Urolithiasis Causes Osteoporosis in Asians: Genetic Evidence from Mendelian Randomization and Pathway Analysis

Abstract Background It is an indisputable fact that patients with urolithiasis are prone to osteoporosis (OP), but the specific mechanism of their association is unclear. Previous studies have focused on the mediation of environmental factors such as diet; however, the potential of urolithiasis itself to induce OP remains uncertain. Methods In this study, we used data from the Japan BioBank (6638 urolithiasis and 7788 OP cases) to investigate the direct causal relationship and mechanism between urolithiasis and OP, applying Mendelian randomization, genetic correlation analysis, colocalization, and pathway analysis. We selected 10 genetic variants as instrumental variables for urolithiasis. Results The results showed a positive association between genetically predicted urolithiasis and OP, with significant direct effects persisting after adjusting for OP-associated factors in 4 models. Reverse analysis revealed no significant causal effect of genetically predicted OP on urolithiasis. While genetic correlation analysis and colocalization did not find conclusive evidence, mediation analysis identified estimated glomerular rate as a significant contributor. Co-risk factor analysis unveiled cardiovascular elements as common risks for both conditions. Bioanalysis implicates that cytokine, metabolic, and calcium signaling pathways may bridge urolithiasis and OP, with BCAS3, DGKH, TBX2, and TBX2-AS1 identified as potential causal genes. Conclusion In conclusion, the study establishes a direct causal link between urolithiasis and OP, independent of environmental factors. Regardless of lifestyle, urolithiasis patients should remain vigilant about the risk of OP and consider regular OP screening. The biological mechanism of urolithiasis combined with OP and related drugs still needs to be further explored.