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Vol.4 No.2 - May/June 2010
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HOST MODULATION

Nov/Dec 2008 — Vol. 2, Iss. 5

Host Modulation for the Treatment of Periodontal Diseases

Ray C. Williams, DMD

Until the 1970s, treatment strategies for periodontal diseases were primarily based on the understanding that plaque bacteria and their products mediated the tissue destruction in periodontal patients. This concept began to change, however, when investigators reported that host responses to the causative bacteria were a major contributor to disease pathogenesis. With a new understanding of host response and periodontal disease pathogenesis, it became apparent that inhibition of certain host response pathways might be an additional strategy, in addition to suppressing the causative bacteria, for treating periodontal diseases. The current understanding of periodontal disease etiology and pathogenesis emphasizes the role of the host in tissue destruction (Figure 1 View Figure).

Initial Studies of Host Modulation
In the early 1970s, Paul Goldhaber and Max Goodson began to implicate arachidonic acid metabolites as important inflammatory mediators of the bone loss of periodontitis. The arachidonic acid metabolites include a variety of fatty acid-derived compounds that are enzymatically produced and released in response to local tissue injury. These metabolites, such as prostaglandins, were implicated as major mediators of tissue loss in periodontal diseases because they are potent stimulators of bone resorption, are present in gingival tissues, and are elevated in diseased individuals.1,2

In 1971 John Vane and colleagues reported that aspirin and aspirinlike drugs, also called nonsteroidal anti-inflammatory drugs (NSAIDs, Table 1), interfered with the arachidonic acid metabolite pathway by blocking the enzyme cyclooxygenase, thus blocking the production of prostaglandins.3 Soon thereafter periodontal investigations began asking the question: “Might the blocking of cyclooxygenase with NSAIDs, thus blocking prostaglandins, have an effect on the bone resorption of periodontitis?”4

Using the beagle experimental periodontitis model, Nyman et al5 examined the modulation of arachidonic acid metabolites with systemic indomethacin and reported that the NSAID indomethacin, given by mouth, suppressed alveolar bone resorption and gingival inflammation in the beagle. Weaks-Dybvig et al6 studied the effects of indomethacin in squirrel monkeys with ligature-induced periodontitis and reported that animals treated with systemic indomethacin had significantly less alveolar bone resorption (height and mass) and suppressed osteoclast density as compared with control animals.

Williams and colleagues7 were the first to report in vivo data on the effect of NSAIDs on the progression of naturally occurring periodontal diseases in an animal model. Over a 12-month treatment period, the effects of the NSAID flurbiprofen were compared with a placebo in aged beagles with naturally occurring periodontitis. The investigators combined experimental agents with conventional nonsurgical and surgical treatment modalities. Their results indicated that daily administration of 0.02 mg/kg flurbiprofen by mouth significantly decreased the rate of radiographic alveolar bone loss at 3, 6, 9, and 12 months in both surgically and nonsurgically treated animal groups when compared with baseline levels. The rate of alveolar bone loss did not decrease significantly over the treatment period for placebo-treated animal groups.7

Other NSAIDs, either systemically or topically administered, also have shown efficacy in treating periodontal diseases in animal models. The propionic acid-derived NSAID ibuprofen at 4 mg/kg and 0.4 mg/kg (sustained release and standard by-mouth formulations) has been shown to be effective in blocking alveolar bone loss in beagles with naturally occurring periodontitis.8 Naproxen (2 mg/kg for 1 month and 0.2 mg for 6 months) was shown to reduce radiographic periodontitis progression in the beagles by 61% when compared with pretreatment levels.9 Williams et al10 also reported a 71% suppression in radiographic bone loss rates for dogs treated with a topical flurbiprofen-propylene glycol gel (0.3 mg/mL daily). Similarly, a topically applied substituted oxazolopyridine derivative was shown to reduce histometric bone resorption, as well as clinical attachment loss and gingival inflammation, in squirrel monkeys with ligature-induced periodontitis.11 Monitoring the effects of two topical NSAIDs, ibuprofen and meclofenamic acid, in cynomolgus monkeys over 20 weeks, Kornman et al12 reported significant inhibition in alveolar bone loss despite continuing signs of clinical gingivitis and plaque accumulation with either agent. Over a 16-week period, Howell et al13 evaluated the antigingivitis effects of topical piroxicam in gel and liquid forms (2 mg/mL) on gingivitis in the beagle dog. Gingival and bleeding indices were significantly reduced after 2 and 4 weeks in the piroxicam-treated dogs as compared with placebo controls; however, no significant differences in plaque scores among the groups were noted. The results of these latter 2 preclinical studies indicate that NSAIDs may act in the presence of significant local factors that would otherwise influence disease progression. Paquette et al14 evaluated topical (S)-ketoprofen formulations in beagle dogs. Following induction of experimental periodontitis, 16 beagles were randomized for (S)-ketoprofen dentifrices (0.1%, 1%), (S)-ketoprofen capsules (10 mg by mouth), or placebo dentifrice, and assessed radiographically over a 2-month period. A significant reduction in gingival inflammation was reported with (S)-keto-profen treatments.

There are also compelling data from human cross-sectional and cohort studies indicating periodontal disease inhibition with NSAIDs. Waite et al15 evaluated the periodontal status among 22 subjects taking NSAIDs for arthritis or ankylosing spondylitis and 22 age-matched controls not taking such medications. Subjects taking NSAIDs had lower gingival index scores and shallower periodontal pocket depths than individuals not taking NSAIDs. In a retrospective cohort study, 75 patients who had taken aspirin or aspirin plus indomethacin for at least 5 years for arthritis had significantly fewer sites with proximal bone loss (10%) as compared with 75 healthy control subjects.16

In a 3-year clinical trial, Williams et al17 followed 44 patients with advanced adult periodontitis to assess long-term and posttreatment effects radiographically. After a 6-month pretreatment period, patients were stratified according to disease progression rates and randomized for 50 mg flurbiprofen or placebo capsules. Patients took study medications by mouth twice daily over a 24-month treatment period. Patients dosing with flurbiprofen demonstrated significantly lower bone loss rates at 12 and 18 months as compared with patients dosing with placebo. A subsequent analysis of 33 compliant patients monitored for the 6-month posttreatment period indicated significantly depressed bone loss rates at 24 months with flurbiprofen treatment and a return to baseline rates upon withdrawal of the agent (Figure 2 View Figure).18

Jeffcoat et al19 subsequently evaluated the short-term effects of systemic flurbiprofen (50 mg twice daily) in 15 refractory periodontitis patients. Standardized radiographs indicated significantly less alveolar bone loss over 2 months with flurbiprofen treatment relative to the placebo treatment. Jeffcoat and colleagues20 later tested the bone-preserving effects of systemic naproxen as an adjunct to mechanical periodontal therapy in patients with rapidly progressive periodontitis. In seven patients taking 500 mg naproxen twice daily for 3 months, a significant decrease in bone loss was detected when compared with the placebo group. This research group also reported significant bone gains with the NSAID meclofenamate sodium (50 mg or 100 mg twice daily perorally) combined with scaling and root planing (SRP) in patients with rapidly progressive periodontitis over a 6-month placebo-controlled clinical trial.21 Flemming and colleagues22 questioned whether aspirin (acetylsalicylic acid) taken by mouth could provide added benefit with mechanical scaling. Thirty patients with untreated moderate to severe adult periodontitis were recruited for this paired-design trial. Participants received supragingival and subgingival scaling in one quadrant after the baseline examination and in two additional randomly selected quadrants after the 6-week examination. Additionally, patients were given placebo (4 times daily) between baseline and the 6 weeks, and acetylsalicylic acid (500 mg 4 times daily) between 6 and 12 weeks. The findings of this study indicated that mechanical scaling plus acetylsalicylic acid resulted in synergistic reductions in gingival inflammation, probing pocket depth, and clinical attachment loss.22

In the mid-1990s, investigators began to examine the effect of topical NSAID formulations on periodontal diseases in human clinical trials. Heasman et al23,24 clinically and radiographically studied 49 adult periodontitis patients randomized for adjunctive topical flurbiprofen or placebo gels. All patients received conventional nonsurgical periodontal therapy at baseline. Over the subsequent 12 months of topical dosing, no clinical effects of flurbiprofen on plaque and bleeding scores, probing depths, and attachment levels were observed; however, significantly more sites in the flurbiprofen-treated group exhibited bone gain when compared with the placebo group. In a 55-patient clinical trial, Jeffcoat and colleagues21 assessed the efficacy of a topical NSAID rinse, ketorolac tromethamine, for treating adult periodontitis. At baseline, patients were randomized for 0.1% ketorolac rinse plus peroral placebo capsule, placebo rinse plus peroral 50-mg flurbiprofen capsule, or placebo rinse and placebo peroral capsule. Patients were monitored radiographically, clinically, and biochemically over a 6-month period during which they administered rinses and capsules twice daily. Although no significant differences among the groups were detected for clinical parameters, patients treated with topical ketorolac or systemic flurbiprofen exhibited significantly reduced alveolar bone loss rates and depressed prostaglandin E2 levels in gingival crevicular fluid as compared with patients treated with placebo. Paquette and colleagues25 conducted a 12-month clinical trial evaluating the clinical effi-cacy of topical (S)-ketoprofen dentifrices. Ninety six patients participated and applied randomized dentifrice formulations (0.3%, 1%, or 3% ketoprofen vs placebo) twice daily. Although intergroup differences in bone loss rates approached significance (P = .06) in the trial, significant strata-by-treatment interactions were detected such that patients with advanced periodontitis dosing with 1% or 3% (S)-ketoprofen demonstrated comparatively greater improvements in disease progression.25 In summary, a great deal of evidence gathered from preclinical and clinical studies since the late 1970s indicates that it is possible to inhibit periodontal disease progression via the local modulation of arachidonic acid metabolites with NSAIDs (Table 2). Serhan et al26 described a novel series of oxygenated arachidonic-acid derivatives called lipoxygenase interaction products or lipoxins. These derivatives (eg, lipoxin A4 and lipoxin B4) arise via 15- or 5-lipoxygenase activities and by cell-to-cell interactions, and appear to serve as endogenous anti-inflammatory mediators.26 Hasturk et al27 reported that these aspirin-induced lipoxins block ligature-induced bone loss in New Zealand rabbits.

Modulation of Host Cytokines in the Treatment of Periodontal Diseases
Host cytokines are another group of inflammatory mediators highly implicated in periodontal disease pathogenesis and intensely investigated as potential chemotherapeutic targets. Cytokines, literally “cell proteins” in etymology, transmit information from one cell to another via autocrine or paracrine mechanisms. Following specific binding to their complementary receptors, proinflammatory cytokines like interleukin-1 (IL-1) and tumor necrosis factor (TNF) trigger intracellular signaling events and catabolic cell behaviors.

Assuma et al28 explored the inhibition of periodontal disease using cytokine receptor antagonists. In their initial experiment, periodontitis was induced in 14 Macaca fasicularis monkeys with subgingivally placed, Porphyromonas gingivalis-soaked silk ligatures. Animals were randomized to one of three groups. The experimental group received gingival injections of soluble human recombinant IL-1 receptor type I plus soluble TNF receptor, each at 6.6 µg/injection over a 6-week period (3 times per week). Two other groups served as controls and received either gingival injections of vehicle alone at the same schedule or no treatment. The results from this study indicated that the soluble receptors of IL-1 and TNF inhibited roughly 80% of the inflammatory cell numbers (ie, polymorphonuclear leukocytes, mononuclear leukocytes, and plasma cells) proximal to the bone, relative to control animals. Similarly, the cytokine receptor antagonist therapy significantly reduced osteoclast cell numbers by 67% and alveolar bone resorption by 60%. A second report included specimens from 11 M. fasicularis monkeys with experimental periodontitis and treated as described above.29 The investigators quantified the average distance from the inflammatory front (ie, a field containing 10 inflammatory cells per field at high magnification) to the alveolar crest. Whereas the inflammatory front distance at 6 weeks measured 0.12 mm in control animals, the distance measured 0.59 mm in the IL-1 receptor- and TNF receptor-treated animals, suggesting inhibition of inflammatory cell extravasation and migration with the antagonists. The data from these experiments suggest that IL-1 and TNF are important mediators of periodontal disease progression and that specific inhibition may slow or alter the disease process.

Modulation of Matrix Metalloproteinases in Periodontal Disease Treatment
There is also intense interest in the ability to block or modulate matrix metalloproteinases (MMPs) as a strategy to modulate the progression of periodontal diseases. In the 1980s, Golub and colleagues30-32 reported that tetracyclines were beneficial in the management of periodontal diseases. It had traditionally been assumed that the beneficial actions of tetracyclines reflected their antimicrobial effects. However, in a series of novel experiments, Golub and colleagues demonstrated that tetracyclines could inhibit connective tissue breakdown and bone loss in periodontitis, arthritis, and osteoporosis by mechanisms unrelated to tetracyclines’ antimicrobial effect. Rather, it was tetracyclines’ inhibition of MMPs that could explain the effect of these drugs on inhibiting periodontal disease progression.

To further examine the role of tetracyclines in blocking periodontal disease progression through host modulation, several human clinical studies were initiated to determine the efficacy of subantimicrobial doses of tetracyclines in the treatment of periodontitis. Treatment with subantimicrobial doses of doxycycline (SDD, 20 mg twice daily) in conjunction with subgingival and/or supragingival scaling and dental prophylaxis improved attachment levels in patients with adult periodontitis when administered for 2-month cycles during a 6-month period and as part of a series of 3-month treatment cycles for 9 months.33

In a large double-blind, placebo-controlled, multicenter clinical trial involving 437 patients with adult periodontitis, adjunctive SDD significantly improved clinical parameters relative to placebo when used in conjunction with supragingival and subgingival scaling and prophylaxis for a 12-month period. In this study, treatment with adjunctive doxycycline (20 mg twice daily) resulted in significant reductions in pocket probing depths and bleeding on probing. It also showed significant gains in clinical attachment levels relative to treatment with adjunctive placebo. Mean attachment gains were shown to be comparable with those reported for SRP.34

In another placebo-controlled clinical study of 190 patients with adult periodontitis, adjunctive treatment with low-dose doxycycline during a 9-month period improved the efficacy of SRP. Treatment with adjunctive SDD significantly augmented the attachment gains that followed a single course of SRP. A clinically significant benefit was realized as early as 3 months after the initiation of treatment. These human clinical trials of SRP plus low dose doxycycline indicate that when the destructive host response mediated by MMPs is blocked, it is possible to block the tissue destruction of periodontitis.35

Triclosan as a Host Modulatory Therapeutic Agent
The anti-inflammatory activity of triclosan is attributable to three possible mechanisms: inhibition of cytokines; inhibition of prostaglandins; and inhibition of collagen-degrading enzymes. There is much interest recently in the discovery that the anti-infective agent triclosan is also anti-inflammatory. Beginning in 1995 with a report by Gaffar and et al,36 several studies have demonstrated the anti-inflammatory properties of triclosan. Subsequently, Modeer and colleagues37 reported the stimulatory effect of IL-1b in gingival fibroblasts in cell culture. The investigators further reported that triclosan reduces the production of IL-1b in gingival fibroblasts.38 The findings greatly extend the profession’s view of triclosan, the active ingredient in Colgate® Total® toothpaste (Colgate-Palmolive Co, New York, NY)—which is approved by the US Food and Drug Administration to aid in the prevention of gingivitis, plaque, and caries, and accepted by the American Dental Association for the prevention and treatment of tooth decay, gingivitis, plaque above the gum line, and bad breath. In the case of the whitening variants, it is approved to whiten teeth by removing surface stains. These approvals suggest that the dentifrice—in addition to being anti-infective—is host modulatory at the local level.

Summary
The concept of modulating host destructive pathways as a strategy for treating periodontal diseases has come a long way since the 1970s. Studies by a number of researchers and clinicians worldwide clearly demonstrate that blocking specific inflammatory mediators and/or enzymes can be efficacious in slowing periodontal disease progression. As new mediators and pathways of periodontal tissue destruction are identified, so will new host modulating strategies for blocking tissue destruction evolve, which is exciting to envision for the future of dental healthcare.

DISCLOSURE
This article originally appeared in a supplement supported by an educational grant from the Colgate-Palmolive Company.

References
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5. Nyman S, Schroeder HE, Lindhe J. Suppression of inflammation and bone resorption by indomethacin during experimental periodontitis in dogs. J Periodontol. 1979;50(9):450-461.

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13. Howell TH, Fiorellini J, Weber HP, et al. Effect of the NSAID piroxicam, topically administered, on the development of gingivitis in beagle dogs. J Periodontal Res. 1991;26(3 Pt 1):180-183.

14. Paquette DW, Fiorellini JP, Martuscelli G, et al. Enantiospecific inhibition of ligature-induced periodontitis in beagles with topical (S)-ketoprofen. J Clin Periodontol. 1997;24(8):521-528.

15. Waite IM, Saxton CA, Young A, et al. The periodontal status of subjects receiving non-steroidal anti-inflammatory drugs. J Periodontal Res. 1981;16(1):100-108.

16. Feldman RS, Szeto B, Chauncey HH, et al. Non-steroidal anti-inflammatory drugs in the reduction of human alveolar bone loss. J Clin Periodontol. 1983;10(2): 131-136.

17. Williams RC, Jeffcoat MK, Howell TH, et al. Altering the progression of human alveolar bone loss with the non-steroidal anti-inflammatory drug flurbiprofen. J Periodontol. 1989;60(9):485-490.

18. Williams RC, Jeffcoat MK, Howell TH, et al. Three-year trial of flurbiprofen treatment in humans: post-treatment period [abstract]. J Dent Res. 1991;70(Spec Iss):1617.

19. Jeffcoat MK, Williams RC, Reddy MS, et al. Flurbiprofen treatment of human periodontitis: effect on alveolar bone height and metabolism. J Periodontal Res. 1988;23(6):381-385.

20. Jeffcoat MK, Page R, Reddy M, et al. Use of digital radiography to demonstrate the potential of naproxen as an adjunct in the treatment of rapidly progressive periodontitis. J Periodontal Res. 1991;26(5):415-421.

21. Jeffcoat MK, Reddy MS, Haigh S, et al. A comparison of topical ketorolac, systemic flurbiprofen, and placebo for the inhibition of bone loss in adult periodontitis. J Periodontol. 1995;66(5):329-338.

22. Flemmig TF, Rumetsch M, Klaiber B. Efficacy of systemically administered acetylsalicylic acid plus scaling on periodontal health and elastase-alpha 1-proteinase inhibitor in gingival crevicular fluid. J Clin Periodontol. 1996;23(3 Pt 1):153-159.

23. Heasman PA, Benn DK, Kelly PJ, et al. The use of topical flurbiprofen as an adjunct to non-surgical management of periodontal disease. J Clin Periodontol. 1993;20(6):457-464.

24. Heasman PA, Collins JG, Offenbacher S. Changes in crevicular fluid levels of interleukin-1 beta, leukotriene B4, prostaglandin E2, thromboxane B2, tumor necrosis factor alpha in experimental gingivitis in humans. J Periodontal Res. 1993;28(4):241-247.

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27. Hasturk H, Kantarci A, Ebrahimi N, et al. Topical H2 antagonist prevents periodontitis in a rabbit model. Infect Immun. 2006;74(4):2402-2414.

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29. Graves DT, Delima AJ, Assuma R, et al. Interleukin-1 and tumor necrosis factor antagonists inhibit the progression of inflammatory cell infiltration toward alveolar bone in experimental periodontitis. J Periodontol. 1998;69(12):1419-1425.

30. Golub LM, Lee HM, Lehrer G, et al. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. J Periodontal Res.1983;18(5): 516-526.

31. Golub LM, Ramamurthy N, McNamara TF, et al. Tetracyclines inhibit tissue collagenase activity. A new mechanism in the treatment of periodontal disease. J Periodontal Res. 1984;19(6): 651-655.

32. Golub LM, Wolff M, Lee HM, et al. Further evidence that tetracyclines inhibit collagenase activity in human crevicular fluid and from other mammalian sources. J Periodontal Res. 1985;20(1):12-23.

33. Crout RJ, Lee HM, Schroeder K, et al. The “cyclic” regimen of low-dose doxycycline for adult periodontitis: a preliminary study. J Periodontol. 1996;67(5):506-514.

34. Caton J, Blieden T, Adams D, et al. Subantimicrobial doxycycline therapy for periodontitis [abstract]. J Dent Res. 1997;76(Spec Iss):1307.

35. Golub LM, Ryan ME, Williams RC. Modulation of the host response in the treatment of periodontitis. Dent Today. 1998;17(10):102-109.

36. Gaffar A, Scherl D, Afflitto J, et al. The effect of triclosan on mediators of gingival inflammation. J Clin Periodontol. 1995;22(6): 480-484.

37. Modeer T, Bengtsson A, Rolla G. Triclosan reduces prostaglandin biosynthesis in human gingival fibroblasts challenged with interleukin-1 in vitro. J Clin Periodontol. 1996;23(10):927-933

38. Mustafa M, Wondimu B, Ibrahim M, et al. Effect of triclosan on interleukin-1 beta production in human gingival fibroblasts challenged with tumor necrosis factor alpha. Eur J Oral Sci. 1998;106(2 Pt 1):637-643.

Figure 1 The current concept of the etiology and pathogenesis of periodontal diseases (adapted from: Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontol 2000. 1997;14:9-11). Figure 2 Rate of alveolar bone loss over a 2-year period in patients taking either a placebo capsule twice daily or flurbiprofen 50 mg twice daily. The rate of bone loss was significantly less in flurbiprofen-treated patients at 12, 18, and 24 months.
Table 1 Table 2