IJCRR

IJCRR - 4(5), March, 2012

Pages: 101-107

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HOST RESPONSE MODULATION: A MYTH OR REALITY?

Author: Kriti Agarwal, Jaideep Mahendra, Little Mahendra, Jananni .M, Rajeshree.R

Category: Healthcare

Abstract:Periodontitis is a complex microbial disease involving various mechanisms that results in
destruction of connective tissue and bone. Past understanding of etiology and pathogenesis of
periodontal disease focused on the microbial aspect. Based on this the therapeutic efforts were
focused on mechanical or chemotherapeutical removal of bacterial plaque. The plaque biofilm
though considered the prime etiologic factor; it has been just associated with the initiation of
disease. Recent investigations have recognized the crucial role played by host responses involved in the progression & severity of the disease. So therapeutic efforts now is focused on altering (modulating) the host responses. The recent treatment strategy lies in modifying the host responses which will also help in evading the other risk factors like environmental and genetic that can modify the periodontal disease susceptibility. Host Modulation Therapy?s are emerging treatment concept in management of periodontal disease. This review focuses on the present concept of host modulation in comprehensive periodontal management and various chemotherapeutic agents currently applied in Host Modulation Therapy.

Full Text:

INTRODUCTION
Periodontal diseases, which cause the destruction of the supporting structures of the dentition, are common chronic infectious diseases of the oral cavity. They are initiated by Gram negative toothassociated pathogens organized as a biofilm, whose presence elicits a host inflammatory response. Thus, periodontal treatment through the ages has focussed on the reduction of bacterial infection by mechanical removal of plaque and calculus from tooth surfaces i.e. SRP. However, recent research into the pathogenesis of periodontal diseases has led to an important paradigm shift. It is now recognised that the major component of the soft and hard tissue destruction seen in periodontitis occurs as a result of activation of the host?s immuneinflammatory defence mechanisms in response to the presence of bacterial plaque.1 Host-derived pro-inflammatory mediators and cytokines,togetherwith proteolytic enzymes such as matrixmetalloproteinases (MMPs), play a significantrole in the changes in connectivetissue and bone metabolism thatlead to the breakdown of periodontalligament (PDL) and alveolar boneresorption. Host modulatorytherapy (HMT) can be combinedwith traditional periodontal therapiesthat reduce the bacterial burden (e.g.SRP) and also risk factor modification(e.g. smoking cessation therapy) toconstitute a comprehensive treatmentstrategy for periodontitis. Three most important potential approaches to host modulation include: a) inhibition of matrix metalloproteinases (MMPs) with antiproteinases b) blocking production of proinflammatory cytokines and prostaglandins with anti inflammatory drugs and c)inhibition of active osteoclasts with bone sparing agents.2 To date, thereis one approved, systemic therapy that isprescribed as a host response modifier inthe treatment of periodontal disease andthat is adjunctive subantimicrobial dosedoxycycline (SDD) which downregulates theactivity of MMPs.

MATRIX METALLOPROTEINASES (MMPs)
Acting as the prototypical endotoxin, lipopolysaccharides(LPS), amajor component of the outer membraneof Gramnegative bacteria, initiate the cascadeof events leading to periodontal tissue destruction.3 The MMPs comprise a family of zinc dependentproteolytic enzymes. MMPs areprimarily responsible for degrading theextracellular matrix in a variety ofpathological conditions including rheumatoidarthritis, osteoarthritis, autoimmuneulcerative skin lesions and alsotumour cell invasion and metastasis.4MMPsalso play a key role in periodontitis, andare produced by each of the major celltypes found in human periodontal tissuesincluding fibroblasts, keratinocytes,macrophages, PMNs (neutrophils) andendothelial cells.5 They are implicated in a number ofprocesses in normal bone remodeling, including boneresorption and bone formation. MMPs are usedas a biomarker of periodontalseverity and as a response to therapy.

Inhibition of MMPs
Currently, clinical therapy inhibiting the mediatorsof connective tissue breakdown (eg MMP) is used for the adjunctivetreatment of periodontitis. This is accomplishedthrough the non-antimicrobial activities of low-dosetetracycline and tetracycline analogs via the inhibitionof MMP-8 and -13 protease mechanisms.6The tetracyclineanalog doxycycline hyclate, available for usespecifically in periodontal disease, is the only collagenaseinhibitor approved by the United States Foodand Drug Administration (FDA) for any human disease.7A major concern, however,was that the long-term administrationof doxycycline might be associated withthe development of antibiotic resistance.Indeed, when antibiotic doses of tetracycline(250 mg daily for 2–7 years) hadpreviously been given to patients withrefractory periodontitis, up to 77% ofthe patients? cultivable subgingival microfloraexhibited tetracycline resistance.8 In light of thisconcern, a low, subantimicrobial dose of doxycycline (SDD) preparation wasintroduced, containing 20 mg doxycycline,as opposed to the 50 or 100 mgdose that is available for antibioticpurposes.9 SDD (20 mgtwice daily) administered for just 2weeks inhibited collagenase activity by60–80% in the gingival tissues ofpatients with chronic periodontitis.9 Because the low-dose formulationsof these drugs have lost their antimicrobial activity,the therapeutic action witnessed is primarily due tothe modulation of the host response. This subantimicrobial-dose doxycycline (SDD) approach has becomewidely established as an effective adjunctivesystemic therapy in the management of periodontitis,along with the traditional mechanical therapies ofscaling and root planing (SRP).

In a recent systematic review,the effectiveness of SRP accompanied by MMP inhibition(by SDD), as an adjunctive treatment, showedimproved outcomes that persisted for 9 months inadults with chronic periodontitis as observed in gainsin clinical attachment level (CAL) and probing depth(PD) reduction.2Recentstudies11, 12 demonstrated the abilityof SDD to be used to maintainbonemass while reducing periodontaldiseaseprogression.In another early clinical study13the efficacy and safety of SDD were evaluated in conjunctionwith SRP in subjects with chronic periodontitis.Here, the more severe the periodontitis, the greaterthe observed attenuation of disease activity by SDD therapy. Although there is strong evidenceto suggest that inhibition ofMMPs in patients with periodontaldisease clearly offers potential indisease management when coupledwith mechanical therapy, suchas SRP, there is only preliminary evidence available to suggest the value of MMP inhibitorytherapies for patients with periimplant diseaseor in those conditions requiring surgical management.2,9

It has been shown that SDD (marketed as Periostat) hasno antibacterial activity and does not produce resistantstrains even after months of use. Adverse effects are alsominimal, with a side effect profile similar to placebo.However, like all tetracyclines, there is the potential formultiple drug interactions, particularly with calcium andmagnesium containing preparations. The drug should alsonot be given to patients who are known to be allergic tothe tetracyclines and is to be avoided in pregnancybecause of the risk of tetracycline stain in developingteeth. Currently, SDD is the only drug regimen approvedspecifically for host modulation in the treatment ofperiodontitis. It is not entirely clear how long SDD needsto be used, but the drug can be safely administered for upto 9 months. One protocol for the use of the drug calls for SDD to be prescribed for 3 months at the beginning oftreatment (scaling and root planing) with reevaluation atthe end of the three month trial of the drug. If thepatient has responded well with respect to changes inclinical parameters, the drug can be discontinued. Forthose individuals not responding well to phase 1 therapy,the drug can be continued as additional treatment isrendered.

Bisphosphonates as bone-sparing agents
Bisphosphonate drugs have wellcharacterized modulatoryroles on osteoclast function and bone metabolism.14Notably, at the tissue level, they decreasebone turnover by decreasing bone resorption and byreducing the number of new bone multicellular units.At the cellular level, they decrease osteoclast and osteoblastrecruitment, decrease osteoclast adhesion,and decrease the release of cytokines by macrophages. Based on these properties, severalgenerations of oral bisphosphonate drugs have beensuccessfully developed for the treatment of postmenopausalosteoporosis, osteopenia, and Paget?s diseaseof bone.15Because of these same properties, apossible use for this class of drugs in the managementof periodontal disease was put forth.A few clinical studies have been performed to examinea possible use for bisphosphonates in the managementof periodontal bone loss. In a study15 of 40subjects with chronic periodontitis,a statistically significantdecrease in the proportion of teeth demonstratingbone losswas observed.

ADVERSE EFFECTS WITH BISPHOSPHONATE DOSING
Bisphosphonates are administered by intravenous (IV)infusion (in the case of treatment for metastatic bonecancers) or orally (for the treatment of decreased bonedensity in osteoporosis). Because of a significant rateof non-compliance and the subsequent decrease inclinical efficacy, IV bisphosphonate delivery has beenused extensively for malignant bone diseases, as wellas in breast, prostate, and lung cancer.17However, anumber of publications18,19 documented the retrospectivereports associating IV bisphosphonate delivery andosteonecrosis of the jaws (ONJ).Clinically, ONJis essentially exposed bone in the maxilla or mandiblethat does not healwithin 8 weeksof identification by health careprofessionals (HCPs). Compromised healing was successfully treated withsystemic antibiotics, local microbial mouthrinse, andaggressive defect management via detoxification andamixture of bone graft and tetracycline. 17This suggeststhat dental health care professionals should treat patients undergoinglong-termoral bisphosphonate treatment with caution. Overall, the use of bisphosphonates for the managementof periodontal diseases has limited promise,especially in affecting alveolar bone loss. However,despite their different mode of action, additional studiesare needed to evaluate their potential as alveolarbone–sparing agents.Considerations related tothe duration of use are relevant, given the reportedrisks associated with ONJ related to the long-term useof high-dose bisphosphonates, contrasting the potentialbenefits of the short-term oral use of these drugs.Despite progression in this area of research and a betterunderstanding of the reported risks, a number ofquestions for future consideration of bisphosphonatesin the treatment of periodontal diseases remain, whichshould be addressed.

TREATMENT RECOMMENDATIONS FOR PATIENTS WITH OSTEOPOROSIS RECEIVING BISPHOSPHONATE THERAPY19:

• Patients informed of risks
• Oral hygiene and dental care emphasized
• Not necessary to require dental examination prior to bisphosphonate therapy or alter dental management
• For patients on bisphosphonates >3 years:

Periodontal disease treatment nonsurgically or conservative surgical therapy Dental-implant placement with informed consent Endodontic treatment preferable to extraction or periapical surgery For invasive procedures, a drug vacation may be helpful but has not been validated

Non steroidal anti inflammatory drugs
Non steroidal anti inflammatory drugs (NSAIDS) have been traditionally utilized in the treatment of pain and acute and chronic inflammation. The antiinflammatory activity of NSAIDS occurs through the inhibition of prostaglandin synthesis. NSAIDS limit the progression of periodontitis through the ability to reduce inflammation and to decrease bone resorption. Several studies have indicated along with SRP, systemically administered NSAIDS like flurbiprofen, naproxen and meclofenamate sodium decrease the rate of alveolar bone loss.

The potential harmful side effects of chronic NSAID therapy include gastrointestinal upset and bleeding. The use of NSAID in periodontitis is still under investigation.

CONCLUSION
There has been a great deal of basic and clinical researchfocusing on the underlying mechanisms ofthe major enzymatic drivers of the aggressive tissuedestruction found in periodontitis. Major drivers of this damage are MMPs and other osteoclastderivedmediators of bone resorption, all of which actas part of the host inflammatory response. Modificationof this host response via the use ofMMPinhibitors,along with the use of bisphosphonates as blockers ofperiodontal tissue destruction, has shown promise inthe therapeutic treatment of these disease states. Althoughquestions remain regarding optimizing treatmentefficacy while limiting any potential adverseeffects, the evidence clearly suggests a strong potentialfor the modulation of the host response in aidingdisease management, when coupled with traditionalmechanical therapy.20

Future approaches
An emerging concept in the study ofinflammation is the idea that inflammation is activelyterminated following an insult rather than just fading away.Resolution of inflammation appears to be promoted byactive mediators designated resolvins and protectins.These specialized molecules are synthesized at the site ofinflammation and help to terminate inflammation and promote regeneration in several ways, includingpromoting removal of cellular debris and reducingrecruitment of neutrophils. Inhibition of inflammatory cytokines through recombinant human IL- 11 is being investigated. The antiinflammatory actions of omega-3 fatty acids havealso been verified for treatment of rheumatoid arthritis(RA). When used to treat RA, omega-3 fatty acids havebeen shown to reduce pain and inflammation and toreduce the need to take other medications such asNSAIDs.

References:

1. Offenbacher S: Periodontal diseases pathogenesis. Annals of Periodontology 1996; 1: 821–878.

2. Reddy MS, Geurs NC, Gunsolley JC: Periodontal host modulation with antiproteinase, anti-inflammatory and bone sparing agents. A systematic review. Annals of Periodontology 2003; 1: 12-37.

3. Kinney JS, Ramseier CA, Giannobile WV: Oral fluid based biomarkers of alveolar bone loss in periodontitis.Ann N Y Acad Sci 2007;1098:230-251.

4. Birkedal-Hansen, H: Role of matrix metalloproteinases in human periodontal diseases. Journal of Periodontology 1993;64: 474–484.

5. Preshaw PM, Hefti AF, Jepsen S, Etienne D, Walker C, Bradshaw H:Subantimicrobial dose doxycycline as adjunctive treatment for periodontitis.A review. J Clin Periodontol 2004; 31: 697–707.

6. Ashley RA: Clinical trials of a matrix metalloproteinase inhibitor in human periodontal disease. SDD Clinical Research Team. Ann N Y Acad Sci 1999; 878:335-346.

7. Sorsa T, Tja¨derhane L, Konttinen YT, et al: Matrix metalloproteinases: Contribution to pathogenesis, diagnosis and treatment of periodontal inflammation.Ann Med 2006; 38:306- 321.

8. Kornman KS, Karl EH: The effect of long-term low-dose tetracycline therapy on the subgingival microflora in refractory adult periodontitis. J of Periodontology 1982; 53: 604–610. 

9. Golub, LM, Ciancio SG, Ramamurthy NS, Leung M, McNamara TF: Lowdose doxycycline therapy: effect on gingival and crevicular fluid collagenase activity in humans. Journal of Periodontal Research 1990; 25: 321– 330.

10. Golub LM, Lee HM, Ryan ME, et al: Tetracyclines inhibit connective tissue breakdown by multiple nonantimicrobial actions. Adv Dent Res 1998; 12: 12-26.

11. Payne JB, Stoner JA, Nummikoski PV, et al: Subantimicrobial dose doxycycline effects on alveolar boneloss in post-menopausal women. J Clin Periodontol 2007; 34:776-787.

12. Reinhardt RA, Stoner JA, Golub LM, et al: Efficacy of sub-antimicrobial dose doxycycline in post-menopausal women: Clinical outcomes. J Clin Periodontol 2007; 34:768-775.

13. Caton JG, Ciancio SG, Blieden TM, et al: Treatment with subantimicrobial dose doxycycline improves the efficacy of scaling and root planing in patients with adult periodontitis. J Periodontol 2000;71: 521-532.

14. Tenenbaum HC, Shelemay A, Girard B, Zohar R, Fritz PC.: Bisphosphonates and periodontics: Potential applications for regulation of bone mass in the periodontium and other therapeutic/diagnostic uses. J Periodontol 2002;73:813-822.

15. Kamel HK: Update on osteoporosis management in long-term care: Focus on bisphosphonates. J Am Med Dir Assoc 2007;8:434-440.

16. Jeffcoat MK, Reddy MS : Alveolar bone loss and osteoporosis: Evidence for a common mode of therapy using the bisphosphonate alendronate. In: Davidovitch Z, Norton LA, eds. Biological Mechanisms of Tooth Movement and Craniofacial Adaptation,vol. 1. Cambridge, MA: Harvard Society for the Advancement of Orthodontics; 1996:365-373.

17. Wang HL, Weber D, McCauley LK: Effect of long-term oral bisphosphonates on implant wound healing: Literature review and a case report. J Periodontol 2007; 78:584-594.

18. Ficarra G, Beninati F, Rubino I, et al: Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment. J Clin Periodontol 2005;32: 1123-1128.

19. Khosla S, Burr D, Cauley J, et al: Bisphosphonate associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22:1479-1491.

20. Giannobile WV:Host response therapeutics for periodontal disease. J Periodontol 2008; 79:1592-1600.