Zoledronic Acid Associated With Higher Risk for Atrial Fibrillation Than Denosumab

Zoledronic acid is associated with a 25% increased risk of atrial fibrillation during its first year of use for osteoporosis compared to treatment with denosumab, shows a US study published in Journal of Bone and Mineral Research.¹

As Randomized placebo-controlled trials of the bisphosphonate zoledronic acid in osteoporosis have produced conflicting results on whether zoledronic acid is associated with an increased risk of atrial fibrillation, investigators in Boston, MA, set out to examine the association in practice. They used real-world data to compare the incidence of atrial fibrillation in patients during the first year of zoledronic acid use with the incidence in patients who took denosumab, a monoclonal antibody to receptor activator of NF-κB ligand (RANKL) which has no known risk of atrial fibrillation.

They examined data on privately insured Americans aged ≥ 50 years with no known arrhythmia or advanced kidney disease, who were initiated on zoledronic acid between January 1, 2010, and June 30, 2019, for osteoporosis or malignant bone disease. These patients were 1:1 propensity score (PS)-matched with patients initiated on denosumab during the same time period.

“Based on 16,235 pairs of zoledronic acid and denosumab initiators (for osteoporosis), we found a greater risk (HR 1.25, 95% CI 1.04-1.50) of atrial fibrillation with zoledronic acid vs denosumab: an absolute risk difference of 3.69 events per 1000 person-years,” said Seoyoung Kim, MD, ScD, Associate Professor of Medicine and Director of the Program in Rheumatologic, Immunologic, and Musculoskeletal Pharmaco Epidemiology at Brigham and Women's Hospital/Harvard Medical School. “We, however, found no difference in the risk of stroke or transient ischemic attack (TIA), or risk of non-vertebral fracture between the two drug groups.”

Seoyoung Kim, MD, ScD

The mean age of patients in the osteoporosis cohort was 71 years and 93% were women. During the first year of use, zoledronic acid was associated with an incident rate of 18.6 cases of atrial fibrillation per 1000 person-year, whereas denosumab was associated with 14.9 cases per 1000 person-years. A similar level of increased risk of atrial fibrillation for zoledronic acid vs denosumab was also found in the 7732 malignancy-related bone disease pairs (HR 1.19; 95% CI 1.00 to 1.43; p = 0.06) but was not statistically significant in this group.

Many previous studies examined the risk of atrial fibrillation among all kinds of bisphosphonate users, but the inclusion of just IV zoledronic acid initiators and a single active comparative treatment, ie, denosumab, was a strength of the study. Kim emphasized, “this type of approach, use of active comparator, is a strength as it can reduce confounding bias in observational studies.”

It has previously been proposed that an effect on calcium might be responsible for the association of increased risk of atrial fibrillation with zoledronic acid, but the findings of this study throw doubt on that hypothesis. “Since both zoledronic acid and denosumab can affect serum calcium levels, it is unclear why zoledronic acid would lead to more atrial fibrillation events,” Kim explained.

She stressed, “While further studies are needed to better understand the mechanism for atrial fibrillation among zoledronic acid users, clinicians should be aware of a modestly increased risk of atrial fibrillation upon initiating the treatment with zoledronic acid. This potential harm should be discussed with patients when making a treatment decision – particularly among patients at high risk for atrial fibrillation.”

Ultimately, patients with osteoporosis do get more benefits than harm from osteoporosis treatments. Kim warned, “While wise decision making is obviously needed for individual patients, in general, many patients with osteoporosis or at high risk for osteoporosis are not getting appropriate treatment. Untreated osteoporosis leads to substantial morbidity and mortality in many patients.”

Reference:

D'Silva KM, Cromer SJ, Yu EW, Fischer M, Kim SC. Risk of Incident Atrial Fibrillation With Zoledronic Acid Versus Denosumab: A Propensity Score-Matched Cohort Study [published online ahead of print, 2020 Nov 2]. J Bone Miner Res. 2020;10.1002/jbmr.4174. doi:10.1002/jbmr.4174