Lower WNT16 expression in patients with adolescent idiopathic scoliosis - potential link to lower bone mass in AIS?

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.

A six years longitudinal cohort study on the changes in bone density and bone quality up to peak bone mass in adolescent idiopathic scoliosis (AIS) with and without 2 years of Calcium and Vit-D supplementation.

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

Role of differentially expressed LBX1 in Adolescent Idiopathic Scoliosis (AIS) paraspinal muscle phenotypes and muscle-bone crosstalk through modulating myoblasts.

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.

Age- and gender-related normative value of whole-body sagittal alignment based on 584 asymptomatic Chinese adult population from age 20 to 89.

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 (<50 years) had stronger correlation with TK. This study comprehensively presented the normative sagittal alignment based on a large asymptomatic population, which could serve as an age- and gender-specific reference value for spine surgeons when planning for correction surgery. Age can influence the recruitment of compensation mechanism that involve more pelvic and lower limb mechanisms for elderly people.

Morphological changes of intervertebral disc in relation with curve severity of patients with Adolescent Idiopathic Scoliosis - a T2-weighted MRI study.

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.

Is ultrasound accurate for radiation-free quantitative assessment of spinal curvatures in patients with idiopathic scoliosis - a systematic review and meta-analysis.

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%, p<0.001). Subgroup analyses showed that pooled correlations were 0.887 for COL method (comprising 356 subjects); 0.924 for SP method (255 subjects); and 0.941 for TP method (117 subjects); all with notable heterogeneity (I2>90%, p<0.001). The overall risk of bias was rated moderate; yet publication bias was noted. Evidences showed that ultrasound was a promising non-invasive method with satisfactory validity and reliability for measuring coronal curvatures utilizing the SP, TP or COL methods. Further development of three-dimensional ultrasound towards scoliosis assessment will facilitate its translational application for managing scoliosis.

Using ultrasound for screening scoliosis to reduce unnecessary radiographic radiation - a prospective diagnostic accuracy study on 442 schoolchildren.

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.

Feasibility and effects of 6-month home-based digitally supported E-Fit program utilizing high-intensity interval exercises in girls with adolescent idiopathic scoliosis: a randomized controlled pilot study.

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.

Relative anterior spinal overgrowth in adolescent idiopathic scoliosis--result of disproportionate endochondral-membranous bone growth? Summary of an electronic focus group debate of the IBSE.

There is no generally accepted scientific theory for the etiology of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this EFG was written by Professor Jack Cheng and his colleagues who used whole spine magnetic resonance imaging (MRI) to re-investigate the relative anterior spinal overgrowth of progressive AIS in a cross-sectional study. The text is drawn from research carried out with his co-workers including measurement of the height of vertebral components anteriorly (vertebral body) and posteriorly (pedicles) in girls with AIS and in normal subjects. The findings confirm previous anatomical studies and support the consensus view that in patients with thoracic AIS there is relatively faster growth of anterior and slower growth of posterior elements of thoracic vertebrae. The disproportionate anteroposterior vertebral size is associated with severity of the scoliotic curves. In interpreting the findings they consider the Roth/Porter hypothesis of uncoupled neuro-osseous growth in the spine but point out that knowledge of normal vertebral growth supports the view that the scoliosis deformity in AIS is related to longitudinal vertebral body growth rather than growth of the canal. In the mechanical mechanism (pathomechanism) they implicitly adopt the concept of primary skeletal change as it affects the sagittal plane of the spine with anterior increments and posterior decrements of vertebral growth and, in the biological mechanism (pathogenesis) propose a novel histogenetic hypothesis of uncoupled endochondral-membranous bone formation. The latter is viewed as part of an 'intrinsic abnormality of skeletal growth in patients with AIS which may be genetic'. The hypothesis that AIS girls have intrinsic anomalies (not abnormalities) of skeletal growth related to curve progression and involving genetic and/or environmental factors acting in early life is not original. While the findings of Professor Cheng and his colleagues have added MRI data to the field of relative anterior spinal overgrowth in AIS their interpretation engenders controversy. Three new hypotheses are proposed to interpret their findings: (1) hypoplasia of articular processes as a risk factor for AIS; (2) selection from the normal population to AIS involves anomalous vertebral morphology and soft tissue factors--this hypothesis may also apply to certain types of secondary scoliosis; and (3) a new method to predict the natural history of AIS curves by evaluating cerebro-spinal fluid (CSF) motion at the cranio-cervical junction. What is not controversial is the need for whole spine MRI research on subjects with non-idiopathic scoliosis.