Importance Romosozumab, a novel anti-osteoporotic agent, confers marked improvement in bone mineral density; however, its cardiovascular safety remains a concern.

Objective To compare the cardiovascular safety of romosozumab to bisphosphonates in patients with osteoporosis.

Design A cohort study using a new-user, active comparator design.

Setting Medical facilities, including clinics and hospitals, visited by a wide range of populations in Japan that are covered by a commercial administrative claims database, collected from March 4, 2019 to August 31, 2021.

Participants Japanese adults aged ≥40 years who were diagnosed with osteoporosis or experienced a fragility fracture. Those who received romosozumab or bisphosphonates after the commercialization of romosozumab started in Japan (March 4, 2019) were included.

Exposure A new prescription of romosozumab or bisphosphonate (based on verification of a 180-day washout period).

Main Outcomes and Measures The primary outcome was the incidence rate of cardiovascular disease (consisting of myocardial infarction and stroke) within one year of prescription. Cardiovascular disease was identified by algorithms with a combination of diagnosis, medical procedure, 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 90 days prior to the index date.

Results Of the 61,558 included prescriptions, 8,806 were for romosozumab and 52,752 were for bisphosphonates. The mean age of the romosozumab group was higher than that of the bisphosphonates group (80.5 vs. 78.3 years, respectively). The majority of patients were female (80.2 vs. 85.3%, respectively). The incidence of cardiovascular disease was 7.98 per 100 person-years for romosozumab versus 7.15 for bisphosphonates (unadjusted incidence rate ratio: 1.12 (95% confidence interval: 1.03-1.21)). An instrumental variable analysis using the two-stage residual inclusion method yielded a hazard ratio of 1.09 (95% confidence interval: 0.79-1.76) for romosozumab compared to bisphosphonates over one year.

Conclusions and Relevance In this large observational study, there was no definitive evidence of increased risk of cardiovascular disease associated with romosozumab use compared with bisphosphonates in patients with osteoporosis. These findings alleviate clinicians’ excessive concerns about the potential cardiovascular safety of romosozumab in treatment decision-making for osteoporosis.

NK has received payment for speaking and educational events from Taisho Pharmaceutical Co., Ltd. and Eisai Co., Ltd.

This study did not receive any funding

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

We used the DeSC database, a commercially available administrative claims database (DeSC Healthcare Inc., Tokyo, Japan; https://desc-hc.co.jp/company). No approval from an ethics committee was required as the data were anonymized.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

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Yes

↵† Ryoji Tominaga and Tatsuyoshi Ikenoue share co-first authorship.

↵‡ Masataka Taguri and Noriaki Kurita share co-last authorship.

All data produced in the present work are contained in the manuscript