Association between the cumulative exposure to bisphosphonates and hospitalization for atherosclerotic cardiovascular events: A population-based study

Background and aims: Although bisphosphonates have been suggested to protect against atherosclerotic cardiovascular (CV) events, evidence is still conflicting. We aimed at investigating the effect of bisphosphonates on hospitalizations for atherosclerotic CV events. Methods: We carried out a retrospective cohort study selecting subjects aged > 40 years, incident users of bisphosphonates. Exposure to bisphosphonates was characterized based on cumulative doses (proportion of days covered, PDC). Treatment's adherence was classified as low (PDC <= 40%), intermediate (PDC 41%-80%), or high (PDC > 80%). A multivariate Cox model was fitted to estimate the association between cumulative time-dependent exposure to bisphosphonates and hospitalization for atherosclerotic CV events (hazard ratio [HR] and 95% confidence interval). Results: Among 82,704 new bisphosphonates users (females 87.0%, mean age 70.7 +/- 10.6 years), 16.1% had a CV hospitalization during a mean follow-up of 6.5 + 2.6 years. Compared with individuals with PDC <= 40%, those exposed for 41-80% or more than 80% showed HRs of CV hospitalization of 0.95 [0.91-0.99] and 0.75 [0.71-0.81], respectively. In the sub-analysis by type of event, a PDC > 80% was associated with a reduced incidence for both coronary and cerebrovascular events (HRs 0.75 [0.68-0.83] and 0.76 [0.70-0.83], respectively). The protective effect was confirmed in stratified analyses by sex and age classes, and in those performed at 1 and 3 years of follow-up. Conclusions: Strict adherence to bisphosphonate treatment was associated with a better CV outcome. Although further studies to investigate possible mechanisms are warranted, bisphosphonates could be considered as having a potential CV benefit beyond the effect on bones.