Osteoporosis causes Nephrolithiasis: A Bidirectional Two-sample Mendelian Randomization Study

Background Epidemiological evidence suggests a strong association between osteoporosis (OP) and nephrolithiasis (NL), yet the causal direction of this relationship remains debated. This study aimed to elucidate the bidirectional causal relationship between OP and NL using a two-sample Mendelian randomization (MR) approach. Methods We utilized genome-wide association study (GWAS) summary statistics from Taiwan Biobank (TWB; osteoporosis: 14,507 cases/ 79,846 controls; nephrolithiasis: 6,318 cases/ 88,035 controls) and BioBank Japan (BBJ; osteoporosis: 9,794 cases/ 159,138 controls; nephrolithiasis: 11,699 cases/ 155,328 controls). Genetic instruments were selected using a suggestive genome-wide threshold of p-value < 1.0 x 10-5, followed by LD clumping and weak-instrument filtering. The primary causal estimates were calculated using the inverse variance weighted (IVW) method. Sensitivity analyses, including weighted median, MR-Egger regression, and MR-PRESSO, were performed to evaluate the robustness of the results and assess pleiotropy. Results In total, 46 SNPs were used for OP-causing-NL in the TWB-to-BBJ analysis, 10 SNPs for OP-causing-NL in the BBJ-to-TWB analysis, 14 SNPs for NL-causing-OP in the TWB-to-BBJ analysis, and 10 SNPs for NL-causing-OP in the BBJ-to-TWB analysis. In the analysis assessing the effect of OP on NL, using genetic instruments from BBJ and outcome data from TWB, we observed a significant causal association (IVW β = 0.211, 95% CI: 0.039-0.384, p = 0.016). This finding was corroborated by the weighted median (p = 0.043) and robust MR-Egger (p = 0.025) analyses, with no evidence of directional pleiotropy (MR-Egger intercept p = 0.858). Conversely, in the reverse analysis, NL did not show a significant causal effect on OP risk in either cohort configuration (IVW p > 0.05). Conclusions Our findings provide suggestive evidence that osteoporosis causally increases the risk of nephrolithiasis, whereas nephrolithiasis does not causally affect osteoporosis risk. Clinically, patients with osteoporosis may represent a high-risk population warranting screening for urinary tract stones.