Discovery of Potential New Drug Targets for Osteoporosis of Various Subtypes With or Without Pathological Fracture Complications: A Drug Target Mendelian Randomization Study

BACKGROUND: Osteoporosis, a prevalent metabolic bone disease, often leads to pathological fractures. Identifying causative relationships between proteins, genetic loci, and osteoporosis can highlight potential therapeutic targets. METHODS: This study employed Mendelian randomization (MR) and summary-data-based MR (SMR) to investigate the causal relationships between protein quantitative trait loci (pQTLs), expression quantitative trait loci (eQTLs), and various forms of osteoporosis, including drug-induced osteoporosis. Data from large-scale proteomic and genomic studies were used. Sensitivity analyses included Bayesian colocalization and HEIDI testing. Potential therapeutic targets were prioritized using phenome-wide association studies (pheWAS), druggable target tests, and protein-protein interaction (PPI) analyses. RESULTS: The MR and SMR analyses identified 17 targets potentially regulating osteoporosis and one specific to drug-induced osteoporosis. Bayesian colocalization confirmed these findings, supporting their validity as therapeutic targets. CONCLUSION: Our study found that SREBF1, TAS1R3, SPTBN1, and RSPO3 have potential for osteoporosis drug development. In addition, we found that GID4, CPTP, and UBE2Q2 have effects on regulating the genesis of osteoporosis. In our study, we also found that IFI16 has an effect on regulating drug-induced osteoporosis. We believe that basic research on osteoporosis drug development should focus on the above targets with sufficient evidence to further promote the progress and development of osteoporosis treatment.