Osteoporosis Drug Linked to Depression and Anxiety

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Studies show a link between depression and osteoporosis. Researchers investigated whether osteoporosis drugs contributed to depression and anxiety.

The osteoporosis drug alendronate increases the risk for depression more than 14-fold in people aged 65 years and younger, and more than 4-fold in people aged 65 years and older. These findings were published in Scientific Reports.

Investigators analyzed over 15 million adverse drug event reports related to individual osteoporosis medications from the Food and Drug Administration Adverse Events Reporting System (FAERS) database between January 2004 and December 2020. People diagnosed exclusively with osteoporosis who were taking osteoporosis medications only were selected for the study in order to eliminate drug interactions and potential side effects with drug combinations from the analysis.

People with osteoporosis were divided by drug regimen: alendronate (n=7821), zoledronate (n=9367), risedronate (n=1168), ibandronate (n=3727), denosumab (n=15,812), and teriparatide (n=45,052). Researchers further subdivided groups into those aged over 65 years and those aged under 65 years to assess influence of age on adverse events (AEs).

The researchers calculated reporting odds ratios (RORs) for depression and anxiety for each of the 6 osteoporosis medications. Compared with  the 5 other osteoporosis medications, alendronate demonstrated significantly elevated odds ratios for both depression (ROR 14.67, 95% CI, 11.55-18.63) and anxiety (ROR 7.10, 95% CI, 5.79-8.71) in individuals under 65 years old. Comparatively, risedronate showed a much lower, but still statistically significant, increased odds ratio for depression (ROR 3.06, 95% CI, 1.70-5.52) in those under 65 years old. In individuals older than 65, alendronate was the only osteoporosis treatment with elevated odds ratios for depression (ROR 3.60, 95% CI, 2.82-4.59) and anxiety (ROR 2.28, 95% CI, 1.84-2.84) compared with the control group.

To verify their findings, the investigators compared data from the World Health Organization’s VigiAccess webpage–which reported significantly more AEs linked to  bisphosphonate use from over 110 different countries–with data from the FAERS database. Again, alendronate exhibited higher ROR for both depression (ROR 4.33, 95% CI, 4.09-4.58) and anxiety (ROR 3.14, 95% CI, 2.97-3.33) compared with other bisphosphonates. This second analysis confirmed that alendronate maintained the strongest association with depression and anxiety in the bisphosphonate class of medications.

The study authors noted other studies which highlighted a link between alendronate and psychological AEs. One study described alendronate’s inhibition of protein tyrosine phosphate receptor type S and type E (PTPRS and PTPRE, respectively) and the significant association between PTPRS and other receptors  and major depression.

The investigators acknowledged several study limitations, including the voluntary nature of FAERS reporting which “does not represent the true population of actual cases and AE frequencies due to underreporting and focus on more severe AEs.” Additionally, the study focused solely on monotherapy for osteoporosis, potentially overlooking information about comorbidities and drug interactions with over-the-counter medications.

 ‘We found that alendronate had the largest and statistically significant association with depression and anxiety out of all bisphosphonates,” the researchers concluded, further noting their findings were supported by VigiAcccess and WHO analysis, but emphasizing their findings still required controlled trials to confirm clinical causality.


Keshishi D, Makunts T, Abagyan R. Common osteoporosis drug associated with increased rates of depression and anxiety. Sci Rep. 2021;11(1):23956. doi:10.1038/s41598-021-03214-x