Chronic Kidney Disease, Osteoporosis, and TNFRSF11A: Causal Insights and Therapeutic Implications Through Mendelian Randomization

Purpose This study aims to evaluate the causal relationship between chronic kidney disease (CKD) and osteoporosis using two-sample Mendelian randomization (MR) and drug-target MR, and to investigate the potential association between TNFRSF11A and estimated glomerular filtration rate (eGFR). Methods The study utilized single nucleotide polymorphisms (SNPs) associated with eGFR and urinary albumin-to-creatinine ratio (UACR) identified by the Chronic Kidney Disease Genetics Consortium, as well as SNPs related to TNFRSF11A as instrumental variables for the MR analysis. The primary method used was inverse-variance weighted (IVW) to assess the causal relationship between CKD and outcomes such as rehabilitation, osteoporosis, and bone mineral density (BMD). Data were obtained from a genome-wide association study (GWAS). MR-Egger regression, weighted median estimation (WME), and weighted mode were employed for result validation, and MR-PRESSO and Q tests were used to assess pleiotropy and heterogeneity. Results In two-sample Mendelian randomization, IVW analysis showed a significant causal relationship between CKD and osteoporosis (OR = 1.022, 95% CI = 1.009–1.035, P < 0.001). MR-Egger regression further supported this finding (OR = 1.023, 95% CI = 1.002–1.045, P = 0.034). Although UACR showed a suggestive impact on ankle bone density (P < 0.05), the results were not robust. No significant causal relationships were found between CKD and fracture risk, total BMD, forearm BMD, vertebral BMD, or hip neck BMD. Additionally, in drug-target Mendelian randomization, IVW analysis indicated that TNFRSF11A is a risk factor for eGFR (OR = 1.014, 95% CI = 1.005–1.023, P < 0.005). Conclusion This study is the first to use Mendelian randomization to confirm a causal link between lower eGFR and osteoporosis, and identify TNFRSF11A as a risk factor for eGFR, highlighting its potential as a therapeutic target for CKD. However, evidence remains insufficient to establish a genetic link between CKD and fracture risk or BMD, requiring further research.