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Bisphosphonates Increase Risk of Incident AF


A meta-analysis shows both IV and oral formulations pose a risk of arrhythmia, the former more so than the latter. But these are very effective drugs. What next?

Bisphosphonates have proven to be highly effective treatment for osteoporosis, osteopenia, and the prevention of fractures. As their use has become more widespread, however, adverse effects are seen with increasing frequency. In particular, bisphosphonates have been linked to the development of atrial fibrillation (AF), with evidence that both oral and intravenous (IV) formulations may increase the risk of this arrhythmia. The mechanism of this relationship has not yet been fully characterized but it has been linked to the release of inflammatory cytokines (particularly following IV administration) and to potential changes in calcium handling in conduction system cells.

In the June 1, 2014 issue of in the American Journal of Cardiology, Sharma and colleagues report on a meta-analysis of 9 large clinical trials (5 randomized controlled trials and 4 observational studies) published between 1966 and 2013 to evaluate the risk of development of AF with oral or IV bisphosphonates. Based on the large amount of pooled data (n=135 347), the authors reported a significant increase in new-onset AF associated with both oral (relative risk [RR] 1.22) and IV (RR 1.4) bisphosphonates. They also compared the 2 formulations using a z statistic, which assesses the 2 risk ratios relative to each other, and found that the risk was higher with the IV preparation compared to oral ones. The mean age of patients in this cohort varied but tended more toward older age (≥65 years).

The findings are important to help begin raising awareness of the risk of AF with the use of the widely prescribed class of bisphosphonates. It should be noted, however, that the analysis may be subject to some residual confounding as these medications are commonly used in older patients, a population already more susceptible to the development of AF. 

So should bisphosphonates be avoided altogether to minimize risk of incident AF? As with any other clinical decision in medicine, the risk associated with use of the drugs ought to be weighed against the known benefits. In this large study, the increase in relative risk of incident AF was reported as 22% with oral preparations, which may be nominal when compared with the risk of osteoporotic fractures. The decision to initiate (or continue) bisphosphonates in an ambulatory outpatient, therefore, should be considered on a case-by-case basis and weighed against the proven benefit of this class in preventing fractures. And, in general, when oral bisphosphonates can be used, they may be the preferred agent given the relatively lower risk of arrhythmia than observed with IV formulations. Whether bisphosphonate use in an individual who already has AF leads to worse control of the AF has not yet been systematically studied.



Sharma A, Einstein AJ, Vallakati A, et al.  Risk of atrial fibrillation with use of oral and intravenous bisphosphonates.  Am J Cardiol. 2014;113:1815-1821. doi: 10.1016/j.amjcard.2014.03.008. Epub 2014 Mar 15.

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