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Abnormal energy metabolism such as lower body weight and body mass index (BMI) and less fat mass is widely reported in patients with adolescent idiopathic scoliosis (AIS) and has been implicated in deformity development. However, the underlying mechanism is largely unclear. LBX1 is one of the promising AIS predisposing genes validated by multicenter studies.This study aimed to identify differentially expressed proteins (DEPs) relating to energy metabolism in AIS by using proteomic and metabolic analysis and to explore if the expression of these DEPs is associated with clinical parameters and modulated by LBX1.This is a cross-sectional study using clinical data and biological samples followed by basic study using a cellular model.Plasma samples were collected from Chinese girls with nonprogressive and progressive AIS (N=7 and 8, respectively) and age-matched healthy girls (N=50). Paraspinal muscle tissues were collected intraoperatively from concave and convex side of the apex of the major spinal curve in AIS (N=24) and either side from nonscoliosis patients (N=14).Radiological Cobb angle and basic anthropometric data of recruited subjects were measured. The DEPs and metabolites were compared in plasma using proteomics and metabolomics technique. The relative expression of selected genes was measured in muscles.Plasma samples from AIS were collected at first clinical visit and were further divided into nonprogressive or progressive groups according to Cobb angle changes in 6-year follow-up. Age-matched healthy girls were recruited as control. High-performance liquid chromatography-mass spectrometry based proteomic analysis was carried out in three groups to identify DEPs and their annotated metabolic pathways. An independent cohort was used for validation by gas chromatography-mass spectrometry based metabolomic analysis. Paraspinal muscles were subjected to quantitative polymerase chain reaction (qPCR) followed by correlation analysis. Human skeletal muscle myoblast (HSMM) was used as the cellular model.The likelihood of aberrant galactose metabolism and glycolysis was found to be associated with AIS curve progression as evidenced by the thirteen DEPs and seven related metabolites according to proteomic and metabolomic analysis. Some of the DEPs showed significantly altered expression in AIS concave and convex sides paraspinal muscles compared with those in nonscoliosis control. Four DEPs were found significantly and negatively correlated with LBX1 in AIS convex side paraspinal muscles. Overexpressing LBX1 in HSMM cells led to increased expression of three DEPs and decreased expression of three DEPs, respectively.This is the first integrated proteomic and metabolomic analysis on AIS. Our findings show dysregulated galactose metabolism and glycolysis pathways in progressive group of AIS, suggesting the presence of abnormal energy metabolism at early stage of this disease, and their association with higher risk of progressing into more severe curvature. Evidence from ex vivo study with human muscle biopsies and in vitro study with human myoblast cells propose the possible effect of LBX1 on these two pathways in skeletal muscles. The present study provides new evidence of LBX1 function in AIS via modulating effect on the expression of energy metabolism related genes. This study might provide new insights into etiopathogenesis and development of novel treatment strategy targeting on abnormal body weight and BMI in patients with AIS. Additionally, the plasma proteomic and metabolomic studies suggested new candidates as biomarkers for establishing predictive model for AIS onset/progression.

The global alignment and proportion (GAP) score was established based on American and European subjects, which might limit its applicability to the Chinese population due to ethnicity-related difference of sagittal alignment.To analyze the applicability of GAP score in the Chinese population and to investigate the age- and gender-associated differences of spinopelvic and GAP score parameters.A prospective cross-sectional radiographic study.Of 692 asymptomatic Chinese volunteers aged between 20 and 79 prospectively recruited between January 2017 and June 2019, 490 subjects were eventually included in this study.The pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), L1-S1 lordosis, L4-S1 lordosis, sagittal vertical axis (SVA), T1 pelvic angle (TPA) and global tilt (GT) were measured on lateral X-rays. The GAP scores and its parameters including relative pelvic version (RPV), relative lumbar lordosis (RLL), lordosis distribution index (LDI) and relative spinopelvic alignment (RSA) were calculated for each subject.Subjects were divided into four groups: Group 1M: male subjects60 years old; Group 1F: female subjects60 years old; Group 2M: male subjects ≥60 years old and Group 2F: female subjects ≥60 years old. The GAP scores and categories were determined and compared between groups. The results of sagittal alignment were compared with the previous studies evaluating the normative sagittal alignment in other populations. Univariate linear regression analysis was carried out between pelvic incidence (PI) and sacral slope (SS), lumbar lordosis (LL) and global tilt (GT) in each group.The distributions of GAP categories and the updated Roussouly classification were statistically different from other populations. Significantly different distribution of GAP categories was observed between Group 1M and Group 2M, Group 1F and Group 2F, and Group 1M and Group 1F. Radiographic measurements and GAP parameters were significantly different between Group 1M and Group 2M, and Group 1F and Group 2F. Gender-related difference of parameters was more prominent between Group 1M and Group 1F. Linear relationship of PI with SS, LL and GT were different from the regression models of "ideal" sagittal alignment in GAP score.The GAP score might be inappropriate in Chinese population due to ethnicity-related alignment difference. Worse feasibility of GAP score was observed in female and old subjects.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) patients suffer from restrictive impairment of pulmonary function (PF) as a consequence of spinal and ribcage deformity. Statistic modelling of scoliotic geometry has been well-established based on low-dose biplanar X-ray device (EOS) imaging. However, the postoperative lung morphology change derived from EOS has not yet been studied adequately till now. METHODS: Twenty-five female AIS patients with severe right-sided major thoracic curve (aged 13–31 years; Cobb angle 45°–92°) underwent posterior spinal fusion (PSF) were prospectively recruited for standing EOS imaging at preoperative, postoperative, and 1-year follow-up (1Y-FU) stages. EOS-based lung morphology at frontal and lateral view was measured respectively to assess serial statistical changes in area and height. RESULTS: At frontal view, left lung area significantly increased postoperatively (104.7 vs. 125.1 cm(2); P0.05). At lateral view, the increase in left lung area was slight without statistically difference (median: 175.8, 178.4, 182.5 cm(2) at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05), while right lung area did not significantly change postoperatively (median: 209.9, 206.7, 212.4 cm(2) at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05). At both frontal and lateral view, left lung height significantly improved at both postoperative and 1Y-FU stage (all P0.05). CONCLUSIONS: EOS imaging demonstrates that left lung area in severe AIS may improve after PSF surgery. EOS may provide useful information about lung morphology change after PSF in severe AIS.

Introduction: A total of 0.1–0.8% of AIS patients progress to severe stages without clear mechanisms, and AIS girls are more prone to curve progression than boys. Recent studies suggest that AIS girls have systemic and persistent low bone-mineral density (BMD), which has been shown to be a significant prognostic factor of curve progression in AIS. The present study aimed to (a) investigate the prevalence of low BMD in patients with severe AIS and (b) assess the sexual dimorphism and independent risk factors of low BMD in severe AIS patients. Materials and Methods: A total of 798 patients (140 boys vs. 658 girls) with AIS who reached surgical threshold (Cobb ≥ 40°) were recruited. BMD were assessed using BMD Z-scores from dual-energy X-ray absorptiometry (DXA). Demographic, clinical, and laboratory values of the subjects were collected from their medical records. Logistic regression analysis was performed to identify independent risk factors of low BMD. Results: The overall prevalence of BMD Z-score ≤ −2 and ≤ −1 were 8.1% and 37.5%, respectively. AIS boys had significantly lower BMD Z-scores (−1.2 ± 0.96 vs. −0.57 ± 0.92) and higher prevalence of low BMD (Z-score ≤ −2: 22.1% vs. 5.2%, p < 0.001; Z-score ≤ −1: 59.3% vs. 32.8%, p < 0.001) than girls. Sex, BMI, serum alkaline phosphatase, and potassium were independent factors of low BMD in the severe AIS patients. Conclusions: The present large cohort of surgical AIS patients revealed that low BMD is more prevalent and severe in boys than in girls with severe curves. Low BMD may serve as a more valuable predictive factor for curve progression to the surgical threshold in boys than girls with AIS.

Using X-ray to evaluate adolescent idiopathic scoliosis (AIS) conditions is the clinical gold standard, with potential radiation hazards. 3D ultrasound has demonstrated its validity and reliability of estimating X-ray Cobb angle (XCA) using spinous process angle (SPA), which can be automatically measured. While angle measurement with ultrasound using spine transverse process-related landmarks (UCA) shows better agreed with XCA, its automatic measurement is challenging and not available yet. This research aimed to analyze and measure scoliotic angles through a novel semi-automatic UCA method. 100 AIS subjects (age: 15.0 ± 1.9 years, gender: 19 M and 81 F, Cobb: 25.5 ± 9.6°) underwent both 3D ultrasound and X-ray scanning on the same day. Scoliotic angles with XCA and UCA methods were measured manually; and transverse process-related features were identified/drawn for the semi-automatic UCA method. The semi-automatic method measured the spinal curvature with pairs of thoracic transverse processes and lumbar lumps in respective regions. The new semi-automatic UCA method showed excellent correlations with manual XCA (R2 = 0.815: thoracic angles R2 = 0.857, lumbar angles R2 = 0.787); and excellent correlations with manual UCA (R2 = 0.866: thoracic angles R2 = 0.921, lumbar angles R2 = 0.780). The Bland–Altman plot also showed a good agreement against manual UCA/XCA. The MADs of semi-automatic UCA against XCA were less than 5°, which is clinically insignificant. The semi-automatic UCA method had demonstrated the possibilities of estimating manual XCA and UCA. Further advancement in image processing to detect the vertebral landmarks in ultrasound images could help building a fully automated measurement method. Level III.

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).

Decreased cortical bone density and bone strength at peak height velocity (PHV) were noted in girls with adolescent idiopathic scoliosis (AIS). These findings could provide the link to the previously reported observation that low bone mineral density (BMD) could contribute as one of the prognostic factors for curve progression that mostly occurs during PHV in AIS. As part of the studies related to aetiopathogenesis of AIS, we assessed bone qualities, bone mechanical strength and bone turnover markers (BTMs) focusing at the peri-pubertal period and PHV in AIS girls. 396 AIS girls in two separate cohorts were studied. Skeletal maturity was assessed using the validated thumb ossification composite index (TOCI). Bone qualities and strength were evaluated with high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA). Cohort-A included 179 girls (11.95 ± 0.95 years old). Girls at TOCI-4 had numerically the highest height velocity (0.71 ± 0.24 cm/month) corresponding to the PHV. Subjects at TOCI-4 had lower cortical volumetric BMD (672.36 ± 39.07 mg/mm3), cortical thickness (0.68 ± 0.08 mm) and apparent modulus (1601.54 ± 243.75 N/mm2) than: (a) those at TOCI-1–3 (724.99 ± 32.09 mg/mm3 (p

Background & Objective The application of ultrasound imaging for spine evaluation could minimize radiation exposure for patients with adolescence idiopathic scoliosis (AIS). A customized three-dimensional (3D) ultrasound imaging system has been demonstrated to provide reliable and valid coronal curvature measurements. However, these measurements were using the spinous processes as anatomical reference, leading to a predictable underestimation of the traditionally used Cobb angles. An alternative 3D ultrasound image reconstruction method was applied to create coronal images with more lateral features for angle measurement. The objective of this study was to test the reliability and the validity of this angle, the ultrasound curve angle (UCA), and compare the UCA with the Cobb angles on X-ray images of patients with AIS. Materials and methods This study was divided into: 1) Investigation of intra- and inter-reliability between two raters for measuring the UCA and two operators for acquiring ultrasound images; 2) Investigation of the validity between the radiographic Cobb angle and the UCA. Fifty patients and 164 patients with AIS, were included in the two stages, respectively. Patients underwent bi-planar X-ray and 3D ultrasound scanning on the same day. The proposed UCA was used to measure the coronal curvature from the ultrasound coronal images, which were formed using a newly customized volume projection imaging (VPI) method. The intra-rater/operator and inter-rater and operator reliability of the UCA were tested by intra-class correlation coefficient (ICC) (3,1) and (2,1), respectively. The validity of UCA measurements as compared to radiographic Cobb angles was tested by inter-method ICC (2,1), mean absolute difference (MAD), standard error of measurement (SEM), Pearson correlation coefficient and Bland–Altman statistics. The level of significance was set as 0.05. Results Excellent intra-rater and intra-operator (ICC (3,1)≥0.973) and excellent inter-rater and inter-operator reliability (ICC (2,1)≥0.925) for UCA measurement, with overall MAD and SEM no more than 3.5° and 1.7° were demonstrated for both main thoracic and (thoraco)lumbar curvatures. Very good correlations were observed between UCA and Cobb angle for main thoracic ( R 2 =0.893) and (thoraco)lumbar ( R 2 =0.884) curves. The mean (SD) measurements in terms of radiographic Cobb and UCA were 27.2 ​± ​11.6° and 26.3 ​± ​11.4° for main thoracic curves; and 26.2 ​± ​11.4° and 24.8 ​± ​9.7° for (thoraco)lumbar curve respectively. One hundred sixty-four subjects (33 male and 131 female subjects; 11–18 years of age, mean of 15.1 ​± ​1.9 years) were included for the validity session. Excellent inter-method variations (ICC (2,K) ≥0.933) with overall MAD and SEM no more than 3.0° and 1.5° were demonstrated for both main thoracic and (thoraco)lumbar curvatures. In addition, Bland–Altman plots demonstrated an acceptable agreement between ultrasound and radiographic Cobb measurements. Conclusion In this study, very good correlations and agreement were demonstrated between the ultrasound and X-ray measurements of the scoliotic curvature. Judging from the promising results of this study, patients with AIS with different severity of curves can be evaluated and monitored by ultrasound imaging, reducing the usage of radiation during follow-ups. This method could also be used for scoliosis screening. The Translational potential of this article: Ultrasound curve angle (UCA) obtained from 3D ultrasound imaging system can provide reliable and valid evaluation on coronal curvature for patients with AIS, without the need of radiation.

Introduction Diabetes and bone health are closely related. We examined the incidence and risk factors of hip fractures in Chinese patients with type 2 diabetes (T2D). Materials and Methods In this prospective cohort, we consecutively enrolled 22,325 adults with T2D above the age of 40 years in the Hong Kong Diabetes Register between 1994 and 2015 with crude hip fracture incidence rate censored in 2017. Results At baseline, the mean age of this cohort was 60.9 ± 10.5 years (mean duration of diabetes 6 years, 52.4% male). During a mean ± standard deviation (SD) follow‐up period of 8.7 ± 5.2 years with 193,553 person‐years, 603 patients were hospitalized due to hip fractures with an incidence (95% confidence interval, CI) of 315.1 (290.4–341.3) per 100,000 person‐years. On multivariable analysis with competing death risk adjusted, the independent hazard ratios (95% CI) for hip fractures in T2D were 2.01 (1.61–2.51) for female sex, 1.08 (1.07–1.09) for age, 0.93 (0.90–0.95) for body mass index, 1.52 (1.25–1.85) for albuminuria and 1.12 (1.02–1.23) for low density lipoprotein‐cholesterol. In men, the 30‐day, 1‐year and 5‐year post‐hip fracture mortality rate (95% CI) were 5.8 (2.4–9.1) %, 29.2 (22.3–35.5) % and 65.9 (57.3–72.8) % respectively. The corresponding rates in women were 3.4 (1.6–5.1) %, 18.6 (14.7–22.4) %, and 46.8 (40.9–52.1) %. Conclusions Southern Chinese patients with T2D have a high risk of hip fracture associated with suboptimal cardiometabolic‐renal risk factors and a high post‐fracture mortality rate. The effects of improving modifiable risk factors on bone health warrants further evaluation., With prospective follow up of nearly 9 years, we identified several risk factors associated with increase hip fracture incidence in Southern Chinese patients with type 2 diabetes in the Hong Kong Diabetes Register. These include female sex, age, body mass index, albuminuria and low density lipoprotein.

The association between the risk of fractures and suboptimal vitamin D (Vit-D) status remains controversial in children. This meta-analysis suggested that serum 25(OH)Vit-D levels were lower in pediatric cases with fractures. 25-hydroxyvitamin D (25(OH)Vit-D) levels less than 50 nmol/L were associated with increased fracture risk in children. This study aimed to assess the association between serum 25(OH)Vit-D and the risk of fractures in children, and to explore the sources of heterogeneity and investigate their impact on results. Systematic review and meta-analysis were conducted for observational studies comparing serum 25(OH)Vit-D levels between fracture and non-fracture pediatric cases. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). Analysis on 17 case-control and 6 cross-sectional studies (2929 fracture cases and 5000 controls) suggested that 25(OH)Vit-D was lower in fracture cases than in controls (pooled mean difference (MD) = − 3.51 nmol/L; 95% confidence interval (CI): − 5.60 to − 1.42) with a heterogeneity (I2) of 73.9%. The sensitivity analysis which merged the case-control studies that had a NOS score ≥ 4 showed a pooled MD of − 4.35 nmol/L (95% CI: − 6.64 to − 2.06) with a heterogeneity (I2) of 35.9%. Pooled odds ratio of fracture in subjects with 25(OH)Vit-D ≤ 50 nmol/L compared to subjects with 25(OH)Vit-D > 50 nmol/L was 1.29 (95% CI: 1.10 to 1.53; I2 < 1%). This study indicated that serum 25(OH)Vit-D levels were lower in pediatric patients with fractures. 25(OH)Vit-D ≤ 50 nmol/L was associated with increased fracture risk in children.

Osteoporosis is a major health issue in boys with Duchenne muscular dystrophy (DMD). Data on the specific bone deficits and microarchitectural alterations in children with DMD were limited. This study aimed to assess the bone microarchitectural alterations in boys with DMD on long-term glucocorticoid using high-resolution peripheral quantitative computed tomography (HR-pQCT). This was a cross-sectional, case–control study. Boys with DMD older than 5 years with no prior history of symptomatic fracture and had been on long-term glucocorticoid treatment were recruited from a single tertiary centre. For each participant, three gender- and age-matched controls were selected randomly from an existing HR-pQCT database of healthy individuals. Nine boys with DMD at a median age of 9.3 years were included. Three were found to have asymptomatic vertebral compression fracture. The HR-pQCT findings of these nine boys were compared with 27 healthy controls. Trabecular microstructure indices at the distal radius were significantly lower but the cortical vBMD was significantly higher in the DMD boys when compared with healthy controls. Lower microarchitectural measurement of trabecular bones, but higher cortical vBMD, was observed in DMD boys on long-term oral glucocorticoid. The results from this study provide preliminary, yet important insights into the bone microarchitecture of this group of patients.

Background Although computed tomography (CT) is commonly used to diagnose the scoliotic spine in patients with adolescent idiopathic scoliosis (AIS) preoperatively, it is limited by the high radiation and prone scanning position. Recently, a new biplanar stereoradiography (EOS) was used to image the scoliotic spine in an upright posture with significantly less radiation in non-severe AIS subjects. However, its reliability to assess preoperative AIS patients remains unreported. Hence, the purpose of this study is to compare the scoliotic curvature between prone (CT) and upright positions (EOS) in preoperative AIS patients. Methods Thirty-three pre-operative AIS patients (mean age:18.4 ± 4.2) were recruited. EOS was used to scan the whole thoracic spine at upright position. Whereas on the same day, a conventional CT scan was used to evaluate the spine in prone position. The three-dimensional reconstruction of EOS and CT of the spine were then generated. Using previous validated techniques, multiple scoliotic parameters in both modalities were determined. The agreement between the two modalities was compared using the Bland-Altman test, whereas the correlation was assessed by the intraclass correlation coefficient (ICC). Results The mean ICC (prone and upright) of intra-rater/inter-rater reliabilities for the measured parameters were 0.985,0.961/0.969,0.903, respectively. Thoracic Cobb angles, intervertebral wedging and lumbar lordosis correlated significantly between upright EOS imaging radiographs (62.9 ± 9.3°,6.4 ± 2.9° and 48.8 ± 12.4°) and prone CT (47.3 ± 10.0°,5.8 ± 2.7° and 27.9 ± 11.4°; P 2 ≥ 0.94; P 2 = 0.834; P P Conclusions Importantly, the image acquisition and reconstruction from EOS can better provide accurate three-dimensional spinal representations of the scoliotic curvature in preoperative AIS patients. Moreover, our findings suggested that scoliotic curvatures in preoperative AIS patients can be largely represented by both imaging modalities despite the difference in body positioning.

Background: Patients with adolescent idiopathic scoliosis (AIS) are found to have a lower level of physical activity, and may have reduced exercise capacity due to spinal deformity. Previous study showed the benefits of high-intensity interval training (HIIT), named E-Fit, which is specifically designed for patients with AIS to improve musculoskeletal health and psychological well-being. To optimize the beneficial effects of training, the current study aimed to investigate the appropriate exercise intensity and metabolic demand in patients with AIS when performing E-Fit. Methods: In all, 22 female subjects, 10 diagnosed with AIS and 12 gender-matched healthy controls, aged between 10 and 16 years, were recruited. Subjects were instructed to perform two trials of a seven min E-Fit. Breath-by-breath gas exchange parameters including oxygen consumption (VO2), heart rate (HR) and the rate of perceived exertion (PRE) were measured during exercise. Demographic data and clinical features of AIS and body composition were obtained. Metabolic demand between AIS and control groups was compared using MANOVA with covariates adjustment. Results: Patients with AIS had an earlier onset of menarche (p = 0.01), higher visceral adipose tissue (p = 0.04) and percentage body fat (p = 0.03) as compared to controls. Patients with AIS showed a significantly higher adjusted means of VO2 average in both the first (p = 0.014) and second trials (p = 0.011) of E-Fit. The adjusted mean of the highest measured VO2 was higher than healthy controls and reached statistical significance in the second trial (p = 0.004). Both the AIS and control group exercised at a similar percentage of VO2 peak (64.26% vs. 64.60%). Conclusion: Patients with AIS showed higher oxygen consumption during E-Fit than heathy controls, which might indicate a higher metabolic cost. Patients with AIS could carry out exercise at a moderate exercise intensity similar to that of healthy controls, but special considerations in designing an exercise program, such as frequent rest intervals, would be useful to avoid fatigue among patients with AIS.

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.

Background Our previous studies found disproportionate anteroposterior vertebral size is associated with severity of the scoliotic curves in adolescent idiopathic scoliosis (AIS) patients. Subsequent studies showed wedging of vertebral bodies (VB) had less contribution than intervertebral discs (IVD) to the anterior–posterior vertebral column length discrepancy in severe-AIS. However, the exact morphological changes of IVD were not clearly defined. This study aimed to evaluate the morphological and pathological changes of IVD and VB in AIS girls and healthy female controls. Methods This study included 33 age-matched female controls and 76 AIS girls with a right-sided thoracic curvature. Wedge angle, height ratio and distance ratio of VB and IVD were measured on the best midline coronal and sagittal planes from reformatted MRI spine. Volumes of VB, IVD and nucleus pulposus (NP) were also evaluated on volumetric images. One-way ANOVA with Bonferroni correction and Pearson correlation tests were used. Results There was significant difference in wedge angle and height ratio of VB and IVD between AIS and controls. In severe-AIS, the position of NP was significantly shifted to the convexity when compared with non-severe AIS and controls. Whereas, the volume of IVD and NP in severe-AIS was found to be significantly smaller. In addition, Cobb angle was significantly correlated with wedge angle and height ratio, and inversely correlated with the volume of NP. Conclusions In addition to wedging of VB and IVD, there was significantly reduced volume of IVD and NP in AIS patients with severe curve, insinuating the mechanical effect of scoliosis leads to a compression on both IVD and NP before significant disc desiccation occurs. We postulate that the compression of IVD and NP can contribute to curve progression in severe-AIS, these patients are more prone to disc degeneration in adulthood if no operative treatment is offered. Further longitudinal study on these parameters is still warranted.

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.

Previous studies have reported abnormal muscle morphology and functions in patients with adolescent idiopathic scoliosis (AIS). To answer whether such abnormalities could be reflected in their circulation and their clinical implication for predicting curve progression to the surgical threshold, this preliminary study explored the presence of baseline muscle-related proteins and their association with curve progression. Plasma samples were collected at the first clinical visit for AIS, with patients divided into non-progressive or progressive groups (N = four and four) according to their Cobb angle in six-year follow-ups, with age- and sex-matched healthy subjects (N = 50). Then, the samples were subjected to isobaric tags for relative and absolute quantitation (iTRAQ) for global comparison of untargeted protein expression. Seventy-one differentially expressed proteins (DEPs) were found elevated in progressive AIS. Functional analysis showed that 18 of these are expressed in muscles and play an essential role in muscle activities. Among the muscle-related DEPs, α-actin had the highest fold change in progressive/non-progressive groups. This preliminary study firstly suggested higher circulating levels of muscle structural proteins in progressive AIS, indicating the likelihood of structural damage at the microscopic level and its association with progression to the surgical threshold. Further studies with larger sample sizes are warranted to validate these novel candidates for early diagnosis and predicting progression.

Background: Balanced global spinopelvic balance is important in the maintenance of the physiological alignment of all body segments above the pelvis with minimum energy expenditure. The key determinants affecting the 3D index-odontoid-hip axis (OD-HA) angle, and in particular its alterations, have not been clearly defined. The aim of this study is to identify the determinants of the 3D OD-HA angle in maintaining global spinopelvic balance in a large Chinese adult cohort of different gender and age groups. Methods: A total of 516 asymptomatic adults were enrolled in this study. Biplanar radiographies were performed to reconstruct the subject’s inter-acetabular axis and C2 odontoid process. The 3D angle formed by the vertical and the line between odontoid and mid-interacetabular axis (OD-HA angle) was computed and projected in the subject’s sagittal and coronal planes. Thoracic kyphosis (TK), lumbar lordosis (LL), T1 pelvic angle (TPA) and sagittal vertical axis (SVA) were measured. Results: The mean values of sagittal and coronal OD-HA were −0.2°±2.5° and 0.2°±1.1°, respectively. Both sagittal and coronal OD-HA had significant correlation with age (r=0.265 and r=−0.143, P

The purpose of this study was to evaluate the morphological changes of intervertebral discs (IVD) and vertebral bodies (VB) in AIS girls according to the subgroups with different curve severity by magnetic resonance imaging (MRI). This study included 33 age-matched female controls and 76 AIS girls with a right-sided thoracic curvature. Wedge angle, height ratio and distance ratio of VB and IVD were measured on the best midline coronal and sagittal planes from reformatted MRI spine. Volumes of VB, IVD and nucleus pulposus (NP) were evaluated on volumetric images. One-way ANOVA with Bonferroni correction was used. There was significant difference in wedge angle and height ratio of VB and IVD between AIS and controls. In severe-AIS, the position of NP was significantly shifted to the convexity when compared with non-severe AIS and controls. Whereas, the volume of IVD and NP in severe-AIS was found to be significantly smaller. On top of coronal wedging of VB and IVD, there was significantly reduced volume of IVD and NP in severe-AIS patients, despite T2 signal of IVD was preserved. The current findings indicate that early mechanical effects on the discs and vertebrae in adolescent scoliotic spine is evident on quantitative imaging. Importantly, these patients may be vulnerable to disc degeneration if no operative treatment is prescribed.

Adolescent idiopathic scoliosis (AIS) patients have lower physical activities when compared with healthy controls, and are associated with lower bone mineral density (BMD), muscle strength and poorer quality of life (QoL). We aimed to assess the feasibility and effects of 6-month home-based digitally supported E-Fit comprised of high-intensity interval exercises for AIS patients. 40 AIS girls aged 11-14 were randomly assigned to E-Fit or control group. E-Fit group participated in an online 6-month home-based exercise program. At baseline, 6-months and 12-months follow-up, BMD using dual-energy X-ray absorptiometry, muscle functions, physical activity using Modified Baecke Questionnaire (MBQ), and QoL using Scoliosis Research Society-22 (SRS-22r) and feedback questionnaire were investigated. 14 in E-Fit and 16 in control group completed the study. Both groups had similar baseline characteristics. At 6-months, E-Fit group showed better improvement and significant interaction effect in left femoral neck bone mineral content (p=0.021) and isometric curl up test (p=0.04). Left arm lean mass showed better improvement between 6-months and 12-months follow-up (p=0.046) and whole-body areal BMD had significant interaction effect at 12-months follow-up (p=0.077). Improvement on self-image, work and sports participation were noted in E-Fit group across time. 70% of E-Fit participants were positive towards domestic application via online platform. E-Fit showed some benefits on bone health, muscle functions, physical activity and QoL measures. Current study indicated some potential physical and psychological benefits of E-Fit for AIS girls. E-Fit was feasible to conduct online at home and might have value of promoting exercise habits among relatively inactive AIS girls.

AIS is three-dimensional spinal deformity with unclear etiopathogenesis. LBX1 is so far the only multi-centers validated AIS predisposing gene. The imbalance of posterior paraspinal muscles is an important factor in AIS etiopathogenesis. It is poorly understood how LBX1 contributes to the abnormal paraspinal muscles and onset/progression of AIS. We aimed to evaluate the expression of LBX1 in paraspinal muscles at the concave and convex side in AIS, and whether alternation of LBX1 expression could affect myoblastsactivities and potentially influence muscle-bone interaction via myokines expression. Paraspinal muscles from AIS and age- and curvature-matched congenital scoliosis (CS) patients were collected for fiber types analysis. Biopsies were also subjected to qPCR to validate expression of myogenic markers, selected myokines and LBX1. Human skeletal muscle myoblast (HSMM) was used for LBX1 loss-of-function study in vitro. Muscle fiber types analysis showed type I and type IIX/IIAX fibers proportion were significantly different between AIS concave and convex but not in two sides of CS. LBX1, myogenic markers and one myokine were significantly imbalanced in AIS but not in CS. Loss-of-function study showed knockdown of LBX1 could inhibit myogenic markers expression and myokines as well. This study provides new insight into the association between imbalanced paraspinal muscle and potential muscle-bone crosstalk in AIS patients and the biological function of predisposing gene LBX1. Further investigation with appropriate animal models is warranted to explore if asymmetric expression of LBX1 could result in distinct muscle phenotypes and bone qualities thus affect the progression of spine curvature in AIS.

Despite application of ultrasound for quantitative measurement of spinal curvatures has been reported with various studies, a systematic review for such is lacking. This systematic review aimed to evaluate (1) reliability of ultrasound; (2) validity of ultrasound using radiographic measurement as gold standard in idiopathic scoliosis patients; and (3) the use of various anatomical landmarks for measurement of spinal curvatures. MEDLINE, EMBASE, CINAHL, and CENTRAL databases were searched. QUADAS-2 quality assessment tool was adopted. Reliability of ultrasound in terms of intra-class correlation coefficient was recorded. Pearson correlation coefficients between ultrasound and radiographic measurements were extracted for meta-analysis. Subgroup analyses based on ultrasound measurement protocols of spinous process (SP), transverse processes (TP) and center of lamina (COL) were conducted. Eleven articles reporting 18 correlation analyses on 766 subjects were eligible for meta-analysis. The mean inter-rater reliability of ultrasound measurement was 0.87±0.07. Pooled correlation for all studies was 0.918 (95% CI: 0.868–0.949), exhibiting substantial heterogeneity (I2=90.50%, p90%, p

Adolescent Idiopathic Scoliosis (AIS) occurs during pubertal rapid growth period and is closely associated with low bone mass. The underlying mechanisms for systemic low bone mass in AIS remains unclear. Wnt signalling pathway is one of the important pathways regulating bone metabolism and influencing bone strength, its family member Wnt16 associates with lower bone mineral density (BMD) in late adulthood, and plays key regulatory role in determining cortical bone quality in adult mice. Our randomized control trial have reported vitamin D (VitD) supplementation significantly improved bone mass and reduced the risk of curve progression in AIS. A case-control study and animal study were employed to answer if WNT16 is associated with the abnormal bone quality in AIS and if the effect of VitD supplementation is associated with Wnt16, respectively. A cohort of 161 AIS and control female subjects were recruited for measurement of anthropometric parameters, bone qualities, and circulating Wnt16 level. In animal study, WT and Wnt16 gKO mice were both subjected to special VitD diet from week 4 and terminated at week 7 and 10 for samples harvesting. AIS showed significantly lower BMD, circulating WNT16 level, and elevated serum level of type I procollagen N-terminal propeptide. Wnt16 gKO mice demonstrated lower cortical bone density compared with WT mice from week 7 of age and Wnt16 gKO were less prone to cortical bone loss induced by high dosage VitD diet. Further study on the biological role of WNT16 and crosstalk with VitD metabolism on bone qualities is warranted which might shed light on prognostic gene of osteopenia and new perspectives for potential target to prevent curve progression.

Adolescent idiopathic scoliosis (AIS) is associated with osteopenia which could persist into adulthood affecting attainment of Peak Bone Mass thus resulting in osteoporosis in late adulthood. We previously reported a randomized double-blinded placebo-controlled trial(the Cal study) showing significant bone health improvement with 2-year calcium(Ca)+Vit-D supplementation for AIS girls. This study addressed the important issue whether bone health improvement from the initial 2-year Ca+Vit-D supplementation could persist as subjects approached towards Peak Bone Mass at 6-year ie after 4-year of supplement discontinuation. This was an extension of the Cal study on AIS girls (11–14 years old, mean age=12.9 years, Tanner stage

To establish the age- and sex-related normative values of sagittal alignment in asymptomatic Chinese adults, and to investigate the changes and possible associated compensation mechanisms across age groups. 584 asymptomatic Chinese adults aged 20–89 years were recruited. Subjects were grouped according to age and gender. Whole-body standing radiographs were acquired for evaluating sagittal alignment from spine to lower limb. Sagittal parameters between gender in different age groups were compared via independent t test. Pearson correlation analysis was used to demonstrate relationships between parameters. Thoracic kyphosis (TK) increased steadily while lumbar lordosis decreased gradually in both genders. Pelvic tilt (PT) in male is greater than in female across all age groups with age related gradual increase. There were significant differences between male and female from 20s to 60s in terms of knee flexion angle (KA) and ankle dorsiflexion angle (AA), but the differences were not significant after 60s. T1 pelvic angle (TPA) was significantly correlated with spinal, pelvic and lower-limb alignment. The older group (≥50 years) had a stronger correlation of TPA with PT and KA, whereas the younger (

Scoliosis screening is important for timely initiation of brace treatment to mitigate curve progression in skeletally immature children. Scoliosis screening programs frequently include the protocol of referring children screened positive with Scoliometer and Moiré Topography for confirmatory standard radiography. Despite being highly sensitive (88%) for detecting those who require specialist referral, the screening program was found to have more than 50% false positive rate that leads to unnecessary radiation exposure. Radiation-free ultrasound has been reported to be reliable for quantitative assessment of scoliosis curves. The aim of this prospective diagnostic accuracy study was to determine the accuracy of ultrasound in determining the referral status for children initially screened positive for scoliosis. 442 schoolchildren with a mean Cobb angle of 14.0 ± 6.6° were recruited. Using x-ray as the gold standard, the sensitivity and specificity of ultrasound in predicting the correct referral status were 92.3% and 51.6% respectively. ROC curve analysis revealed an area under curve of 0.735 for ultrasound alone and 0.832 for ultrasound plus scoliometer measurement. The finding provided strong evidences on the accuracy of ultrasound in determining the referral status that could result in more than 50% reduction of unnecessary radiation exposure for children undergoing scoliosis screening.

Radiation exposure with repeated radiography required at follow-up poses serious health concerns for scoliosis patients. Although spinous process angle (SPA) measurement of spinal curvatures with ultrasound has been reported with promising results, an evidence-based account on its accuracy for translational application remains undefined. This prospective study involved 952 idiopathic scoliosis patients (75.7% female, mean age 16.7 ± 3.0 y, Cobb 28.7 ± 11.6°). Among 1432 curves (88.1%) detected by ultrasound, there was good correlation between radiologic Cobb angles measured manually on EOS (E_Cobb) whole-spine radiographs and automatic ultrasound SPA measurement for upper spinal curves (USCs) (r = 0.873, apices T7-T12/L1 intervertebral disc) and lower spinal curves (LSCs) (r = 0.740, apices L1 or below) (p0.001). Taller stature was associated with stronger correlation. For E_Cobb30°, 66.6% USCs and 62.4% LSCs had absolute differences between E_Cobb and predicted Cobb angle calculated from SPA ≤5°. Ultrasound could be a viable option in lieu of radiography for measuring coronal curves with apices at T7 or lower and Cobb angle30°.

Purpose The EOS-imaging system is increasingly adopted for clinical follow-up in scoliosis with the advantages of simultaneous biplanar imaging of the spine in an erect position. Skeletal maturity assessment using a hand radiograph is an essential adjunct to spinal radiography in scoliosis follow-up. This study aims at testing the feasibility and validity of a newly proposed EOS workflow with sequential spine-hand radiography for skeletal maturity assessment and bracing recommendation. Methods EOS spine-hand radiographs from patients with diagnosis of idiopathic scoliosis, including both sexes and an age range of ten to 14 years, were scored using the Thumb Ossification Composite Index (TOCI), Sanders and Risser methods. Intraclass correlation coefficients (ICCs) were calculated for inter/intraobserver agreement and were tested with Cronbach's alpha values. Results In all, 60 EOS-spine hand radiographs selected from subjects with diagnosis of adolescent idiopathic scoliosis (AIS), including 32 male patients (mean age 11.53 years; 10 to 14) and 28 female patients (mean age 11.50 years; 10 to 13) who underwent sequential spine-hand low dose EOS imaging were generated for analysis. The overall interobserver (ICC = 0.997) and intraobserver agreement (α > 0.9) demonstrated excellent agreement for TOCI staging; ICC > 0.994 for both TOCI and Sanders staging comparing traditional digital versus EOS hand radiography; ICC ≥ 0.841 for agreement on bracing recommendation among TOCI versus the Risser and Sanders system. Conclusion With the proposed new EOS workflow it was feasible to produce high image quality for skeletal maturity assessment with excellent reliability and validity to inform consistent bracing recommendation in AIS. The workflow is applicable for busy daily clinic settings in tertiary scoliosis centres with reduced time cost, improved efficiency and throughput of the radiology department. Level of evidence III

It is well-documented that melatonin deficiency has been linked to the etiopathogenesis of adolescent idiopathic scoliosis. In this study, we intended to apply melatonin in melatonin-deficient mice to ascertain whether melatonin could reduce the incidence/severity of scoliosis, and investigate the role of melatonin on bone mineral density in scoliosis. A total of 80 mice were divided into 4 groups: 20 quadrupedal mice and 20 bipedal mice served as controls; 20 quadrupedal and 20 bipedal mice received oral melatonin (8 mg/kg BW) daily. After 5th, 10th, 15th and 20th weeks of treatment, radiographs and in vivo micro-CT were used to determine the incidence of scoliosis and bone qualities, respectively. Upon sacrifice, the levels of melatonin were measured in each group. At 20th week, the occurrence of scoliosis was 80%, 30%, 22% and 5% in bipedal, quadrupedal, bipedal + melatonin and quadrupedal + melatonin group, respectively. The trabecular bone quality of the vertebral body was significantly ameliorated in the melatonin-treated bipedal models. Likewise, the number of osteoclasts was significantly less in those treated with melatonin. Our results indicated that melatonin deficiency may be crucial for scoliotic development, and restoration of melatonin levels can prevent scoliotic development with the improvement in bone density.

Idiopathic Scoliosis (IS) is a relatively common condition and is estimated to affect as many as 3 % of youth aged 10–17 years (in the United States an estimated approximately 1.4 million otherwise healthy individuals). A clear understanding of the etiology will better direct optimization of evaluation, treatments and therapies, especially early treatments with less invasive methods. A mechanistic explanation of factors combining to initiate and then cause progression of this common condition-- in otherwise healthy pre-teenage and teenage patients--will be discussed. A recent well-designed structured systematic review states that ‘strong evidence is lacking for a consistent pattern of occurrence and any abnormality’, in other words there is no strong evidence for ‘other associated diagnoses’ in IS. And so, certain important inherent factors of IS merit greater discussion. Inherent, or intrinsic factors include: a natural susceptibility to develop a lateral and rotational deformity in the immature rapidly growing erect human spine, inherent torsion associated at the induction of deformity, biomechanics related to curve progression, and anthropology/bipedal gait. We know more today about factors related to the condition and its etiology than we have previously. Across multiple disciplines, a mechanistic approach to understanding the etiopathogenesis of IS, allows a reasonable ‘theory’ for IS etiology and its progression. We will discuss these inherent intrinsic factors in order to further add to our understanding of the theoretical etiopathogenesis. A better understanding of the etiology (and progression) may better direct ways to optimize evaluation, treatments and therapies, especially early treatments with less invasive methods.

International audience; Background: Biplanar X-ray system providing anteroposterior and sagittal plane with an ultra-low radiation dose and in weight-bearing position is increasingly used for spine imaging. The original three-dimensional (3D) reconstruction method from biplanar X-rays has been widely used for clinical parameters, however, the main issue is that manual adjustments of the 3D model was quite time-consuming and limited to thoracolumbar spine. A quasi-automated 3D reconstruction method of the spine from cervical vertebra to pelvis was proposed, which proved fast and accurate in 57 patients with adolescent idiopathic scoliosis. The aim of this study was to compare the newly developed technique of quasi-automatic 3D measurement with classical 2D measurements in a large cohort.Methods: A total of 494 adults with biplanar EOS X-ray scanning were included in this study and divided into health and deformity group according to the presence of spinal deformity. The proposed method of quasi-automatic 3D measurement was applied to all these subjects. The radiographic parameters included: thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), sagittal vertical axis (SVA), T1 pelvic angle (TPA) in sagittal plane, and cobb angle in coronal plane. Comparison was made between quasi-automatic and manual measurement.Results: The mean age was 53.7±19.9 years old. In the whole population, the mean differences between the two methods were 3.9° for TK (30.5°±9.9° vs. 26.5°±9.3°, P30°, respectively. Correlation analysis showed r2 for all clinical parameters ranged from 0.667 to 0.923. On average, the new method takes 5 minutes to compute all the parameters for one case.Conclusions: In conclusion, this ergonomic and efficient quasi-automatic method for full spine proved fast and accurate measurement in a large population, which showed great potential in extensive clinical application

Scoliosis screening is important for timely initiation of brace treatment to mitigate curve progression in skeletally immature children and adolescents. School scoliosis screening programs in Hong Kong follow the protocol of referring children screened positive with a scoliometer and Moire topography for confirmatory standard radiography. Despite being highly sensitive (88%) in detecting those who require specialist referral, the screening program was found to have a false-positive rate >50%, which could lead to unnecessary X-ray radiation. Radiation-free ultrasound has been reported to be valid and reliable for quantitative assessment of curve severity in scoliosis patients. The aim of this prospective diagnostic accuracy study was to determine the accuracy of ultrasound in determining the threshold of referral that requires X-ray for children screened positive with the scoliometer and Moire topography. Our study recruited 442 schoolchildren with a mean Cobb angle of 14.0 ± 6.6°. The sensitivity and specificity of ultrasound in predicting the correct referral status, confirmed by X-ray, were 92.3% and 51.6%, with positive and negative predictive values of 29.0% and 96.9%, respectively. Receiver operating characteristic curve analysis revealed area under the curve values of 0.735 for ultrasound alone and 0.832 for ultrasound in combination with measurement of angle of trunk rotation. The finding supports the accuracy of using ultrasound to determine referral status, which could result in a >50% reduction of unnecessary radiation for children undergoing scoliosis screening.