Antidepressant Use and Bone Health: Evidence From Mendelian Randomisation

Abstract

Background: Antidepressant use has been associated with adverse skeletal outcomes in observational studies, but whether this association is causal remains unclear due to potential confounding factors. This study employed Mendelian randomisation (MR) to systematically evaluate the causal associations between genetically predicted antidepressant use and the risks of osteoporosis and fractures at multiple anatomical sites.

Methods: Using publicly available genome-wide association studies (GWAS) datasets, we defined genetically predicted antidepressant use as the exposure and osteoporosis and fractures (spine, leg, and wrist) as outcomes. Genome-wide significant single nucleotide polymorphisms (SNPs) were selected as instrumental variables following dataset harmonisation. The inverse-variance weighted (IVW) method was used as the primary MR approach, supplemented by MR-Egger regression, weighted median, and weighted/simple mode methods. Heterogeneity tests, funnel plots, and leave-one-out sensitivity analyses were performed to assess the robustness and consistency of the results.

Results: MR analysis demonstrated significant positive causal associations between antidepressant use and osteoporosis across two independent datasets (ukb-a-87 and ukb-b-12141), with IVW odds ratios of 1.0035 and 1.0016, respectively. Genetically proxied antidepressant use showed significant causal effects on fractures at all examined sites, with wrist fractures displaying the strongest association (IVW: odds ratio (OR) = 1.0027, p = 0.0041). Effect directions remained consistent across multiple MR methods, with no significant heterogeneity detected. Leave-one-out analyses confirmed no single SNP disproportionately influenced the results.

Conclusion: This MR study provides evidence that antidepressant use may directly influence bone metabolism and increase fracture susceptibility, particularly at the wrist. These findings highlight the importance of bone health monitoring in patients receiving antidepressant therapy, especially those at elevated fracture risk. Further mechanistic studies and longitudinal validation are warranted.