This study aimed to identify circulating microRNAs (miRNAs) as potential biomarkers for muscle mass wasting in post-menopausal osteoporotic women. One hundred seventy-nine miRNAs were analyzed in plasma samples from 28 post-menopausal osteoporotic women, and the cohort was divided into tertiles based on appendicular skeletal muscle mass index (ASMMI). Five miRNAs (hsa-miR-221-3p, hsa-miR-374b-5p, hsa-miR-146a-5p, hsa-miR-126-5p, and hsa-miR-425-5p) were down-regulated, and two miRNAs (hsa-miR-145-5p and hsa-miR-25-3p) were up-regulated in the first tertile (relative-low ASMMI) compared to the third tertile (relative-high ASMMI). Receiver operating characteristic (ROC) curves showed that hsa-miR-126-5p, hsa-miR-146a-5p, and hsa-miR-425-5p, and hsa-miR-126-5p, hsa-miR-146a-5p, hsa-miR-145-5p, and hsa-miR-25-3p had the highest diagnostic potential with AUCs of 0.914 and 0.901, respectively. The study identified two miRNA signatures specifically associated with muscle mass wasting in post-menopausal osteoporotic women, providing a potential tool for early diagnosis and monitoring of osteosarcopenia.This study aimed to identify circulating microRNAs (miRNAs) as potential biomarkers for muscle mass wasting in post-menopausal osteoporotic women. One hundred seventy-nine miRNAs were analyzed in plasma samples from 28 post-menopausal osteoporotic women, and the cohort was divided into tertiles based on appendicular skeletal muscle mass index (ASMMI). Five miRNAs (hsa-miR-221-3p, hsa-miR-374b-5p, hsa-miR-146a-5p, hsa-miR-126-5p, and hsa-miR-425-5p) were down-regulated, and two miRNAs (hsa-miR-145-5p and hsa-miR-25-3p) were up-regulated in the first tertile (relative-low ASMMI) compared to the third tertile (relative-high ASMMI). Receiver operating characteristic (ROC) curves showed that hsa-miR-126-5p, hsa-miR-146a-5p, and hsa-miR-425-5p, and hsa-miR-126-5p, hsa-miR-146a-5p, hsa-miR-145-5p, and hsa-miR-25-3p had the highest diagnostic potential with AUCs of 0.914 and 0.901, respectively. The study identified two miRNA signatures specifically associated with muscle mass wasting in post-menopausal osteoporotic women, providing a potential tool for early diagnosis and monitoring of osteosarcopenia.