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 (6,638 urolithiasis and 7,788 OP cases) to investigate the direct causal relationship and mechanism between urolithiasis and OP, applying Mendelian randomization (MR), genetic correlation analysis, colocalization, and pathway analysis. We selected ten genetic variants as instrumental variables (IVs) 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 four 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 eGFR as a significant contributor. Co-risk factor analysis unveiled cardiovascular elements as common risks for both conditions. Bioanalysis implicates cytokine, metabolic, and calcium signaling pathways may bridge urolithiasis and OP, with BCAS3, DGKH, TBX2, and TBX2-AS1 identified as potential causal genes.

Conclusions: 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.