Unravelling Osteoporosis: Key Genes and Potential Therapies

ABSTRACT Osteoporosis is a metabolic bone disease characterised by decreased bone mass and increased fracture risk, especially in aging women. Current treatments have limitations and side effects, prompting the need for novel therapeutic targets. Using Mendelian randomisation (MR) on the basis of GWAS data from the FinnGen consortium, we identified druggable genes associated with osteoporosis. Transcriptomic profiling, single‐cell RNA sequencing (scRNA‐seq) and immune infiltration analysis were employed to explore gene expression patterns and immune relevance. Gene set enrichment analysis and gene set variation analysis were used to investigate related signalling pathways. Three genes—FMO4, PSMA4 and VEGFA—were significantly associated with osteoporosis risk. FMO4 showed a protective association and was enriched in vascular and immune cells, suggesting roles in oxidative stress and microenvironment regulation. PSMA4, involved in proteasome activity, was upregulated in macrophages and T cells, potentially influencing bone remodelling through immune‐related protein degradation. VEGFA expression correlated positively with osteoporosis risk, possibly via ER‐β–mediated signalling that promotes osteoblast apoptosis. All three genes were involved in key pathways, including calcium signalling, Wnt/β‐catenin, PI3K/Akt and Hedgehog signalling. Immune analysis revealed strong associations with dendritic cells and macrophages. This study identifies FMO4, PSMA4 and VEGFA as key genes associated with osteoporosis, analyses their molecular mechanisms and regulatory networks and elucidates their relationship with the disease. Furthermore, it suggests 52 candidate compounds potentially interacting with VEGFA and 8 with PSMA4, offering a basis for further investigation into their therapeutic potential.