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Pathophysiology of osteonecrosis of the jaws induced by bisphosphonates and RANK-L inhibitors

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Author(s):
Rafael Scaf de Molon
Total Authors: 1
Document type: Doctoral Thesis
Press: Araraquara. 2016-05-23.
Institution: Universidade Estadual Paulista (Unesp). Faculdade de Odontologia. Araraquara
Defense date:
Advisor: Joni Augusto Cirelli
Abstract

The pathogenesis of the osteonecrosis of the jaw (ONJ) and its risk factors still remain poorly understudied and continue to be the focus on ongoing studies to establish a proper diagnosis, prevention and treatment. Thus, the aims of this study were: (1) to develop in mice, an experimental model of osteonecrosis induced by bisphosphonates (BPs) and RANK-L inhibitors associated with spontaneously periodontal disease. Then, (2) using the same experimental model in mice, to investigate if the discontinuation of these drugs alters the clinical and radiographic features of ONJ. In addition, (3) the influence of systemic diseases such as rheumatoid arthritis (RA), and ONJ was assessed as a possible risk factor for worsening ONJ characteristics. The analyses in all studies were established through radiographic, by means of micro-computed tomography, and histological assessments. In the first study, a new experimental animal model using different antiresorptive drugs was established with clinical features similar to what occurs in humans, with extensive necrotic areas and exposed bone o the oral cavity. The results of the study 2 showed that discontinuing OPG-Fc, a RANK-L inhibitor, but not BPs reversed all the clinical and radiographic features of ONJ. Furthermore, the results of study 3 suggest that treatment with high doses of BPs associated with the presence of RA exacerbated the incidence and severity of ONJ in mice. These data evidenced that BPs and RANK-L inhibitors possess great similarity in the radiographic and histologic findings, including the incidence of osteonecrosis and bone exposure, but only the OPG-Fc discontinuation completely reverses ONJ features. The data further support the relevance of RA as a risk factor for ONJ development. (AU)