Multinational Investigation of Fracture Risk with Antidepressant Use by Class, Drug, and Indication

OBJECTIVES: Antidepressants increase the risk of falls and fracture in older adults. However, risk estimates vary considerably even in comparable populations, limiting the usefulness of current evidence for clinical decision making. Our aim was to apply a common protocol to cohorts of older antidepressant users in multiple jurisdictions to estimate fracture risk associated with different antidepressant classes, drugs, doses, and potential treatment indications. DESIGN: Retrospective (2009–2014) cohort study. SETTING: Five jurisdictions in the United States, Canada, United Kingdom, and Taiwan. PARTICIPANTS: Older antidepressant users—subjects were followed from first antidepressant prescription or dispensation to first fracture or until the end of follow-up. MEASUREMENTS: The risk of fractures with antidepressants was estimated by multivariable Cox proportional hazards models using time-varying measures of antidepressant dose and use vs nonuse, adjusting for patient characteristics. RESULTS: Between 42.9% and 55.6% of study cohorts were 75 years and older, and 29.3% to 45.4% were men. Selective serotonin reuptake inhibitors (SSRIs) (48.4%-60.0%) were the predominant class used in North America compared with tricyclic antidepressants (TCAs) in the United Kingdom and Taiwan (49.6%-53.6%). Fracture rates varied from 37.67 to 107.18 per 1,000. The SSRIs citalopram (hazard ratio [HR] = 1.23; 95% confidence interval [CI] = 1.11-1.36 to HR = 1.43; 95% CI = 1.11-1.84) and sertraline (HR = 1.36; 95% CI = 1.10-1.68), the SNRI duloxetine (HR = 1.41; 95% CI = 1.06-1.88), TCAs doxepin (HR = 1.36; 95% CI = 1.00-1.86) and imipramine (HR = 1.16; 95% CI = 1.05-1.28), and atypicals (HR = 1.34; 95% CI = 1.14-1.58) increased fracture risk in some but not all jurisdictions. In the United States and the United Kingdom, fracture risk with all classes was higher when prescribed for depression than chronic pain, a trend that is likely explained by drug choice. CONCLUSION: The fracture risk for patients may be reduced by selecting paroxetine, an SSRI with lower risk than citalopram, the SNRI venlafaxine over duloxetine, and the TCA amitriptyline over imipramine or doxepin. There is uncertainty about the risk associated with the atypical antidepressants.