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Longitudinal Changes of Circulating miRNAs During Bisphosphonate and Teriparatide Treatment in an Animal Model of Postmenopausal Osteoporosis.

ABSTRACT: MicroRNAs regulate bone homeostasis, and circulating microRNAs have been proposed as novel bone biomarkers. The effect of anti-osteoporotic treatment on circulating microRNAs has not been described in detail. Therefore, we performed a comprehensive analysis of microRNA serum levels in ovariectomized (OVX) and sham-operated (SHAM) rats over 12 weeks of antiresorptive or osteoanabolic treatment. Forty-two Sprague Dawley rats underwent SHAM surgery (n = 10) or ovariectomy (n = 32). After 8 weeks, OVX rats were randomized to antiresorptive treatment with zoledronate (n = 11), osteoanabolic treatment with teriparatide (n = 11), or vehicle treatment (n = 10). Serum samples were collected at weeks 8, 12, 16, and 20 after surgery. A total of 91 microRNAs were analyzed by RT-qPCR in serum samples collected at week 20. Based on the results, 29 microRNAs were selected for longitudinal analysis at all four study time points. Changes in bone mineral density and microstructure were followed up by in vivo micro-CT and ex vivo nano-CT. Ovariectomy resulted in the loss of trabecular bone, which was reversed by osteoanabolic and antiresorptive treatment. Differential expression analysis identified 11 circulating miRNAs that were significantly regulated after treatment. For example, miR-107 and miR-31-5p increased in vehicle-treated OVX animals, whereas they decreased during teriparatide treatment. Additional miRNAs were identified that showed significant correlations to bone microstructure or bone miRNA expression, including miR-203a-3p, which exhibited a significant negative correlation to vertebral and tibial trabecular bone volume fraction (%). Longitudinal analysis confirmed eight microRNAs with significant changes in serum over time that were prevented by teriparatide and zoledronate treatment (miR-34a-5p, miR-31-5p, miR-30d-3p, miR-378a-5p) or teriparatide treatment only (miR-375-3p, miR-183-5p, miR-203a-3p, miR-203b-3p). Gene target network analysis identified WNT and Notch signaling as the main signaling pathways controlled by these miRNAs. Thus, ovariectomy results in time-dependent deregulation of circulating miRNAs compared with SHAM animals. Anti-osteoporotic treatments can rescue this effect, showing that bone-related miRNAs might act as novel biomarkers for treatment monitoring. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

SUBMITTER: Weigl M

PROVIDER: S-EPMC8252367 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPostmenopausal osteoporosis (PMOP) is a common condition that leads to a loss of bone density and an increased risk of fractures in women. Recent evidence suggests that exosomal miRNAs are involved in regulating bone development and osteogenesis. However, exosomal miRNAs as biomarkers for PMOP diagnosis have not been systematically evaluated. In this study, we aim to identify PMOP-associated circulating exosomal miRNAs and evaluate their diagnostic performance.MethodsWe performed next-generation sequencing and bioinformatics analysis of plasma exosomal miRNAs from 12 PMOP patients and 12 non-osteoporosis controls to identify PMOP-associated exosomal miRNAs, and then validated them in an independent natural community cohort with 26 PMOP patients and 21 non-osteoporosis controls. Exosomes were isolated with the size exclusion chromatography method from the plasma of elder postmenopausal women. The plasma exosomal miRNA profiles were characterized in PMOP paired with controls with next-generation sequencing. Potential plasma exosomal miRNAs were validated by qRT-PCR in the validation cohort, and their performance in diagnosing PMOP was systematically evaluated with the receiver operating characteristic curve.ResultsTwenty-seven miRNAs were identified as differentially expressed in PMOP versus controls in sequencing data, of which six exosomal miRNAs (miR-196-5p, miR-224-5p, miR320d, miR-34a-5p, miR-9-5p, and miR-98-5p) were confirmed to be differentially expressed in PMOP patients by qRT-PCR in the validation cohort. The three miRNAs combination (miR-34a-5p + miR-9-5p + miR-98-5p) demonstrated the best diagnostic performance, with an AUC = 0.734. In addition, the number of pregnancies was found to be an independent risk factor that can improve the performance of exosomal miRNAs in diagnosing PMOP.ConclusionsThese results suggested that the plasma exosomal miRNAs had the potential to serve as noninvasive diagnostic biomarkers for PMOP.

Project description:ContextIn postmenopausal women, bone mineral density (BMD) declines after teriparatide therapy is stopped. The pattern of BMD loss after teriparatide therapy is stopped in men is less clear.ObjectiveThe aim of the study was to determine whether the pattern of teriparatide-induced bone accrual and post-teriparatide bone loss differs between postmenopausal women and eugonadal men.DesignWe conducted a prospective cohort substudy.PatientsThe study included 14 postmenopausal women and 17 eugonadal men, ages 46-85 yr, with lumbar spine or femoral neck BMD T-scores below -2.InterventionTeriparatide (37 microg sc daily) was administered for 24 months, followed by 12 months off therapy.Main outcome measuresWe measured BMD at various anatomic sites by dual-energy x-ray absorptiometry, trabecular spine BMD by quantitative computed tomography, and bone turnover markers during the treatment and observation periods. The response to teriparatide administration and discontinuation was compared between females and males.ResultsBMD of the spine, femoral neck, total hip, and trabecular spine increased similarly during the treatment period in men and women, whereas BMD at the radius was stable in men but decreased by 8.1 +/- 3.3% in women (P < 0.0001). After teriparatide was stopped, BMD at the posterior-anterior spine decreased by 7.1 +/- 3.8% in women and by 4.1 +/- 3.5% in men (P = 0.036). BMD at the total hip and femoral neck decreased by 3.8 +/- 3.9 and 3.1 +/- 4.3%, respectively, in women but remained stable in men (P < 0.05 for both sites). BMD at the distal radius remained stable in men but increased in women by 1.6 +/- 3.1% (P = 0.069).ConclusionsTeriparatide appears to increase BMD similarly in postmenopausal women and eugonadal men with osteoporosis. After teriparatide is stopped, the decline in BMD is greater in women than in men. If confirmed in larger cohorts, these findings would suggest that the indication for immediate antiresorptive therapy after teriparatide may not be as urgent in men as in women.

Project description:INTRODUCTION:Long-term treatment is used in patients with osteoporosis, and bisphosphonates (BPs) are the most commonly prescribed medications. However, in some patients this therapy is not effective, cause different side effects and complications. Unfortunately, at least one year is needed to identify and confirm an ineffectiveness of BPs therapy on bone mineral density (BMD). Among other factors, a response to BPs therapy may also be explained by genetic factors. The aim of this study was to analyze the influence of SOST, PTH, FGF2, FDPS, GGPS1, and LRP5 gene variants on the response to treatment with aminobisphosphonates. MATERIALS AND METHODS:Women with postmenopausal osteoporosis were included to this study if they used aminobisphosphonates for at least 12 months. Exclusion criteria were: persistence on BPs therapy less than 80%, bone metabolic diseases, diseases deemed to affect bone metabolism, malignant tumours, using of any medications influencing BMD. The study protocol was approved by the local ethics committee. The BMD at the lumbar spine and femoral neck were measured using dual x-ray absorptiometry (GE Lunar) before and at least 12 months after treatment with BPs. According to BMD change, patients were divided in two groups-responders and non-responders to BPs terapy. Polymorphic variants in SOST, PTH, FGF2, FDPS, GGPS1, and LRP5 genes were determined using PCR analysis with TaqMan probes (Thermo Scientific). RESULTS:In total, 201 women with BPs therapy were included in the study. No statistically significant differences were observed in age, age at menopause, weight, height, BMI and baseline BMD levels between responders (122 subjects) and non-responders (79 subjects). As single markers, the SOST rs1234612 T/T (OR = 2.3; P = 0.02), PTH rs7125774 T/T (OR = 2.8, P = 0.0009), FDPS rs2297480 G/G (OR = 29.3, P = 2.2×10-7), and GGPS1 rs10925503 C/C+C/T (OR = 2.9; P = 0.003) gene variants were over-represented in non-responders group. No significant association between FGF2 rs6854081 and LRP5 rs3736228 gene variants and response to BPs treatment was observed. The carriers of T-T-G-C allelic combination (constructed from rs1234612, rs7125774, rs2297480, and rs10925503) were predisposed to negative response to BPs treatment (OR = 4.9, 95% CI 1.7-14.6, P = 0.005). The C-C-T-C combination was significantly over-represented in responders (OR = 0.1, 95% CI 0.1-0.5, P = 0.006). CONCLUSIONS:Our findings highlight the importance of identified single gene variants and their allelic combinations for pharmacogenetics of BPs therapy of osteoporosis. Complex screening of these genetic markers could be used as a new strategy for personalized antiresorptive therapy.

Project description:The efficacy of generic teriparatide in improving BMD at lumbar spine in patients with osteoporosis was similar to that of alendronate. It provided a new choice for osteoporosis treatment in Chinese population.IntroductionTo determine whether the efficacy of generic teriparatide is noninferior to alendronate for Chinese postmenopausal women with osteoporosis.MethodsEligible patients were randomly assigned (2:1) in a 48-week, open-label design to receive 20 µg sc daily teriparatide or 70 mg oral weekly alendronate. Primary outcome was percentage change in BMD at the lumbar spine from baseline to 48 weeks and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint.ResultsThree hundred ninety-one and 196 participants were randomly assigned to the teriparatide or alendronate group, of whom 379 and 194 receiving at least one dose of teriparatide and alendronate treatment were eligible for the efficacy analysis. Teriparatide was non-inferior to alendronate for BMD change at lumbar spine (treatment difference: 0.7%, 95% CI: - 0.3 to 1.7%), which excluded the predefined non-inferiority margin of - 1.5%. However, teriparatide was not statistically superior to alendronate in improving BMD at lumbar spine (P = 0.169). At 48 weeks, changes in BMD at total hip were - 1.0% and 2.2% in teriparatide and alendronate group, respectively (P < 0.001). The incidence of new fracture showed no statistical difference between groups (P = 0.128). Serum P1NP and β-CTX levels significantly increased in the teriparatide group and markedly decreased in alendronate group (all P < 0.001 vs baseline). The adverse events (AEs) and serious AEs were more common in the teriparatide group than in the alendronate group, which were mainly teriparatide-related hypercalcemia, elevated alkaline phosphatase or parathyroid hormone, dizziness, and arthralgia.ConclusionsTeriparatide was not inferior to alendronate in increasing BMD at lumbar spine in Chinese postmenopausal women, and they achieved these effects through different mechanisms.

Project description:ObjectiveAn increasing risk of developing osteoporosis which is characterized by bone production weakness and microarchitectural deterioration is found among postmenopausal women. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues in response to local disease severity including bone diseases. Herein, we set out to identify candidate miRNAs predictable for osteoporosis incidence in postmenopausal elderly women.MethodsThe circulating miRNA expression profiles deposited in the dataset accessioned as GSE201543 were downloaded from the GEO database. The study included 176 postmenopausal women who underwent BMD testing, including 96 women reporting osteoporosis and 70 women reporting normal BMD. All subjects were submitted their serum samples for measurements of bone metabolism markers.ResultsThe miRNA expression profiles of the GSE201543 dataset were differentially analyzed and found 97 miRNAs being upregulated concomitantly with 31 miRNAs being downregulated in the serum samples between osteoporotic postmenopausal women and postmenopausal women with normal BMD. Osteoporotic postmenopausal women were demonstrated with elevated serum levels of miR-340-5p and miR-506-3p when compared to normal postmenopausal women. Pearson correlation analysis demonstrated that circulating miR-340-5p and miR-506-3p expressions were increased as BAP, β-CTx, and PINP levels increased, but osteocalcin and 25-(OH)VitD levels are declined in osteoporotic postmenopausal women. Results of the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) showed circulating miR-340-5p and miR-506-3p expressions alone or combined together produced 0.843 AUC, 0.851 AUC, and 0.935 AUC, respectively, when used to predict the incidence of osteoporosis in postmenopausal women.ConclusionOur work suggested that circulating miR-340-5p and miR-506-3p function as osteo-miRNAs in postmenopausal women and may serve as potential noninvasive biomarkers for the incidence of osteoporosis in postmenopausal women.

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Longitudinal Changes of Circulating miRNAs During Bisphosphonate and Teriparatide Treatment in an Animal Model of Postmenopausal Osteoporosis.

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