Understanding inconsistency in the results from observational pharmacoepidemiological studies: the case of antidepressant use and risk of hip/femur fractures

Purpose: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs.

Methods: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources.

Results: Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates.

Conclusion: We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences.