Bisphosphonates and Osteonecrosis of the Jaw: Moving from the Bedside to the Bench

Abstract

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.

Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

“…Results obtained using an animal model provide some support for the hypothesis that suppression of bone turnover plays a role in the pathogenesis of ONJ [65,66]. A proportion (up to one third) of beagles treated with high doses of bisphosphonates develop areas of necrotic bone in the mandible, although the exposed bone characteristic of ONJ in humans is not seen.…”

Inflammation, fracture and bone repair

“…All of these treatments are focused either to enhance bone formation by osteoblasts (bone anabolic approaches) or to block bone resorption by osteoclasts (anti-resorptive approaches) [128–130]. While some of these therapies are in clinical use [131], unexpected adverse effects, restricted clinical indications and the need to improve the final formulation has led to restrictions in their use [70, 132, 133]. …”

Surgical treatment of bisphosphonate-associated osteonecrosis: Prognostic score and long-term results

“…Interestingly, before the first case series of bisphosphonateassociated ONJ (Marx, 2003;Migliorati, 2003) and before recent animal models (Allen, 2009;Hokugo et al, 2010;Kikuiri et al, 2010;Pautke et al, 2012;Kuroshima and Yamashita, 2013) were published, the same jawbone pathology was described in an animal model by Gotcher and Jee (1981). Soon after the first publications of ONJ, a similarity of this pathology to the historical 'phossy jaw' was recognized (Miles, 1972;Abu-Id et al, 2008;Marx, 2008).…”

“…The unique involvement of the jawbone as a side effect of BP treatment seems to be explainable by special anatomical peculiarities (Landesberg et al, 2011), higher bone turnover in the alveolar process (Allen, 2009), biomechanical strain (predilection sides; Marx, 2014), frequency of surgical interventions (mostly tooth extraction; Cafro et al, 2008;own results), rapid infection by the resident mouth flora (Sedghizadeh et al, 2008), different geno-and phenotypic features of mesenchymal stem cells (MSCs) depending on their origin (Matsubara et al, 2005), and higher susceptibility of MSCs from the jawbone to BP (viability etc. ; Stefanik et al, 2008).…”