Integrative Transcriptomic and Network Analysis of Shared Osteo-Immune Regulatory Programs in Postmenopausal Osteoporosis and Osteosarcoma Within Central Mexican Cohorts

Osteoporosis (OP) and osteosarcoma (OS) are biologically distinct skeletal disorders that share dysregulated bone remodeling, inflammatory signaling, and microenvironmental interactions. This study performed an integrative transcriptomic analysis to identify shared osteoimmune regulatory programs in circulating monocytes from postmenopausal women with OP and OS tumors from Central Mexican cohorts. Two independent RNA-seq cohorts were analyzed separately and then integrated: circulating monocytes from postmenopausal women with OP and controls (7 OP and 7 controls), and donor-matched OS tissues (7 tumors and 7 healthy bone samples). Differential expression, module-based filtering, pathway enrichment, cross-cohort functional integration, directional concordance, and targeted interaction network analyses were performed. The OP cohort showed 169 differentially expressed genes, whereas the OS cohort showed 2135 genes. Module-based filtering retained 82 genes in OP and 278 in OS, with only six genes directly shared. However, pathway-level integration identified convergent signals involving PI3K-Akt, HIF-1 signaling, lipid and atherosclerosis, phagosome, endoplasmic reticulum protein processing, focal adhesion, proteoglycans in cancer, and cancer-related pathways. Directional analysis of 27 shared pathway-associated genes revealed predominantly discordant regulation, with CTNNB1 emerging as a central network node. These findings suggest that OP and OS converge through specific osteoimmune pathways rather than through a uniform shared gene program.