Project Summary/Abstract Antiresorptive agents, such as bisphosphonates (BPs) and denosumab (Dmab), are commonly used to treat osteoporosis and bone malignancies. While their therapeutic effects have long been documented, their side effects can be serious and devastating. One such side effect has been identified as osteonecrosis of the jaws (ONJ), exposed bone in the maxillofacial region for at least 8 weeks in the presence of antiresorptive medications. Although it has been studied extensively, its pathophysiology remains largely elusive. Osteoclast inhibition has been shown to be crucial in ONJ pathogenesis, as these cells play a central role in the maintenance of normal bone homeostasis. Osteoclasts not only are the master bone resorbing cells, but they communicate with other cells in their vicinity to coordinate bone modeling and remodeling. Despite distinct pharmacologic effects of BPs and Dmab, the incidence and appearance of ONJ is similar. BPs inhibit protein farnesylation, leading to inhibition of osteoclast function, while Dmab binds to receptor activator of NFKB ligand (RANKL), inhibiting differentiation of osteoclast precursors. Thus, these similar, but distinct effects of BPs and Dmab may affect ONJ pathophysiology. Utilizing different types of antiresorptives, we will study the effects of osteoclastic inhibition on ONJ development in Aim 1. Aim 2 will identify differential gene expression during ONJ development utilizing diverse antiresorptives. This study will provide insight into the involvement of osteoclast function in ONJ pathophysiology. In addition, differential gene expression during ONJ development will be identified. Importantly, these studies will begin to delineate ONJ pathophysiology and identify potential therapeutic strategies. Finally, these proposed studies will prepare the fellowship applicant for a career as a clinician-scientist.