Search

Introduction: Adult hypophosphatasia (HPP) patients present with diffuse heterogenous symptoms often mimicking rheumatological diseases or osteoporosis and therefore accompanied by delayed diagnosis. The aim of this study was to identify circulating miRNAs in adult HPP patients and to identify potential associations with clinical patients' characteristics., Methods: We utilized untargeted miRNA biomarker discovery by small RNA-sequencing to investigate cell-free miRNA profiles in 24 adult HPP patients (pathogenic variant of the ALPL gene, HPP-related clinical symptoms and repeatedly low ALP) and 24 healthy controls (CTRL)., Results: Patients and CTRL were comparable in age (47.9±14.2 vs. 45.9±8.8y, p=0.980) and sex (55.5% vs. 47.8% females, p=1.000). In total, 91% of patients reported musculoskeletal pain, 41% diffuse neurological symptoms and 64% history of fractures. In total, 84 miRNAs were significantly differently expressed between HPP and CTRL in next generation sequencing (NGS) analysis(p<0.05). Of these, 14 miRNAs were selected (selection criteria: p<0.05, tissue specificity index >0.7, log2 FC >+0.8 or < -0.8) for validation using RT-qPCR, which verified 6 of 14 selected miRNAs (p<0.05; miR-122-3p, miR-140-5p, miR-143-3p, miR-155-5p, miR-451a, miR-92a-3p). Target prediction and enrichment analysis identified associations with the musculoskeletal system and the central nervous system. In total, 37 miRNAs correlated with ALP levels, but only three miRNAs with PLP (pyridoxal-5'-phosphate)., Conclusions: These findings highlight a profound involvement of multiple organ systems and the potential of miRNAs as biomarkers for the effect of HPP on various systems., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Established bone turnover markers do not reflect fracture risk in idiopathic male and premenopausal osteoporosis and the role of microRNAs (miRNAs) in these patients is currently unclear. miRNAs are a class of small non-coding RNAs that regulate gene expression and bone tissue homeostasis. They are considered a new class of endocrine regulators with promising potential as biomarkers., Objective: Evaluation of circulating miRNA signatures in male and female subjects with idiopathic and postmenopausal osteoporotic low-traumatic fractures., Design, Setting, and Patients: This was a case-control study of cross-sectional design of 36 patients with prevalent low-traumatic fractures and 39 control subjects Main Outcome Measures: One hundred eighty-seven miRNAs were quantified in serum by qPCR, compared between groups and correlated with established bone turnover markers., Results: Significant differences in serum levels of circulating miRNAs were identified in all three subgroups (46 in premenopausal, 52 in postmenopausal, 55 in male). A set of 19 miRNAs was consistently regulated in all three subgroups. Eight miRNAs [miR-152-3p, miR-30e-5p, miR-140-5p, miR-324-3p, miR-19b-3p, miR-335-5p, miR-19a-3p, miR-550a-3p] were excellent discriminators of patients with low-traumatic fractures, regardless of age and sex, with area under the curve values > 0.9. The 11 remaining miRNAs showed area under the curve values between 0.81 and 0.89. Correlation analysis identified significant correlations between miR-29b-3p and P1NP, and miR-365-5p and iPTH, TRAP5b, P1NP and Osteocalcin, as well as BMD L1-L4 and miR-19b-3p, miR-324-3p, miR-532-5p, and miR-93-5p., Conclusions: Specific serum miRNA profiles are strongly related to bone pathologies. Therefore miRNAs might be directly linked to bone tissue homeostasis. In particular, miR-29b-3p has previously been reported as regulator of osteogenic differentiation and could serve as a novel marker of bone turnover in osteoporotic patients as a member of a miRNA signature.

Context: Severe burn injury causes a massive stress response, consecutively heightened serum levels of acute phase proteins, cortisol, and catecholamines with accompanying disturbance in calcium metabolism., Objective: Evaluation of early and prolonged changes of serum bone turnover markers (BTMs) and regulators of bone metabolism., Design: Longitudinal observational design., Setting: University clinic., Patients: A total of 32 male patients with a median age of 40.5 years and a median burned total body surface area of 40% (83% patients with full thickness burn injury)., Interventions: None., Main Outcome Measures: Comparison of changes of BTM/regulators of bone metabolism in the early (d 2–7) and prolonged (d 7–56) phases after trauma., Results: All investigated BTM/regulators significantly changed. During the early phase, pronounced increases were observed for serum type 1 collagen cross-linked C-telopeptide, intact N-terminal propeptide of type I procollagen, sclerostin, Dickkopf-1, bone-specific alkaline phosphatase, fibroblast growth factor 23, and intact parathyroid hormone levels, whereas 25-hydroxyvitamin D, albumin, serum, and ionized calcium levels decreased. Changes of osteoprotegerin, osteocalcin, and phosphate were less pronounced but remained significant. In the prolonged phase, changes of intact N-terminal propeptide of type I procollagen were most pronounced, followed by elevated sclerostin, osteocalcin, bone-specific alkaline phosphatase, and lesser changes for albumin levels. Calcium and ionized calcium levels tardily increased and remained within the limit of normal. In contrast, levels of intact parathyroid hormone, fibroblast growth factor 23, C-reactive protein, and to a lesser extent serum type 1 collagen cross-linked C-telopeptide and phosphate levels declined significantly during this phase of investigation., Conclusions: Ongoing changes of BTM and regulators of bone metabolism suggest alterations in bone metabolism with a likely adverse influence on bone quality and structure in male patients with severe burn injuries.

Context: The role of sclerostin as a key regulator of bone formation remains unknown after Roux-en-Y gastric bypass (RYGB) or laparoscopic sleeve gastrectomy (SG)., Objectives: The study objectives were evaluation of sclerostin and Dickkopf-1 (DKK-1) serum levels after surgery and correlations with bone turnover markers (P1NP, CTX), parathyroid hormone (iPTH) and areal bone mineral density (BMD), changes at total body, lumbar spine and total hip., Design and Setting: This was a prospective observational single-center two-arm study in premenopausal women with acute adipositas over 24 months., Participants: Participants were 52 premenopausal women (40 ± 8 years, BMI 43.4) after RYGB and 38 premenopausal women (41 ± 7 years, BMI 45.7) after SG., Main Outcome Measures: Prior to surgery and 1, 3, 6, 9, 12, 18, and 24 months after surgery sclerostin, DKK-1, CTX, P1NP levels and BMD were measured., Results: Sclerostin, CTX and (to a lesser extent) P1NP increased after surgery and remained elevated during the entire study period (P < 0.001). DKK-1 declined during months 3-9 (P < 0.005) and then remained unchanged, serum phosphate continuously increased (P < 0.001), iPTH remained within the upper normal limit. Sclerostin increases were significantly positively correlated with CTX and P1NP increases and negatively correlated with BMD loss. BMD independently declined regardless of RYGB and SG. Elevations of sclerostin, CTX, P1NP, and phosphate, but not DKK-1 and iPTH, were significant discriminating factors for BMD loss (AUC 0.920)., Conclusion: Rapid and sustained increases of sclerostin, CTX, and to a lesser extent, P1NP cause an increase in bone metabolism and result in BMD loss at all skeletal sites.

Context: There are no specific biochemical bone markers available for osteogenesis imperfecta (OI), and the role of sclerostin as a key regulator of bone formation in OI is unknown., Objectives: We aimed to evaluate the role of sclerostin and its association with bone turnover markers as well as body composition parameters in adult patients with different types of OI., Design, Setting, and Participants: This was a case-control study in 27 adult patients and 50 healthy age- and gender-matched controls., Main Outcome Measures: Serum sclerostin levels and bone turnover markers including serum osteocalcin, amino terminal propeptide of type I procollagen, and CrossLaps as well as body composition parameters were determined in mild OI stage I (OI-I) and moderate-severe OI stages III-IV (OI-III-IV), according to Sillence classification. Data were compared with healthy controls., Results: Sclerostin levels were significantly lower in OI-I (19.9 ± 10.9 pmol/L; P < .001) and OI-III-IV (13.3 ± 10.0 pmol/L; P < .001) compared with healthy adults (45.3 ± 14.9 pmol/L), even after adjustment for age, sex, bone mineral content, and body mass index. CrossLaps and PTH were significantly lower in OI-I (0.197 ± 0.15 ng/L; P = .007 and 33.7 ± 19.1 pg/L; P = .033, respectively) and OI-III-IV (0.221 ± 0.18 ng/L; P = .039, and 27.9 ± 14.7 pg/L; P = .001, respectively) than in healthy controls (0.322 ± 0.15 ng/L and 45.0 ± 16.6 pg/L). Amino-terminal propeptide of type I procollagen was below the reference range for OI-I and OI-III-IV. Patients with OI were shorter and lighter and had a decreased bone mineral content (P < .001) but similar fat distribution and lean body mass, compared with controls. Serum sclerostin levels were not related to any bone marker except osteocalcin, the number of prevalent fractures, or body composition readings., Conclusion: Decreased sclerostin levels in OI might reflect a down-regulation or negative feedback mechanism to prevent further bone loss.