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

jonas bovijn*, kristi krebs, Chia-Yen chen, Ruth Boxall, Jenny C. Censin, Teresa Ferreira, sarah pulit, Craig A. Glastonbury, Samantha Laber , Iona Y Millwood, Kuang Lin, Liming Li, Zhengming Chen, Lili Milani, George Davey Smith, Robin G. Walters, Benjamin M Neale, Reedik Mägi, Cecilia M Lindgren*, Michael V Holmes*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

54 Citations (Scopus)
227 Downloads (Pure)


Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase III 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 Here we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with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 mg/month; 0.09 g/cm2 higher bone mineral density (BMD)], 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 (MI) and/or coronary revascularization and major adverse cardiovascular events (MACE). The same variants were also associated with increased risk of type 2 diabetes mellitus (T2D) and higher systolic blood pressure (SBP) and central adiposity. Taken 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.
Original languageEnglish
Article numbereaay6570
Number of pages22
JournalScience Translational Medicine
Issue number549
Publication statusPublished - 24 Jun 2020


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