Calcified Tissue International

, Volume 86, Issue 5, pp 335–342 | Cite as

Risk of Atrial Fibrillation Associated with Use of Bisphosphonates and Other Drugs Against Osteoporosis: A Cohort Study

  • Peter Vestergaard
  • Kristoffer Schwartz
  • Else Marie Pinholt
  • Lars Rejnmark
  • Leif Mosekilde


We studied the association between bisphosphonate use and risk of atrial fibrillation or flutter and the effect of confounders such as heart and lung disease in a nationwide retrospective cohort from Denmark. All users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) were the exposed group and three age- and gender-matched controls from the general population (n = 310,683) were the nonexposed group. The main outcome measure was atrial fibrillation or atrial flutter. Before initiation of treatment against osteoporosis, no excess of atrial fibrillation or flutter was present for any drug except for etidronate (OR = 1.22, 95% CI 1.15–1.29). After initiation of treatment, raloxifene was not associated with any excess risk of atrial fibrillation (OR = 0.98, 95% CI 0.72–1.33). Etidronate (HR = 1.08, 95% CI 1.02–1.14) and alendronate (HR = 1.09, 95% CI 1.00–1.20) were associated with an excess risk of atrial fibrillation after treatment start if statistical adjustments were made for cardiovascular disease. However, this association disappeared upon statistical adjustment for chronic obstructive pulmonary disease (COPD) (etidronate HR = 1.04, 95% CI 0.98–1.10; alendronate HR = 1.05, 95% CI 0.96–1.15). In patients using etidronate (12.5% vs. 3.8%) and alendronate (11.4% vs. 4.6%) major differences were present in prevalence of COPD at start of treatment compared to matched controls. In conclusion, oral bisphosphonates do not seem to be associated with an excess risk of atrial fibrillation. Any excess risk seen in prior studies may be due to confounding from COPD.


Bisphosphonate Alendronate Etidronate Raloxifene Atrial fibrillation Chronic obstructive pulmonary disease 



This study was funded by an unrestricted grant from Servier Denmark and the Dandy Foundation. None of the sponsors had any role in obtaining data, analyzing data, or writing the report.


  1. 1.
    Black D, Delmas P, Eastell R, Reid I, Boonen S, Cauley J et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822CrossRefPubMedGoogle Scholar
  2. 2.
    Lyles K, Colon-Emeric C, Magaziner J, Adachi J, Pieper C, Mautalen C et al (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809CrossRefPubMedGoogle Scholar
  3. 3.
    Abrahamsen B, Eiken P, Brixen K (2009) Atrial fibrillation in fracture patients treated with oral bisphosphonates. J Intern Med 265:581–592CrossRefPubMedGoogle Scholar
  4. 4.
    Charlson M, Pompei P, Ales K, MacKenzie C (1987) A method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40:373–383CrossRefPubMedGoogle Scholar
  5. 5.
    Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM (2008) Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 168:826–831CrossRefPubMedGoogle Scholar
  6. 6.
    Sorensen H, Christensen S, Mehnert F, Pedersen L, Chapurlat R, Cummings S et al (2008) Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 336:813–816CrossRefPubMedGoogle Scholar
  7. 7.
    Bunch TJ, Anderson JL, May HT, Muhlestein JB, Horne BD, Crandall BG et al (2009) Relation of bisphosphonate therapies and risk of developing atrial fibrillation. Am J Cardiol 103:824–828CrossRefPubMedGoogle Scholar
  8. 8.
    Loke Y, Jeevanantham V, Singh S (2009) Bisphosphonates and atrial fibrillation: systematic review and meta-analysis. Drug Saf 32:219–228CrossRefPubMedGoogle Scholar
  9. 9.
    Frost L, Vestergaard P, Mosekilde L (2004) Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern Med 164:1675–1678CrossRefPubMedGoogle Scholar
  10. 10.
    Frost L, Vestergaard P (2004) Alcohol and risk of atrial fibrillation or flutter: a cohort study. Arch Intern Med 164:1993–1998CrossRefPubMedGoogle Scholar
  11. 11.
    Frost L, Hune L, Vestergaard P (2005) Overweight and obesity as risk factors for atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study. Am J Med 118:489–495CrossRefPubMedGoogle Scholar
  12. 12.
    Vestergaard P, Mosekilde L (2003) Hyperthyroidism, bone mineral, and fracture risk—a meta-analysis. Thyroid 13:585–593CrossRefPubMedGoogle Scholar
  13. 13.
    Tanko LB, Bagger YZ, Christiansen C (2003) Low bone mineral density in the hip as a marker of advanced atherosclerosis in elderly women. Calcif Tissue Int 73:15–20CrossRefPubMedGoogle Scholar
  14. 14.
    Vestergaard P, Rejnmark L, Mosekilde L (2009) Hypertension is a risk factor for fractures. Calcif Tissue Int 84:103–111CrossRefPubMedGoogle Scholar
  15. 15.
    Andersen T, Madsen M, Jørgensen J, Mellemkjær L, Olsen J (1999) The Danish National Hospital Register. Dan Med Bull 46:263–268PubMedGoogle Scholar
  16. 16.
    Mosbech J, Jørgensen J, Madsen M, Rostgaard K, Thornberg K, Poulsen T (1995) The Danish National Patient Register: evaluation of data quality [in Danish]. Ugeskr Laeger 157:3741–3745PubMedGoogle Scholar
  17. 17.
    Frost L, Vestergaard P, Mosekilde L, Mortensen L (2005) Trends in incidence and mortality in the hospital diagnosis of atrial fibrillation or flutter in Denmark, 1980–1999. Int J Cardiol 103:78–84CrossRefPubMedGoogle Scholar
  18. 18.
    Vestergaard P, Rejnmark L, Mosekilde L (2005) Fracture risk associated with systemic and topical corticosteroids. J Intern Med 257:374–384PubMedCrossRefGoogle Scholar
  19. 19.
    Vestergaard P, Mosekilde L (2003) Fracture risk associated with smoking—a meta-analysis. J Intern Med 254:572–583CrossRefPubMedGoogle Scholar
  20. 20.
    Dimal H, Domej W, Leb G, Lau K (2001) Bone loss in patients with untreated chronic obstructive pulmonary disease is mediated by an increase in bone resorption associated with hypercapnia. J Bone Miner Res 16:2132–2141CrossRefGoogle Scholar
  21. 21.
    Forli L, Halse J, Haug E, Bjortuft O, Vatn M, Kofstad J et al (2004) Vitamin D deficiency, bone mineral density and weight in patients with advanced pulmonary disease. J Intern Med 256:56–62CrossRefPubMedGoogle Scholar
  22. 22.
    De Laet C, Kanis J, Oden A, Johanson H, Johnell O, Delmas P et al (2005) Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int 16:1330–1338CrossRefPubMedGoogle Scholar
  23. 23.
    Hanrahan JP, Grogan DR, Baumgartner RA, Wilson A, Cheng H, Zimetbaum PJ et al (2008) Arrhythmias in patients with chronic obstructive pulmonary disease (COPD): occurrence frequency and the effect of treatment with the inhaled long-acting beta2-agonists arformoterol and salmeterol. Medicine (Baltimore) 87:319–328CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Peter Vestergaard
    • 1
  • Kristoffer Schwartz
    • 2
  • Else Marie Pinholt
    • 2
  • Lars Rejnmark
    • 1
  • Leif Mosekilde
    • 1
  1. 1.Department of Endocrinology and Metabolism CAarhus University HospitalArhus CDenmark
  2. 2.Department of Oral and Maxillofacial SurgeryUniversity HospitalCopenhagen NDenmark

Personalised recommendations