Comparative cardiovascular safety of romosozumab versus bisphosphonates in Japanese patients with osteoporosis: a new-user, active comparator design with instrumental variable analyses.

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This study analyzed the association of romosozumab, a human monoclonal antibody with bone-forming and bone resorption-inhibiting effects, and bisphosphonates with the development of cardiovascular disease among patients with osteoporosis. A new-user design was employed to address selection bias, and instrumental variable analysis was used to address confounding by indication. Japanese patients aged ≥40years, diagnosed with osteoporosis or experienced a fragility fracture, were admitted to medical facilities covered by a commercial administrative claims database, and newly prescribed romosozumab or bisphosphonates after the commercialization of romosozumab in Japan (March 4, 2019) were included based on verification of a 180-day washout period. Cardiovascular disease (myocardial infarction or stroke) was identified based on information regarding diagnosis, medical procedures, and drug codes. Facility-level prescription preference for romosozumab was used as an instrumental variable, defined as the proportion of romosozumab prescribed at the patient's facility within 90days prior to the index date. Of the 59 694 included prescriptions, 8808 were for romosozumab and 50 886 were for bisphosphonates. The mean age in the romosozumab group was higher than that in the bisphosphonates group (80.5 vs. 78.2years, respectively), and most patients were females (85.3 vs. 80.2%, respectively). The incidence of cardiovascular disease within 1year of prescription was 12.3 per 100 person-years for romosozumab versus 11.4 for bisphosphonates (unadjusted incidence rate ratio: 1.08, 95% confidence interval: 1.00-1.18). An instrumental variable analysis using the two-stage residual inclusion method yielded a hazard ratio of 1.30 (95% confidence interval: 0.88-1.90) for romosozumab compared with bisphosphonates over 1year. Although possibly underpowered, this study showed that no definitive evidence of increased cardiovascular risk associated with romosozumab use compared with bisphosphonates was observed in patients with osteoporosis. These findings should be further validated by larger pharmacoepidemiological studies to alleviate clinicians' concerns about romosozumab's safety.