Correspondence

Alendronate and Atrial Fibrillation

N Engl J Med 2007; 356:1895-1896May 3, 2007

Article

To the Editor:

In this issue of the Journal, Black et al.1 report on a significant increase in the risk of serious atrial-fibrillation adverse events (defined as events resulting in hospitalization or disability or judged to be life-threatening) associated with once-yearly infusions of intravenous zoledronic acid for the treatment of osteoporosis in postmenopausal women. However, there was no increased risk of all adverse events of atrial fibrillation with such infusions.

We reviewed the results of the Fracture Intervention Trial (FIT), a randomized study of alendronate sponsored by Merck, which involved 6459 postmenopausal women (mean age, 69 years).2,3 The University of California at San Francisco coordinating center collected the data, created the data set, and provided reports to the data and safety monitoring board. At the board's request, a physician at the coordinating center who was unaware of study-group assignments confirmed potential atrial-fibrillation adverse events. The final 1997 analysis that was reported to the Food and Drug Administration showed 47 serious atrial-fibrillation adverse events (1.5%) among patients receiving alendronate versus 31 (1.0%) among those receiving placebo during an average of 4 years (relative hazard, 1.51; 95% confidence interval [CI], 0.97 to 2.40; P=0.07) (Figure 1Figure 1Cumulative Incidence of Serious Atrial Fibrillation in the 1997 Fracture Intervention Trial.). There was no increased risk of all atrial-fibrillation adverse events: 81 events (2.5%) versus 71 events (2.2%) (relative hazard, 1.14; 95% CI, 0.83 to 1.57; P=0.42). At that time, a true association between atrial fibrillation and the administration of alendronate was considered to be very unlikely in view of numerous comparisons of potential adverse events, no association for all atrial-fibrillation adverse events, and no apparent biologic plausibility.

The trend toward an increased risk of serious but not atrial-fibrillation adverse events in the FIT trial resembles the pattern observed in the study of zoledronic acid by Black et al.1 How potent bisphosphonates might increase the risk of serious atrial fibrillation is unclear. However, parenteral administration of bisphosphonates stimulates the release of inflammatory cytokines,4 and increased levels of inflammatory cytokines have been associated with an increased risk of atrial fibrillation.5 It is not known whether oral bisphosphonates also increase cytokine levels. Shifts of calcium within atrial cells can predispose patients to atrial fibrillation.6 Potent bisphosphonates cause a very small decrease in serum calcium levels,7 but the relevance of this finding to atrial electrophysiology is uncertain. Explanations must account for an increased risk of only serious atrial fibrillation.

The possibility of an increased risk of atrial fibrillation should be examined in other studies of bisphosphonates and assessed in trials of potent inhibitors of bone resorption. This potential risk must be weighed against the reduction in fracture risk.

Steven R. Cummings, M.D.
California Pacific Medical Center Research Institute, San Francisco, CA 94105

Ann V. Schwartz, Ph.D.
Dennis M. Black, Ph.D.
University of California, San Francisco, San Francisco, CA 94107

Dr. Cummings reports receiving consulting and advisory-board fees from Amgen and Organon, lecture fees from Merck and Lilly, and grant support from Amgen, Novartis, Lilly, and Pfizer. Dr. Black reports receiving grant support and honoraria from Novartis and Merck. No other potential conflict of interest relevant to this letter was reported.

7 References

1. 1

   Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822
   Full Text | Web of Science | Medline

2. 2

   Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-1541
   CrossRef | Web of Science | Medline

3. 3

   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;280:2077-2082
   CrossRef | Web of Science | Medline

4. 4

   Hewitt RE, Lissina A, Green AE, Slay ES, Price DA, Sewell AK. The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood gammadelta T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol 2005;139:101-111
   CrossRef | Web of Science | Medline

5. 5

   Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006-3010
   CrossRef | Web of Science | Medline

6. 6

   Van Wagoner DR, Nerbonne JM. Molecular basis of electrical remodeling in atrial fibrillation. J Mol Cell Cardiol 2000;32:1101-1117
   CrossRef | Web of Science | Medline

7. 7

   Vasikaran SD. Bisphosphonates: an overview with special reference to alendronate. Ann Clin Biochem 2001;38:608-623
   CrossRef | Web of Science | Medline

Citing Articles (69)

Citing Articles

1. 1

   J.-J. Body, P. Bergmann, S. Boonen, J.-P. Devogelaer, E. Gielen, S. Goemaere, J.-M. Kaufman, S. Rozenberg, J.-Y. Reginster. (2012) Extraskeletal benefits and risks of calcium, vitamin D and anti-osteoporosis medications. Osteoporosis International 23:S1, 1-23
   CrossRef

2. 2

   C. W. Rhee, J. Lee, S. Oh, N. K. Choi, B. J. Park. (2012) Use of bisphosphonate and risk of atrial fibrillation in older women with osteoporosis. Osteoporosis International 23:1, 247-254
   CrossRef

3. 3

   E. Barrett-Connor, A. S. Swern, C. M. Hustad, H. G. Bone, U. A. Liberman, S. Papapoulos, H. Wang, A. Papp, A. C. Santora. (2012) Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials. Osteoporosis International 23:1, 233-245
   CrossRef

4. 4

   Celeste J. Hamilton, Sophie A. Jamal, Earl R. Bogoch. 2011. Osteoporosis and Metabolic Disorders. , 35-55.
   CrossRef

5. 5

   Mickaël Rousière. (2011) De l’importance de prendre en charge l’ostéoporose. La Presse Médicale 40:10, 900-909
   CrossRef

6. 6

   René Rizzoli, Jean-Yves Reginster. (2011) Adverse drug reactions to osteoporosis treatments. Expert Review of Clinical Pharmacology 4:5, 593-604
   CrossRef

7. 7

   Pei-Yu Lu, Chi-Feng Hsieh, Yi-Wen Tsai, Weng-Foung Huang. (2011) Alendronate and Raloxifene Use Related to Cardiovascular Diseases: Differentiation by Different Dosing Regimens of Alendronate. Clinical Therapeutics 33:9, 1173-1179
   CrossRef

8. 8

   Ian R. Reid. (2011) Bisphosphonates in the treatment of osteoporosis: a review of their contribution and controversies. Skeletal Radiology 40:9, 1191-1196
   CrossRef

9. 9

   René Rizzoli, Jean-Yves Reginster, Steven Boonen, Gérard Bréart, Adolfo Diez-Perez, Dieter Felsenberg, Jean-Marc Kaufman, John A. Kanis, Cyrus Cooper. (2011) Adverse Reactions and Drug–Drug Interactions in the Management of Women with Postmenopausal Osteoporosis. Calcified Tissue International 89:2, 91-104
   CrossRef

10. 10

    Ewa Sewerynek. (2011) Bisphosphonates and the risk of atrial fibrillation in elderly women with osteoporosis. Aging Health 7:4, 585-589
    CrossRef

11. 11

    Michael Pazianas, Bo Abrahamsen. (2011) Safety of bisphosphonates. Bone 49:1, 103-110
    CrossRef

12. 12

    S. Christensen, F. Mehnert, R. D. Chapurlat, J. A. Baron, H. T. Sørensen. (2011) Oral bisphosphonates and risk of ischemic stroke: a case–control study. Osteoporosis International 22:6, 1773-1779
    CrossRef

13. 13

    P. Hadji. (2011) Managing bone health with zoledronic acid: a review of randomized clinical study results. Climacteric 14:3, 321-332
    CrossRef

14. 14

    Brian J. Gates, Shyamal Das. (2011) Management of osteoporosis in elderly men. Maturitas 69:2, 113-119
    CrossRef

15. 15

    E. Michael Lewiecki. (2011) Safety of Long-Term Bisphosphonate Therapy for the Management of Osteoporosis. Drugs 71:6, 791-814
    CrossRef

16. 16

    R. Rizzoli. (2011) Bisphosphonates for post-menopausal osteoporosis: are they all the same?. QJM 104:4, 281-300
    CrossRef

17. 17

    Sigrun Ressler, Brigitte Mlineritsch, Richard Greil. (2011) Zoledronic acid for adjuvant use in patients with breast cancer. Expert Review of Anticancer Therapy 11:3, 333-349
    CrossRef

18. 18

    Jenny Folkesson, Janet Goldenstein, Julio Carballido-Gamio, Galateia Kazakia, Andrew J. Burghardt, Ana Rodriguez, Roland Krug, Anne E. de Papp, Thomas M. Link, Sharmila Majumdar. (2011) Longitudinal evaluation of the effects of alendronate on MRI bone microarchitecture in postmenopausal osteopenic women. Bone 48:3, 611-621
    CrossRef

19. 19

    Socrates E. Papapoulos. (2011) Use of bisphosphonates in the management of postmenopausal osteoporosis. Annals of the New York Academy of Sciences 1218:1, 15-32
    CrossRef

20. 20

    Mary Kamienski, Denise Tate, CPT Marielos Vega. (2011) The Silent Thief. Orthopaedic Nursing 30:3, 162-171
    CrossRef

21. 21

    Li Gong, Russ B. Altman, Teri E. Klein. (2011) Bisphosphonates pathway. Pharmacogenetics and Genomics 21:1, 50-53
    CrossRef

22. 22

    Luis Arboleya, Mercedes Alperi, Sara Alonso. (2011) Adverse effects of bisphosphonates. Reumatolog ía Cl ínica (English Edition) 7:3, 189-197
    CrossRef

23. 23

    Patricia A. Howard, Brian J. Barnes, James L. Vacek, Warren Chen, Sue-Min Lai. (2010) Impact of Bisphosphonates on the Risk of Atrial Fibrillation. American Journal Cardiovascular Drugs 10:6, 359-367
    CrossRef

24. 24

    A. L. Lamberg, E. Horvath-Puho, S. Christensen, H. T. Sørensen. (2010) Use of oral bisphosphonates and risk of venous thromboembolism: a population-based case-control study. Osteoporosis International 21:11, 1911-1917
    CrossRef

25. 25

    Francesca Marini, Maria Luisa Brandi. (2010) Pharmacogenetics of osteoporosis. Expert Review of Endocrinology & Metabolism 5:6, 905-910
    CrossRef

26. 26

    David M. Reid. (2010) Update on the Use of Zoledronic Acid in the Management of Osteoporosis. Current Osteoporosis Reports 8:3, 145-150
    CrossRef

27. 27

    Rohit Bhuriya, Mukesh Singh, Janos Molnar, Rohit Arora, Sandeep Khosla. (2010) Bisphosphonate use in women and the risk of atrial fibrillation: A systematic review and meta-analysis. International Journal of Cardiology 142:3, 213-217
    CrossRef

28. 28

    Bo Abrahamsen. (2010) Bisphosphonate adverse effects, lessons from large databases. Current Opinion in Rheumatology 22:4, 404-409
    CrossRef

29. 29

    Bo Abrahamsen. (2010) Adverse Effects of Bisphosphonates. Calcified Tissue International 86:6, 421-435
    CrossRef

30. 30

    E. M. Lewiecki, C. Cooper, E. Thompson, F. Hartl, D. Mehta, S. E. Papapoulos. (2010) Ibandronate does not increase risk of atrial fibrillation in analysis of pivotal clinical trials. International Journal of Clinical Practice 64:6, 821-826
    CrossRef

31. 31

    Marco L. Lolli, Barbara Rolando, Paolo Tosco, Shilpi Chaurasia, Antonella Di Stilo, Loretta Lazzarato, Eva Gorassini, Riccardo Ferracini, Simonetta Oliaro-Bosso, Roberta Fruttero, Alberto Gasco. (2010) Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs). Bioorganic & Medicinal Chemistry 18:7, 2428-2438
    CrossRef

32. 32

    A. John Camm. (2010) Review of the cardiovascular safety of zoledronic acid and other bisphosphonates for the treatment of osteoporosis. Clinical Therapeutics 32:3, 426-436
    CrossRef

33. 33

    J. Chris Gallagher, Adarsh J. Sai. (2010) Bisphosphonate use in osteoporosis. Menopause 17:1, 5-7
    CrossRef

34. 34

    Marc C. Hochberg. 2010. Osteoporosis. , 317-329.
    CrossRef

35. 35

    Anne L Langston, Marion K Campbell, William D Fraser, Graeme S MacLennan, Peter L Selby, Stuart H Ralston. (2010) Randomized trial of intensive bisphosphonate treatment versus symptomatic management in paget's disease of bone. Journal of Bone and Mineral Research 25:1, 20-31
    CrossRef

36. 36

    Michael Pazianas, Juliet Compston, Christopher L-H Huang. (2010) Atrial fibrillation and bisphosphonate therapy. Journal of Bone and Mineral Research 25:1, 2-10
    CrossRef

37. 37

    Weng-Foung Huang, Yi-Wen Tsai, Yu-Wen Wen, Fei-Yuan Hsiao, Ken N. Kuo, Chia-Rung Tsai. (2010) Osteoporosis treatment and atrial fibrillation. Menopause 17:1, 57-63
    CrossRef

38. 38

    J SCHOUSBOE. 2010. Cost-Effectiveness of Interventions to Reduce Osteoporosis-Related Fractures in MenCurrent Data, Controversies, and Challenges. , 613-627.
    CrossRef

39. 39

    Piet Geusens. (2009) Strategies for treatment to prevent fragility fractures in postmenopausal women. Best Practice & Research Clinical Rheumatology 23:6, 727-740
    CrossRef

40. 40

    Naomi Kemeny-Suss, Amanda Kasneci, Daniel Rivas, Jonathan Afilalo, Svetlana V. Komarova, Lorraine E. Chalifour, Gustavo Duque. (2009) Alendronate affects calcium dynamics in cardiomyocytes in vitro. Vascular Pharmacology 51:5-6, 350-358
    CrossRef

41. 41

    Beth Nochowitz, Sherry Siegert, Mitzi Wasik. (2009) An Update on Osteoporosis. American Journal of Therapeutics 16:5, 437-445
    CrossRef

42. 42

    Atul F. Kamath. (2009) Current Controversies in Bisphosphonate Therapy. Orthopedics 32:7, 473-475
    CrossRef

43. 43

    Daniel H Solomon, Laura Rekedal, Suzanne M Cadarette. (2009) Osteoporosis treatments and adverse events. Current Opinion in Rheumatology 21:4, 363-368
    CrossRef

44. 44

    Kurt A. Kennel, Matthew T. Drake. (2009) Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management. Mayo Clinic Proceedings 84:7, 632-638
    CrossRef

45. 45

    K. A. Kennel, M. T. Drake. (2009) Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management. Mayo Clinic Proceedings 84:7, 632-638
    CrossRef

46. 46

    Sumio Matzno, Tomoko Nishiguchi, Takeshi Akiyoshi, Setsuko Anami, Toshikatsu Nakabayashi, Kenji Matsuyama. (2009) Synergistic action of statins and nitrogen-containing bisphosphonates in the development of rhabdomyolysis in L6 rat skeletal myoblasts. Journal of Pharmacy and Pharmacology 61:6, 781-788
    CrossRef

47. 47

    B. Abrahamsen, P. Eiken, K. Brixen. (2009) Atrial fibrillation in fracture patients treated with oral bisphosphonates. Journal of Internal Medicine 265:5, 581-592
    CrossRef

48. 48

    Bruno Frediani, Luca Cavalieri, Giovanni Cremonesi. (2009) Clodronic Acid Formulations Available in Europe and their Use in Osteoporosis. Clinical Drug Investigation 29:6, 359-379
    CrossRef

49. 49

    Francesca Marini, Maria Luisa Brandi. (2009) Pharmacogenetics of Osteoporosis: Future Perspectives. Calcified Tissue International 84:5, 337-347
    CrossRef

50. 50

    , Hans Peter Dimai, Peter Pietschmann, Heinrich Resch, Elisabeth Preisinger, Astrid Fahrleitner-Pammer, Harald Dobnig, Klaus Klaushofer. (2009) Österreichischer Leitfaden zur medikamentösen Therapie der postmenopausalen Osteoporose – Update 2009. Wiener Medizinische Wochenschrift 159:S122, 1-34
    CrossRef

51. 51

    T. Jared Bunch, Jeffrey L. Anderson, Heidi T. May, Joseph B. Muhlestein, Benjamin D. Horne, Brian G. Crandall, J. Peter Weiss, Donald L. Lappé, Jeffrey S. Osborn, John D. Day. (2009) Relation of Bisphosphonate Therapies and Risk of Developing Atrial Fibrillation. The American Journal of Cardiology 103:6, 824-828
    CrossRef

52. 52

    Yoon Kong Loke, Vinodh Jeevanantham, Sonal Singh. (2009) Bisphosphonates and Atrial Fibrillation. Drug Safety 32:3, 219-228
    CrossRef

53. 53

    Seth M Arum. (2008) New developments surrounding the safety of bisphosphonates. Current Opinion in Endocrinology, Diabetes and Obesity 15:6, 508-513
    CrossRef

54. 54

    Michael Freundlich, Uri S. Alon. (2008) Bisphosphonates in children with hypercalciuria and reduced bone mineral density. Pediatric Nephrology 23:12, 2215-2220
    CrossRef

55. 55

    Francesca Marini, Alberto Falchetti, Sandra Silvestri, Yu Bagger, Ettore Luzi, Annalisa Tanini, Claus Christiansen, Maria Luisa Brandi. (2008) Modulatory effect of farnesyl pyrophosphate synthase ( FDPS ) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis*. Current Medical Research and Opinion 24:9, 2609-2615
    CrossRef

56. 56

    Matthew T. Drake, Bart L. Clarke, Sundeep Khosla. (2008) Bisphosphonates: Mechanism of Action and Role in Clinical Practice. Mayo Clinic Proceedings 83:9, 1032-1045
    CrossRef

57. 57

    &NA;. (2008) Adverse-effect profiles of bisphosphonates are largely determined by their route of administration. Drugs & Therapy Perspectives 24:7, 23-26
    CrossRef

58. 58

    Piet P Geusens, Christian H Roux, David M Reid, Willem F Lems, Silvano Adami, Jonathan D Adachi, Philip N Sambrook, Kenneth G Saag, Nancy E Lane, Marc C Hochberg. (2008) Drug Insight: choosing a drug treatment strategy for women with osteoporosis—an evidence-based clinical perspective. Nature Clinical Practice Rheumatology 4:5, 240-248
    CrossRef

59. 59

    &NA;. (2008) A Once-Yearly IV Bisphosphonate for Osteoporosis. Obstetrics & Gynecology 111:5, 1208-1209
    CrossRef

60. 60

    Roland D Chapurlat. (2008) Single annual injectable treatment for postmenopausal osteoporosis. Expert Opinion on Drug Delivery 5:5, 583-591
    CrossRef

61. 61

    Alessandro Gozzetti, Luigi Gennari, Daniela Merlotti, Stefania Salvadori, Vincenzo Paola, Annalisa Avanzati, Beatrice Franci, Elena Marchini, Monica Tozzi, Maria Stella Campagna, Ranuccio Nuti, Francesco Lauria, Giuseppe Martini. (2008) The Effects of Zoledronic Acid on Serum Lipids in Multiple Myeloma Patients. Calcified Tissue International 82:4, 258-262
    CrossRef

62. 62

    Diane S. Aschenbrenner. (2008) IS THERE A LINK BETWEEN BISPHOSPHONATES AND ATRIAL FIBRILLATION?. AJN, American Journal of Nursing 108:3, 37
    CrossRef

63. 63

    John T Schousboe. (2008) Cost Effectiveness of Screen-and-Treat Strategies for Low Bone Mineral Density. Applied Health Economics and Health Policy 6:1, 1-18
    CrossRef

64. 64

    (2007) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 16:11, i-xii
    CrossRef

65. 65

    Ann Cranney, Jonathan D. Adachi. (2007) Bisphosphonates for the Treatment of Postmenopausal Osteoporosis: An Update. Clinical Reviews in Bone and Mineral Metabolism 5:3, 145-152
    CrossRef

66. 66

    (2007) Yearly Zoledronic Acid in Postmenopausal Osteoporosis. New England Journal of Medicine 357:7, 711-715
    Full Text

67. 67

    Jacyntha A. Sterling. (2007) Hospital Pharmacy Pulse - Recent Publications on Medications and Pharmacy. Hospital Pharmacy 42:7, 657-660
    CrossRef

68. 68

    Compston, Juliet, . (2007) Treatments for Osteoporosis — Looking beyond the HORIZON. New England Journal of Medicine 356:18, 1878-1880
    Full Text

69. 69

    Black, Dennis M., Delmas, Pierre D., Eastell, Richard, Reid, Ian R., Boonen, Steven, Cauley, Jane A., Cosman, Felicia, Lakatos, Péter, Leung, Ping Chung, Man, Zulema, Mautalen, Carlos, Mesenbrink, Peter, Hu, Huilin, Caminis, John, Tong, Karen, Rosario-Jansen, Theresa, Krasnow, Joel, Hue, Trisha F., Sellmeyer, Deborah, Eriksen, Erik Fink, Cummings, Steven R., . (2007) Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis. New England Journal of Medicine 356:18, 1809-1822
    Full Text