Toward a Precision Medicine Approach to Medication-Related Osteonecrosis of the Jaw

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There is a fundamental gap in understanding how certain individuals treated with antiresorptives such as bisphosphonates and denosumab developed medication-related osteonecrosis of the jaw (MRONJ) while others do not. Without this knowledge, it is difficult to use the antiresorptives in a safe manner. Our long term research goal is to identify, validate and implement clinically useful biomarkers of MRONJ and ultimately, to proactively provide a Precision Medicine approach for antiresorptive therapies while minimizing the risk of MRONJ. Built upon compelling preliminary findings, our overall objectives are to further validate pharmacogenomic markers that predispose patients to bisphosphonates-related ONJ, to identify genetic and serum biomarkers for denosumab-related ONJ, and to create a predictive model for future clinical implementation of a Precision Medicine strategy for antiresorptive therapies. Our central hypothesis is that MRONJ is the result of interplay between genetic predisposition and drug exposure, and that because of their differing mechanisms of action, the genetic predispositions for MRONJ linked to bisphosphonates and denosumab differ. We have assembled a multidisciplinary team to carry out the following specific aims: 1). Identify genetic variants associated with bisphosphonate-related ONJ. 2). Identify genetic and serum biomarkers for denosumab-related ONJ. 3). Build and validate predictive models for MRONJ. This project is significant because study proposed study will not only identify validated genetic and/or serum biomarkers for MRONJ and advance the understanding of the pathophysiology of MRONJ but also have translational importance in the antiresorptive treatments for a wide range of diseases. The proposed study is innovative because: First, this is the first pharmacogenomic study for denosumab-related MRONJ. Second, using bone turnover markers as biomarkers for MRONJ is novel. Third, Using RANK and RANKL-containing extracellular vesicles as biomarkers is novel. Fourth, identifying biomarkers unique for BP-related vs. DEN-related MRONJ for clinical implementation is novel. Lastly, we will not only use a commonly adopted method for risk prediction analyses but also two advanced methods that are capable of considering non-linear and interaction effects. In summary, we believe our proposed studies will identify biomarkers for MRONJ, enhance our understanding of the underlying mechanisms of MRONJ development, and provide an opportunity to improve treatment of osteoporosis and cancer patients needing antiresorptive therapy in a personalized manner.