Antiresorptive medications, particularly bisphosphonates (BPs) and denosumab are potent inhibitors of osteoclast function and are used to manage skeletal diseases such as bone malignancy or osteoporosis. Although clinically important, these medications are associated with medication related osteonecrosis of the jaw (MRONJ), a rare but serious side effect, that can cause debilitating pain and morbidity. Moreover, the fear of developing MRONJ has contributed to a progressive decline in patient compliance with antiresorptive use, and a looming crisis in osteoporosis. Improving MRONJ prevention, diagnosis and treatment would have a great impact in health care of patients with skeletal diseases. From studies supported by the parent grant, our well-established, interdisciplinary team of clinician-scientists has made important contributions to the pathophysiology, diagnosis and management of MRONJ. Collectively, our studies have provided significant insight into MRONJ pathogenesis. In control animals with dental disease, bone resorbs away from the inflammatory nidus. In contrast, osteoclast inhibition leads to bone being exposed to inflammation, and to osteonecrosis adjacent to inflammatory foci. Epithelial migration occurs in both control and antiresorptive treated animals. However, with inhibition of bone resorption, the epithelium descends towards the alveolar crest, and eventually rims the necrotic bone, resulting in bone exposure. Extraction of teeth with dental disease, results in conspicuous MRONJ. In contrast, after extraction of healthy teeth in animals on antiresorptives mucosal and socket healing is achieved. Through our studies, we have developed and characterized animal models of MRONJ by inducing experimental periodontal or periapical disease and treating with high-dose antiresorptives, in the absence of tooth extraction. These models capture early tissue changes during MRONJ initiation. Based on our published and preliminary findings, we hypothesize that initiation of the pathophysiologic framework that eventually leads to clinically exposed bone involves an interplay among dying osteocytes, challenged soft tissue homeostasis, and a distorted immune response. Our objective is to determine the early pathophysiologic mechanisms of MRONJ initiation and progression and to pursue effective therapeutic interventions. To meet our objective and test our hypothesis, we propose three Specific Aims. Aim 1: Determine the extent to which HMGB1 released from necrosing osteocytes contributes to MRONJ initiation and progression Aim 2: Delineate macrophage involvement in MRONJ initiation and progression. Aim 3: Define the role of macrophage and osteocyte heme-oxygenase-1 (HO-1) in MRONJ initiation and progression.