDS, 2008. On immediate/early loading of

39. Alf Eliasson 2008. On the role of number of fixtures, surgical

40. Victoria Fröjd DDS, 2010. On Ca2+ incorporation and

41. Lory Melin Svanborg DDS, 2011. On the importance of

42. Byung-Soo Kang MSc, 2011. On the bone tissue response to

43. Kostas Bougas DDS, 2012. On the influence of biochemical

45. Ramesh Chowdhary DDS, 2014. On efficacy of implant

46. Anders Halldin MSc, 2015. On a biomechanical approach

47. Francesca Cecchinato MSc, 2015. On magnesium-modified

48. Jonas Anderud DDS, 2016. On guided bone regeneration

49. Silvia Galli DDS, 2016. On magnesium-containing implants

50. Bruno Chrcanovic DDS MSc, 2017. On Failure of Oral

Materials and Methods

Results and Conclusions

Material och metodik

Resultat och Diskussion

This dissertation is based on the following papers, which will be

I. Chrcanovic BR, Albrektsson T, Wennerberg A. Reasons for

II. Chrcanovic BR, Albrektsson T, Wennerberg A. Smoking

III. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.

IV. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.

V. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.

VII. Chrcanovic BR, Kisch J, Albrektsson T, Wennerberg A.