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Adverse Cardiac Effects of Bisphosphonates

      To the Editor:
      Pittman et al
      • Pittman C.B.
      • Davis L.A.
      • Zeringue A.L.
      • et al.
      Myocardial infarction risk among patients with fractures receiving bisphosphonates.
      recently reported that bisphosphonate use was associated with an increased risk of incident acute myocardial infarction (AMI) in their observational study of elderly veterans with a history of osteoporotic fractures. Of note, they also reported that “the timing of AMI correlated closely with the timing of bisphosphonate therapy initiation.”
      In 2012, Boonen et al
      • Boonen S.
      • Reginster J.Y.
      • Kaufman J.M.
      • et al.
      Fracture risk and zoledronic acid therapy in men with osteoporosis.
      reported that annual intravenous infusion of 5 mg of the bisphosphonate zoledronic acid was associated with significantly more AMI events than placebo in men over age 50 with osteoporosis (P=.03) but stated that “none of the events were considered by the investigator to be related to the study drug.” It was not explained how the investigator determined whether zoledronic acid played a role in causing the significant increase in AMI events associated with its use. It should be noted that this study was funded by the manufacturer and that the significant increase in myocardial infarction in the patients receiving the study drug was not mentioned in the article's abstract but rather was buried in the “Safety” section of their article.
      An earlier study of a similar regimen of zoledronic acid vs placebo for treatment of postmenopausal osteoporosis found that serious atrial fibrillation occurred more frequently in the zoledronic acid group (P<.001).
      • Black D.M.
      • Delmas P.D.
      • Eastell R.
      • et al.
      HORIZON Pivotal Fracture Trial
      Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.
      Given that we now have at least 3 studies documenting significantly increased rates of adverse cardiac outcomes with the use of bisphosphonates, it may be time to conduct a large randomized clinical trial examining the cardiac safety of bisphosphonate therapy.

      References

        • Pittman C.B.
        • Davis L.A.
        • Zeringue A.L.
        • et al.
        Myocardial infarction risk among patients with fractures receiving bisphosphonates.
        Mayo Clin Proc. 2014; 89: 43-51
        • Boonen S.
        • Reginster J.Y.
        • Kaufman J.M.
        • et al.
        Fracture risk and zoledronic acid therapy in men with osteoporosis.
        N Engl J Med. 2012; 367: 1714-1723
        • Black D.M.
        • Delmas P.D.
        • Eastell R.
        • et al.
        • HORIZON Pivotal Fracture Trial
        Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.
        N Engl J Med. 2007; 356: 1809-1822

      Linked Article

      • Myocardial Infarction Risk Among Patients With Fractures Receiving Bisphosphonates
        Mayo Clinic ProceedingsVol. 89Issue 1
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          To determine if bisphosphonates are associated with reduced risk of acute myocardial infarction (AMI).
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      • In reply—Adverse Cardiac Effects of Bisphosphonates
        Mayo Clinic ProceedingsVol. 89Issue 7
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          I appreciate Dr Keller's comments and agree with his call for additional research focusing on the cardiovascular effects of bisphosphonate therapy. A prospective clinical study would be a welcome addition to our knowledge base on this topic. Given the association of oral calcium supplementation with myocardial infarction and other cardiovascular events,1 future studies of bisphosphonates and cardiovascular events should also analyze the effects of oral calcium supplementation. There is a paucity of data on female subjects, and future studies should be designed to include this population.
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