CircRNAs as biomarkers for osteoporosis: a systematic review and meta-analysis

With population ageing, osteoporosis (OP) is increasing worldwide. Circular RNAs (circRNAs) show aberrant expression in OP and may serve as non-invasive biomarkers, but their overall diagnostic performance and sources of heterogeneity remain unclear. This study aimed to systematically evaluate the diagnostic accuracy of circRNAs as potential non-invasive biomarkers for OP and to explore sources of heterogeneity.

PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), WanFang, and VIP were searched from inception to 25 November 2025. Studies evaluating circRNAs or circRNA panels for osteoporosis (OP) using DXA-derived bone mineral density (BMD) as the reference standard were included. Methodological quality was assessed using QUADAS-2. A bivariate random-effects model was used to pool sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios, and the area under the summary receiver operating characteristic curve. Subgroup analyses, meta-regression, sensitivity analyses, and Deeks' funnel plot asymmetry test were performed.

12 articles comprising 14 independent studies (801 OP patients and 640 non-OP controls) were included. The pooled SEN was 0.87 and SPE was 0.79; PLR and NLR were 4.24 and 0.16, respectively, with a DOR of 26.24 and an AUC of 0.91, indicating good overall discriminatory ability. Spearman correlation (r = -0.169, P = 0.563) suggested no obvious threshold effect. Subgroup analyses and meta-regression showed that diagnostic performance tended to be better in studies enrolling postmenopausal OP patients, with mean age < 65 years, larger sample sizes, non-serum/plasma samples (peripheral blood mononuclear cells or exosomes), and down-regulated circRNAs. Deeks' funnel plot indicated no significant publication bias, and sensitivity analyses suggested that the main findings were robust.

CircRNAs demonstrate favorable diagnostic accuracy for osteoporosis and may serve as promising non-invasive biomarkers for screening and risk stratification. Current evidence supports their role as adjunctive tools that complement, rather than replace, DXA-derived bone mineral density assessment and traditional clinical risk factor evaluation. However, they should not be considered stand-alone diagnostic tests. Further large-scale prospective studies are required before routine clinical application can be recommended.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251240922.