Bisphosphonates and osteonecrosis of the jaw: moving from the bedside to the bench

Osteonecrosis of the jaw (ONJ) has received significant attention as a potential side effect of bisphosphonate treatment. The limited understanding of the underlying pathophysiology of the condition emphasizes the need to transition ONJ research from the bedside to the bench, supplementing ongoing clinical research with animal/basic science studies. The goal of this review is to briefly highlight the most commonly proposed mechanisms for ONJ and then summarize our laboratory's recent efforts to begin transitioning ONJ research to an animal model. Remodeling suppression, disrupted angiogenesis and infection have all been proposed to connect bisphosphonates to ONJ, although most supportive data for each of these are either indirect or nonexistent. Our laboratory has begun studying the dog as a potential model of ONJ. We have shown regions of necrotic bone matrix within the mandible of dogs treated with oral or intravenous bisphosphonate. We hypothesize these regions are the result of remodeling suppression, and if combined with additional factors such as dental intervention or infection, would result in manifestation of exposed oral lesions, the clinical definition of ONJ. Although these findings suggest the dog may be a viable animal model to study ONJ, many questions remain unanswered. No matter what animal model is found to mimic the clinical presentation of ONJ, once established it will allow significant progress toward understanding the specific role of bisphosphonates in the pathophysiology of ONJ and if/how the entity of ONJ can best be treated and prevented.