HOST MODULATION THERAPY IN

PERIODONTAL DISEASES
Presenter
DR KASSIM ABDULAZEEZ
Department of periodontics
18/02/2019
 OUTLINE
• 1.INTRODUCTION
• 2.DEFINITION OF TERMS
• 3.PATHOGENESIS OF PERIODONTAL DISEASES
• 4.HOST MODULATION THERAPY
• 5.HOST MODULATORY AGENT
• 6.HOST MODULATION AND PERIODENTAL
• MANAGEMENT
• 8.CONCLUSION
• 9.REFERENCE
 INTRODUCTION
• Host modulation therapy (HMT) is a treatment
concept that aims to reduce tissue distruction
and stabilize or even regenerate the
periodontium by modifying or downregulating
destructive aspect of the host response and
upregulating protective or regenerative
response.HMT’s are systemic or locally
delivered pharmaceuticals that are prescribe
as part of periodontal therapy and adjuncts.
 DEFINITION
• 1.HOST
• Host can be defined as “ the organism from which a
parasite obtains its nourishment” or in the
transplantation of tissue, “the individual who receives
a graft”
• 2.MODULATION
• It is the alteration of function or status of something in
response to a stimulus or an altered chemical or
physical environment
• (Taber’s Medical Dictionary,2004)
• 3.SUBSTANTIVITY PROPERTY:
• The quality of prolonged contact time
between a substance and a substrate.it is
influenced by the concentration of the
medication, the PH,temperature and length of
contact of the solution with oral surfaces.
• It’s very important in topical HMT’s
PATHOGENESIS OF PERIODONTAL DISEASE

• Periodontal disease is a common chronic disease

affecting the periodontium.It encompasses
multifactorial aetiologies involving biofilm and
the generation of an inflammatory
response.Bacterial biofilm has been shown to be
the primary aetiologic factor in the initiation of
gingival inflammation and subsequent
destruction of the periodontal tissue
• ( Haffajee & Socransky 1994 )
• Plaque appears to be essential for the
development of periodontal disease.However, the
severity and the pattern of disease are not
explained solely by the amount of plaque present.
• It has been recognised that although bacterial
pathogens initiate the periodontal inflammation,
the host response to these pathogenes is equally,if
not more important in mediating connective tissue
breakdown, including bone loss.
• Other acquired and environmental risk factor
such as diabetes , cigrate smoking, stress as
well as genetically transmitted trait such as
interleukin -1(IL-1) gene polymorphism may
accentuate the host inflammatory response to
bacteria challenge and eventually the
susceptibility of the disease
• (Kinane & Chestnut 2000, Albadar 2000)
 \\\\

• THE MICROBIAL CHALLENGE:

• This consist of
• 1.Antigen.
• 2.Lipopolysacharide (LPS)
• 3.Other virulence factor stimulated from host
• response.
• These result in disease limited to the gingiva
and the periodontal ligament
• ORGANISM IMPLICATED
• Organism involved in periodontal disese
• Porphyromonas gingivalis
• Aggregobacter Actinomycetes comitans
• Tannerella forsythia
• HOST RESPONSE
• Protective host response to these bacteria
challenge include the production of
• PRO INFLAMMATORY MEDIATORS
• ANTI INFLAMMATORY MEDIATORS
• ANTIBODIES
• These response can be protective and
destructive to the host.
 INFLAMMATORY MEDIATORS
PRO-INFLAMMATORY MEDIATORS ANTI-INFLAMMATORY MEDIATORS

Proteolytic enzyme= MMP(Matrix

metalloproteinase),LPS
TNF-& TNF-B

PG-E2,Thromboxane B2 Lipoxin A4, B4

IL-1A,IL-1B,IL-6,IL-8 IL-4,IL-10,IL-11,IL-12

IgE,IgG IgA
 MATRIX METALLOPROTEINASE AND
ITS PATHOPHYSIOLOGICAL ROLE
• Matrix metalloproteinase are a family of
calcium and zinc dependent endopeptidases
responsible for a number of physiological
event e.g.
• Hard and soft tissue remodelling
• Tooth eruption
• Wound healing
• Immunity and angiogenesis
• MMPs were initially described by Jerome Gross
and Charles Lapiere in 1962 who observed its
enzymatic activity i.e collagen triple helix
degradation
• MMPs are the prime mediators involved in
tissue destruction in various pathological
conditions e.g
• Periodontitis, Bone resorption,Fibrosis,Tumor
progression and metastasis e.t.c
• For collagen to have access to its substrate, proteoglycan
and fibronectin must be removed by the action of
specific matrix metalloproteinase e.g. STROMELYSIN
(MMP-3)
• The primary source of MMPs, are
• Fibrobast
• Keratinocyte
• Neutrophil
• Macrophages and
• Endothelial cells
 Classification of MMPs
• MMPs can be classified either
• 1.On the basis of its substrate specificities and Physical
structures
• e.g
collagenase,gellatinase,metalloelastase,stromelysin,matrilysin
e.t.c
• 2.Sources of production
• e.g
• Host derived (produced by neutrophil)or bacteria
derived(produced by actinobacillus actinomycetes comitant
and porphyromonas gingivalis)
• MMP 1=Interstitial collagenase 1
• MMP 2,9=Gelatinase
• MMP 3,10,11=Stromelysin
• MMP 7,26=Matrilysin
• MMP 8=Neutrophil collagenase 2
• MMP 12=Metalloelastases
• MMP 14,15,24,25=Membrane type MMP
• In periodontics,the predominant MMPs are MMP-
8(Collagenase 8), MMP-9(Gelatinase-B) and MMP-
13 (Collagenases, bone and cartilage destruction).
• Whereas ,in healthy tissue normal collagenase
turn over is regulated predorminantly by MMP-1
(Fibroblast derived collagenase),all these
destructive enzyme are primarily secreted by
Neutrophils and are responsible for degradation of
Type 1 collagen in periodontal tissue
• PROTECTIVE ASPECT OF THE HOST RESPONSE
• This include:
• Recruitment of neutrophil
• Production of protective antibodies
• The release of anti-inflammatory cytokines
including-Transforming growth factor-B
• Interleukin 4,10 &12
(Page et al 1998)
 RATIONALE FOR HOST MODULATION
• Homeostasis is essential for the defense of the host,
hence host modulation becomes necessary for
• 1.To restore the balance or pro and anti-
• inflammatory mediators
• 2.As an adjunctive treatment option
• 3.To decrease patient susceptibility
• 4.To aid in risk assessment and risk reduction
• strategy
• 5.To facilitate regeneration
 HOST MODULATION THERAPY
• This is a treatment concept that aims to reduce
tissue destruction and stabilize or even regenerate
the periodontium by modifying or down regulating
destructive aspects of the host response and
upregulating protective or regenerative responses.
• It ameliorates excessive or pathologically elevated
inflammatory processes to enhance the
opportunities for wound healing and periodontal
stability
• It was first introduced to dentistry by william
(1990) and Golub et al (1992) and then
expanded on by many other scholars in the
dental profession.
• HMTs are systemically or locally delivered
pharmaceuticals that are prescribed as part of
periodontal therapy and are used as adjuncts
to conventional periodontal treatments such
as scaling ,root planing and surgery.
 CLASSIFICATION OF HOST MODULATING
AGENT
• 1.SYSTEMICALLY ADMINISTERED AGENTS
• NSAIDs( Aspirin,indomethacin,flurbiprofen)
• SUB ANTIMICROBIAL DOSE DOXYCYCLINE
• BIPHOSPHONATE
• CHEMICALLY MODIFIED TETRACYCLINE
• MODULATORS OF HOST RECEPTORS
• MODULATORS OF NOS ACTIVITIES
• 2.LOCALLY ADMINISTERED AGENTS
• ENAMEL MATRIX PROTEIN(Edmogain)
• GROWTH FACTORS
• BONE MORPHOGENIC PROTEINS
• ( BMP-2,BMP-7)
• TOPICAL NSAIDs
•
 HOST MODULATORY AGENTS
• Various HMT have been developed or proposed
to block pathways responsible for periodontal
tissue breakdown.
• They include:
• 1.Agents that Modulate Matrix
• metalloproteinases (MMPs)
• e.g. Tetracycline, Chemically modified
tetracyclines (CMTs), SDD(Subantimicrobial dose
doxycycline),Biphosphonate
• 2.Agents that inhibits Arachidonic acid metabolites:
• (a) COX-1 inhibitors:
• Indomethacin,Naproxen,Flurbiprofen
• (b) COX-2 inhibitors:
• Rofecoxib
• (c) COX and LOX inhibitors:
• Triclosan, Topical Ketoprofen
• (d) LOX inhibitors: Lipoxins
• (e) Omega-3 fatty acid
• 3.Agent that modulate bone metabolism
• (a).Conventional therapy (scaling and root planing)
• (b).Tumor necrotic factor-alpha
• (c).Anticytotoxic drugs
• (d).Anti resorptive agent e.g.
• -Biphosphonates
• -Hormone Replacement therapy(HRT)
• -Calcium supplement
• -Disruption of RANKL/RANK/OPG
• -Vitamin D
• -Statin
• 4.Agents that regulate immune and inflammatory
responses:
• (a)Suppressing proinflammatory cytokines
• (IL-1 & TNF-@ receptor antagonist)
• (b)Nitric oxide inhibition
• (c)Generation of protective antibodies
• through vaccines
• (d)Infusion /supplementary anti-inflammatory
• cytokines IL-4 and IL-10
• 5.New emerging host modulation therapy
• Azithromycin
• Parathyroid hormone
INHIBITORS OF MATRIX
METALLOPROTEINASE
 EXOGENOUS INHIBITORS OF MATRIX
METALLOPROTEINASE
• 1.TETRACYCLINE
• Tetracycline is a broad spectrum antibiotics
prescribed for many systemic and periodontal
infection. Due to its high concentration and
secretion in gingival crevicular fluid,they provide
effective antimicrobial cover locally for periodontal
pathogens.
• In addition to its antibacterial properties,it also
possess anti collagenase.due to inhibition of MMPs.
• MMPs are zinc and calcium dependent
endopeptidases.
• Tetracycline causes chelation of these ions in MMPs
there by directly inhibiting the tissue degradation by
these enzymes.
• It scavenge and inhibits production of oxygen
metabolite by Neutrophils(PMN) thereby decreasing
host inflammatory response and prevent destruction
of endogenous MMPs inhibitors
• It also inhibits osteoclast and osteoblast MMPs
• -
• 2.CHEMICALLY MODIFIED TETRACYCLINE(CMTs)
• Chemically modified tetracycline are those which
lack dimethylamino group on the 4th carbon atom
in their molecular structure.They have been
modified to remove all antibiotic properties
• Mechanism of action
• (a) Inhibits or chelates the calcium atom that
matrix metalloproteinase (MMPs) require for
their action
• (b)inhibits already active MMPs
• (c)Down-regulates MMPs expression
• (d)Scavenges reactive oxygen species
• (e)Modulates the osteoclast functions
• EXAMPLES
• CMT-3 and CMT-8
• Both lack antibiotic activities but retain anti-MMP activity.
• They have been shown to promote bone formation and
enhance wound healing.
 Advantages over Tetracycline
• 1.No development of bacterial resistance
compared to the traditional tetracycline
• 2.There is less incidence of adverse effect such as
GIT disturbances, super infection e.t.c
• 3.It has anti collagenase property that is very
important to inhibit the periodontal tissue
destruction
• 4.substantivity of the drug and high
concentration in gingival crevicular fluid.
• 5.Rifkin et al.reported that CMTs could also
inhibit parathyroid hormone induced bone
resorption
 SUB ANTIMICROBIAL DOSE
DOXYCYCLINE(SDD)
• SDD was introduced in 1998 for host moduation
therapy due to the adverse reactions observed
from prolong use of tetracycline(GIT disturbance
and emergence of resistant strains of bacteria)
• Currently, it is approved for systemic use by FDA
for the treatment of periodontitis.
• SDD administration is In dosage of 20mg b.d as an
adjunct for patient with chronic periodontitis.
Mechanism of action
• It can be administered for a short term
duration of 1-3 months or for longer duration
of up to 9 months.
• It has a more predictable outcome.
• Mechanism of action is similar to tetracycline.
• Example of SDD
• Periostat
 PERIOSTAT:
• It is a subantimicrobial dose of Doxycycline
hyclate capsule of 20mg, prescribed twice daily
for patient with chronic periodontitis
• It is used systemically as a modulating agent
• It acts by down regulating matrix
metalloproteinases (MMPs), a family of zinc
dependent enzymes that are capable of degrading
extracellular matrix molecule and collagen
• INDICATIONS FOR PERIOSTAT
• 1.Patient who have not responded to
nonsurgical therapy
• 2.Patient with generalized recurrent site of 5mm
or greater pocket depth that bleed on probing
• 3.Patient with mild to moderate chronic
periodontitis and a high susceptibility to rapid
periodontal disease progression
• 4.Aggresive periodontitis
• 5.Motivated patient
• CONTRAINDICATIONS OF PERIOSTAT
1.Allergies
2.pregnancy
3.children < 12 years
4.periodontal abscess
5.when antibiotic regimen is necessary
6. patient on contraceptive
 AGENT THAT INHIBITS ARACHIDONIC
ACID METABOLISM
• In periodontal disease, prostaglandins and
other arachidonic acid (AA) metabolites have
been established as the mediators of tissue
destruction (Offenbacher et al 1993).
• AA are metabolised via the cyclooxygenase
(COX) or lipoxygenase (LOX) Pathways.
• One proposed approach to modulate the host
response is inhibition of enzymes responsible
for the release of these destructive products.
• Inhibitors of arachidonic acid can be administered
Locally and Systemically administered NSAID (non
steroidal anti inflammatory drugs)
• NSAIDs are usually weak organic acid that
selectively(COX-2) and non selectively (COX-1)
• Inhibits the synthesis of AA metabolite there by
blocking the production of prostaglandins,
thromboxane and prostacyclin
• (Fitzgerad & Patrono 2001)
• NB: local administration is possible because
these agent are lipophilic acid which binds to
and are absorbed by the gingival
• Examples include:
• Ketorolac,Triclosan,Indomethacin
Trimethamine rinse, S-ketoprofen dentrifices
• CURRENTLY NO NSAIDS HAVE BEEN
APPROVED FOR USE AS HMTs
• TRICLOSAN(2,4,4,1-trichloro-2hydroxyl-diphenyl ether)
• It’s a well known lipid soluble antibacterial agent
• It has anti inflammatory properties
• It inhibits cyclooxygenase and lipooxygenase pathways.
• It reduce the level of TNF alpha
• Use as dentrifrices containing sodium flouride
• (0.243%),TRICLOSAN(0.3%) with 2.0% PVM/MA
copolymer(poly vinyl methyl maleic acid).
• It has a substantivity of 5 hours
 AGENTS THAT MODULATE BONE
METABOLISM
• BIPHOSPHONATE
• They are bone seeking agent that inhibits bone
resorption by disrupting osteoclastic activity.
• They interfere with osteoclastic metabolism and
secretion of lysosomal enzyme
• It possess anticollagenase properties
• Treatment with biphosphonate significantly
increase bone density compared to placebo
• (Reddy M S et al J Periodontol 1995)
• DISADVANTAGE
• 1.Inhibition of bone calcification
• 2.Inducing changes in white blood cell count
• 3.Avascular necrosis of the jaw following
• biphosphonate therapy with the resultant
• risk of bone necrosis following dental
• extraction
• 4.Currently is not approved for use
 AGENT THAT REGULATE IMMUNE
INFLAMMATORY RESPONSE
• They include
• 1.TNF alpha antagonist
• Influximab
• Golimumab
• Centrolizamab
• 2.Anticytokin drugs
• IL-1 Receptor antagonist
• Anakinra
• AMG 714
• 3.RANKL Inhibitor
• Denosumab
• CIMETIDINE
• Histamine receptor antagonist cimetidine is a potent
inhibitor or porphyromonas gingivalis induced
periodontal inflammation,it can inhibit tissue
distruction and influence the inflammatory cells
• PROBIOTICS
• ( a preparation containing viable prepared micro
organism)
• When included in periodontal dressing at a
concentration of 108 CFU ML.
3.Anti oxidants
 COMBINATION OF HOST RESPONSE
MODULATORS
• SDD (20mg bid) + flurbiprofen (50mg,4 times a
day)
• CMT + Flubiprofen
• (Leung M K et al 1995)
• CMT8 + Biphosphonate (clodronate)
• (Liavaneras A et al 2001)
 NEW EMERGING AGENTS
• 1.Azythromycine
• A type of macrolide antibiotics
• Has anti inflammatory activities by suppressing
the production of pro inflammatory cytokines
• 2.Teriparatide
• An anabolic agent.its a biosynthetic human
parathyroid hormone when administered
intermittently activate osteoblastic activity thus
stimulating new bone formation
 HOST MODULATION AND PERIODONTAL
MANAGEMENT
• Periodontal management suggest a much
more broader concept of periodontal care than
treatment.understanding the importance of
host response and the impact of risk factors
now allows clinicians to provide different but
complementary treatment strategies
simultaneously for their patient.
• If the decision is made to use an HMT,this must
be discussed with the patient and
• The rationale for treatment thoroughly
explained.
• This may take some time at the chair side but
it is time well spent because of
• 1.It enhances compliance
• 2.It initiates and substain risk factors
modification such as smoking, diabetic control
and not missing appointments.
• The management of patient with periodontal disease can
therefore involve the following complementary treatment
strategies
• 1.Patient education and motivation
• 2.Reduction of bacterial burden by high quality scaling
• and root planing
• 3.Site specific antibacterial treatment with local
• delivery system
• 4.Host response modulation
• 5.Risk factors reduction/modification
• 6.Periodontal surgery
 CONCLUSION
• The concept of Host modulation therapy in
periodontal medicine is emerging.it offers the
opportunity to improve the treatment
outcome that can be anticipated following
SRP(Scaling and root planing).
• Clinical trial has demonstrated a clear
treatment benefit.In the nearest future HMT
may become the best adjuctive treatment to
periodontal diseases.
 REFERENCES

• Ah MK, Johnson GK, Kaldahl WB, et al:The effect of

smoking on the response to periodontal therapy,J Clinical
Periodontol 1994;21:91
• Taylor JJ, Preshaw PM,Donaldson PT,Cytokine gene
polymorphism and immunoregulation in periodontal
disease,periodontol 2000 35:158,2004
• Oringer RJ; Research, science ,and Therapy Committee of
the American Academy of Periodontology.Modulation of
the host response in periodontal therapy.J Periodontol
2002;73:460-70
•

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