Bisphosphonates and atrial fibrillation: systematic review and meta-analysis

Drug Saf. 2009;32(3):219-28. doi: 10.2165/00002018-200932030-00004.


Background: Bisphosphonates are widely used in osteoporosis, but there have been concerns about a potential link between bisphosphonate therapy and atrial fibrillation.

Objective: We aimed to systematically evaluate the risk of atrial fibrillation associated with bisphosphonate use.

Methods: We searched MEDLINE, regulatory authority websites, pharmaceutical company trial registers and product information sheets for randomized controlled trials (RCTs) and controlled observational studies published in English through to May 2008. We selected RCTs of bisphosphonates versus placebo for osteoporosis or fractures, with at least 3 months of follow-up, and data on atrial fibrillation. For the observational studies, we included case-control or cohort studies that evaluated the risk of atrial fibrillation in patients exposed to bisphosphonates compared with non-exposure. Data on atrial fibrillation as the primary outcome, and stroke and cardiovascular mortality as secondary outcomes, were extracted. DATA SYNTHESIS/RESULTS: We calculated pooled odds ratio (OR) using random effects meta-analysis, and estimated statistical heterogeneity with the I2 statistic. Bisphosphonate exposure was significantly associated with risk of atrial fibrillation serious adverse events in a meta-analysis of four trial datasets (OR 1.47; 95% CI 1.01, 2.14; p = 0.04; I2 = 46%). However, meta-analysis of all atrial fibrillation events (serious and non-serious) from the same datasets yielded a pooled OR of 1.14 (95% CI 0.96, 1.36; p = 0.15; I2 = 0%). We identified two case-control studies, one of which found an association between bisphosphonate exposure (ever users) and atrial fibrillation (adjusted OR 1.86; 95% CI 1.09, 3.15) while the other showed no association (adjusted OR 0.99; 95% CI 0.90, 1.10). Both studies failed to demonstrate a significant association in 'current' users. We did not find a significant increase in the risk of stroke (three trial datasets; OR 1.00; 95% CI 0.82, 1.22; p = 0.99; I2 = 0%) or cardiovascular mortality (three trial datasets; OR 0.86; 95% CI 0.66, 1.13; p = 0.28; I2 = 31%).

Conclusion: While there are some data linking bisphosphonates to serious atrial fibrillation, heterogeneity of the existing evidence, as well as paucity of information on some of the agents, precludes any definitive conclusions on the exact nature of the risk.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Administration, Oral
  • Atrial Fibrillation / chemically induced*
  • Bone Density Conservation Agents / adverse effects*
  • Bone Density Conservation Agents / therapeutic use
  • Cardiovascular Diseases / chemically induced
  • Cardiovascular Diseases / mortality
  • Diphosphonates / adverse effects*
  • Diphosphonates / therapeutic use
  • Humans
  • Osteoporosis / drug therapy
  • Randomized Controlled Trials as Topic
  • Risk Assessment
  • Stroke / chemically induced


  • Bone Density Conservation Agents
  • Diphosphonates