Study design

A retrospective cohort study was conducted to evaluate the risk of cardiovascular and cerebrovascular events among postmenopausal women and men initiating osteoporosis treatment with denosumab or zoledronic acid. An active comparator, new user, as‐treated design was used, with the index event defined as initiation of either therapy.^{[ 13 , 14 ]} Confounding by covariates at initial treatment choice was controlled using propensity score modeling and inverse probability of treatment weighting (IPTW).^{[ 15 , 16 ]} Similarly, potentially informative censoring was addressed using censoring weighted estimation functions.^{[ 17 ]}

The protocol was submitted to the European Medicines Agency (EMA) before the conduct of the study and the protocol is posted on ENCePP (https://www.encepp.eu/encepp/viewResource.htm?id=42980). To further ensure the integrity of the study, we followed a staged approach to assessing covariate balance before proceeding to outcome evaluation.^{[ 18 ]} Investigators who provided input during the study on propensity score model specifications and adequacy of covariate balance were prevented from accessing outcome data to avoid bias from knowledge about how analytic decisions might affect treatment effect estimates.