Lifelong genetically lowered sclerostin and risk of cardiovascular disease

Background Inhibition of sclerostin is a novel therapeutic approach to lowering fracture risk. However, phase III randomised controlled trials (RCTs) of romosozumab, a monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events. Methods We used two independent genetic variants (rs7209826 and rs188810925) in SOST (encoding sclerostin) associated with bone mineral density (BMD) as proxies for therapeutic inhibition of sclerostin. We estimated the effects on risk of osteoporosis, fracture, coronary heart disease (CHD) and a further 22 cardiometabolic risk factors and diseases, by combining data from up to 478,967 participants of European ancestry from three prospective cohorts and up to 1,030,836 participants from nine GWAS consortia. In addition, we performed meta-analyses of cardiovascular outcome data from phase III RCTs of romosozumab. Results Meta-analysis of RCTs identified a higher risk of cardiac ischemic events in patients randomised to romosozumab (25 events among 4,298 individuals; odds ratio [OR] 2·98; 95% confidence interval [CI], 1·18 to 7·55; P=0·017). Scaled to the equivalent dose of romosozumab (210mg/month; 0·09 g/cm 2 higher BMD), the SOST variants associated with lower risk of fracture (OR, 0·59; 95% CI, 0·54-0·66; P= 1·4×10 −24 ), and osteoporosis (OR, 0·43; 95% CI, 0·36-0·52; P=2·4×10 −18 ). The SOST variants associated with higher risk of myocardial infarction and/or coronary revascularisation (69,649 cases; OR, 1·18; 95% CI, 1·06-1·32; P=0·003) and type 2 diabetes (OR 1·15; 95% CI, 1·05-1·27; P=0·003), higher systolic blood pressure (1·3mmHg; 95% CI 0·8-1·9; P=5·9×10 −6 ) and waist-to-hip-ratio adjusted for BMI (0·05 SDs; 95% CI, 0·02 to 0·08; P=8·5×10 −4 ). Conclusions Genetically and therapeutically lowered sclerostin leads to higher risk of cardiovascular events. Rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors is warranted.