Osteoporosis is a common bone disease; however, its pathophysiology is yet unclear. This study aimed to investigate candidate genes in osteoporosis and its pathomechanism. Microarray datasets Genomic Spatial Event-7429, 13850, 56815, and 7158, comprising data obtained from blood samples of osteoporosis patients and healthy controls, were downloaded from the Gene Expression Omnibus database. Differentially expressed genes were identified via intersection of the four datasets, using Affy and Limma software packages. Functional and pathway enrichment analysis of differentially expressed genes were conducted using the database for annotation, visualization, and integrated discovery database. Thereafter, proteinprotein interactions between the products of differentially expressed genes and key modules were analyzed using the search tool for the retrieval of interacting genes/proteins database and Cytoscape software. Furthermore, a transcriptional regulatory network was established with the differentially expressed genes, using the Web-based gene set analysis toolkit database. In total, 702 differentially expressed genes were filtered from the intersection of the four datasets, which were primarily enriched in functions and pathways associated with glutamate secretion, Adenosine triphosphate binding, extracellular region, and phosphatidylinositol 3-kinase-protein kinase B signaling pathway. Furthermore, 361 nodes and 846 edges were present in the protein-protein interaction network. Two significant modules were obtained, each containing 22 key genes. Transcriptional factor-target gene regulatory network analysis revealed two vital transcription factors, Forkhead Box O4 and LIM Homeobox 3. Genes including endothelin receptor type A, XC chemokine receptor 1, 5-hydroxytryptamine receptor 2a, phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-4, glutamate metabotropic receptor 5, kiss-1 metastasis suppressor, 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-2, cholinergic receptor muscarinic 3, g protein subunit gamma 4, neurotensin receptor 1, neuromedin U, neuromedin B, breast cancer gene 1 associated RING domain 1, exonuclease 1, replication factor C subunit 2, restriction site associated DNA 52 homolog DNA repair protein, DNA topoisomerase III alpha, Hemolytic uremic syndrome 1 checkpoint clamp component, timeless circadian regulator, breast cancer gene 1 DNA repair associated, tumor protein p53 and claspin are potential key genes for osteoporosis and may help elucidate the underlying pathomechanism, and transcription factors Forkhead Box O4 and LIM Homeobox 3 are potential therapeutic targets for osteoporosis.