Departments
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.
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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. |
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Table 1 |
Table 2 |