Antiresorptive agents, such as bisphosphonates (BPs) and Denosumab, are used to manage bone malignancy and metabolic bone diseases. Antiresorptive related osteonecrosis of the jaws (ONJ), a serious complication, particularly of the most potent regimens, presents as clinically exposed bone in the maxillofacial region for more than 8 weeks, and is associated with severe pain, swelling, infection, fistulae, and jaw fracture. ONJ pathophysiology remains largely elusive. ONJ presence under medications with distinct pharmacologic actions strongly points to osteoclast inhibition as central in disease pathogenesis. A puzzling, unanswered, question is ONJ's predilection for the jaws. ONJ is most commonly associated with tooth extraction in patients receiving high dose antiresorptives. However, in adults, teeth are extracted mainly due to severe periodontal disease or extensive caries that cause pulpal necrosis and periapical disease. Furthermore, several ONJ patients present without history of tooth extraction. From studies supported by this grant, we have reported the importance of dental disease for the establishment of ONJ in rats and mice. Interestingly, in both animal models, histologically necrotic bone is present. However, bone exposure, consistent with clinical ONJ, is seen in only 33% of the animals with osteonecrosis, suggesting that bone exposure is not prerequisite for bone necrosis. Equipped with these models, we have established qualitative and quantitative measures that mimic patient ONJ and evaluate disease burden. Preliminary data, presented herein, indicate that osteonecrotic changes occur as early as two weeks, while extraction of diseased teeth leads to incomplete soft tissue healing and bone exposure. Pharmacologic treatments alleviate ONJ severity, providing possible interventional tactics with clinical implications. Osteoblast lineage experiments demonstrate expansion of osteoblast precursors in the alveolar bone of BP treated mice with dental disease. Importantly, inflammation and BP treatment induce osteonecrosis in calvariae and femurs of mice, suggesting that, given the right conditions, other bones are subject to BP-associated osteonecrosis. Our objective is to characterize pathophysiologic mechanisms of ONJ and explore potential interventional approaches to ameliorate disease severity. We hypothesize that severe dental disease plays a central role in antiresorptive induced ONJ. We propose: 1. To study early responses in ONJ development, and elucidate the effect of BP withdrawal and diseased tooth extractions in ONJ progression, 2. To explore cyclooxygenase (COX) pathway involvement in ONJ pathophysiology, and 3. To study the effects of BPs and inflammation on calvariae and femoral defect healing.

Public Health Relevance

Bisphosphonates and Denosumab are drugs used to treat bone metastasis in cancer patients and osteoporosis. However, both medications have been associated with significant oral complications including exposure of the jaw bone to the oral cavity, abscesses and jaw fractures. No treatment for these complications exists, because we do not understand the mechanisms of their development. In this application, we investigate mechanisms of jaw bone necrosis and explore possible treatment approaches. Results of this research can potentially lead to novel therapeutic approaches that can reduce the incidence, severity, and progression of the disease.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Wan, Jason
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University of California Los Angeles
Schools of Dentistry/Oral Hygn
Los Angeles
United States
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de Molon, Rafael Scaf; Hsu, Chingyun; Bezouglaia, Olga et al. (2016) Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study. J Bone Miner Res 31:1596-607
de Molon, Rafael Scaf; Shimamoto, Hiroaki; Bezouglaia, Olga et al. (2015) OPG-Fc but Not Zoledronic Acid Discontinuation Reverses Osteonecrosis of the Jaws (ONJ) in Mice. J Bone Miner Res 30:1627-40
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