Fiorillo et al.

BMC Oral Health (2022) 22:291

https://doi.org/10.1186/s12903-022-02330-y

RESEARCH Open Access

Impact of bisphosphonate drugs on dental

implant healing and peri‑implant hard and soft
tissues: a systematic review
Luca Fiorillo1,2 , Marco Cicciù1* , Tolga Fikret Tözüm3 , Cesare D’Amico1 , Giacomo Oteri1    and
Gabriele Cervino1   

Abstract
Objective: Implantology represents the gold standard for oral rehabilitation, unfortunately, often, despite there are
no local contraindications to this type of rehabilitation, there are uncertainties regarding the general health of our
patients. Many patients nowadays take bisphosphonate drugs, often without first seeking advice from an oral sur-
geon or a dentist. The purpose of this review is precisely to highlight any contraindications to this type of treatment
reported in the literature, in patients who take or have taken bisphosphonate drugs.
Methods: For this study the scientific information sources were consulted using as search terms “(“bisphosphonate
AND “dental implant”)”, obtaining 312 results, these were subsequently skimmed according to the inclusion and exclu-
sion criteria, and further evaluated their relevance to the study and the presence of requested outcomes.
Results: Only 9 manuscripts (RCTs, Multicentric studies and Clinical Trials) were included in this review, as they
respected the parameters of this review, they were analyzed and it was possible to draw important results from them.
Surely from this study it is understood that the use of bisphosphonate drugs does not represent an absolute con-
traindication to implant therapy, it is evident how adequate pharmacological prophylaxis, and an adequate protocol
reduce the risks regarding implant failures. Furthermore, the values of marginal bone loss over time seem, even if
not statistically significant, to be better in implant rehabilitation with bisphosphonate drugs association. Only a few
molecules like risedronate, or corticosteroids, or some conditions like smoking or diabetes have shown a high risk of
surgical failure.
Conclusion: Although this study considered different studies for a total of 378 patients and at least 1687 different
dental implants, showing better results in some cases for dental implant therapy in cases of bisphosphonate intake,
further clinical, randomized and multicentric studies are needed, with longer follow-ups, to fully clarify this situation
which often negatively affects the quality of life of our patients and places clinicians in the face of doubts.
Keywords: Dental implant, Bisphosphonate, Osteoporosis, Osseointegration, Oral surgery, Bone tissue

Introduction
Rationale
Implantology is a rehabilitation procedure aimed at
*Correspondence: [email protected] those who have lost their natural teeth through the
1
Department of Biomedical and Dental Sciences, Morphological use of titanium fixture. Artificial teeth are designed to
and Functional Images, University of Messina, Via Consolare Valeria, 1, replace real teeth that are missing both in terms of aes-
98100 Messina, Italy thetics and chewing function. State-of-the-art dental
Full list of author information is available at the end of the article

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Fiorillo et al. BMC Oral Health (2022) 22:291 Page 2 of 12

implantology techniques, such as those practiced in Objectives

dental clinics, allow permanent rehabilitation of chew- The purpose of this systematic review is to analyze litera-
ing and avoid the hassles associated with the use of ture to understand the impact of Bisphosphonate drugs
removable prostheses, ensuring an aesthetic result on dental implant therapy, with the aim to evaluate dif-
equal to that of natural teeth [1, 2]. ferent clinical and radiographic outcomes reported in
In very general, dental implant surgery consists literature. The type of studies that were taken under con-
of placement of a titanium dental implant into the sideration included: studies with test and control groups,
bone of the affected dental arch with the aim of bone Randomized Controlled Trials (RCTs), Controlled Trials
integration (osseointegrated implantology).Usu- and Multicentric studies, which evaluated the clinical
ally, the implant integration time varies according to differences between patients rehabilitated with dental
the affected bone: maxilla (4–6 months); mandibular implants who take these drugs or less, were included.
(3–4 months) [3, 4]. This manuscript that brings together different clinical
There are several factors effecting the estimated heal- studies and evaluates different outcomes, aims to clarify
ing time by the implantologist, that can slow down this therapy in certain patients, providing a contribution
osseointegration [5]. Complete osseointegration of where currently the literature appears conflicting.
dental implants is successful in the vast majority of
cases. International studies based on the scientific and Materials and methods
rigorous evaluation of over 1,200,000 implants have Eligibility criteria
indicated that the average success rate is over 98%. For The inclusion criteria are as follows:
smokers, the success rate drops to 85% [6]. The implan-
tology intervention is one of the practices related to • Recent studies (last 15 years), to avoid the risk of run-
oral surgery, and represents a surgical intervention on ning into drugs that are no longer used and safe.
the hard and soft tissues of the maxillary bones [7, 8]. • Human studies
Systemic or general contraindications, on the other • Studies on subjects with no other absolute contrain-
hand, have to do with the patient’s systemic health and dications to implant therapy
any pharmacological or radiation therapies. Among • Studies concerning completed implant-prosthetic
these, one that jumps to attention and that is often therapy
underestimated during a first dental visit is the current • Studies which are present and legible or accessible:
or past intake (considering their half-life) of bisphos- title-abstract-full text.
phonate drugs. Bisphosphonates are a category of drugs
that inhibit bone remodeling, which is why they are
used for the treatment of various metabolic and onco- Information sources
logical disorders, affecting bone tissue; osteoporosis, The research sources are the most common and reliable
osteopenia, osteogenesis imperfecta, Paget’s disease, scientific research channels according to the scientific
multiple myeloma, malignant hypercalcemia and bone community:
metastases following cancer [9, 10].
Bisphosphonates are very effective drugs that reduce Scopus Elsevier®
Web of Science®
•
the incidence of fractures, as they increase bone den-
Google Scholar®
•
sity. They have the characteristic of binding to cal-
Pubmed®
•
cium and for this reason they are deposited in the
MDPI® database
•
bone tissue. Bisphosphonates can cause bone lesions •
of the maxilla and/or jaw associated with local signs
and symptoms of various types and severities, such as
ulceration of the oral mucosa that lines the bone, expo- Search strategy Selection process
sure of bone in the oral cavity, pain in the teeth and/ The search strategy planned to insert the following word
or to the jaw/jaw bones, swelling or inflammation, string in the information sources, according to the previ-
numbness or a feeling of ’heavy jaw’, increased tooth ous paragraphs:
mobility, tooth loss [11]. Before undertaking any surgi-
cal-implant therapy, it is necessary to acquire and ana- "(biphosphonate) AND (dental implant)".
lyze a complete medical history of the patient and, in Thanks to the filters of the sources of scientific
the case of the presence of bisphosphonate therapy, the information, it is possible to perform a quick screen-
duration of treatment must be confirmed, as well as the ing of the results so as to reduce the work by the indi-
route of administration of the same. vidual authors in case there are manuscripts not of
Fiorillo et al. BMC Oral Health (2022) 22:291 Page 3 of 12

interest with the topic. Some of the filters that were Study risk of bias assessment
used included considering recent studies (15 years), The risk of bias was assessed according to the studies
human studies, clinical studies (RCTs, Multicentric, and method proposed by Cochrane and Higgins et al.
Clinical Trials). These filters have been applied to all (RoB 2) [16–21].The risk of bias between the studies
used information sources engines. was assessed, in addition, as there were randomized
Furthermore, recent works were considered, in clinical trials, the level of bias within the individual
accordance with inclusion and exclusion criteria, and studies was assessed.
only some types of studies were selected, using the The analysis of the citations was carried out with the

vier® as a search engine. The pre and post index differ-

filters already present in the scientific information Fi-index Tool [22] on the first author using Scopus Else-
sources.
Subsequently, once the studies were obtained, they ence result is 0.35, low and tolerable given the inherence
were subjected to a first screening through independ- of the citations and the line of scientific research.
ent reading by the authors of "title" and "abstract",
and then the full text was read (logically, if they were
not discarded earlier as they did not meet the inclu- Synthesis methods
sion criteria already when reading "title" or "abstract"). The studies were read by the authors individually and
Authors independently analyzed results with this pro- were subsequently discussed and analyzed, each author
cess: Title-Abstract-Full text reading. created tables and cards with the main results of all the
The revision method is in accordance with the articles included, these were reviewed and are exposed in
PRISMA statement, with methodology and subdivi- the "results" and "discussion" sections. The synthesis was
sion in the manuscript according to their parameters, done manually by the authors, any doubts were clarified
as well as with the presence of the PRISMA flow chart by a third expert author (G.C.).
[12–14].
This review is registered at PROSPERO with ID num-
ber 342214 with date 25/06/2022. PROSPERO is an Results
international database of prospectively registered sys- Study selection
tematic reviews in health and social care. The studies taken into consideration are the result of
As regards the identification of the study objective, he a careful analysis by the authors. From a first survey on
also made use of the PICO—Population Intervention scientific search engines, as explained in paragraph 3.2,
Comparison Outcome system [15], with the following 312 works were obtained. In this case there are studies
question: dating back to 1978. Only the Randomized Controlled
Does implant therapy have different outcomes in Trial (RCT), Multicentric studies and Clinical Trial stud-
patients who undergo bisphosphonate drug therapy ies are taken into consideration, obtaining a number of
than in patients who do not take bisphosphonates? 273 results. Following an analysis of the results, by first
reading titles and abstracts, and in the event of uncer-
and as additional questions:
tainty of the full text by two independently authors, the
What about clinical and radiographical outcomes of results selected and compatible with the review criteria
dental implant therapy (paragraph 2.4)? are 9. According to the review method used (see Materi-
als and Methods section), the PRISMA flow chart (Fig. 1)
is presented. Some examples of the studies that were
Data items collected through the keywords by the use of scientific
The outcomes considered are all those extrapolated search engines, but that were excluded after an analysis
from the individual articles as outcomes: by the authors are these: Aspenberg et al. [23] study, was
about implant used for hip fracture and not about den-
• Bleeding on Probing (BoP); tal implant; Meidan et al. [24] paper was about the use
• Probing Depth (PD); of technetium 99 m-methylene diphosphonate scintigra-
• Mobility of dental implant; phy for the clinical evaluation of peri-implant tissue, and
• Thread exposure (TE); not correlated to bisphosphonate therapy and new dental
• Bone Marginal loss; implants insertion; Trbakovic et al. [25] manuscript was
• implant stability quotient (ISQ); about the use of granular calcium phosphate compound
• Bone mineral density (BMD); and a composite bisphosphonate-linked hyaluronic acid-
• Implant survival; calcium phosphate hydrogel in a rabbit model for bone
• Soft tissue condition. regeneration.
Fiorillo et al. BMC Oral Health (2022) 22:291 Page 4 of 12

Fig. 1 PRISMA flow chart

Study characteristics Results of individual studies

The main characteristics of the selected studies are The results present in these selected studies will be listed
included in Table 1 below respecting the following below in Table 2 and divided as follows (Table 2):
parameters (Table 1):
• Authors—Authors of the single study
• Authors—Authors of the single study • Sample size—Sample size of the study
• Year—Year of publication of the study • Type of groups—subdivision of the groups and type
• Type of study—Article type • Main outcomes results—principal data results of the
• Control Group—Describe the presence of a control study (separated by semicolon)
group and type • Statistic—statistical data (respectively to “Main out-
• Follow-up—follow up time duration comes results" and separated by semicolon)
Fiorillo et al. BMC Oral Health (2022) 22:291 Page 5 of 12

Table 1 Studies characteristics

Authors Year Type of study Methodology Control group Follow up

Abtahi et al. [26] 2019 RCT​ Double-blind, split-mouth Uncoated zoledronate dental implant 8 weeks
Abtahi et al. [27] 2016 RCT​ Double blind, split-mouth Uncoated zoledronate dental implant 5 years
Tallarico et al. [28] 2016 Multicentric Study – – 3 years
Zuffetti et al. [29] 2015 RCT​ Split-mouth No topical administration of bisphosphonate 1 year
Mozzati et al. [8] 2015 Clinical Trial – – 10 years
López-Cedrún et al. [32] 2013 Multicentric Study – – 3 years
Griffiths [33] 2012 RCT​ Split-mouth No bisphosphonate oral administration 18 months
Abtahi et al. [34] 2012 RCT​ Double-blind, split-mouth Uncoated zoledronate dental implant 6 months
Shabestari et al. [35] 2010 Multicentric Study – – 5 years

Results of syntheses et al. [8] realized a very large sample size study about
In Abtahi et al. [26] study, zoledronate coated vs this topic. They evaluated more than 200 patients with
uncoated dental implants were compared. These two oral bisphosphonate therapy and inserted more than
types of implants were indistinguishable by a blinded 1000 dental implants after a standard antibiotic prophy-
operator. A total of 30 dental implants in 16 patients were laxis [31]. During 24 months follow-up, there were no
placed. Implant stability values were constant over fol- BRONJ (Bisphosphonate related osteonecrosis of the
low-up time, with no statistical differences. About blind jaw) cases. 16 dental implants failures were recorded on
qualitative scoring, 13 of the 15 control implants and 16 different patients with absence of infection but rep-
two of 15 coated implants showed small marginal bone resented by mobility. Authors, so highlighted patients
defects. A second study of Abtahi et al. [27] evaluated risk factors related to a specific bisphosphonate therapy
the same patients with 5 years of follow-up. Marginal (risedronate) and other patients-related features as dia-
bone loss increased over time in both groups, but results betes, corticosteroid therapy or smoking. Furthermore,
were satisfactory for test group. For example, at 5 years regenerative surgery maneuvers or post-extractive
the bisphosphonate coated dental implants performed a dental implant surgery seems to represent a risk fac-
0.20 mm of marginal bone loss vs 0.70 of median value tor. López-Cedrún et al. [32] with their multicentric
for dental implants in control group. Unfortunately, 2 studies evaluated 9 patients with BRONJ associated to
patients died at 5 years follow up, so there are 4 dental dental implants. Most of cases interested the poste-
implants missing (Table 3). rior mandible with the presence of pain and swelling,
Tallarico et al. [28] study evaluated the effect of den- with suppuration in other cases. The bone exposition
tal implant surgery on bisphosphonate administered was present, with radiolucent lesions at radiographi-
patients. After a pharmacological prophylaxis 98 dental cal examination too. The treatments consisted of den-
implants were inserted (Table 4). tal implant removal and bone sequestrectomy. Griffiths
Only one of 98 dental implants failed during the heal- [33] in his pilot study, evaluated the differences in Bone
ing period in < 90 years old patients, and no other den- Mass Density (BMD) around dental implants in patients
tal implants or prosthetic failures or complications who performed a therapy with oral bisphosphonates at
occurred during follow-up period. 155 dental implants time of dental implant surgery or after dental implant
in 39 patients were placed in Zuffetti et al. [29] study. surgery. He performed CT scans and evaluated BMD
These patients were fully or partially edentulous. Pros- with Hounsfield (HU) unit scale. A less evident decreas-
thetic phase started 10 weeks after dental implant ing trend in BMD surrounding an implant when alen-
insertion, two groups were subdivided: test and con- dronate was administered for 6 months after the
trol groups. Test group was characterized by a 3% chlo- implant had successfully undergone osseointegration
dronate solution mixed with a surfactant (Tween-20) for 6 months. Abtahi et al. [34] in their oldest study
at a 1:3 ratio topically administered both at the implant (2012), already evaluated the effect of bisphosphonate
surface and at the implant preparation bone site [30]. A coated dental implants on bone tissue. In this case,
total of 6 dental implant failed in control group vs zero dental implants were placed in a chamber, and then
in test group. Furthermore, results showed better results baked at 60 °C until 150 °C. This process took to have a
in test group than in control group regards: Implant cross-linked layer of fibrinogen with small amounts of
survival, bone marginal loss and complications. Mozzati pamidronate and ibandronate covalently bound to the
Table 2 Selected study individual results
Authors Sample size Type of groups Main outcomes results Statistic

Abtahi et al. [26] 32 dental implants on 16 patients 1. Zolendronate coated dental implant 0.17 mm of marginal bone loss between P < 0.006
groups
2. Uncoated dental implant No implant stability differences
Fiorillo et al. BMC Oral Health

Abtahi et al. [27] 32 dental implants on 16 patients 1. Zolendronate coated dental implant Marginal bone loss difference between P = 0.04
groups at 18 month was 0.50 mm
2. Uncoated dental implant Marginal bone loss difference between P = 0.04
groups at 5 years was 0.34 mm
Tallarico et al. [28] 98 dental implants in 32 patients 1. Dental implants in 6 month alen- Dental implant success 98%; Prostheses Differences on 1, 2 o 3 years of follow up
dronated administration stopping patients success 98%; Survival rate 100%; Median P = 0.059
(2022) 22:291

marginal bone loss 1.35 mm; No differ-

ences between 1, 2 and 3 years of follow
up on marginal bone loss Soft peri-implant
tissue with positive parameters;
Zuffetti et al. [29] 155 dental impla ts in 39 patients 1. Standard dental implant procedure Dental implant survival was 100% in test P = 0.001
group and 91.3% in control group
2. Standard dental implant procedure + a Marginal bone loss of 0.85 mm in test P = 0.15
3% chlodronate and surfactant solution group and 1.12 mm in control group after
rinse both at the implant surface and one year
implant site Marginal bone loss of 0.98 mm in test P = 0.15
group and 1.26 mm in control group after
5 years
Mozzati et al. [8] 1267 dental implants on 235 patients 1. Oral bisphosphonate administred Dental implant failure rate of 6.8% –
patients
López-Cedrún et al. [32] 57 dental implants on 9 patients 1. Oral bisphosphonate administred – –
patients
Griffiths [33] 10 patients 1. Standard dental implant procedure Bone mineral density (BMD) evaluation –
2. Standard dental implant procedure with was lower in oral bisphosphonate patients
70 mg tablet or placebo of alendronate
weekly for 6 months
Abtahi et al. [34] 32 dental implants on 16 patients 1. Pamidronate and ibandronate coated Dental implant success rate of 100%; 100%
dental implant Larger implant stability quotient (ISQ) for
bisphosphonate coated dental implant at
6 months
2. Uncoated dental implant Bone marginal loss was higher in non- P = 0.0001; P = 0.003
coated dental implants at 6 months
Shabestari et al. [35] 46 dental implants in 21 patients 1. Dental implant surgery in patients that Bleeding on Probing (BoP); Probing Depth Not significant differences between groups
started oral bisphosphonate therapy after (PD) in all outcomes (P < 0.05)
healing
2. Dental implant surgery in patient who Mobility; Thread exposure (TE)
undergone oral bisphosphonate therapy
Page 6 of 12
Fiorillo et al. BMC Oral Health (2022) 22:291 Page 7 of 12

Table 3 Abtahi et al. [26, 27] studies dental implants bone marginal loss between groups

X axis: bone marginal loss in mm; y axis: follow up time in months

Table 4 Tallarico et al. [28] dental implant surgery prophylaxis in bisphosphonate patients

6 months before surgery Suspension of the BPs before surgery and if possible after surgery Professional hygiene
7 days before and after surgery Amoxicillin and clavulanic acid, 1 tablet every 12 h (2 g for day) Metronidazole 250 mg; 2
tablets every 8 h (1.5 g for day) Chlorhexidine gluconate 0.2% (oral rinse)
Day surgery Oral rinse with chlorhexidine gluconate 0.2% for 1 min Flapless or mini-flap approach
Copious irrigation during implants sites preparation Two-stage implants placement
Post-surgical Ibuprofen 600 mg every 8 h for 2 days (later on if needed) Periodic (3–6 months) follow-up

titanium surface. They did not lose dental implants dur- Reporting biases
ing follow-up time and there were no surgical complica- The bias of the studies included in the review was
tions. According to Authors, the bisphosphonate coated assessed according to what is described in the materials
dental implants showed a larger increase in ISQ value, and methods section.
as showed in Table 2. Marginal bone loss, showed better Below, Table 6 further clarify the results of the risk of
results in bisphosphonate coated implants vs uncoated bias present, that could be defined as low.
ones (Table 5). Shabestari et al. [35] in their multicentric
study, evaluated the effect and some survival parame- Certainty of evidence
ters of dental implant surgery in two different groups of Table 5 reports important data regarding changes in
patients (Table 2). They did not show any differences on marginal bone levels around implants "associated" with
BoP, PD or TE between the group that received dental bisphosphonate drugs. Somehow it is possible to easily
implants during bisphosphonate therapy and the group identify a trend from this chart. Certainly, the marginal
who became bisphosphonate therapy after healing. No bone loss around dental implants, just like teeth, is con-
one of the implants showed mobility and all patients stant and progressive, and is defined by the recent con-
were considered peri-implantitis free. According to sensus conferences as approximately 0.1 mm per year
Shabestari et al. [35], implant location, the presence of [36]. However, already from Table 3 it is possible to high-
opposing dentition, or prosthetic rehabilitation type light differences between implants coated with bisphos-
had no influence on clinical and radiological parameters phonates and uncoated implants. This suggests that in
after dental implant surgery in BP patients. Authors fol- some way the effect of these molecules contrasts bone
lowed-up a disomogeneous group of patients for 5 years resorption, even in this clinical condition. In Table 5 all
in some cases after implant insertion. the studies that took into consideration the marginal
Fiorillo et al. BMC Oral Health (2022) 22:291 Page 8 of 12

Table 5 Bone level changes on dental implants affected by bisphosphonates

X axis: marginal bone levels variations in mm; Y axis: time in months. Data sources have been specified

Table 6 Risk of bias definition

Abtahi Abtahi Tallarico Zuffetti Mozzati López- Griffiths [33] Abtahi Shabestari
et al. et al. et al. [28] et al. et al. [8] Cedrún et al. et al. [35]
[26] [27] [29] et al. [32] [34]

Random Sequence generation + + − + − − + + −

Allocation concealment + + + + + + + + +
Blinding of participants and personnel + + − − − − − + −
Blinding of outcome data + + − − − − − − −
Selective reporting + + + + + + + + +
Other bias + + + + + + − + +

bone has been included, thus obtaining a homogeneous actually, in the logarithmic trend line, show superimpos-
graph of results, which compared over time, show a trend able results. By carrying out a paired t-test with two sam-
and overlapping values. Logarithmic trend lines were also ples, and inserting the values, in fact has been noticed
drawn, which somehow follow the results obtained by that the result is not statistically significant. The two-
the individual authors, but show what could be the pro- tailed P value equals 0.1483. By conventional criteria, this
gression over time. Furthermore, in Table 7 below, those difference is considered to be not statistically significant.
trend lines up to 15 years have been projected to under-
stand how limited bone loss could be on implants, associ- Discussion
ated in some way with therapy with these drugs. According to Abtahi et al. [26] there are no statistical
In this case (Table 6), the mean values of all studies differences between the use of bisphosphonate coated
with implants associated with bisphosphonate drugs dental implant or uncoated ones during the early heal-
were considered, admitting the missing values as 0. In the ing phase. Uncoated dental implants just presented
graph about dental implants not related to bisphospho- more marginal bone loss than test group. Another
nates, on the other hand, the parameter of 0.1 mm per study of Abtahi et al. [27] with 5 years of follow up,
year of bone loss was set. It is necessary to clarify that concludes that bisphosphonate coated dental implant
by "associated" with bisphosphonates it means either a could prolong preservation of the peri-implant mar-
patient undergoing drug therapy or an implant coated ginal bone. Tallarico et al. [28] reported that bisphos-
with these molecules. The data after 10 and 15 years phonate therapy in patients did not significantly affect
Fiorillo et al. BMC Oral Health (2022) 22:291 Page 9 of 12

Table 7 Trend lines regarding bone marginal loss on implants "associated" with bisphosphonates and non "associated" implants

X axis: median bone marginal loss, Y axis: time in months

implant survival and prosthetic rehabilitation success the study had a big limitation, represented by a limited
rate. Authors specify that an accurate treatment time pool of patients and furthermore not all patients com-
selection and a minimally invasive surgical approach pleted the same follow-up time.
are required. Zuffetti et al. [29] showed how topical Bisphosphonates are stable molecules analogous to
administration of bisphosphonate drugs could posi- inorganic pyrophosphates and have been shown to be
tively affect dental implants survival and pre and post effective in the treatment of osteolytic lesions associ-
loading phases. Mozzati et al. [8] reported no cases ated with bone metastases, multiple myeloma, malig-
of BRONJ after dental implant surgery in oral bis- nant hypercalcemia, Paget’s disease and osteoporosis.
phosphonate treated patients, these procedures so, Several publications in recent years have suggested that
could be safely done but attention to techniques that osteonecrosis of the jaw is associated with bisphospho-
enhance and support healing as platelet concentrates. nate therapy. Strategies for diagnosing and managing
López-Cedrún et al. [32] in their study, showed how patients with bisphosphonate-induced osteonecrosis of
dental implant associated BRONJ have similar clinical the jaw are very difficult. It is important for patients to
features and outcomes of treatments of those seen in be informed of the risk of this complication, so that they
patients with BRONJ with no dental implants. Lesions have the opportunity to assess the need for dental treat-
may develop in early or late phase of dental implant or ment before starting therapy [37]. If osteonecrosis of the
prosthetic rehabilitation. Griffith [33] concluded that jaw is present, management should be conservative: oral
bisphosphonate could suppress regional phenomenon chlorhexidine and antibiotics. Surgical treatment should
related to healing if patients take these drugs before be reserved for those patients who are symptomatic.
and at time of implant surgery, but these drugs could Preventive therapeutic measures must be taken before,
have positive effects after 6 months under normal con- during and after bisphosphonate treatment, as stated in
ditions. Abtahi et al. [34] already in 2012, suggested the guidelines. Currently, it is a well-known fact that this
that a thin bisphosphonate fibrinogen coating, could type of BP molecules is in some way connected to bone
improve the osteointegration of dental implants in the necrosis, which is mostly seen in the jaws. This is a rare
human bone. Surely, according to authors, this could complication but, obviously, of considerable severity
open new possibilities in orthopedic surgery, through and difficult to treat. Bisphosphonates have a high affin-
osteoporotic bone and dental rehabilitation. Still many ity for bone tissue, in particular they act by inhibiting the
issues about bisphosphonate-associated osteonecrosis activity of osteoclasts. The result will obviously be the
remain unclear, according to Shabestari et al. [35], this reduction of bone matrix resorption. Although osteone-
multicentric study did not show correlation between crosis has so far been reported mainly in patients under-
this pathology and dental implant surgery. However, going intravenous administration of bisphosphonates, an
Fiorillo et al. BMC Oral Health (2022) 22:291 Page 10 of 12

increasing number of cases are reported among patients analyze a complete medical history of the patient and in
undergoing oral bisphosphonates for the treatment of the case of the presence of bisphosphonate therapy, the
osteoporosis or Paget’s disease. The first reported cases duration of treatment must be confirmed, as well as tak-
of osteonecrosis of the jaws associated with bisphospho- ing into consideration the route of administration of the
nate therapy date back to 2003 [11]. Osteonecrosis of the itself.
jaw or jaw is a disabling disease of a progressive nature
and with little tendency to healing. The onset signs are Limitations
very subtle and extremely variable and range from gum The main limitation of this study is that the result repre-
inflammation that does not heal, to the loss of a tooth, sented was not retrieved directly from analysis of clinical
to the slow or non-healing of an extraction, to a peri- cases, but the data was extrapolated from different stud-
odontitis picture, to the presence of dental abscesses or ies which showed a scarce diversity of protocols among
fistulas in the mouth or externally, on the skin. The dental them, such as types of surgeries, year of publication, and
approach is fundamentally based on prevention and cer- type of drug taken by the patient. Unfortunately, even the
tainly on the direct relationship with the other specialists outcomes of the individual studies are not easily super-
involved in patient management. In the event that some imposed and it was not possible to conduct a meta-anal-
oral surgery interventions are necessary and cannot be ysis. All the single outcomes have been reported in the
postponed, the dentist decides under close advice and Table 2 with the corresponding statistical result. Only
collaboration with the specialist doctor how to proceed the overlapping outcomes were subjected to further sta-
for the treatment of infection, pain, in order to reduce/ tistical analysis. Despite the use of different sources of
avoid the risk of osteonecrosis. adopting specific treat- scientific information, often some manuscripts can be
ment protocols and using fewer traumatizing techniques excluded from the filters of electronic search engines. It
for the tissues. Any dental extraction or surgical proce- is also always important to bear in mind that some manu-
dure should be completed before the start of bisphospho- scripts may present different keywords, incorrect or not
nate therapy, taking into account the time required for in accordance with the Medical Subject Headings (Mesh)
healing. The risk/benefit profile should be considered for word.
each patient before starting chronic therapy and in cases
where there are local or systemic risk factors for oste- Conclusions
onecrosis of the jaw, the possibility of alternative estro- Thanks to this study it is possible to clarify the effects
gen therapy should be considered, such as in patients of these molecules on the bone, during and after the
with postmenopausal osteoporosis. Since the primary implant-prosthetic rehabilitation therapy.
objective is the elimination of all potential sites of infec- Table 5 reports important data regarding changes in
tion, patients should be informed on the best way to treat marginal bone levels around implants "associated" with
oral hygiene. In addition, regular dental visits should be bisphosphonate drugs. Somehow it is possible to easily
scheduled [38–42]. identify a trend from this chart. Certainly, the marginal
Given that osteonecrosis of the jaw is more frequently bone loss around dental implants, just like teeth, is con-
associated with traumatic dental procedures for the stant and progressive, and is defined by the recent con-
bone, endodontic therapies should be preferred to den- sensus conferences as approximately 0.1 mm per year
tal extractions and invasive periodontal procedures [36]. However, already from Table 3 it is possible to high-
in predisposed patients. Dental implants should also light differences between implants coated with bisphos-
be avoided. As a result, literature shows that a careful phonates and uncoated implants. This suggests that in
examination of the patients under or previous bispho- some way the effect of these molecules contrasts bone
sphonate therapy before planning of dental insertions is resorption, even in this clinical condition. In Table 5 all
very important for successful results. Even low, there is the studies that took into consideration the marginal
always a risk of developing bisphosphonate-induced oste- bone has been included, thus obtaining a homogeneous
onecrosis of the jaw, as well as the risk failure of implants graph of results, which compared over time, show a trend
[43]. Additionally, some studies show that some types of and overlapping values. Logarithmic trend lines were also
bisphosphonate molecules may be more related to the drawn, which somehow follow the results obtained by
risk of BRONJ if the patient receives a dental implant. the individual authors, but show what could be the pro-
For example, one molecule that is reported as more risky gression over time. Furthermore, in Table 7 below, those
is risedronate. Other factors related to a higher risk of trend lines up to 15 years have been projected to under-
BRONJ in case of implant surgery are smoking, diabetes stand how limited bone loss could be on implants, associ-
and the use of corticosteroids [8]. Before undertaking any ated in some way with therapy with these drugs.
surgical-implant therapy, it is necessary to acquire and
Fiorillo et al. BMC Oral Health (2022) 22:291 Page 11 of 12

In this case (Table 6), the mean values of all stud- Funding
No funding.
ies with implants associated with bisphosphonate drugs
were considered, admitting the missing values as 0. In the Availability of data and materials
graph about dental implants not related to bisphospho- The datasets generated during the current study are not publicly available due
to individual research work but are available from the corresponding author
nates, on the other hand, the parameter of 0.1 mm per on reasonable request.
year of bone loss was set. It is necessary to clarify that
by "associated" with bisphosphonates it means either a Declarations
patient undergoing drug therapy or an implant coated
with these molecules. The data after 10 and 15 years actu- Ethics approval and consent to participate
Not applicable.
ally, in the logarithmic trend line, show superimposable
results. By carrying out a paired t-test with two samples, Consent for publication
and inserting the values, in fact has been noticed that Not applicable.
the result is not statistically significant. The two-tailed P Competing interests
value equals 0.1483. By conventional criteria, this differ- No conflict of interest.
ence is considered to be not statistically significant.
Author details
The data extrapolated by this investigation offer an 1
Department of Biomedical and Dental Sciences, Morphological and Func-
overview about guidelines to be followed in case of tional Images, University of Messina, Via Consolare Valeria, 1, 98100 Messina,
performing oral surgical treatment of bisphosphonates Italy. 2 Multidisciplinary Department of Medical‑Surgical and Odontostoma-
tological Specialties, University of Campania “Luigi Vanvitelli”, 80121 Naples,
drug patients related. Implant surgery, if correlated Italy. 3 Department of Periodontics, University of Illinois at Chicago, College
with a suitable pharmacological prophylaxis, appears of Dentistry, Chicago, IL, USA.
to be safe, for patients and for the predictability of
Received: 7 March 2022 Accepted: 12 July 2022
our rehabilitations, the data show no statistically sig-
nificant differences regarding the marginal bone loss
around the implants, despite the values being slightly in
favor. implants associated with bisphosphonates. Cer-
tainly, more randomized clinical trials, more multicen- References
1. Diesendorf M. The mystery of declining tooth decay. Nature.
tric studies, are needed to shed light on this condition 1986;322(6075):125–9.
that often limits the quality of life related to oral health 2. Poole DF, Newman HN. Dental plaque and oral health. Nature.
(ORQoL) of our patients, and places the clinician in 1971;234(5328):329–31.
3. Norcia A, Cicciù M, Matacena G, Bramanti E. Dental implant positioning
front of a dilemma and doubts that are still unresolved. by using the root way. A predictable technique for postextractive surgery.
full clarified by the guidelines. Minerva Stomatologica. 2016;65(6):393–402.
Thanks to this study it is possible to clarify the effects 4. Cicciù M, Cervino G, Terranova A, Risitano G, Raffaele M, Cucinotta F, San-
tonocito D, Fiorillo L. Prosthetic and mechanical parameters of the facial
of these molecules on the bone, during and after the bone under the load of different dental implant shapes: a parametric
implant-prosthetic rehabilitation therapy. Implant study. Prosthesis. 2019;66:41–53.
surgery, if correlated with a suitable pharmacological 5. Urist MR. Bone: formation by autoinduction. Science.
1965;150(3698):893–9.
prophylaxis, appears to be safe, for patients and for the 6. Chrcanovic BR, Albrektsson T, Wennerberg A. Smoking and den-
predictability of our rehabilitations, the data show no tal implants: a systematic review and meta-analysis. J Dent.
statistically significant differences regarding the mar- 2015;43(5):487–98.
7. Lombardi T, Berton F, Salgarello S, Barbalonga E, Rapani A, Piovesana F,
ginal bone loss around the implants, despite the values​​ Gregorio C, Barbati G, Di Lenarda R, Stacchi C. Factors influencing early
being slightly in favor. implants associated with bispho- marginal bone loss around dental implants positioned subcrestally: a
sphonates. Certainly, more randomized clinical trials, multicenter prospective clinical study. J Clin Med. 2019;8(8):66.
8. Mozzati M, Arata V, Giacomello M, Del Fabbro M, Gallesio G, Mortel-
more multicentric studies, are needed to shed light on laro C, Bergamasco L. Failure risk estimates after dental implants
this condition that often limits the quality of life related placement associated with plasma rich in growth factor-Endoret in
to oral health (ORQoL) of our patients, and places the osteoporotic women under bisphosphonate therapy. J Craniofac Surg.
2015;26(3):749–55.
clinician in front of a dilemma and doubts that are still 9. Cicciù M, Herford AS, Juodžbalys G, Stoffella E. Recombinant human
unresolved. full clarified by the guidelines. bone morphogenetic protein type 2 application for a possible treatment
of bisphosphonates-related osteonecrosis of the jaw. J Craniofac Surg.
Acknowledgements 2012;23(3):784–8.
None. 10. Nastro E, Musolino C, Allegra A, Oteri G, Cicciù M, Alonci A, Quartarone
E, Alati C, De Ponte FS. Bisphosphonate-associated osteonecrosis of the
Author contributions jaw in patients with multiple myeloma and breast cancer. Acta Haematol.
Conceptualization, methodology, investigation, writing—original draft 2007;117(3):181–7.
preparation, L.F.; writing—review and editing, C.D.A.; supervision, G.C, T.F.T. 11. Chadha GK, Ahmadieh A, Kumar S, Sedghizadeh PP. Osseointegration
and G.O.; Project administration, M.C. All authors read and approved the final of dental implants and osteonecrosis of the jaw in patients treated
manuscript.
Fiorillo et al. BMC Oral Health (2022) 22:291 Page 12 of 12

with bisphosphonate therapy: a systematic review. J Oral Implantol. 32. López-Cedrún JL, Sanromán JF, García A, Peñarrocha M, Feijoo JF, Limeres
2013;39(4):510–20. J, Diz P. Oral bisphosphonate-related osteonecrosis of the jaws in dental
12. Liu H, Zhou X, Yu G, Sun X. The effects of the PRISMA statement to implant patients: a case series. Br J Oral Maxillofac Surg. 2013;51(8):874–9.
improve the conduct and reporting of systematic reviews and meta- 33. Griffiths GR. Bone density around endosseous implants in patients
analyses of nursing interventions for patients with heart failure. Int J Nurs taking alendronate: a pilot study. Int J Periodontics Restor Dent.
Pract. 2019;66:e12729. 2012;32(3):e101–8.
13. Tian JH, Ge L, Li L. The PRISMA Extension Statement. Ann Intern Med. 34. Abtahi J, Tengvall P, Aspenberg P. A bisphosphonate-coating improves
2015;163(7):566. the fixation of metal implants in human bone. A randomized trial of
14. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, dental implants. Bone. 2012;50(5):1148–51.
Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catala-Lopez F, 35. Shabestari GO, Shayesteh YS, Khojasteh A, Alikhasi M, Moslemi N, Aminian
Gotzsche PC, Dickersin K, Boutron I, Altman DG, Moher D. The PRISMA A, Masaeli R, Eslami B, Treister NS. Implant placement in patients with
extension statement for reporting of systematic reviews incorporating oral bisphosphonate therapy: a case series. Clin Implant Dent Relat Res.
network meta-analyses of health care interventions: checklist and expla- 2010;12(3):175–80.
nations. Ann Intern Med. 2015;162(11):777–84. 36. Duan X-B, Wu T-X, Guo Y-C, Zhou X-D, Lei Y-L, Xu X, Mo A-C, Wang
15. da Costa Santos CM, de Mattos Pimenta CA, Nobre MR. The PICO strategy Y-Y, Yuan Q. Marginal bone loss around non-submerged implants is
for the research question construction and evidence search. Rev Lat Am associated with salivary microbiome during bone healing. Int J Oral Sci.
Enfermagem. 2007;15(3):508–11. 2017;9(2):95–103.
16. Bachelet VC, Pardo-Hernandez H. Quality of reporting and risk of bias 37. Jeffcoat MK. Safety of oral bisphosphonates: controlled studies on alveo-
of randomized clinical trials published in Spanish and Latin American lar bone. Int J Oral Maxillofac Implants. 2006;21(3):349–53.
journals. Medwave. 2019;19(1): e7573. 38. Schmitt CM, Buchbender M, Lutz R, Neukam FW. Oral implant survival in
17. Savovic J, Turner RM, Mawdsley D, Jones HE, Beynon R, Higgins JPT, patients with bisphosphonate (BP)/antiresorptive and radiation therapy
Sterne JAC. Association Between risk-of-bias assessments and results of and their impact on osteonecrosis of the jaws. A systematic review. Eur J
randomized trials in cochrane reviews: the ROBES meta-epidemiologic Oral Implantol. 2018;11(Suppl 1):S93-s111.
study. Am J Epidemiol. 2018;187(5):1113–22. 39. Kumar MN, Honne T. Survival of dental implants in bisphosphonate users
18. Yang ZR, Sun F, Zhan SY. Risk of bias assessment: (1) overview. Zhonghua versus non-users: a systematic review. Eur J Prosthodont Restor Dent.
Liu Xing Bing Xue Za Zhi. 2017;38(7):983–7. 2012;20(4):159–62.
19. Mansournia MA, Higgins JP, Sterne JA, Hernan MA. Biases in randomized 40. Troiano G, Zhurakivska K, Muzio LL, Laino L, Cicciù M, Russo LL. Combina-
trials: a conversation between trialists and epidemiologists. Epidemiol- tion of bone graft and resorbable membrane for alveolar ridge preserva-
ogy. 2017;28(1):54–9. tion: a systematic review, meta-analysis, and trial sequential analysis. J
20. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic Periodontol. 2018;89(1):46–57.
J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration’s tool for 41. Fama F, Cicciu M, Sindoni A, Nastro-Siniscalchi E, Falzea R, Cervino G,
assessing risk of bias in randomised trials. BMJ. 2011;343: d5928. Polito F, De Ponte F, Gioffre-Florio M. Maxillofacial and concomitant seri-
21. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, ous injuries: an eight-year single center experience. Chin J Traumatol Engl
Savović J, Schulz KF, Weeks L, Sterne JAC. The Cochrane Collaboration’s Ed. 2017;20(1):4–8.
tool for assessing risk of bias in randomised trials. BMJ. 2011;343: d5928. 42. Sortino F, Cicciù M. Strategies used to inhibit postoperative swell-
22. Fiorillo L. Fi-index: a new method to evaluate authors Hirsch-index reli- ing following removal of impacted lower third molar. Dent Res J.
ability. Publ Res Q. 2022;6:66. 2011;8(4):162–71.
23. Aspenberg P, Malouf J, Tarantino U, García-Hernández PA, Corradini C, 43. Ata-Ali J, Ata-Ali F, Peñarrocha-Oltra D, Galindo-Moreno P. What is
Overgaard S, Stepan JJ, Borris L, Lespessailles E, Frihagen F, Papavasiliou the impact of bisphosphonate therapy upon dental implant sur-
K, Petto H, Caeiro JR, Marin F. Effects of teriparatide compared with vival? A systematic review and meta-analysis. Clin Oral Implants Res.
risedronate on recovery after pertrochanteric hip fracture: results of a 2016;27(2):e38-46.
randomized, active-controlled, double-blind clinical trial at 26 weeks. J
Bone Joint Surg Am. 2016;98(22):1868–78.
24. Meidan Z, Weisman S, Baron J, Binderman I. Technetium 99m-MDP Publisher’s Note
scintigraphy of patients undergoing implant prosthetic procedures: a Springer Nature remains neutral with regard to jurisdictional claims in pub-
follow-up study. J Periodontol. 1994;65(4):330–5. lished maps and institutional affiliations.
25. Trbakovic A, Hedenqvist P, Mellgren T, Ley C, Hilborn J, Ossipov D, Ekman
S, Johansson CB, Jensen-Waern M, Thor A. A new synthetic granular
calcium phosphate compound induces new bone in a sinus lift rabbit
model. J Dent. 2018;70:31–9.
26. Abtahi J, Henefalk G, Aspenberg P. Impact of a zoledronate coating on
early post-surgical implant stability and marginal bone resorption in the
maxilla-A split-mouth randomized clinical trial. Clin Oral Implants Res.
2019;30(1):49–58.
27. Abtahi J, Henefalk G, Aspenberg P. Randomised trial of bisphosphonate-
coated dental implants: radiographic follow-up after five years of loading.
Int J Oral Maxillofac Surg. 2016;45(12):1564–9.
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