Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.

抑制硬化素是降低骨质疏松症患者骨折风险的一种治疗方法。然而，romosozumab（一种抑制硬化素的一流单克隆抗体）的 3 期随机对照试验 (RCT) 数据表明严重心血管事件的不平衡，监管机构已发布营销授权，并警告心血管疾病。在这里，我们对 romosozumab 已发表和未发表的心血管结果试验数据进行荟萃分析，并研究模拟硬化蛋白治疗抑制的遗传变异是否与较高的心血管疾病风险相关。多达三项随机对照试验的荟萃分析表明，罗莫佐单抗可能会增加心血管事件的风险。缩放至 romosozumab 的等效剂量（每月 210 毫克；每平方厘米 0.09 克，骨矿物质密度更高）， SOST基因变异与较低的骨折和骨质疏松风险相关（与 romosozumab 的治疗效果相称），并且与心肌梗塞和/或冠状动脉血运重建以及主要不良心血管事件的风险较高。相同的变异还与 2 型糖尿病、较高的收缩压和中心性肥胖的风险增加相关。总之，我们的研究结果表明，抑制硬化素可能会增加心血管风险，因此需要对 romosozumab 和其他硬化素抑制剂的心血管安全性进行严格评估。