The potential impact of bisphosphonates on major adverse cardiovascular events: a study of 1,097,406 patients

Abstract Introduction Up to 19.7% of adults worldwide suffer from osteoporosis, and the risk of acquiring the disease increases with age.1 A common therapy for osteoporosis is the bisphosphonate class of drugs. These drugs act in part by inhibiting osteoclasts, cells that resorb bone and experience increased activity relative to bone-forming osteoblasts with aging.2 As adults age, the risk of developing atherosclerosis increases, putting patients at an increased risk of major adverse cardiovascular events (MACE).3 Atherosclerotic plaques become calcified as they mature, which is the basis of CT coronary artery calcium score, a tool used to aid cardiovascular risk assessment and help guide clinical treatment in patients with coronary artery disease. One possible mechanism which could contribute to the calcification of atherosclerotic plaques involves the presence of arterial osteoblast and osteoclast-like cells, a phenomenon which has been described in a growing body of research4–7 The goal of this study was to use the TriNetX medical database to evaluate the effect of bisphosphonate use on the development of major adverse cardiovascular events in patients with osteoporosis. Materials and Methods The TriNetX research network was used for this study, with cohorts created via International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX system. Both cohorts consisted of adult patients with a diagnosis of osteoporosis (M81). One cohort of patients was receiving treatment with alendronate, risedronate, ibandronate, or zoledronic acid while the other cohort was prohibited from those medications. The cohorts were balanced by propensity score matching and the greedy nearest neighbor algorithm for age, race, gender, and ethnicity, resulting in 548,703 patients in each arm. They were then compared for the outcomes of acute myocardial infarction (I21), cerebral infarction (I63), and mortality starting one year after meeting the index criteria (1 year of treatment for the bisphosphonate group). Results Bisphosphonate treatment was associated with a composite 16% increased risk of MACE (17.9% vs 15.4%, RR 1.16, 95% CI (1.15,1.17), p value <0.0001. The risk ratios for the individual outcomes were 1.13 for acute myocardial infarction, 1.17 for cerebral infarction, and 1.18 for all-cause mortality. Conclusion The findings from our study suggests use of bisphosphonates for osteoporosis is associated with increased risk of MACE. Given the high rates of osteoporosis and atherosclerosis in the general adult population, future prospective studies will be needed to confirm these results and determine whether alternative agents such as denosumab have similar effects.