利用代谢组学鉴定用于早期预测唑来膦酸抗骨质疏松疗效和不良反应的新生物标志物及其机制研究

原发性骨质疏松症是老龄化社会的重要健康问题，因疗程长、疗效和安全性存在个体差异、缺乏早期预测指标面临治疗困境。本项目组前期药物基因组学研究发现甲羟戊酸通路、SOST/LRP5/β-catenin和NF-kB信号通路关键酶编码基因遗传变异与双膦酸盐药物疗效有关。拟在此基础上利用代谢组学测试平台（UPLC-MS/MS），选择能显著提高骨密度并降低骨折风险且利于减少疾病负担的唑来膦酸进行治疗200例绝经后骨质疏松症前瞻性观察三年，评价疗效和安全性的同时监测上述三条信号通路代谢产物，并与公共数据库及来源于100例年龄匹配健康绝经后妇女的三条通路代谢产物参考值进行比对分析。进一步利用绝经后骨质疏松大鼠模型和原代细胞培养阐明唑来膦酸治疗中代谢产物与疗效和不良反应有关的分子机制。通过以上三个层面研究鉴定出用于早期预测唑来膦酸抗骨质疏松疗效和不良反应的新生物标志物，为实现个体化治疗提供重要手段和理论依据。

Osteoporosis is an important health problem in an aging society, which is confronted with treatment difficulties due to the long course of treatment, individual differences in efficacy and safety, and lack of early predictors. In order to solve these problems, we performed several pharmacogenomics studies recently. We found that the genetic variation of the key enzyme encoding genes of mevalonate pathway, SOST/LRP5/β-catenin and NF-kB signaling pathway were associated with the efficacy of bisphosphonate. Therefore, we plan to perform a three-year prospective clinical investigation for two hundred postmenopausal osteoporosis whom will be treated by zoledronate using the metabolomics test platform (UPLC/MS/MS). We choose zoledronate because it can significantly increase the bone density and reduce the risk of fractures and reduce the burden of disease. During the study, not only the efficacy and safety are evaluated, but metabolites in the above mentioned three signaling pathways will be monitored as well. The results will be compared with the public database and the reference range obtained from 100 age-matched healthy postmenopausal women. Furthermore, the postmenopausal osteoporosis rat model and primary cell culture were used to elucidate the molecular mechanism of the metabolites associated with the efficacy and adverse reactions of zoledronate therapy. New biomarkers for early prediction of anti-osteoporosis efficacy and adverse reactions of zoledronate will be identified depending on the above three levels, which provided important means and theoretical basis for individualized treatment for osteoporosis.