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Objective • This study aimed to investigate the potential plasma miRNA-mRNA regulatory networks in postmenopausal women with osteoporosis (OP) and osteoporotic vertebral fracture (OVF). Methods • The study employed a cross-sectional design, and the microarray dataset GSE93883 was acquired from the Gene Expression Omnibus (GEO) to assess plasma miRNA profiles in postmenopausal women with osteoporosis (OP) and osteoporotic vertebral fracture (OVF). Subsequently, plasma microRNA-4739 (miR4739) and Insulin-like Growth Factor Binding Protein-4 (IGFBP-4) levels were validated in a well-defined cohort comprising 210 postmenopausal women. This cohort consisted of three distinct groups: healthy controls (HC, n = 70), OP patients (n = 70), and OVF patients (n = 70). Results • Analysis of the GSE93883 dataset revealed a stepwise increase in four miRNAs (hsa-miR-4739, hsamiR-4505, hsa-miR-4459, hsa-miR-665) in plasma samples from HC to OP patients to OVF patients. Conversely, plasma miR-4666a-3p showed a gradual decrease. We predicted six genes targeted by miR-4739 using six online databases. Plasma miR-4739 levels were significantly higher in OP and OVF patients compared to HC, especially in OVF patients. However, plasma IGFBP4 exhibited an inverse pattern. Pearson analysis demonstrated a significant negative correlation between plasma miR-4739 and plasma IGFBP-4 in OP and OVF patients. Receiver operating characteristic (ROC) curve analysis of plasma miR-4739 yielded a sensitivity of 35.71% and specificity of 95.71% for predicting the presence of OP and a sensitivity of 71.43% and specificity of 95.71% for predicting OVF, with an AUC of 0.865. Moreover, the area under the curve (AUC) for IGFBP-4 was higher than that for plasma miR-4739 when differentiating OP patients from OVF patients. Conclusions • Circulating miR-4739 and IGFBP-4 demonstrated a negative correlation in OP and OVF patients, suggesting their potential as diagnostic biomarkers for OP and OVF in the future. [ABSTRACT FROM AUTHOR]