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Bisphosphonates and Atrial Fibrillation

Systematic Review and Meta-Analysis

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Abstract

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 data-sets 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; I 2 = 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.

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References

  1. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000; 11(1): 83–91

    Article  PubMed  CAS  Google Scholar 

  2. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 1999; 282(14): 1344–52

    Article  PubMed  CAS  Google Scholar 

  3. McClung MR, Geusens P, Miller PD, et al. Effect of rise-dronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001; 344(5): 333–40

    Article  PubMed  CAS  Google Scholar 

  4. Reid DM, Hughes RA, Laan RF, et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. J Bone Miner Res 2000; 15(6): 1006–13

    Article  PubMed  CAS  Google Scholar 

  5. Cohen S, Levy RM, Keller M, et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 1999; 42(11): 2309–18

    Article  PubMed  CAS  Google Scholar 

  6. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996; 348(1996): 1535–41

    Article  PubMed  CAS  Google Scholar 

  7. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998; 280(24): 2077–82

    Article  PubMed  CAS  Google Scholar 

  8. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356(18): 1809–22

    Article  PubMed  CAS  Google Scholar 

  9. Lyles KW, Colón-Emeric CS, Magaziner JS, et al., for the HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357: 1799–809

    Article  PubMed  CAS  Google Scholar 

  10. Silverman SL, Watts NB, Delmas PD, et al. Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study. Osteoporos Int 2007; 18(1): 25–34

    Article  PubMed  CAS  Google Scholar 

  11. American Dental Association. Report of the Council of Scientific Affairs: expert panel recommendations. Dental management of patients on oral bisphosphonate therapy, June 2006 [online]. Available from URL: http://www.ada.org/prof/resources/topics/osteonecrosis.asp [Accessed 2008 Jan 27]

  12. US Food and Drug Administration. Early communication of an ongoing safety review [online]. Available from URL: http://www.fda.gov/cder/drug/early_comm/bisphosphonates.htm [Accessed 2008 Jan 27]

  13. US Food and Drug Administration. What is a serious adverse event? [online]. Available from URL: http://www.fda.gov/medwatch/report/DESK/advevnt.htm [Accessed 2008 Feb 22]

  14. Loke YK, Price D, Herxheimer A. Adverse effects. In: Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions, version 5.0.0. The Cochrane Collaboration, 2008 [online]. Available from URL: http://www.cochrane-handbook.org [Accessed 2009 Feb 5]

  15. Deeks JJ, Higgins JP, Altman DG. Identifying and measuring heterogeneity. In: Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions, version 5.0.0. The Cochrane Collaboration, 2008 [online]. Available from URL: http://www.cochrane-handbook.org [Accessed 2009 Feb 5]

  16. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med 2007; 356(18): 1895–6

    Article  PubMed  CAS  Google Scholar 

  17. Karam R, Camm J, McClung M. Yearly zoledronic acid in postmenopausal osteoporosis [letter]. N Engl J Med 2007; 357: 712–3

    PubMed  CAS  Google Scholar 

  18. Mortensen L, Charles P, Bekker PJ, et al. Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up. J Clin Endocrinol Metab 1998; 83: 396–402

    Article  PubMed  CAS  Google Scholar 

  19. Novartis Pharmaceuticals UK Ltd. Zometa: last updated Jul 4,2008 [online]. Available from URL: http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=14062. [Accessed 2008 Sep 23]

  20. Sørensen HT, Christensen S, Mehnert F, et al. Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 2008; 336: 813–6

    Article  PubMed  Google Scholar 

  21. Heckbert SR, Li G, Cummings SR, et al. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008; 168: 826–31

    Article  PubMed  CAS  Google Scholar 

  22. Merck. Statement by Merck & Co., Inc., regarding the fracture intervention trial (FIT) with FOSAMAX® (alendronate sodium) and incidence of atrial fibrillation [online]. Available from URL: http://www.merck.com/newsroom/press_releases/product/2007_0502.html [Accessed 2008 Jan 27]

  23. Cummings SR, Mesenbrink P, Eriksen EF, et al. Risk factors for serious adverse events of atrial fibrillation in the Horizon-PFT trial of zoledronic acid [abstract no. 1056]. Presented at 29th Annual Meeting of the American Society for Bone and Mineral Research; 2007 Sep 16–19; Honolulu

  24. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003; 108: 3006–10

    Article  PubMed  Google Scholar 

  25. Reszka AA, Rodan GA. Mechanism of action of bisphosphonates. Curr Osteoporos Rep 2003; 1(2): 45–52

    Article  PubMed  Google Scholar 

  26. Kadar E, Rush JE, Wetmore L, et al. Electrolyte disturbances and cardiac arrhythmias in a dog following pamidronate, calcitonin, and furosemide administration for hypercalcemia of malignancy. J Am Anim Hosp Assoc 2004; 40(1): 75–81

    PubMed  Google Scholar 

  27. Elisaf M, Kalaitzidis R, Siamopoulos KC. Multiple electrolyte abnormalities after pamidronate administration. Nephron 1998; 79(3): 337–9

    Article  PubMed  CAS  Google Scholar 

  28. Schussheim DH, Jacobs TP, Silverberg SJ. Hypocalcemia associated with alendronate [letter]. Ann Intern Med 1999; 130

    PubMed  CAS  Google Scholar 

  29. Ruigómez A, Johansson S, Wallander MA, et al. Incidence of chronic atrial fibrillation in general practice and its treatment pattern. J Clin Epidemiol 2002; 55(4): 358–63

    Article  PubMed  Google Scholar 

  30. US Food and Drug Administration. Update of safety review follow-up to the October 1, 2007 early communication about the ongoing safety review of bisphosphonates [online]. Available from URL: http://www.fda.gov/Cder/Drug/early_comm/bisphosphonates_update_200811.htm [Accessed 2009 Feb 5]

  31. Abrahamsen B, Eiken P, Brixen K. Atrial fibrillation in fracture patients treated with oral bisphosphonates. J Intern Med. Epub 2009 Jan 6

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Acknowledgements

There was no funding source for this study. The authors have no conflicts of interest to declare.

Note in Proof In November 2008, the FDA reported their own evaluation of placebo-controlled clinical trials covering 19 687 patients receiving bisphosphonates (alendronate, ibandronate, risedronate and zoledronic acid) and 18 358 placebo-treated patients.[30]

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Loke, Y.K., Jeevanantham, V. & Singh, S. Bisphosphonates and Atrial Fibrillation. Drug-Safety 32, 219–228 (2009). https://doi.org/10.2165/00002018-200932030-00004

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