As a crucial physiological transition during the women's life, menopause occurs with growing risks of health issues like osteoporosis. To identify postmenopausal osteoporosis-related genes, we performed transcriptome-wide expression analyses for human Peripheral Blood Monocytes (PBM) using Affymetrix 1.0 ST arrays in 40 Caucasian postmenopausal women with discordant Bone Mineral Density (BMD) levels.We performed Multiscale Embedded Gene Co-Expression Network Analysis (MEGENA) to study functionally orchestrating clusters of differentially expressed genes in form of functional networks. Gene Sets Net Correlations Analysis (GSNCA) was applied to assess how the co-expression structure of pre-defined gene set differs in high and low BMD groups. Bayesian Network (BN) analysis was used to identify important regulation patterns between potential risk genes for osteoporosis. siRNA-based Gene Silencing in vitro experiment was performed to validate the findings from BN analysis.MEGENA showed that "T cell receptor signaling pathway" as well as "osteoclast differentiation pathway" were significantly enriched in the identified compact network which is significantly correlated with BMD variation. GSNCA revealed that the co-expression structure of "Signaling by TGF-beta Receptor Complex pathway" is significantly different between the two BMD discordant groups, and the hub genes in postmenopausal low and high BMD group are FURIN and SMAD3 respectively. With siRNA in vitro experiments, we confirmed the regulation relationship of TGFBR2-SMAD7 and TGFBR1-SMURF2.The present study suggests that biological signals involved in monocyte recruitment, monocyte/macrophage lineage development, osteoclast formation, osteoclast differentiation might function together in PBMs that contributes to the pathogenesis of postmenopausal osteoporosis.