Review of the cardiovascular safety of zoledronic acid and other bisphosphonates for the treatment of osteoporosis

Background: In 2 large, randomized, placebocontrolled trials, yearly 5-mg infusions of the bisphosphonate zoledronic acid were associated with increased bone mineral density and reduced fracture incidence in patients with osteoporosis, previous fracture, or both.

Objective: This review evaluated the cardiovascular risks of bisphosphonates (with a focus on zoledronic acid) for the treatment of osteoporosis and put these potential risks into perspective, summarizing available evidence from randomized clinical trials.

Methods: A search of PubMed (1991-September 2009) for preclinical and clinical trials was conducted using the following search terms: arrhythmia, atrial fibrillation, bisphosphonate, osteoporosis, cardiovascular adverse events, bone mineral density, fracture incidence, stroke, alendronate, etidronate, ibandronate, risedronate, and zoledronic acid. New analyses using unpublished data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Recurrent Fracture Trial (HORIZON-RFT) were also performed to evaluate the cardiovascular risk of zoledronic acid using stepwise Cox proportional hazards regression and risk modeling. After selection of risk factors for the model, treatment-by-factor interactions were evaluated at the 0.10 level of significance.

Results: Atrial fibrillation (AF) serious adverse events (SAEs) were observed among more patients receiving zoledronic acid (1.3%) than placebo (0.5%) over 36 months in HORIZON-PFT (P < 0.001), but the overall incidence of AF events was not significantly different between groups. The timing of AF SAEs did not correspond with drug administration or the pharmacokinetic profile of the drug. Nearly all women with sick sinus syndrome had predisposing conditions. An electrocardiography study after the third yearly infusion found no differences between those who received zoledronic acid versus placebo. Cardiovascular deaths, stroke, and other nonarrhythmia cardiovascular adverse events (AEs) were not significantly different between groups, but arrhythmia was more common in the zoledronic acid group than in the placebo group (6.9% vs 5.3%; P = 0.003). In analyses of pooled data from HORIZON-PFT and HORIZON-RFT to determine risk factors associated with the likelihood of experiencing AF, atrial flutter, or stroke, the only treatment-by-factor interaction was age (hazard ratio = 0.963; P < 0.067), which may be attributable to the fact that, among those aged > or =85 years, AF AEs occurred in 5.9% of the placebo group and 5.3% of the zoledronic acid group. Preclinical and other clinical trials of zoledronic acid for the treatment of osteoporosis or other indications did not identify an effect on AF AEs. A reanalysis of risedronate controlled clinical trials found no difference in the incidence of AF among active-treatment or placebo groups. In alendronate trials, AF SAEs occurred in 1.5% of the alendronate group and 1.0% of the placebo group (P = 0.07); the overall incidence of AF AEs was similar.

Conclusion: Despite the greater incidence of AF SAEs among zoledronic acid recipients versus placebo recipients in one study (not observed in other trials of this agent), clinical data for zoledronic acid, risedronate, and alendronate indicate no significant differences from placebo in overall incidence of AF AEs.