San Francisco, CA - By most accounts, the data are positive, impressive, and a dream for postmenopausal women and clinicians wanting to reduce the number of infusions needed to lower the risk of bone fracture. A once-yearly single infusion of zoledronic acid (Reclast, Novartis) during a three-year period significantly reduced the risk of vertebral fracture by 70%, hip fracture by 41%, and nonvertebral fracture by 25% [1].

The bad news is that the drug might have unintended effects on the heart.

The results from this study, in addition to another analysis, suggest a possible link between bisphosphonate treatment, the drug class to which zoledronic acid belongs, and atrial fibrillation in women who take the medication. In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) fracture trial, for example, significantly more patients treated with zoledronic acid developed atrial fibrillation compared with those treated with placebo.

"The events were uniformly distributed over time, with the vast majority of events occurring more than 30 days after infusions, by which time zoledronic acid is undetectable in the circulation," write lead HORIZON investigator Dr Dennis Black (University of California, San Francisco) and colleagues in the May 3, 2007 issue of the New England Journal of Medicine.

In addition to the observed events in HORIZON, Black, Dr Steven Cummings (California Pacific Medical Center Research Institute, San Francisco, CA), and Dr Ann Schwartz (University of California, San Francisco) also reviewed the results of the Fracture Intervention Trial (FIT), a randomized study with alendronate (Fosamax, Merck), another bisphosphonate, and found a similar trend of increased risk of serious atrial fibrillation with the drug [2].

"The possibility of an increased risk of atrial fibrillation should be examined in other studies of bisphosphonates and assessed in a trial of potent inhibitors of bone resorption," write Cummings, Schwartz, and Black in a letter to the editor. "This potential risk must be weighed against the reduction in fracture risk."

The HORIZON fracture trial is an international, multicenter, randomized, double-blind, placebo-controlled trial involving 7736 postmenopausal women. Patients were randomly assigned to receive either a 15-minute intravenous administration of 5 mg of zoledronic acid or placebo at baseline, 12 months, and 24 months. Patients were treated with calcium and vitamin D during the three-year trial.

As noted, zoledronic acid significantly reduced the risk of vertebral, hip, and nonvertebral fracture. However, serious atrial fibrillation—defined as requiring hospitalization, resulting in disability, or judged to be life threatening—occurred more frequently in the zoledronic-acid-treatment arm. A total of 50 patients treated with zoledronic acid developed the arrhythmia, compared with just 20 patients in the placebo arm. However, there was no difference observed in the incidence of stroke or the incidence of death from stroke in the two treatment arms.

With these data, Black and Cummings, investigators of the HORIZON trial, along with Schwartz, reviewed data from the Merck-sponsored FIT study, another bisphosphonate trial involving 6459 postmenopausal women. With alendronate, there was an approximately 50% increase in the risk of developing serious atrial fibrillation in women who took the drug daily compared with women who took placebo. Overall, 47 women developed atrial fibrillation in the alendronate arm compared with 31 in the placebo-treatment arm.

Cummings, Schwartz, and Black write that the mechanism behind the increased risk is unclear. Parenteral administration of bisphosphonates stimulates and releases inflammatory cytokines, and increased levels of cytokines are associated with an increased risk of atrial fibrillation. However, it is not known whether oral bisphosphonates also increase cytokine levels, they note.

While the findings might be due to chance, investigators say further studies with zoledronic acid, as well as a reanalysis of data from other bisphosphonate studies, should be explored. An editorial in the New England Journal of Medicine by Dr Juliet Compston (University of Cambridge, UK) notes that further clinical trials are needed, as a "causal relationship must be given serious consideration," while adding that further treatment choices for patients are still to be welcomed [3]. These new drugs provide a means of improving adherence and treatment outcomes in osteoporosis, she writes.

Alendronate is approved for the treatment of postmenopausal osteoporosis and Paget's disease, a chronic bone disorder. Zoledronic acid is currently approved for Paget's disease.