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

Abstract

Context MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs which regulate gene expression. They originate from various tissues including bone and regulate different biological mechanisms including bone metabolism. Objective The aim of this project was to investigate circulating miRNAs as promising biomarkers for treatment monitoring in women with postmenopausal osteoporosis on denosumab (DMAB) therapy. Design, Setting and Patients In this prospective, observational, single-centre study twenty-one postmenopausal women treated with DMAB were included for a longitudinal follow-up of two years. Interventions and Main Outcome Measures Next-generation sequencing (NGS) was performed to screen for serological miRNAs at defined time points (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 (DXA) were assessed and correlated to miRNAs. Results BMD at the hip (5,5%, p = 0.0006) and lumbar spine significantly increased (11,4%, p-value = 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 found to be mainly transcribed in blood cells including monocytes. Correlation analysis identified a 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. Conclusions Two years of DMAB-treatment resulted in the upregulation of 7 miRNAs, four 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.

Week-by-week changes in serum levels of bone-related circulating microRNAs and bone turnover markers

“…There is only preliminary information about osteoporosis therapy’s effects on miRNAs, due to which the magnitude of the response has yet to be discovered, for example, the effect of bisphosphonate therapy on miRNA in man. There is some evidence for changes in miR-33-3p and mir-133a in response to teriparatide, as well as increases in miR-26b-5p and miR-454-3p of 100% to 200%, 26 although no change was reported by others. 27 The need for more consistency in these studies is likely explained by the high variability in miRNA measurements and points to the need to have studies that are sufficiently powered.…”

The regulatory role of microRNAs in common eye diseases: A brief review

“…Studies revealed that circulating miRNAs could also serve as potential biomarkers for AMD detection (Urbańska et al, 2022;Elshelmani and Rani, 2023), as reported in other chronic diseases, such as cancer (El-Daly et al, 2023), osteoporosis (Messner et al, 2022), epilepsy (Xie et al, 2023), pulmonary hypertension (Düzgün et al, 2023), nephropathies (Sun et al, 2022), and hepatitis (Jiang et al, 2023). Furthermore, the significance of circulating miRNAs in numerous therapeutic areas makes them a promising asset for translational medicine applications (Pozniak et al, 2022).…”

The MicroRNAs in the Pathophysiology of Osteoporosis

“…Similarly, Messner et al analyzed miRNA from patients’ serum with osteoporosis treated with Denosumab. They selected three (miR-454-3p, miR-26b-5p, and miR-584-5p), which were defined by the authors as top biomarker candidates for osteoporosis [ 93 ].…”