Circulating miRNAs as biomarkers of skeletal fragility in pituitary disorders

Background. Endocrine disorders such as acromegaly, Cushing’s syndrome, and growth hormone deficiency (GHD) are associated with skeletal fragility that is not fully captured by bone mineral density (BMD) assessment. Circulating microRNAs (miRNAs), key regulators of bone metabolism, may serve as novel biomarkers of bone quality. Methods. This study investigated circulating serum miRNA profiles in patients with acromegaly (n=20), Cushing’s syndrome (n=14), and GHD (n=10) compared with unaffected controls (n=20). A panel of 14 bone-related miRNAs was analyzed through quantitative PCR. Results. Distinct, disease-specific expression patterns were observed: in acromegaly, seven miRNAs (miR-100-5p, miR-148a-3p, miR-194- 5p, miR-21-5p, miR-23a-3p, miR-29b-3p, and miR-422a ) were significantly upregulated; in Cushing’s syndrome, only miR-550a-3p was upregulated; in GHD, five miRNAs (miR-125b-5p, miR-133a- 3p, miR-145-5p, miR-30e-5p, miR-335-5p) were downregulated. Across all endocrine conditions, osteoporotic patients displayed a consistent downregulation of 13 circulating miRNAs, suggesting a shared molecular fingerprint of secondary osteoporosis. Diagnostic performance analyses revealed that multi-miRNA signatures provided higher accuracy than individual markers, with AUC values >0.9 for acromegaly and GHD, and a 13-miRNA osteoporosis signature reaching an AUC of 1.0. These findings support the role of circulating miRNAs as integrative biomarkers of skeletal fragility in endocrine disorders. Conclusion. Circulating miRNA profiles mirror the molecular mechanisms underlying endocrine-related osteoporosis and may complement conventional imaging for early diagnosis, risk stratification, and monitoring. Their integration into clinical practice could enable a transition toward dynamic, molecularly informed assessment of bone health.