host modulation therapy

Post Graduate Department Of Periodontics & Oral Implantology

Presented by, Dr. Muzafar 2nd Year MDS

Under The Guidance Of, Dr. Suhail Majid, Guide & Head

Host Modulation Therapy

• Host:- defined as the “the organism from which a parasite obtains its nourishment” or in the transplantation of the tissue,’ the individual who receives graft.

• Modulation is defined as “ alteration of function or status of something in response to a stimulus or an altered chemical or physical environment.

• Concept of host modulation was 1st introduced by Williams (1990) and Golub et al (1992)

• Periodontists previously believed that p. disease was an consequence of aging and uniformly distributed.

• Thought that severity was directly correlated with plaque

• Disease progression occurred in a continuous, linear manner throughout life.

• Better epidemiologic data, there has been shift about prevalence and progression of periodontitis

• Well established that periodontitis is not related to aging

• Disease severity is not correlated with plaque pts with abundant plaque and calculus deposits with

widespread gingivitis but have minimal deep pockets, In contrast ; despite maintaining high standard of plaque

control , succumb to aggressive forms of periodontitis with deep pockets , tooth mobility and early tooth lost,

the former group of patients is periodontal disease resistant,

Whereas the latter is periodontal disease susceptible.

• This host response to the bacterial challenge presented by subgingival plaque is the important determinant of disease severity.

• Although plaque bacteria are capable of causing direct damage to the periodontal tissues(antigens, lipopolysaccharide (LPS), and other virulence factors stimulates like H2S, butyric acid, other enzymes ).

• majority of the destructive events occurring in the periodontal tissues result from activation of destructive processes that occur as part of the host immune-inflammatory response to plaque bacteria.– Host response is essentially protective bt

paradoxically can also result in tissue damage : breakdown of connective tissue fibers in the periodontal ligament and resorption of alveolar bone.

• The nature of host response to the presence of plaque is modified by genetic factors( seen in aggressive periodontitis) and systemic and environmental factors( smoking , diabetes, stress).

to modify or reduce destructive aspects of host response: so that immune-inflammatory response to plaque is less damaging; host modulation therapies has been developed;

– Treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or downregulating destructive aspects of host response and upregulating protective or regenerative responses.(CARRANZA)

Definition:-

• HMTs are systemically or locally delivered pharmaceuticals that are prescribed as part of periodontal therapy and are used as adjuncts to conventional periodontal treatments.

• Historically , treatment has focused on reducing the bacterial challenge by the use of SRP, improved oral hygiene, and periodontal surgery.– However , the outcomes ( chronic disease) are not always

predictable or stable.

• Periodontal disease and health can be seen as balance between Persisting bacterial burden and proinflammatory destructive

events in the tissue.• Removal of plaque by SRP targets one aspect by reducing bacterial burden• Antigenic challenge that drives the inflammatory response in the host

tissue.• Bacterial challenge is never completely eliminated after SRP and

recolonization occurs.

HMTs offers the potential for downregulating destructive

aspects and upregulating protective aspects of host response,

• In combination with conventional treatments to reduce the bacterial burden, the balance between health ( resolution of inflammation and wound healing) and disease progression ( continued proinflammatory events) is tipped in the direction of healing.

• Poor oral hygiene Normal Exogenous infection Pathogenic flora Antibody response Neutrophil clearance

Pocketing and bone loss Gingivitis

Inflammation & tissue destruction Bacterial penetration

Cytokines &

inflammatory mediation Monocyte lymphocyte axis Systemic exposure

The host monocyte-lymphocytic axis is stimulated, local release of inflammatory mediators such as

arachidonic acid metabolites and cytokines. intern directly cause the local tissue destruction, as periodontal pocketing and alveolar bone loss in patients.

In addition, local environmental conditions secondary to these inflammatory and destructive events (such as low oxygen tension and iron availability) continue to support a pathogenic flora and perpetuate the cycle of events proposed.

• HMTs offer the opportunity for modulating or reducing this destruction by treating aspects of the chronic inflammatory response.

• HMTs do not “switch off” normal defense mechanism or inflammation; instead, they ameliorate excessive of pathologically elevated inflammatory processes to enhance opportunities for wound healing.

• Specific aspects of disease pathogenesis for modulationa) Regulation of immune and inflammatory responses.b) Regulation of excessive production of matrixmetalloproteinase’sc) Regulation of arachidonic acid metabolitesd) Regulation of bone metabolism.

.

Systemically Administered Agents :- NSAIDsBisphosphonatesSubantimicrobial- Dose Doxycycline

Locally administered Agents :-

Topical NSAIDs Enamel matrix proteins Growth factors Bone morphogenetic

proteins

Host modulating agents

• NSAIDs inhibit the formation of prostaglandins, including prostaglandin E2 (PGE2) (Grenier et al 2002).– Produced by neutrophils, macrophages, fibroblasts, and gingival epithelial

cells in response to lipopolysaccaride(LPS).

• Upregulates bone resorption by osteoclasts;(Heasman PA and Collins j p 1993)

• Levels of PGE2 are elevated in pts with periodontitis ( Plamondon and sorsa jp 2002)

• It also inhibits fibroblasts function and has inhibitory effects on the immune response (Grossi and Genco Ann Periodontics 1997).

Nonsteroidal antiinflammatory drugs

NSAIDs

Gram neg bacteria LPS activates # Neutrophils # Macrophage PGE2 Osteoclast

# Fibroblast cells cells # Gingival epi. Cells BONE

RESORPTION

Mechanism:-

• Inhibits prostaglandins• Reduce inflammation

– Used to treat pain, acute inflammation, and chronic inflammatory conditions.

– Inhibits osteoclastic activity in periodontitis (Howell TH in oral bio med 1993).

• NSAIDs such as indomethacin(williams RC jp 1987), flurbiprofen (jeffcoat MK JP 1989), and naproxen(Howell TH 1993) administered daily for up to 3 years, significantly slowed the rate of alveolar bone loss compared with placebo.

Action:-

Disadvantages when used as a HMT for periodontitis.

• Administration for extended periods is necessary for periodontal benefits to become apparent, and are associated with significant side effects:– gastrointestinal problems, – hemorrhage (from decreased platelet aggregation), – and renal and hepatic impairment.

• research shows that the 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, often referred to as a “rebound effect.”[ (William RC j dent res 1991)

selective cyclooxygenase-2 (COX-2) inhibitors offers as adjunctive treatments in the management of periodontitis.

• cyclooxygenase, which converts arachidonic acid to prostaglandins, exists in two functionally distinct isoforms, COX-1 and COX-2.

• • COX-1 has antithrombogenic and cytoprotective functions.

• inhibition of COX-1 by nonselective NSAIDs causes side effects– gastrointestinal ulceration – and impaired hemostasis.

• .

– use of selective COX-2 inhibitors reduce periodontal

inflammation without the side effects typically observed

after long-term (nonselective) NSAID therapy.

– selective COX-2 inhibitors slowed alveolar bone loss in

animal models(Bezerra MM jp 1993) and modified

prostaglandin production in human periodontal tissues

(Vardar S JPeriodontol 2003). However, the selective

COX-2 inhibitors were later identified to be associated

with significant and life-threatening adverse effects,

resulting in some drugs being withdrawn from the market.

NSAIDs (including the selective COX-2 specific inhibitors) are presently not indicated as adjunctive HMTs in the treatment of periodontal disease

summary,

Role ofarachidonic acidmetabolites.

Mode of interception

SignificantContributors

Agentsemployed

Author’s coments

Prostaglandinsand otherarachidonic acidmetabolites withinthe periodontaltissues play a rolein thepathogenesis.

Inhibition of arachidonic acid metabolite byblocking of the cyclooxygenase pathway

Goldhaberet al (1973)Nyman et al(1979)Weaks-Dybvig et al(1982)Offenbacheret al (1987)Jeffcoat etal (1991)

Indomethacin,Flurbiprofen,S-Ketoprofen,Triclosan.

Systemic dailyadministration forperiods up to threeyears ,showed significant reduction in rate ofbone loss, major disadvantage ofrebound effect

Author Purpose Host MAgent

Parameters Subjects Results

Ishihara y,nishihara tet al(1991)

demonstrate thelipopolysaccharide isolated from a.a comitans strain induced bone resorption

Indomethacindexamethasone

PGE2 and IL-1levels

Mouse PGE2 and IL-1participate in LPSinduced boneresorption in vitro.

Howell th,fiorellini i,weber hp etal (1991)

To study the effects of piroxicam inpreventing gingival inflammationand plaque formation

Piroxicam Gingivalinflammationplaque index

Beagle dogs

Significantly inhibitthe development ofgingival inflammation

Roy S,Feldman,Szeto B et al(1983)

To evaluate the effect on boneresorption: A retrospective study

Aspirin (asp) oraspirin plusindomethcin

Radiographs

Humans Percentage bone lossfor the entiredentition was lower inasa group

OffenbacherS, Odle BMet al (1989)

metabolites of cyclooxygenase(co) during the progression of periodontitis

Flurbiprofen Crevicular fluidlevels of PGE2and TXB2

Rhesus monkey

prevented rise inTXB2, but did notaffect increase in PGE2.

HeasmanPA, et al(1993)

efficacy offlurbiprofen (50mg) on bothdeveloping and establishedgingivitis

Flurbiprofen GCFconcentrationof PGE2, TXB2and LTB4,Bleeding index

Human control gingivalinflammation with bothpreventive and therapeuticproperties

• The bisphosphonates are bone-seeking agents . inhibit bone resorption by disrupting osteoclast activity.

• interfere with osteoclastic metabolism and secretion of lysosomal enzymes (Weinreb M et al J Periodontal 1994) possess anticollagenase properties (Nakaya H et al J Periodontol 2000)

• treatment with the bisphosphonate significantly increased bone density compared with placebo ( Reddy MS et al J Periodontol 1995)

• In human studies, these agents resulted in enhanced alveolar

bone status and density (Rocha M et al J Periodontol 2001)

• The ability of bisphosphonates to modulate osteoclast activity clearly may be useful in the treatment of periodontitis,

Bisphosphonates

• Some bisphosphonates have the unwanted effects– inhibiting bone calcification – inducing changes in white blood cell counts. – avascular necrosis of the jaws following bisphosphonate therapy,

with the resultant risk of bone necrosis following dental extractions (Carter G, Goss AN Med J Aust 2005)

• Bisphosphonate-related osteonecrosis of the jaw, although primarily associated with intravenous administration of bisphosphonates rather than oral administration,

• has impeded the development of bisphosphonates as an HMT to manage periodontitis.

• As with NSAIDs, at present there are no bisphosphonate drugs that are approved and indicated for treatment of periodontal diseases

Author Purpose Hostmodulatingagent

Parameters Subjects

Results

Shoji K,HoriuchiH (1995)

Efficacy of risendronate to preventalveolar bone resorption

Risendronate

Bone mineraldensity

Rats. In preventing bone resorption in periodontitis

M young H ,P ark JY et al(2 001 )

evaluate the clinic al availabilityof bisphosphonate in auto genousfree bone grafts

Bisphosphonates

Clinicalmeasurements,histomorphological review

Rats Clinical application ofbisphosphonates fordecreasing resorption ofgrafted bone

Durate P M ,Gurgel B C D e t a l(2 0 0 5

To evaluate whether alendronate (ald) influenceBone healing around titan iumimplants

Alendronate Estrogen levels

rats . Alendronate may preventnegative influence of estrogen deficiency on bone healing around titanium implants

Howell 1991, His-Ming 2004,Holzhausen 2005,Gurkan 2005,Durate 2005.

Inhibition ofosteoclast/MMP activitythrough chelation ofcations.

Bisphosphonates(Alendronate),Hormonereplacementtherapy.(HRT),OPG- Fctherapeutic agents

Osteoporosis andosteopenia may beindicators forperiodontaldiseases.

humans improves theclinical outcome of nonsurgical periodontaltherapy and may be an appropriate adjunctive treatment to preserve periodontal bone mass.

» Sub-Antimicrobial-Dose Doxycycline

• Sub-antimicrobial-dose doxycycline (SDD) is a 20-mg dose of doxycycline (Periostat) that is approved and indicated as an adjunct to SRP in the treatment of chronic periodontitis.

• It is taken twice daily for 3 months, up to a maximum of 9 months of continuous dosing.

• therapeutic effect by enzyme, cytokine, and osteoclast inhibition rather than by any antibiotic effect.

Sub-antimicrobial dose doxycycline

• studies have found no detectable antimicrobial effect on the oral flora or the bacterial flora in other regions of the body.

• At present SDD (Periostat) is the only systemically administered HMT specifically indicated for the treatment of chronic periodontitis that is approved by the US Food and Drug Administration (FDA) and accepted by the American Dental Association (ADA).

• In addition, a modified-release SDD was recently approved by the FDA (Oracea) for the treatment of the common skin disorder rosacea and is routinely prescribed within the dermatology community.

• Studies conducted by Preshaw et al in J Periodontol 2008 utilizing this same modified-release SDD versus placebo with periodontitis as an adjunct to SRP resulted in significantly greater clinical benefits than SRP alone in the treatment of periodontitis.

• There has also been considerable off-label use of this new modified-release SDD for the treatment of periodontal diseases based on the understanding that once-a-day administration can increase the level of compliance as compared to twice-a-day oral administration.

• Tetracycline's work well as host modulation agents because of their pleiotropic effects on multiple components of the host response . The only enzyme (MMP) inhibitors that have been approved for clinical use and tested for the treatment of periodontitis .

• Golub et al (J Periodont Res 1985). reported that the semisynthetic compound (e.g., doxycycline) was more effective than the parent compound tetracycline in reducing excessive collagenase activity in the GCF of chronic periodontitis patients.

•

Mechanisms of Action

• doxycycline was found to be a more effective inhibitor of collagenase than either minocycline or tetracycline (Burns FR 1989) and

• because of its safety profile, pharmacokinetic properties, and ready systemic absorption. to eliminate the side effects of long-term tetracycline therapy, especially the emergence of tetracycline-resistant organisms, SDD capsules were prepared and tested( Golub LM1985)

• Each capsule contained 20 mg of doxycycline versus the commercially available 50 mg and 100 mg, antimicrobially effective, capsules or tablets.

• clinical studies using sub-antimicrobial doses of doxycycline have shown no difference in the composition or resistance level of the oral flora (Thomas J; jp 2000)

• no appreciable differences in either fecal or vaginal microflora ( Walker C; J Clin Periodontol 2005)

• no overgrowth of opportunistic pathogens, such as Candida, in the oral cavity, gastrointestinal system, or genitourinary system.

• doxycycline ( other members of the tetracycline family) has the ability to downregulate MMPs,

• a family of zinc-dependent enzymes that are capable of degrading extracellular matrix molecules, including collagen (Birkedal-Hansen H J Periodontol 1993

• MMPs are secreted by fibroblasts, keratinocytes, macrophages, PMNs, endothelial cells and play a key role in periodontitis.

• Excessive MMPs are released in inflamed periodontal tissues, resulting in breakdown of the connective tissue matrix.

• The predominant MMPs in periodontitis, particularly MMP-8 and MMP-9, derive from PMNs (Golub LM et al J Clin Periodontol 1995) and are extremely effective in degrading type I collagen, the most abundant collagen type in gingiva and periodontal ligament (Mariotti A Periodontol 2000 )

• Levels of PMN-type MMPs have been shown to increase with severity of periodontal disease and decrease after therapy (Golub LM, Ciancio et al J Periodontal Res 1990)

• The rationale for using SDD as a HMT in the treatment of periodontitis is that doxycycline downregulates the activity of MMPs by a variety of synergistic mechanisms, including reductions in cytokine levels, and stimulates osteoblastic activity and new bone formation by upregulating collagen production

Golub et al 1985 reported that a 2-week regimen of SDD reduced collagenase in GCF and in the adjacent gingival tissues surgically excised for therapeutic purposes.

He found using SDD therapy adjunctive to routine scaling and prophylaxis cause continued reductions in the excessive levels of collagenase in the GCF after 1 month of treatment.

After cessation of SDD administration, however, there was a rapid rebound of collagenase activity , suggesting that a 1-month treatment regimen with this host modulation agent was insufficient to produce a long-term benefit(Ashley RA 1999)

In contrast, during the same study, a 3-month regimen produced a prolonged drug effect without a rebound in collagenase levels to baseline during the no-treatment phase of the study.

these reductions in collagenase levels were gains in the relative attachment levels in the SDD group( Ashley RA 1999)

history of allergy or hypersensitivity to tetracyclines.

pregnant or lactating women or children less than 12 years old (because of the potential for discoloration of the developing dentition).

reduce the efficacy of oral contraceptive.

There is a risk of increased sensitivity to sunlight (manifested by an exaggerated sunburn) seen with higher doses of doxycycline, although this has not been reported in using the sub-antimicrobial dose.

Contraindications:

Doxycycline at antibiotic doses (≥100 mg) is associated with adverse effects, including

photosensitivity, hypersensitivity reactions, nausea, vomiting, and esophageal irritation.

SDD (20-mg dose), it was reported that the drug was well tolerated, and the profile of unwanted effects was virtually identical in the SDD and placebo groups (Caton JG JP2000; Novak MJ J Periodontol 2002)

Side Effects:-

• Combining with Periodontal Surgery or Local Delivery Systems:-

• SDD was used as an adjunct to flap surgery revealed better probing depth reductions in surgically treated sites greater than 6 mm compared with surgically treated sites in patients given placebo (Gapski R J Periodontol 1999)

• greater reductions in ICTP (carboxy-terminal peptide, a breakdown product of collagen) than the placebo group, indicating that collagenolytic activity was reduced in the patients taking SDD.

• SDD can also be combined with the local delivery of antibiotics into the periodontal pocket through sustained-delivery systems. The two treatment approaches target different aspects of the pathogenic process: – local delivery systems deliver antimicrobial concentrations of

an antibacterial agent directly into the site of the pocket, whereas SDD is a systemic host response modulator.

• (SRP + local antibiotics) can be combined with HMT (SDD) to maximize the clinical benefit for patients (Novak MJ J Periodontol 2008)

Author Purpose Hostmodulatingagent

Parameters Subjects Results

Crout RJ,Lee HM,et al(1996)

check for potency of low dosedoxycycline

Low dosedoxycycline

CAL, PD and GCFCollagenase activity andPeriodontal ligamentdegradation

Human LDD inhibits tissuedestruction in the absence ofantimicrobial property.Long term LDD could be auseful adjunct toinstrumentation

Golub LM, LeeHM et al (1997)

inhibitor of matrixmetalloproteinases(MMP’s) administered to human , can reduce bone type collagendegradation in inflammatory exudates

Doxycycline Collagenaseactivity

Human Reduction of excessiveMMP activity withconcomitant reduction in collagen degradationproducts

Golub LM ,Mc NamaraT F et al(2 001 )

clinically effective doseregimens using subantimicroaldose doxycycline (SDD) as anadjunctive therapy in patients withadult periodontitis

Doxycycline Clinical attachment level Human s significant potential asan oral adjunctive therapy inthe long term managementof adult periodontitis

Novak M J ,Dawson D R , e ta l 2 0 0 8

combination of systemicallyadministered host-modulating therapy & locally administered topical antimicrobialtherapy , asadjuncts to scaling and rootplaning(SRP),would providesignificantly improved clinicalbenefits in the treatment ofuntreated moderate to severechronic periodontitis(CP)compared to SRP alone .

Low dose(20mg) doxycycline hyclate ,doxycyclineHyclate gel

(CAL) ,(BOP), and the gingivalindex(GI)

Humans criticalrole in disrupting theprogression ofperiodontal breakdown

• Nonsteroidal Antiinflammatory Drugs

– Topical NSAIDs have shown benefit in the treatment of periodontitis.

– chronic periodontitis who received topical ketorolac mouthrinse reported that gingival crevicular fluid (GCF) levels of PGE2 were reduced by approximately half over 6 months and that bone loss was halted ( Jeffcoat MK et al:. J Periodontol 1995..

– topically administered NSAIDs have not been approved as local HMTs for the management of periodontitis.

Locally Administered Agents

http://www.expertconsultbook.com/expertconsult/b/linkTo?type=journalArticle&isbn=978-1-4377-0416-7&title=A+comparison+of+topical+ketorolac,+systemic+flurbiprofen,+and+placebo+for+the+inhibition+of+bone+loss+in+adult+periodontitis&author=Jeffcoat%C2%A0MK+Reddy%C2%A0MS+Haigh%C2%A0S&date=1995&volume=66&issue=&firstPage=329&shortTitle=J%20Periodontol

– Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic Proteins:-

local HMTs used as adjuncts to surgical procedures, not only to improve wound healing but also to stimulate regeneration of lost bone, periodontal ligament, and cementum, restoring the complete periodontal attachment apparatus.

These have included – enamel matrix proteins – bone morphogenetic proteins (BMP-2, BMP-7),– growth factors (platelet-derived growth factor, – Insulin like growth factor. – and tetracyclines.

• The locally applied HMTs currently approved by the FDA for adjunctive use during surgery are – enamel matrix proteins (Emdogain), – recombinant human platelet-derived growth

factor-BB (GEM 21S),– and BMP-2 (INFUSE).

• The initial local host modulatory agent approved by the FDA for adjunctive use during surgery to assist with clinical attachment gain and wound healing was Emdogain;

• this has been followed by platelet-derived growth factor combined with a resorbable synthetic bone matrix (GEM 21S) to assist in regenerative procedures , wound healing, particularly in patients with diabetes

• rhBMP-2 (INFUSE) soaked on to an absorbable collagen sponge to assist with ridge and sinus augmentation and healing of fractures by the orthopedic community.

• NO synthase inhibitors:-

• Lietao et al (2005) reported that nitric oxide synthase (NOS) inhibitors have protective effects against bone resorption and inflammatory process in periodontitis in rats.

• Lappin et al. in 2000 reported that inducible NOS (iNOS) is responsible for nitric oxide (NO) production by epithelial and inflammatory cells in response to proinflammatory cytokines in some inflammatory diseases such as rheumatoid arthritis and periodontal disease.

Newer Agents for Host Modulation

Although NO has an antimicrobial protective activity, its elevated concentration in the tissues has a cytotoxic effect toward the host cells.

Leitao et al. in 2005 found a reduction of alveolar bone loss and gingival inflammation after the use of a selective iNOS inhibitor – mercaptoethylguanidine – confirming that NO has a deleterious role in the pathophysiology of periodontitis and that its modulation may prevent tissue destruction.

– Recombinant human interleukin-11

According to Trepicchion et al 1995, IL-11 was shown to have anti-inflammatory effects by inhibition of TNF-α and other proinflammatory cytokines.

Leng et al. in 1995 observed that it indirectly minimizes tissue injury through stimulation of tissue inhibitor of metalloproteinase-1 (TIMP-1).

Martuscelli et al. in 2000 investigated the ability of recombinant human IL-11 (rhIL-11) to reduce periodontal disease progression. – Significant reduction in the rate of clinical attachment and

radiographic bone loss were observed after an 8-week period of rhIL-11 administration twice a week (Elias JA. J Immunol. 1997)

• Omega-3 fatty acid

• Vardar et al. in 2005 evaluated the use of omega-3 fatty acids for blocking arachidonic acid cascade in induced periodontal disease in rats.

• results in the inhibition of production of not only prostaglandins derived from the COX pathway but also leukotrienes derived from the lipooxygenase pathway. The combined use of omega-3 fatty acid with celecoxib, acts as synergism for anti-inflammatory effect.

• Therapy resulted in significant superior reductions on periodontal tissue levels of prostaglandins, leukotriene B4, and platelet-activating factor

• Disruption of Cell Signaling Pathway

• preventing cell activation seek to inhibit the intracellular transduction of signals produced when ligands bind to their membrane receptors.

• Inhibition of signal transduction pathways abolish both cell activation by cytokines or other stimuli and the production of proinflammatory cytokines.

• Cytokines and bacterial components activate many signal transduction pathways .– include the mitogen-activated protein kinase (MAPK) pathway,– phosphatidylinositol-3 protein kinase (PI3) pathway, – janus kinase-signal transducer and activator of transcription (Jak-

STAT),– and nuclear factor kappa B (NF-kB) .

• Therapeutic strategies have been directed toward many of these major signaling pathways, notably MAPK and NF-kB, which are discussed below

• MAPK inhibitors• Inhibit LPS-induced MMP, cytokine (IL-1b, TNF-α, IL-6,

IL-8), and prostaglandin expression.( Lee JC, Immunopharmacology. 2000)

• NF-kB family inhibitors• Inhibit NF-kB–dependent expression (IL-1, TNF-α, IL-6,

IL-8), MMPs, and others (Kimura A1998)

• Disruption of the RANKL/RANK/Osteoprotegerin Axis

• The RANKL/RANK interaction is responsible for differentiation and maturation of osteoclast precursor cells to activate osteoclasts.

• Osteoprotegerin acts as a decoy receptor, expressed by osteoblastic cells, which binds to RANKL and inhibits osteoclast development (Kong YY 1999) Several studies have shown the opposite effect of RANKL and osteoprotegerin in bone modulation.

• Periodontal pathogens and destructive host responses are involved in the initiation and progression of periodontitis.

• Therefore the successful long-term management

require a treatment strategy that address both etiologic components.

• Evidence for the role of MMPs, cytokines, and other mediators in the pathogenesis of periodontal disease distinguishes them as viable targets for a chemotherapeutic approach.

summary

• adjunctive therapies such as host modulation to enhance the efficacy of existing mechanical procedures contributes favorably to an integrated approach for the long-term, clinical management of periodontitis.

• HMTs are an emerging treatment concept in the management of periodontitis.

• The use of HMT as an adjunct may be particularly useful in susceptible, high-risk patients in whom a prolonged and excessive host response occurs to presence of bacteria ,promotes the activity of MMPs and osteoclasts.

• SDD is the only systemically administered HMT currently approved and indicated as an adjunct to SRP for treating periodontitis. Clinical trials have demonstrated a clear treatment benefit when using SDD versus SRP alone.

• In the future, a range of HMTs targeting different aspects of the destructive cascade of breakdown events in the periodontal tissues are likely to be developed as adjunctive treatments for periodontitis

• The goal is to maximize the treatment response by reducing inflammation and inhibiting destructive processes in the tissues, which will result in enhanced periodontal stability after conventional periodontal treatments such as SRP and surgery.

• the use of HMT to better manage chronic periodontal disease have applications to other chronic systemic diseases such as arthritis, diabetes, osteoporosis, and cardiovascular disease.

• In addition, studies utilizing locally applied antimicrobials as part of an intensive periodontal therapy (IPT) regimen have shown very promising results both in periodontal disease and overall health status of high risk patients..

• The proper management of local infection and inflammation (periodontitis) will have a significant impact on general overall health of the population.

• The three main sub-families of MAPKs are extracellular-regulated kinases (ERK-1/-2), c-Jun N-terminal activated

kinases (JNK) and p38.

host modulation therapy

Education

host tissue

nature of host response

chronic inflammatory

plaque disease progression

periodontal disease

concept of host modulation

plaque bacteria

periodontal pocketing