Association Between SSRI Use and Hip Fractures and the Effect of Residual Confounding Bias in Claims Database Studies

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Abstract
Although use of selective serotonin reuptake inhibitor (SSRI) antidepressants has been associated with hip fractures in claims data studies, it has been suggested that such results may be confounded by cognitive and functional status for which no information is available in claims data. Using survey data, we determined the magnitude of such bias and corrected the association between SSRI use and hip fractures accordingly. We used the Medicare Current Beneficiary Survey to determine the association between SSRI use and 5 potential confounding factors not measured in Medicare claims data: body mass index, smoking, activities of daily living score, cognitive impairment, and Rosow-Breslau physical impairment scale. For 7126 participants aged ≥65 years, we estimated the association between SSRI use and these potential confounders. Combined with literature estimates of the associations between confounders and hip fractures, we were able to compute the extent of residual confounding bias caused by a failure to adjust for these factors. Comparing SSRI users with nonusers, there was considerable overestimation of an association with hip fractures if activities of daily living scores (+21.5% bias) or Rosow-Breslau impairment scales (+10.6%) are unmeasured in claims data. All 5 unmeasured confounders together resulted in net confounding of +9.6% (range: −0.3% to + 39%). After correction for this bias, the strength of association observed in claims data after bias correction (RR = 1.8; 95% CI = 1.5 to 2.1) was comparable to a recent clinical study (RR = 1.5; 0.6 to 3.8), but the claims data study achieved formal statistical significance due to its much large size (8239 vs. 288 hip fractures). Epidemiologic claims data studies tend to overestimate the relation between antidepressant use and hip fractures. However, after correcting for such bias, a significant association persists.

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