Cardiovascular Safety of Denosumab Across Multiple Indications

Abstract

We have read with great interest the recently published work by Seeto and colleagues,(1) which comprehensively reviewed the currently available evidence to evaluate the cardiovascular safety of denosumab across multiple indications. This well-conducted systematic review and meta-analysis found a 46% increase in cardiovascular adverse events (CAEs) for denosumab when compared with bisphosphonates in postmenopausal women but no imbalance in CAEs when compared with placebo. In contrast, no statistically significant results were found in other indications. Although we appreciate the authors' efforts in conducting this in-depth study, we have two minor concerns. First, this systematic review and meta-analysis only included trials that enrolled more than 100 participants; therefore, 34 records and three full-text articles were excluded mainly because of inadequate population size.(1) We reviewed both the eligibility criteria of this study and the protocol registered with PROSPERO (CRD42019135414), and neither of them elaborated the reason for the exclusion. In general, clinical trials that randomize less than 100 participants are considered to have a relatively modest sample size, a scenario that, while not leading to a null finding, is more likely to result in overestimation of the treatment effect than studies with adequate sample size.(2) However, this does not mean that trials with a population size <100 should be systematically excluded, a procedure that may have induced bias and influenced the conclusions.(3) Instead, subgroup analysis based on the sample size could be performed to check the robustness of the results. Second, despite the effort of Seeto and colleagues’ aim to pursue a robust design, the present study remains limited by several possible sources of bias, mainly derived from CAEs not being the primary outcome of the included studies. Although the results of this study should be interpreted with caution because of potential bias and confoundings, this study provides directions for future research. Compared with previous research, the absolute risk of CAEs was similar between denosumab (1.4% ~ 4.0%) and nonsteroidal anti-inflammatory drugs (NSAIDs) (2.3% ~ 2.7%),(4) which suggests that only a well-designed, randomized clinical trial, with CAEs as the primary outcome and enrolling approximately 20,000 patients, can establish the relative risks of denosumab and address this important public health issue.(5) The authors have no conflicts of interest. Authors’ roles: LS: Contributed substantially to conception and design; drafted the article; gave final approval of the version to be published; agreed to act as a guarantor of the work. X-DW: Contributed substantially to conception and design; drafted the article; gave final approval of the version to be published; agreed to act as a guarantor of the work. WH: Contributed substantially to conception and design; drafted the article; gave final approval of the version to be published; agreed to act as a guarantor of the work. Author Contributions: LS: Conceptualization; data curation; writing-original draft; writing-review and editing. X-DW: Conceptualization; data curation; writing-original draft; writing-review and editing. WH: Conceptualization; data curation; writing-original draft; writing-review and editing.