Bisphosphonates and Atrial Fibrillation

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; 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.

[1]  K. Brixen,et al.  Atrial fibrillation in fracture patients treated with oral bisphosphonates , 2009, Journal of internal medicine.

[2]  P Geusens,et al.  Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. , 2001, The New England journal of medicine.

[3]  S. Cummings,et al.  Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. , 2007, The New England journal of medicine.

[4]  H K Genant,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. , 1999, JAMA.

[5]  S. Cummings,et al.  Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures , 1996, The Lancet.

[6]  Ana Ruigómez,et al.  Incidence of chronic atrial fibrillation in general practice and its treatment pattern. , 2002, Journal of clinical epidemiology.

[7]  D. Reid,et al.  Efficacy and Safety of Daily Risedronate in the Treatment of Corticosteroid‐Induced Osteoporosis in Men and Women: A Randomized Trial , 2000 .

[8]  S. Cummings,et al.  Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study , 2008, BMJ : British Medical Journal.

[9]  M. Elisaf,et al.  Multiple Electrolyte Abnormalities after Pamidronate Administration , 1998, Nephron.

[10]  S. Wallach,et al.  Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. , 1999, Arthritis and rheumatism.

[11]  S. Silverberg,et al.  Hypocalcemia associated with alendronate. , 1999, Annals of internal medicine.

[12]  M. McClung,et al.  Yearly zoledronic acid in postmenopausal osteoporosis. , 2007, The New England journal of medicine.

[13]  S. Cummings,et al.  Alendronate and atrial fibrillation. , 2007, The New England journal of medicine.

[14]  A. LaCroix,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. , 1998, JAMA.

[15]  S. Silverman,et al.  Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: The risedronate and alendronate (REAL) cohort study , 2006, Osteoporosis International.

[16]  M. Hooper,et al.  Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis , 2000, Osteoporosis International.

[17]  Bruce M Psaty,et al.  Inflammation as a Risk Factor for Atrial Fibrillation , 2003, Circulation.

[18]  S. Boonen,et al.  Zoledronic acid and clinical fractures and mortality after hip fracture. , 2007, The New England journal of medicine.

[19]  S. Cummings,et al.  Use of alendronate and risk of incident atrial fibrillation in women. , 2008, Archives of internal medicine.

[20]  G. Rodan,et al.  Mechanism of action of bisphosphonates , 2003, Current osteoporosis reports.

[21]  J. Digennaro,et al.  Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up. , 1998, The Journal of clinical endocrinology and metabolism.