Chicago, IL - Women who have ever taken alendronate (Fosamax, Merck), the bisphosphonate widely prescribed for preservation of bone density that recently went off patent, have an increased risk of developing atrial fibrillation (AF), according to a population-based, case-control study in the April 28, 2008 Archives of Internal Medicine [1].

In multivariate analyses, the odds ratio (95% CI) for incident AF associated with current or past alendronate use among nearly 1700 women in a clinical practice setting was 1.86 (1.09-3.15), with a disproportionate share of the risk concentrated among those who were previously but are no longer on the drug.

"Bisphosphonates have been proven to prevent fractures in people at very high risk of fracture," lead author Dr Susan R Heckbert (University of Washington, Seattle) observed for heartwire, and for those people, "the benefits in fracture prevention from taking alendronate will outweigh the possible risk of atrial fibrillation."

For others, including patients "maybe at only moderate risk of fractures or for patients who are at particularly high risk of atrial fibrillation, such as those with coronary disease, heart failure, or diabetes," she said, "they and their physicians need to do the best they can with the available evidence to weigh the benefits and risks."

Heckbert et al observe that their work supports two prior studies that had suggested bisphosphonates might promote AF; published last year and reported then by heartwire, they were the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial of zoledronic acid (Zometa, Novartis) [2] and the Fracture Intervention Trial (FIT) using alendronate [3]. In contrast to those studies, according to the group, the current analysis shows increased risk of AF overall and also specifically in the acute-care setting.

An accompanying editorial [4] lists several notes of caution regarding the group's findings, including some related to the study's observational nature (such as the possible presence of uncontrolled confounders, like hyperthyroidism) and the fact that "the association [between alendronate and AF] has not been consistently reported and the biological plausibility of the finding is uncertain." Conclude the authors, Drs Jane A Cauley and Kristine E Ensrud (University of Pittsburgh, PA), "At this time, it seems that the benefits of bisphosphonate treatment in patients with osteoporosis outweigh the risk of AF."

Heckbert studied 719 patients with AF, classifying them according to duration of the arrhythmia and whether the diagnosis had been made in an outpatient or acute-care setting. They were matched with 966 non-AF controls according to age, treated hypertension, and calendar year of diagnosis.

The AF risk didn't vary by history of cardiovascular disease, treated hypertension, or age. Significantly increased AF risks were observed among patients who used statins and among diabetics, but there were so few patients involved, little can be made of the observations, according to Heckbert.

The bisphosphonate-AF link observed in the current analysis and the HORIZON and FIT studies, she said, "was and still is a completely unexpected effect," whose mechanism, if the effect is real, remains undefined. Speculating, Heckbert said infusions of the drugs could cause an inflammatory response, "and inflammation is known to be related to the development of atrial fibrillation." Or, she said, the treatment may affect the metabolism of calcium or other ions to which the atrium may be sensitive.

Heckbert said she knows no reason why their findings wouldn't apply to men. "We would have liked to study this in men," she said, but in their database, "you could count on one hand the number of men who had atrial fibrillation and were taking a bisphosphonate."