Compared with other first-line osteoporosis treatments, alendronate therapy yielded an increased risk for depression and anxiety, according to an analysis of adverse events reports.

The findings were published in Scientific Reports.

According to study background, bisphosphonate therapy, primarily alendronate, is among the most prescribed treatments for osteoporosis, a disease affecting more than 10 million Americans older than 50 years. Recently, case reports have shown alendronate and other bisphosphonates may increase depressive symptoms.

To evaluate these associations, Dro Keshishi, a third-year student at the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, and colleagues analyzed more than 100,000 adverse events reports from the FDA Adverse Event Reporting System (FAERS) and the WHO’s VigiAccess adverse drug reactions global database.

Outcomes of interest included depression, or depressive disorder-related adverse events, and anxiety, which were defined in FAERS by following Medical Dictionary for Regulatory Activities (MedDRA) terms. Drug therapies studied included alendronate, zoledronate, risedronate, ibandronate, denosumab (Prolia, Amgen) and teriparatide (Forteo, Eli Lilly; Bonsity, Alvogen).

In an analysis of patients aged 65 years or younger, the reported OR with alendronate therapy was 14.67 (95% CI, 11.55-18.63) for depression and 7.1 (95% CI, 5.79-8.71) for anxiety. Among the other therapies, only risedronate demonstrated an elevated OR, although only for depression and at a lower magnitude (3.06; 95% CI, 1.7-5.52), whereas zoledronate (0.167; 95% CI, 0.074-0.38) and denosumab (0.2; 95% CI, 0.1-0.39) were significantly associated with decreased anxiety.

Furthermore, among patients older than 65 years, alendronate was the only therapy associated with increased reported OR for depression (3.6; 95% CI, 2.82-4.59) and anxiety (2.28; 95% CI, 1.84-2.84) compared with the control teriparatide, whereas zoledronate (0.32; 95% CI, 0.21-0.5), ibandronate (0.26; 95% CI, 0.13-0.52) and denosumab (0.26; 95% CI, 0.18-0.36) showed significant decreases in the OR for anxiety.

In the VigiAccess analysis, the bisphosphonates as a class yielded significantly higher reported ORs for depression and anxiety, with alendronate demonstrating the highest magnitude in depression (4.33; 95% CI, 4.09-4.58) and anxiety (3.14; 95% CI, 2.97-3.33).

“We found that alendronate had the largest and statistically significant association with depression and anxiety out of all bisphosphonates,” Keshishi and colleagues concluded. “This association was supported by VigiAccess/WHO analysis. Controlled trials are necessary to adjudicate the clinical causality.”

PERSPECTIVE

 

E. Michael Lewiecki, MD, FACE, FACP

This report is an analysis of voluntary submissions from patients, health care providers and legal representatives about adverse effects with bisphosphonates and denosumab, using teriparatide as a control. It was found that there was a greater risk for anxiety and depression with alendronate compared with teriparatide at all ages, and a reduced risk for anxiety and depression with denosumab in those aged at least 65 years. These findings are intriguing.

The authors suggested some potential mechanisms for an association between bisphosphonate use and psychiatric events. They also describe limitations of the study, including its observational nature, selection bias due to the voluntary input of data, and recognition that associations are not necessarily the same as causality.

Should we change our prescribing behavior based on this information? For me, the answer is no. If this report leads to a prospective randomized trial to test the hypothesis that bisphosphonates increase the risks for anxiety and depression, I will look forward to the results. Meanwhile, my choice of medications for patients with osteoporosis will remain the same.

E. Michael Lewiecki, MD, FACE, FACP

Director, New Mexico Clinical Research & Osteoporosis Center

Director, Bone Health TeleECHO, UNM Health Sciences Center