Chronic kidney disease and osteoporosis: a two-sample Mendelian randomization study

Purpose: The study aims to assess the causal relationship between chronic kidney disease and osteoporosis through two-sample Mendelian randomization. Methods: The Chronic Kidney Disease Genetics Consortium identified specific single nucleotide polymorphisms (SNPs) linked to eGFR and UACR, used as instrumental variables in a two-sample Mendelian Randomization (MR) analysis. This analysis, primarily using the inverse variance-weighted (IVW) method, aimed to explore the causal connections between CKD and bone health risks, specifically fractures, osteoporosis, and BMD. Data for these bone health risks were sourced from a GWAS database. Validation of results employed MR-Egger regression, weighted median estimation (WME), and weighted mode. The MR-PRESSO and MR-Egger intercept tests checked for horizontal pleiotropy in SNPs, while the Q-test and leave-one-out analysis assessed result heterogeneity. Results : IVW results (OR=1.022, 95% CI=1.009-1.035, P<0.001) and MR-Egger regression results (OR=1.023, 95% CI=1.002-1.045, P=0.034) both indicate a causal relationship between CKD and osteoporosis. IVW suggests a suggestive impact of UACR on ankle bone density (IVW: β=-0.158, 95% CI: -0.312 to 0.005, P=0.043; WME: β=-0.12, 95% CI: -0.327 to 0.017, P=0.037), but the results are not robust. No causal relationship was observed for fractures, whole-body bone density, forearm bone density, vertebral bone density, and hip neck bone density. Conclusion: Our MR analysis indicated that lower eGFR is associated with osteoporosis (OP). Although CKD potentially affects skeletal health and may causally link to OP, current evidence is insufficient to confirm its genetic impact on fractures and bone density. Additional analysis with more cases is needed.