Causal Effects of Atrial Fibrillation and Warfarin Use on Osteoporosis Risk: A Two-Sample Mendelian Randomization...

A number of observational studies have previously reported an association between atrial fibrillation (AF), long-term warfarin therapy, and an increased risk of osteoporosis (OP). The proposed mechanisms behind this association involve chronic inflammation or vitamin K-dependent bone metabolism. However, the presence of confounding factors and methodological limitations precludes the drawing of causal conclusions. The present Mendelian randomisation (MR) study investigates the existence of genetic evidence for causal links between AF, warfarin use and OP development.

The two-sample MR was performed using summary statistics from European-ancestry genome-wide association studies. Genetic instruments for AF (111 independent SNPs) and warfarin use (9 SNPs) were selected at stringent significance thresholds (p < 5 × 10^-8). The OP dataset comprised 7751 cases and 476,847 controls from UK Biobank. The primary analyses employed inverse-variance-weighted (IVW) regression, supplemented by MR-Egger, weighted median methods, and sensitivity analyses evaluating pleiotropy and heterogeneity.

IVW analysis showed no causal association between genetic predisposition to AF and OP risk (OR = 1.0006, 95% CI 0.9998-1.0014, p = 0.114), with the extremely tight confidence interval from our large, high-precision sample ruling out any clinically meaningful effect. In a similar manner, genetically proxied warfarin exposure demonstrated no substantial influence on OP susceptibility (IVW OR = 1.0445, 95% CI: 0.941-1.159, p = 0.412). Sensitivity analyses were conducted to assess the stability of the results, and no evidence of horizontal pleiotropy (MR-Egger intercept p > 0.05) or heterogeneity (Cochran's Q p > 0.05) was identified. Iterative leave-one-out analyses demonstrated that no individual SNP exerted a disproportionate influence on the estimates.

This study, informed by genetic research, challenges established causal relationships between AF, warfarin use and the risk of OP. The observed clinical associations may be attributable to residual confounding or comorbidities present in ageing populations, rather than direct pharmacological effects. These findings provide a scientific basis for the clinical prioritisation of the management of thromboembolic risk over speculative concerns regarding bone health in the treatment of AF.