Osteoporosis (OP) prevalence is significantly higher in type 2 diabetes (T2DM) patients, but the connecting molecular mechanisms are unclear. This study identified diabetes-related gene signatures in OP using integrated bulk and single-cell RNA-seq datasets from OP and T2DM. Bioinformatics and machine learning (LASSO, RF, SVM-RFE) analyses were employed, with hub genes validated clinically and in an OVX mouse model. We identified 40 immune-related diabetes-associated genes (DRGs), including four hub genes (BCL2L11, IL1R2, IL4R, TLR4) for OP diagnosis. A nomogram based on these showed high accuracy (AUC = 0.925), validated externally (p < 0.01). Immune infiltration revealed changes in plasma cells, NK cells, and macrophages. Single-cell analysis highlighted myeloid-specific DRG enrichment and active roles in RESISTIN and VISFATIN pathways. Pseudotime analysis linked DRG score negatively to differentiation. Elevated IL1R2 in OP mice was confirmed. The four identified genes represent diagnostic value and potential therapeutic targets for modulating the T2DM-OP interaction. Our results further uncover critical myeloid-mediated mechanisms underlying this comorbidity, thereby providing new insights for future therapeutic development.
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