SSRIs may be associated with increased fracture risk in middle-aged women without mental disorders

Women without mental illness who started SSRIs and a cohort of women who started H2 antagonists or proton-pump inhibitors (without SSRIs) were compared, with a main study outcome of hip, humerus, radius, or ulna fractures 1 or more days after starting therapy.


Selective serotonin reuptake inhibitors (SSRIs) may be associated with increased fracture risk among perimenopausal women without mental disorders, according to a new study.

Because an SSRI has been approved for use in patients without psychiatric disease, such as for treating vasomotor symptoms, there is increasing interest in understanding the potential risks of SSRI therapy in these patients. Researchers used data from the PharMetrics Claims Database, which included commercial health plan information from U.S. managed care plans, to look at whether use of SSRIs is related to risk for fracture in middle-aged women without psychiatric disorders. Women 40 to 64 years of age without mental illness who started taking SSRIs were compared with a cohort of women who started taking H2 antagonists or proton-pump inhibitors (without SSRI therapy). Data from 1998 to 2010 were used. The main study outcome was hip, humerus, radius, or ulna fractures 1 or more days after starting therapy.

SSRIs included were citalopram hydrobromide, escitalopram oxalate, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and sertraline hydrochloride; H2 antagonists were cimetidine, ranitidine, famotidine, nizatidine, and roxatidine; and PPIs were esomeprazole, lansoprazole, omeprazole, pantoprazole, dexlansoprazole, and rabeprazole. Patients were excluded if they started more than 1 SSRI or more than 1 H2 antagonist or PPI on the same day. Those in the SSRI cohort could switch from one SSRI to another SSRI but were censored if they switched to another class of antidepressants or added another class of antidepressants. Those in the H2 antagonist/PPI cohort were censored if they started taking an antidepressant during follow-up but were allowed to switch to or add another H2 antagonist or PPI. The study results were published online June 25 by Injury Prevention.

A total of 137,031 women were included in the SSRI cohort and 236,294 women were included in the H2 antagonist/PPI cohort. The SSRI cohort had higher fracture rates than the H2 antagonist/PPI cohort, beginning 6 months after the drugs were started. Hazard ratios for SSRIs versus H2 antagonists/PPIs were 1.76 (95% CI, 1.33 to 2.32) at 1 year, 1.73 (95% CI, 1.33 to 2.24) at 2 years, and 1.67 (95% CI, 1.30 to 2.14) at 5 years. At 5 years, the average fracture rate was 2.1 per 1,000 person-years for the SSRI cohort versus 1.2 per 1,000 person-years for the H2 antagonist/PPI cohort.

The authors noted that they could not analyze whether different SSRI doses had different effects on fracture risk and that it is not known whether their results would apply specifically to women prescribed SSRIs for vasomotor menopausal symptoms, among other limitations. However, they concluded that fracture risk appears to increase in perimenopausal women without psychiatric disorders with SSRIs and that the effect appeared to be sustained over time.

“Our finding suggests that, if feasible, shorter duration of treatment might mitigate the risk of developing excess fractures,” the authors wrote. “Since the number of SSRI users without psychiatric disorders is expected to increase following the FDA approval of paroxetine for the treatment of [vasomotor menopausal symptoms], particularly at lower doses, future efforts should be made to examine how SSRI dose (cumulative, daily or both) might modify fracture risk over time.”