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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE019465-05A1
Application #
8761983
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wan, Jason
Project Start
2008-12-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
Hiyari, S; Atti, E; Camargo, P M et al. (2015) Heritability of periodontal bone loss in mice. J Periodontal Res 50:730-6
Aghaloo, Tara; Hazboun, Renna; Tetradis, Sotirios (2015) Pathophysiology of Osteonecrosis of the Jaws. Oral Maxillofac Surg Clin North Am 27:489-96
Pirih, F Q; Hiyari, S; Barroso, A D V et al. (2015) Ligature-induced peri-implantitis in mice. J Periodontal Res 50:519-24
Aghaloo, Tara L; Cheong, Simon; Bezouglaia, Olga et al. (2014) RANKL inhibitors induce osteonecrosis of the jaw in mice with periapical disease. J Bone Miner Res 29:843-54
Aghaloo, Tara L; Dry, Sarah M; Mallya, Sanjay et al. (2014) Stage 0 osteonecrosis of the jaw in a patient on denosumab. J Oral Maxillofac Surg 72:702-16
de Molon, Rafael Scaf; Cheong, Simon; Bezouglaia, Olga et al. (2014) Spontaneous osteonecrosis of the jaws in the maxilla of mice on antiresorptive treatment: a novel ONJ mouse model. Bone 68:11-9
Chaichanasakul, Thawinee; Kang, Benjamin; Bezouglaia, Olga et al. (2014) Diverse osteoclastogenesis of bone marrow from mandible versus long bone. J Periodontol 85:829-36
Cheong, Simon; Sun, Shuting; Kang, Benjamin et al. (2014) Bisphosphonate uptake in areas of tooth extraction or periapical disease. J Oral Maxillofac Surg 72:2461-8

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