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

在理解某些个体如何使用抗吸收药治疗方面存在根本性的差距， 双膦酸盐和狄诺塞单抗发生药物相关性颌骨骨坏死（MRONJ）， 其他人则没有。如果没有这些知识，就很难以安全的方式使用抗吸收药。我们的长期 研究目标是鉴定、验证和实施临床上有用的MRONJ生物标志物，并最终 积极主动地为抗吸收治疗提供精准医学方法，同时最大限度地降低 MRONJ。基于令人信服的初步发现，我们的总体目标是进一步验证 使患者易患双膦酸盐相关ONJ的药物基因组学标志物， 地舒单抗相关ONJ的血清生物标志物，并建立未来临床应用的预测模型。 实施精准医疗策略进行抗骨吸收治疗。我们的核心假设是， MRONJ是遗传易感性和药物暴露之间相互作用的结果， 不同的作用机制，与双膦酸盐相关的MRONJ的遗传易感性， denosumab不同。我们组建了一个多学科团队，以实现以下具体目标：1）。 识别与二膦酸盐相关ONJ相关的遗传变异。2）。鉴定基因和血清 地舒单抗相关ONJ的生物标志物。3）。构建并验证MRONJ的预测模型。这个项目是 意义重大，因为拟议的研究不仅会识别经过验证的遗传和/或血清生物标志物， MRONJ和推进MRONJ的病理生理学的理解，但也有翻译 在广泛疾病的抗吸收治疗中的重要性。建议的研究是创新的 因为：首先，这是第一项地舒单抗相关MRONJ的药物基因组学研究。第二，用骨 作为MRONJ的生物标志物的转换标志物是新颖的。第三，使用含有RANK和RANKL的细胞外 囊泡作为生物标志物是新颖的。第四，鉴定BP相关与DEN相关MRONJ独特的生物标志物 用于临床实施是新颖的。最后，我们不仅会采用一种普遍采用的风险预测方法， 分析，但也有两个先进的方法，能够考虑非线性和相互作用的影响。在 总之，我们相信我们提出的研究将确定MRONJ的生物标志物，增强我们对 MRONJ发展的潜在机制，并提供了改善治疗的机会。 骨质疏松症和癌症患者需要个性化的抗吸收治疗。

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.