Proteomic profiling of bone tissue reveals distinct pathways in men and women with osteoporosis.

BACKGROUND: Osteoporosis is characterised by an imbalance in bone remodelling, yet the detailed molecular mechanisms underlying its pathogenesis remain unclear. This study aimed to identify key proteins and regulatory pathways associated with severe osteoporosis in women and men. METHODS: Bone specimens were collected during surgery from 13 women and 12 men with osteoporotic fractures, along with 8 female and 7 male controls with violent fractures. Differentially abundant proteins (DAPs) in bone tissues were identified via nontargeted liquid chromatography-tandem mass spectrometry proteomics. Functional enrichment and pathway analyses were performed; the diagnostic potential of core DAPs was evaluated through multivariate receiver operating characteristic (ROC) analysis, and correlations between DAPs and clinical parameters were assessed. RESULTS: DAPs of women with osteoporotic fractures were primarily associated with immunoinflammatory response, while DAPs of men with osteoporotic fractures were predominantly related to oxidative stress. ROC analysis revealed strong associations between core upregulated proteins and osteoporosis in both women [area under the ROC curve (AUC) = 0.908, 95% confidence interval (CI): 0.676-1] and men (AUC = 0.851, 95% CI: 0.366-1). After adjusting for age, HLA-C in women was significantly negatively correlated with bone mineral density (P < .05), while NDUFA11, COX7A2, NDUFAB1, UQCRC1, COX5A and VDAC1 in men were significantly positively correlated with β-C-terminal telopeptide of type I collagen (P < .05). CONCLUSION: This study identified sex-specific proteomic profiles and molecular pathways associated with osteoporosis, with ageing emerging as a central upstream driver of these differences. These findings may help elucidate the sex differences in the pathogenesis of osteoporosis and provides a foundation for the discovery of new therapeutic targets and the development of personalised precision treatment strategies.