Circulating miRNAs Respond to Denosumab Treatment After 2 Years in Postmenopausal Women With Osteoporosis—the MiDeTe study

• Published in: The journal of clinical endocrinology and metabolism Vol. 108; no. 5; pp. 1154 - 1165
• Main Authors: Messner, Zora, Carro Vázquez, David, Haschka, Judith, Grillari, Johannes, Resch, Heinrich, Muschitz, Christian, Pietschmann, Peter, Zwerina, Jochen, Hackl, Matthias, Kocijan, Roland
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.05.2023
• Subjects: Absorptiometry; Biomarkers; Blood cells; Bone Density; Bone Density Conservation Agents - pharmacology; Bone Density Conservation Agents - therapeutic use; Bone mineral density; Bone turnover; Circulating MicroRNA; Clinical; Collagen; Complications and side effects; Correlation analysis; Denosumab; Denosumab - pharmacology; Denosumab - therapeutic use; Dual energy X-ray absorptiometry; Female; Humans; Instrument industry; Lumbar Vertebrae; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Monoclonal antibodies; Monocytes; Next-generation sequencing; Osteoporosis; Osteoporosis, Postmenopausal - drug therapy; Osteoporosis, Postmenopausal - genetics; Post-menopause; Postmenopausal women; Postmenopause; Prospective Studies; Reverse transcription; Spine (lumbar); United States; Austria; anti-osteoporotic therapy; miRNAs; osteoporosis; denosumab; postmenopausal osteoporosis
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgac667

Abstract Context MicroRNAs (miRNAs)—short, single-stranded, noncoding RNAs—regulate several biological processes, including bone metabolism. Objective We investigated circulating miRNAs as promising biomarkers for treatment monitoring in women with postmenopausal osteoporosis on denosumab (DMAB) therapy. Methods In this prospective, observational, single-center study, 21 postmenopausal women treated with DMAB were included for a longitudinal follow-up of 2 years. Next-generation sequencing (NGS) was performed to screen for serological miRNAs at baseline, month 6, and month 24. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to confirm NGS findings in the entire cohort. Bone turnover markers (BTM) P1NP and CTX, and bone mineral density (BMD) by dual x-ray absorptiometry were assessed and correlated to miRNAs. Results BMD at the hip (5.5%, P = 0.0006) and lumbar spine significantly increased (11.4%, P = 0.017), and CTX (64.1%, P < 0.0001) and P1NP (69.3%, P < 0.0001) significantly decreased during treatment. NGS analysis revealed significant changes in miRNAs after 2 years of DMAB treatment but not after 6 months. Seven miRNAs were confirmed by RT-qPCR to be significantly changed during a 2-year course of DMAB treatment compared to baseline. Four of these were mainly transcribed in blood cells, including monocytes. Correlation analysis identified significant correlation between change in miRNA and change in BTMs as well as BMD. Based on effect size and correlation strength, miR-454-3p, miR-26b-5p, and miR-584-5p were defined as top biomarker candidates, with the strongest association to the sustained effect of denosumab on bone in osteoporotic patients. Conclusion Two years of DMAB treatment resulted in upregulation of 7 miRNAs, 4 of which are mainly transcribed in monocytes, indicating a potential impact of DMAB on circulating osteoclast precursor cells. These changes were associated to BMD gain and BTM suppression and could therefore be useful for monitoring DMAB treatment response.