Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics

SOST variants that mimic therapeutic inhibition of sclerostin for osteoporosis are associated with higher risk of cardiovascular disease. Safety and sclerostin Antibodies that inhibit sclerostin are used to treat osteoporosis because they increase bone mineral density and reduce fracture risk; however, phase 3 trials have identified potential cardiovascular safety concerns. Using meta-analysis, Bovijn and colleagues found probable higher risk of adverse cardiovascular events associated with sclerostin antibody use. Analysis of variants in SOST, the gene that encodes sclerostin, showed that variants associated with increased bone mineral density (mimicking the effects of therapeutic inhibition of sclerostin) were linked to cardiometabolic risk factors and disease. Results highlight the importance of evaluating the cardiovascular safety of sclerostin inhibition. 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 Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with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.

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