Introduction

Until the 1970s, treatment strategies for periodontal disease 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).

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 acidderived 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 aspirin-like drugs, also called nonsteroidal anti-inflammatory drugs (NSAIDs), 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 affect on the bone resorption of periodontitis (Figure 2)?"⁴

Utilizing the beagle experimental periodontitis model,Nyman et al 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.⁵ Weaks-Dybvig et al 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.⁶

Williams and co-workers were the first to report in vivo data on the effect of NSAIDs on the progression of naturally occurring periodontal disease in an animal model. Over a 12-month treatment period, the effects of the NSAID flurbiprofen (Figure 3) 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 to baseline levels. The rate of alveolar bone loss did not decrease significantly over the treatment period for placebotreated animal groups.⁷