Analysis Details Potential Cardiovascular Risk Associated with Romosozumab

Jonas Bovijn, MBChB, MSc

Data from a new analysis is reinforcing the heightened concern surrounding the detrimental impact use of the novel osteoporotic therapy romosozumab can have on cardiovascular health. 



Results of the statistical analysis, which included data from a pair of phase 3 clinical trials and the UK Biobank cohort, concluded patients whose DNA carried genetic markers mimicking the effects of the novel sclerostin inhibitor had an 18% greater chance of suffering a heart attack.

“Our findings support the warning labels issued by regulatory authorities such as the FDA and EMA, and suggest that the cardiovascular effects seen in some trials of this medicine are real,” said lead investigator Jonas Bovjin, MBChB, MSc, of the Big Data Institute at the University of Oxford, in a statement. “This emphasizes the importance of conducting further rigorous clinical studies to evaluate the cardiovascular safety of this class of medicines.”

A collaborative effort between investigators from Oxford, University of Tartu, Broad Institute, Massachusetts General Hospital, and the University of Bristol, the current study was designed to assess the potential for cardiovascular complications associated with romosozumab using data from clinical trials and the UK Biobank cohort in 2 separate analyses.

The first meta-analyzed cardiovascular outcomes data from the BRIDGE, ARCH, and unpublished FRAME trials, which were the only phase 3 clinical trials reported cardiovascular outcomes associated with use of romosozumab. The second portion of the study aimed to use this data to estimate the effect of bone mineral density (BMD)-increasing alleles in the SOST gene, which mimics the effects of 210 mg romosozumab monthly for 1 year, on risk of therapeutic and cardiovascular outcomes using individual-level data from the UK Biobank study.

Results of the combined analysis assessing the effects on osteoporosis and risk of fracture suggested use of romosozumab lowered risk of osteoporosis by 57% (OR, 0.43; 95% CI, 0.36 to 0.52; P=2.4×10^-18) and bone fracture by 41% (OR, .59; 95% CI, .54-.66; P=1.4x10^-24). Investigators noted these associations remained consistent in analyses examining risk by fracture site.

When examining potential associations between SOST variants and cardiovascular outcomes, results of the investigators’ estimates indicated the effects were associated with an 18% (OR, 1.18; 95% CI, 1.06-1.32; P=.003) increase in risk of myocardial infarction and/or coronary revascularization and a 12% (OR, 1.12; 95% CI, 1.03-1.21; P=.007) increase in risk of major adverse cardiovascular events (MACE). Further analysis indicated BMD-increasing SOST variants were associated with an increased risk of hypertension (OR, 1.12; 95% CI, 1.05-1.20; P=8.9×10^-4) and type 2 diabetes mellitus (OR, 1.15; 95% CI, 1.05-1.27; P=.003).

“'This new medicine is effective at lowering risk of fracture, which can be life-threatening particularly for the elderly,” said study investigator Michael Holmes, PhD, associate professor with the MRC Population Health Research Unit and Nuffield Department of Population Health at the University of Oxford. “Patients and their healthcare providers should jointly consider whether the benefits of fracture prevention outweigh the potential risk of heart disease.”



This study, “Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics,” was published in Science Translational Medicine.