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

Abstract

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. J Am Geriatr Soc 68:1494‐1503, 2020.

Tricyclic Antidepressant Use and Risk of Fractures: A Meta-Analysis of Cohort Studies through the Use of Both Frequentist and Bayesian Approaches

“…Our prior meta-analysis included both case-control and cohort studies; however, case-control studies are commonly limited by recall bias and might lead to an inaccurate estimate of the associated effect size. Furthermore, the previous meta-analysis was published eight years ago, and thus it was not able to integrate findings from recently published studies [27][28][29][30][31]. Therefore, our current study focused on the integration of related cohort studies only, and we were able to include four large and well-designed studies [27][28][29][30][31] that have not been included in any prior meta-analyses.…”

“…Furthermore, the previous meta-analysis was published eight years ago, and thus it was not able to integrate findings from recently published studies [27][28][29][30][31]. Therefore, our current study focused on the integration of related cohort studies only, and we were able to include four large and well-designed studies [27][28][29][30][31] that have not been included in any prior meta-analyses. We replaced the original study by Lewis et al [19] in the previous meta-analysis with an updated report by Cauley et al [30] because both studies used the same data source, and the updated report [23] had a larger sample size and would provide more reliable results.…”

“…and Y.B.) independently examined reference lists from the original studies [23,[26][27][28][29][30][31] and related meta-analyses and reviews [24,[34][35][36][37].…”

“…As a result, we conducted a meta-analysis using both cohort and case-control studies to examine the association between TCA use and fractures [24]. However, the prior meta-analysis was conducted eight years ago, and thus several large eligible cohort studies undertaken in recent years were not included [27][28][29][30][31]. Therefore, an updated meta-analysis was warranted.…”

“…The link between SSRIs use and fracture risk was also examined extensively [ 11 , 12 ]. Many studies reported that TCA use is significantly associated with osteoporotic fractures [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]; however, other studies found that such an association was not significant [ 25 , 26 , 27 , 28 ]. As a result, we conducted a meta-analysis using both cohort and case-control studies to examine the association between TCA use and fractures [ 24 ].…”