Pathophysiology of Biphosphonate-Induced ONJ in a Novel Animal Model

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DESCRIPTION (provided by applicant): In recent years, osteonecrosis of the jaw (ONJ) has been identified as a potential complication of bisphosphonate (BP) treatment. This bone disorder is characterized by the accumulation of necrotic bone with exposure in the oral cavity that persists for more than 6 to 8 weeks. ONJ is observed most frequently in cancer patients treated with the potent nitrogen (N-)BPs zoledronate (ZOL) or pamidronate for inhibition of bone metastases, but it has also been reported to a much lesser extent in alendronate (ALN)-treated osteoporotic patients. While multiple case report studies suggest that the incidence and severity of ONJ are associated with the potency of N-BPs to inhibit osteoclastic bone resorption and cumulative dose of these drugs, no mechanism-based cause and effect relationship has yet been established. Therefore, the development of animal models to study the pathophysiology of ONJ will be a fundamental tool to enhance our understanding of this bone disorder. Our long-term goal is to elucidate the causes and pathophysiology of ONJ in order to create the basis for new effective strategies for prevention and treatment. The objectives of this proposal are to develop an animal model for ONJ, and to establish the effects of N-BPs of different potencies on the removal of necrotic bone and bone healing. Our central hypothesis is that ONJ is a two-stage process: 1) risk factors initiate processes in the oral cavity that cause necrosis of hard tissues; and 2) N-BPs, well-proven to inhibit osteoclastic resorption, block the removal of necrotic bone, causing an accumulation of necrotic bone in the jaw that in and of itself delays the initiation and subsequent progress of bone healing. We plan to test our central hypothesis by utilizing rice rats (Oryzomys palustris) with established periodontitis and determine the effects of ZOL and ALN on: 1) the progression of the periodontal damage by performing an ex-vivo evaluation of the periodontal disease, including a radiographic assessment of the alveolar bone, the evaluation of soft tissue involvement and tooth mobility, and by conducting a histometric analysis of the periodontal tissue; 2) the removal of necrotic bone by the assessment of necrotic bone accumulation using histochemical/histological techniques, and also on indices of bone resorption by using quantitative histomorphometry; 3) new bone formation and angiogenesis, as indices of bone healing, in the periodontium by using quantitative histomorphometry and immunohistochemical techniques; and 4) the expression of genes associated with bone resorption, bone formation, and angiogenesis using real time PCR techniques. We postulate that the well- known and desirable anti-resorptive effect of N-BPs has a central role in the development of ONJ. Consequently, at the completion of this project, it is our expectation to provide direct evidence that the potent BP ZOL will induce a higher accumulation of necrotic bone in the jaw, with subsequent impairment of bone healing as compared to that induced by the less potent BP ALN. It is also our expectation to develop an animal model for ONJ that will facilitate further advances in our knowledge and understanding of this bone disorder. Project Narrative: Osteonecrosis of the jaw (ONJ) is a potential adverse side effect of bisphosphonate (BP) treatment. Multiple case report studies suggest that the incidence and severity of ONJ are associated with the potency of BP and cumulative dose of the drug. However, this bone disorder is poorly understood, due in part to lack of appropriate animal models for ONJ. The proposed research will provide insight into a tissue-level mechanism for the development of ONJ-like lesions in marsh rice rats, an animal model for periodontitis, and will elucidate the basis, at the cellular and molecular levels, for the higher incidence of the BP zoledronate to induce ONJ- like lesions as compared with the BP alendronate.