OBJECTIVE Osteoporosis is underdiagnosed because of the lack of a convenient diagnostic method. Circulating microRNAs (miRNAs) emerge as novel biomarkers for disease diagnosis. Here, we conducted a case-control study that included a total of 448 serum samples collected from 182 healthy participants, 132 osteopenia participants, and 134 osteoporosis patients. METHODS Circulating miRNAs dysregulated during osteoporosis were screened and analyzed in three randomly determined sub-cohorts: the discovery cohort identified 22 candidate miRNAs; the training cohort tested the candidate miRNAs and constructed Index 1, comprising five miRNAs by logistic regression, and Index 2, comprising four miRNAs, was developed by linear combination. RESULTS Both indices were tested in the validation cohort and showed statistically significant results in distinguishing osteoporosis patients from healthy and osteopenic patients. Moreover, Index 1 also showed improved performance over traditional bone turnover biomarkers type I pro-collagen (tPINP) and type I collagen (β-CTx). CONCLUSIONS In conclusion, circulating miRNAs are potential biomarkers for osteoporosis. The diagnostic panel of circulating miRNAs could be a complementary method for dual-energy X-ray absorptiometry (DXA) in mass screening and routine examination to enhance the osteoporosis detection rate.