Osteoporosis (OP) is a disease characterized by bone mass loss, bone microstructure damage, increased bone fragility, and easy fracture. The molecular mechanism underlying OP remains unclear.In this study, we identified 217 genes associated with OP, and formed a gene set [OP-related genes gene set (OPgset)].The highly enriched GOs and pathways showed OPgset genes were significantly involved in multiple biological processes (skeletal system development, ossification, and osteoblast differentiation), and several OP-related pathways (Wnt signaling pathway, osteoclast differentiation, steroid hormone biosynthesis, and adipocytokine signaling pathway). Besides, pathway crosstalk analysis indicated three major modules, with first module consisted of pathways mainly involved in bone development-related signaling pathways, second module in Wnt-related signaling pathway and third module in metabolic pathways. Further, we calculated degree centrality of a node and selected ten key genes/proteins, including TGFB1, IL6, WNT3A, TNF, PTH, TP53, WNT1, IGF1, IL10, and SERPINE1. We analyze the K-core and construct three k-core sub-networks of OPgset genes.In summary, we for the first time explored the molecular mechanism underlying OP via network- and pathway-based methods, results from our study will improve our understanding of the pathogenesis of OP. In addition, these methods performed in this study can be used to explore pathogenesis and genes related to a specific disease.