Upregulation of microRNA-96-5p is associated with adolescent idiopathic scoliosis and low bone mass phenotype.

Bone densitometry revealed low bone mass in patients with adolescent idiopathic scoliosis (AIS) and its prognostic potential to predict curve progression. Recent studies showed differential circulating miRNAs in AIS but their diagnostic potential and links to low bone mass have not been well-documented. The present study aimed to compare miRNA profiles in bone tissues collected from AIS and non-scoliotic subjects, and to explore if the selected miRNA candidates could be useful diagnostic biomarkers for AIS. Microarray analysis identified miR-96-5p being the most upregulated among the candidates. miR-96-5p level was measured in plasma samples from 100 AIS and 52 healthy girls. Our results showed significantly higher plasma levels of miR-96-5p in AIS girls with an area under the curve (AUC) of 0.671 for diagnostic accuracy. A model that was composed of plasma miR-96-5p and patient-specific parameters (age, body weight and years since menarche) gave rise to an improved AUC of 0.752. Ingenuity Pathway Analysis (IPA) indicated functional links between bone metabolic pathways and miR-96-5p. In conclusion, differentially expressed miRNAs in AIS bone and plasma samples represented a new source of disease biomarkers and players in AIS etiopathogenesis, which required further validation study involving AIS patients of both genders with long-term follow-up.

Effects of a Home-Based Exercise Intervention (E-Fit) on Bone Density, Muscle Function, and Quality of Life in Girls with Adolescent Idiopathic Scoliosis (AIS): A Pilot Randomized Controlled Trial.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) patients have lower physical activity levels than normal adolescents, and there is an association with poorer bone and muscle health. This study evaluated the effects of a home-based exercise intervention (E-Fit) on bone mineral density (BMD), muscle function, and quality of life (QoL) in AIS-affected girls. METHODS: A total of 40 AIS females aged 11 to 14 years were randomly assigned to the E-Fit or control group. The E-Fit group performed modified 7-min high-intensity interval training (HIIT) 5 days per week for 6 months. Outcome measures including BMD using dual-energy X-ray absorptiometry (DXA), muscle strength and endurance tests, physical activity levels, and QoL using self-reported questionnaires were assessed at baseline and at 6-month and 12-month follow-up. RESULTS: In total, 14 patients in the E-Fit and 16 in the control group completed the study. The E-Fit group showed a marginally significant interaction effect in the whole body areal BMD at the 6- (p = 0.096) and 12-month follow-ups (p = 0.085). The left arm lean mass in the E-Fit group showed a statistically significant interaction effect between the 6- and 12-month follow-ups (p = 0.046). The E-Fit group showed improvements in physical activity participation, as measured by the Modified Baecke Questionnaire (MBQ), with a significant interaction effect in work index (p = 0.043), sport index (p = 0.050), and total score (p = 0.016) from baseline to the 12-month follow-up. Improvement on self-image were noted in E-Fit group across time. CONCLUSIONS: The present results provided some evidence to support the positive benefits of E-Fit for bone health and muscle function in AIS girls.

Best Performance Parameters of HR-pQCT to Predict Fragility Fracture: Systematic Review and Meta-Analysis.

Osteoporosis is a systemic skeletal disease characterized by low bone mass and bone structural deterioration that may result in fragility fractures. Use of bone imaging modalities to accurately predict fragility fractures is always an important issue, yet the current gold standard of dual-energy X-ray absorptiometry (DXA) for diagnosis of osteoporosis cannot fully satisfy this purpose. The latest high-resolution peripheral quantitative computed tomography (HR-pQCT) is a three-dimensional (3D) imaging device to measure not only volumetric bone density, but also the bone microarchitecture in a noninvasive manner that may provide a better fracture prediction power. This systematic review and meta-analysis was designed to investigate which HR-pQCT parameters at the distal radius and/or distal tibia could best predict fragility fractures. A systematic literature search was conducted in Embase, PubMed, and Web of Science with relevant keywords by two independent reviewers. Original clinical studies using HR-pQCT to predict fragility fractures with available full text in English were included. Information was extracted from the included studies for further review. In total, 25 articles were included for the systematic review, and 16 articles for meta-analysis. HR-pQCT was shown to significantly predict incident fractures and/or major osteoporotic fractures (MOFs). Of all the HR-pQCT parameters, our meta-analysis revealed that cortical volumetric bone mineral density (Ct.vBMD), trabecular thickness (Tb.Th), and stiffness were better predictors. Meanwhile, HR-pQCT parameters indicated better performance in predicting MOFs than incident fractures. Between the two standard measurement sites of HR-pQCT, the non-weight-bearing distal radius was a more preferable site than distal tibia for fracture prediction. Furthermore, most of the included studies were white-based, whereas very few studies were from Asia or South America. These regions should build up their densitometric databases and conduct related prediction studies. It is expected that HR-pQCT can be used widely for the diagnosis of osteoporosis and prediction of future fragility fractures. © 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).

Association of higher bone turnover with risk of curve progression in adolescent idiopathic scoliosis.

OBJECTIVE: Emerging evidence suggest abnormal bone metabolism and defective bone qualities are associated to etipathogenesis of Adolescent Idiopathic Scoliosis (AIS). Systemic low bone mass is important prognosticator to predict risk of curve progression in AIS. The underlying mechanism is still unclear. We hypothesize that aberrant bone turnover correlates with bone qualities in AIS and associates to risk of curve progression. SUBJECTS AND METHODS: Two cohorts were included in this study. The case-control study recruited 161 AIS girls and 161 ethnic/age-matched healthy girls. The longitudinal cohort recruited 128 AIS girls with two-year follow-up. Areal bone mineral density (BMD) at femoral necks were measured with dual-energy x-ray absorptiometry (DXA), and bone qualities of distal radius by high-resolution peripheral quantitative computed tomography (HR-pQCT). Time-lapse analysis of registered HR-pQCT images estimated local bone remodeling quantitatively. Serum levels of CTX and P1NP were measured with ELISA kits. RESULTS: AIS presented significantly higher serum level of P1NP. In both AIS and control, the negative correlations were consistently observed between serum CTX/P1NP levels and most cortical bone quality parameters after adjustment to age. Significant correlation between serum bone turnover markers and trabecular bone parameters have been observed only in control. Progressive AIS has significant increase of serum P1NP level at first clinic visit. Time lapse register analysis showed high bone resorption and low net bone gain was associated with risk of progression in AIS. CONCLUSIONS: Our study characterized AIS with higher serum bone turnover markers, which may contribute to defective bone qualities in AIS. For the first time, we showed that progressive AIS had higher systemic bone turnover markers level and local bone remodeling. This fresh evidence indicated association between disrupted bone turnover and risk of progression of AIS, which set the foundation of new prognostic method and of novel treatment target to curve progression. This study demonstrated the importance of bone metabolism in developing disease management of AIS to achieve goal of early prediction and non-surgical modulation.

A validated composite model to predict risk of curve progression in adolescent idiopathic scoliosis.

BACKGROUND: In adolescent idiopathic scoliosis (AIS), the continuous search for effective prognostication of significant curve progression at the initial clinical consultation to inform decision for timely treatment and to avoid unnecessary overtreatment remains a big challenge as evidence of the multifactorial etiopathogenic nature is increasingly reported. This study aimed to formulate a composite model composed of clinical parameters and circulating markers in the prediction of curve progression. METHOD: This is a two-phase study consisting of an exploration cohort (120 AIS, mean Cobb angle of 25°± 8.5 at their first clinical visit) and a validation cohort (51 AIS, mean Cobb angle of 23° ± 5.0° at the first visit). Patients with AIS were followed-up for a minimum of six years to formulate a composite model for prediction. At the first visit, clinical parameters were collected from routine clinical practice, and circulating markers were assayed from blood. FINDING: We constructed the composite predictive model for curve progression to severe Cobb angle > 40° with a high HR of 27.9 (95% CI of 6.55 to 119.16). The area under curve of the composite model is higher than that of individual parameters used in current clinical practice. The model was validated by an independent cohort and achieved a sensitivity of 72.7% and a specificity of 90%. INTERPRETATION: This is the first study proposing and validating a prognostic composite model consisting of clinical and circulating parameters which could quantitatively evaluate the probability of curve progression to a severe curvature in AIS at the initial consultation. Further validation in clinic will facilitate application of composite model in assisting objective clinical decision.

Abnormal lacuno-canalicular network and negative correlation between serum osteocalcin and Cobb angle indicate abnormal osteocyte function in adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a prevalent spinal deformity occurring during peripubertal growth period that affects 1-4% of adolescents globally without clear etiopathogenetic mechanism. Low bone mineral density is an independent and significant prognostic factor for curve progression. Currently, the cause underlying low bone mass in AIS remains elusive. Osteocytes play an important role in bone metabolism and mineral homeostasis, but its role in AIS has not been studied. In the present study, iliac bone tissues were harvested from 21 patients with AIS (mean age of 14.3 ± 2.20 yr old) with a mean Cobb angle of 55.6 ± 10.61° and 13 non-AIS controls (mean age of 16.5 ± 4.79 yr old) intraoperatively. Acid-etched scanning electron microscopy (SEM) images of AIS demonstrated abnormal osteocytes that were more rounded and cobblestone-like in shape and were aligned in irregular clusters with shorter and disorganized canaliculi. Further quantitative analysis with FITC-Imaris technique showed a significant reduction in the canalicular number and length as well as an increase in lacunar volume and area in AIS. SEM with energy-dispersive X-ray spectroscopy analysis demonstrated a lower calcium-to-phosphorus ratio at the perilacunar/canalicular region. Moreover, microindentaion results revealed lower values of Vickers hardness and elastic modulus in AIS when compared with controls. In addition, in the parallel study of 99 AIS (27 with severe Cobb angle of 65.8 ± 14.1° and 72 with mild Cobb angle of 26.6 ± 9.1°) with different curve severity, the serum osteocalcin level was found to be significantly and negatively associated with the Cobb angle. In summary, the findings in this series of studies demonstrated the potential link of abnormal osteocyte lacuno-canalicular network structure and function to the observed abnormal bone mineralization in AIS, which may shed light on etiopathogenesis of AIS.-Chen, H., Zhang, J., Wang, Y., Cheuk, K.-Y., Hung, A. L. H., Lam, T.-P., Qiu, Y., Feng, J. Q., Lee, W. Y. W., Cheng, J. C. Y. Abnormal lacuno-canalicular network and negative correlation between serum osteocalcin and Cobb angle indicate abnormal osteocyte function in adolescent idiopathic scoliosis.

Unique local bone tissue characteristics in iliac crest bone biopsy from adolescent idiopathic scoliosis with severe spinal deformity.

Adolescent idiopathic scoliosis is a complex disease with unclear etiopathogenesis. Systemic and persistent low bone mineral density is an independent prognostic factor for curve progression. The fundamental question of how bone quality is affected in AIS remains controversy because there is lack of site-matched control for detailed analysis on bone-related parameters. In this case-control study, trabecular bone biopsies from iliac crest were collected intra-operatively from 28 severe AIS patients and 10 matched controls with similar skeletal and sexual maturity, anthropometry and femoral neck BMD Z-score to control confounding effects. In addition to static histomorphometry, micro-computed tomography (µCT) and real time-PCR (qPCR) analyses, individual trabecula segmentation (ITS)-based analysis, finite element analysis (FEA), energy dispersive X-ray spectroscopy (EDX) were conducted to provide advanced analysis of structural, mechanical and mineralization features. µCT and histomorphometry showed consistently reduced trabecular number and connectivity. ITS revealed predominant change in trabecular rods, and EDX confirmed less mineralization. The structural and mineralization abnormality led to slight reduction in apparent modulus, which could be attributed to differential down-regulation of Runx2, and up-regulation of Spp1 and TRAP. In conclusion, this is the first comprehensive study providing direct evidence of undefined unique pathological changes at different bone hierarchical levels in AIS.

A Critical Comparison Between Two Scanning Protocols of High-Resolution Peripheral Quantitative Computed Tomography at the Distal Radius in Adolescents.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a unique technology for assessing bone mineral density and bone microarchitecture. Currently, no universally accepted protocol for selecting the region of interest (ROI) at the distal radius has been established for growing subjects. This study aimed (1) to investigate the differences in HR-pQCT measurements of 2 different ROI protocols applied to the distal radius of healthy adolescents and (2) to identify the least common area of ROI (the least common ROI) between the protocols. Twenty-six boys and 26 girls aged between 13 and 16 yr old were recruited. Nondominant distal radius was scanned by 2 HR-pQCT protocols, namely, the "5-mm protocol," where the distal end of ROI started at 5 mm proximal to a reference line, and the "4% protocol," where the ROI started at 4% of the ulnar length proximal to another reference line. The least common ROI between the 2 protocols was identified and the slice numbering within the common ROI was determined. Bland-Altman plots were used to check the agreement of the least common ROIs between the 2 protocols. Paired t-test and Wilcoxon signed-rank test were used for analysis. In boys, significant differences between protocols were found in most parameters with the maximum difference observed in the cortical area (25.0%, p < 0.001). In girls, differences were observed only for total volumetric bone mineral density (3.6%, p = 0.032). The number of slices in the least common ROI was 66 (60.0%) and 57 (51.8%) in boys and girls, respectively. Good agreements on all HR-pQCT parameters from the least common ROI between the 2 protocols were found. Significant differences in bone parameters were noted between the 2 protocols. When comparing the 2 protocols, observed gender differences could reflect the differences in skeletal growth at the peripubertal period between genders. Least common ROI could be useful for cross-center comparisons and when merging datasets from different centers.