This document discusses host modulation therapy for the treatment of periodontitis. It defines host modulation as the alteration of the host response to reduce tissue destruction. Potential host modulating agents discussed include nonsteroidal anti-inflammatory drugs, bisphosphonates, and subantimicrobial-dose doxycycline. Subantimicrobial-dose doxycycline is currently the only systemic host modulating therapy approved to treat periodontitis. The document also explores new and emerging host modulating therapies that may be developed in the future to provide additional treatment options for periodontitis.

1. HOST
MODULATION
THERAPY
Presnted by,
OLGA MCFRANCIS
FINAL YEAR PART 1
DEPARTMENT OF PERIODONTICS,
GOVT DENTAL COLLEGE,
TRIVANDRUM

2. Contents
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3. Introduction
• Host can be defined as "the organism from which a parasite obtains it's
nourishment," or in the transplantation of tissue,"the individual who
receives the graft."
• Modulation is defined as "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).
• The concept of host modulation was first introduced to dentistry by
Williams and Golub et al .
• In 1990, Williams concluded "there are compelling data from studies
in animals and human trials indicating that pharmacological agents,
that modulate the host responses believed to be involved in the
pathogenesis of Periodontal destruction,may be efficacious in slowing
the progression of Periodontitis

4. Pathogenesis of Periodontitis

5. Pathogenesis of Periodontitis

6. The Periodontal Balance

7. • Elevations in the proinflammatory or destructive mediators in
response to bacterial challenge are encountered by elevations in
the anti-inflammatory or protective mediators such as cytokines IL-
4 and IL-10, other mediators such as IL-1ra (receptor antagonist),
and tissue inhibitors of metalloproteinases (TIMPs)
• HMT is a means of treating the host side of the host- bacteria
interaction.
• Host response is responsible for most of tissue breakdown, leading
to clinical signs of periodontitis .
• HMTs offer the opportunity for modulating or reducing this
destruction by treating aspects of chronic inflammatory response.
• They ameliorate excessive or pathologically elevated inflammatory
processes to enhance the opportunities for wound healing and
Periodontal stability.

8. Potential Adjunctive
Therapeutic Approaches

9. • HMTs can be used to reduce excessive levels of enzymes,
cytokines,and prostanoids and should not reduce levels below
constitutive levels.
• HMTs can modulate osteoclast and osteoblast function.
• Use of systemic HMTs for treatment of a patient 's periodontal
condition may also provide benefits for other inflammatory
disorders such as arthritis, cardiovascular disease,dermatologic
conditions, diabetes, rheumatoid arthritis, and osteoporosis.

10. HOST MODULATING AGENTS
Systemically Administered Agents Locally Administered Agents
Nonsteroidal Anti-inflammatory Drugs
Bisphosphonates Subantimicrobial- Dose Doxycycline Nonsteroidal Anti-inflammatory Drugs
Enamel Matrix Proteins
Growth Factors ,
Bone Morphogenic Proteins
Classification of Host
Modulating Agents

11. Nonsteroidal Anti-inflammatory Drugs
Systemically
Administered Agents
• NSAIDs inhibit the formation of prostaglandins,
including PGE2, which is produced by neutrophils,
macrophages,fibroblasts,and gingival epithelial
cells in response to the presence of LPS , a
component of the cell wall of gram-negative
bacteria.
• PGE2 upregulates bone resorption by osteoclasts.
• Levels of PGE2 is elevated in periodontal disease
• PGE2 also inhibits fibroblast function and has an
inhibitory and modulatory effects on the immune
response.

12. • NSAIDs are used to treat pain, acute
inflammation, and a variety of chronic
inflammatory conditions.
• Short term administration of NSAIDs
reduced gingival crevicular fluid (GCF)
MMP-8 levels.
• Low dose aspirin as an adjunct periodontal
therapy was beneficial in reducing
periodontal attachment loss.
• Systemic NSAIDs such as Indomethacin,
Flurbiprofen, Naproxen significantly reduced
the rate of alveolar bone loss
• Eg: Salicylates( Aspirin), Indomethacin,
Propionic Acid derivatives ( Ibuprofen,
Flurbiprofen,Naproxen)

13. • Gastrointestinal problems, hemorrhage
(from decreased platelet aggregation) and
renal and hepatic impairment .
• Periodontal benefits of taking long term
NSAIDs are lost when patients stop taking
the drugs, with a return to or even an
acceleration of the rate of bone loss seen
before NSAID therapy.
• It is referred to as " Rebound effect".
• Nonselective COX-1 inhibitors cause
gastrointestinal and impaired hemostasis.
• Selectve COX-2 inhibitors cause life
threatening adverse effects such as
Myocardial Infarction.

14. Bisphosphonates
• They are Bone- seeking agents that inhibit
bone resorption by disrupting osteoclast
activity.
• They interfere with osteoblast metabolism and
secretion of lysosomal enzymes and also
possess anticollagenase properties.

15. Uses of Bisphosphonates
• The ability of bisphosphonates to modulate
osteoclast activity may be useful in the
treatment of periodontitis.
• They increase bone density.
• They reduce alveolar bone resorption.
• eg: Alendronate

16. Adverse effects of Bisphosphonates
• They have unwanted effects of inhibiting bone calcification and
inducing changes in white blood cell counts.
• Recent reports of avascular necrosis following bisphosphonate
therapy, with the resultant risk of bone necrosis following dental
extractions.
• Bisphosphonate - related osteonecrosis of the jaw (BRONJ) , primarily
with intravenous administration rather oral administration, has
impeded bisphosphonates as an HMT to manage periodontitis.
• As with NSAIDs , at present no bisphosphonate drugs are approved
and indicated for treatment of periodontal diseases.

17. Bisphosphonate- related osteonecrosis
of Jaw ( BRONJ)

18. Subantimicrobial-Dose
Doxycycline (SDD)
• It is a 20 mg dose of doxycycline (Periostat) ,indicated as an
adjunct to Scaling Root Planing(SRP) in the treatment of
chronic periodontitis.
• It is taken twice daily for 3 months,upto a continuous dose of 9
months.
• It exerts it's therapeutic effect by enzyme ,cytokine,and
osteoblast inhibition rather than by any antibiotic effect.
• At present,SDD (Periostat) is the only systemically
administered HMT specifically indicated for the treatment of
periodontitis approved by FDA and ADA

19. • SDD is used as an adjunct to SRP and must not be used as a stand alone
therapy (monotherapy).
• SDD is used in conjunction with SRP ,the gold standard of non-surgical therapy.
• Tetracyclines used systemically as a host modulation agent( SDD).
• They are used in chronic periodontitis,to specific and more aggressive types of
periodontitis.
• They are used in patients with systemic diseases such as diabetes, rheumatoid
arthritis,and rosacea.
• As an adjunct to mechanical therapies, the goal of tetracycline therapy has
been to enhance reattachment or even to stimulate new attachment of
supporting apparatus and osseous formation.

20. SDD - Mechanism
of Action
• MMPs are a family of zinc-dependent enzymes capable of degrading extracellular
Matrix Proteins including collagen.
• MMPs are secreted by fibroblasts,keratinocytes, macrophages,PMNs, endothelial cells
and play an important role in periodontitis.
• Excessive quantities of MMPs are released in inflamed periodontal tissues, resulting in
breakdown of the connective tissue matrix.
• The predominant MMPs in periodontitis, MMP-8 and MMP-9 derive from PMNs and are
extremely effective in degrading type I collagen,the most abundant collagen type in
gingiva and periodontal ligament.
• SDD as a HMT in the treatment of periodontitis downregulates the activity of MMPs by a
variety of synergestic mechanisms, including reductions in cytokine levels, stimulates
osteoblastic activity , new bone formation by upregulating collagen production.

21. SDD-Effects on
Periodontal tissues
Schematic of periodontal pocket
indicating the pleiotropic
mechanisms by which doxycycline
inhibits its connective tissue
breakdown. Downregulation of
destructive events occuring in the
periodontal tissues by doxycycline
results from modulation of a
variety of different
proinflammatory pathways

22. Locally Administered Agents
Nonsteroidal Anti-inflammatory Drugs
• Topical NSAIDs have shown benefit in the
treatment of periodontitis.
• Patient with chronic periodontitis who
received topical ketorolac mouth rinse
reported that GCF levels of PGE2 were
reduced by half over 6 months and bone
loss was halted.
• Locally Administered ketoprofen is also
used.
• Topically administered NSAIDs have not
been approved as local HMTs for the
management of periodontitis.

23. Enamel Matrix Proteins, Growth Factors ,
and Bone Morphogenic Proteins
• They are investigated for potential use as adjuncts to
surgical procedures,improve wound healing, stimulate
regeneration of lost bone, periodontal
ligament,cementum, restoring the complete periodontal
attachment apparatus.
• They include enamel matrix proteins, bone morphogenic
proteins (BMP-2,BMP-7) , growth factors (platelet
derived growth factor, insulin- like growth factor) and
tetracyclines.
• The locally applied HMTs currently approved by FDA for
Adjunctive use during surgery are enamel matrix proteins
( Emdogain), recombinant human platelet derived
growth factor -BB(GEM 21S), BMP-2( INFUSE).

25. Adverse effects associated with adminstration of BMPs including:
• Osteolysis
• Seroma or Hematoma
• Infection
• Arachnoiditis
• Dysphagia
• Increased neurologic deficits
• Cancer

26. Host Modulation and Comprehensive
Periodontal Management
Periodontal Management includes :
• Medical and dental history and examination (clinical charting and radiograhs)
• Assessment of risk factors
• Diagnosis
• Development of a treatment strategy
• Initail and Definitive treatment planning
• Review of treatment outcome
• Reevaluation
• Long term supportive periodontal therapy ( maintanence care)
• Assessment of prognosis

27. Complementary Treatment Strategies in Periodontitis

28. • Patient education and motivation, including oral hygiene
instructions;use of powered toothbrushes , antiseptics in rinses,
toothpastes,and irrigation:and explanation of the rationale for any
adjunctive treatments.
• Reduction of bacterial burden by high quality SRP
• Site - specific antibacterial treatment with local delivery systems or
systemic antimicrobial therapy in select cases.
• Host response modulation by HMT.
• Risk factor modification and risk reduction strategies.
• Periodontal surgery with or without HMT
Management of Patients with Periodontitis

29. Emerging Host Modulatory
Therapies
• In the future, variety of HMTs will be developed as adjunctive treatments for
periodontitis.
• One of the most promising groups of potential HMTs is the chemically
modified tetracycline s(CMTs).
• These nonantibiotic tetracycline analogs are tetracycline molecules that is
modified to remove all antibiotic properties,but which retain host modulatory,
anticollagenolytic effects.
• They are more potent inhibitors of proinflammatory mediators and can
increase levels of anti-inflammatory mediators such as IL-10.
• CMT-3 and CMT-8 (both of which lack antibiotic activity but retain anti-
MMP activity) inhibit osteoclastic bone resorption,promote bone
formation,enhance wound healing and inhibit proteinases produced by
periodontal pathogens.

30. • CMTs are being studied for other effects,such as inhibition of tumor cell invasion and
attenuation of intimal thickening after arterial injury.
• Other potential HMTs include anticytokine drugs developed for the management of
rheumatoid arthritis.
• Cytokines such as TNF-a have been targeted by TNF-a antagonists ( eg: infliximab,
etanercept).
• n-3 polysaturated fatty acids (n-3PUFA;Fish oil) , as an adjunct to oral hygiene
instructions, can significantly lower GCF,IL-8,IL-6,PGE2 levels .
• Combination therapy with n-3PUFA and low dose aspirin as an adjunct to regenerative
procedures using decalcified freeze dried bone allografts result in greater probing
depth reductions and gains in clinical attachment.
• Collagenase inhibitors known as polyenolic zinc binding compounds(PEZBINs) for
periodontitis.

31. • PEZBINs are based on the natural product curcumin, which contains a calcium and
zinc binding beta-diketone moiety,that has anti-inflammatory properties.
• Semi synthetic glucosaminoglycan ether ( SAGE) or Sulfated polysaccharide to
suppress inflammatory mediators in high risk individuals such as smokers and
those with diabetes.
• Human periodontal stem cells can modulate neutrophil function and reduce
excessive inflammation.
• Bone marrow derived mesenchymal stem cells have shown great potential for
periodontal regeneration.

32. Conclusion
Periodontal pathogens and destructive host
responses are involved in the initiation and
progression of periodontitis. Thus successful
long-term management of this disease
needs a strategy that integrates therapies
that address both etiologic components.
HMTs are an emerging treatment concept in
the management of periodontitis. HMTs
ameliorates excessive or pathologically
elevated inflammatory processes to
enhance the opportunities for wound
healing and periodontal stability. SDD is the
only systemically administered HMT
approved,and it is indicated as an adjunct
to scaling and root planing for treating
periodontitis.

33. Bibliography
Newman and Carranza's CLINICAL PERIODONTOLOGY
Third South Asia Edition

34. THANK YOU