3D external shape analysis and barycentremetry can provide early signs of progression in adolescent idiopathic scoliosis.

PURPOSE: Our objective was to analysis the barycentremetry, obtained from the external envelope reconstruction of biplanar radiographs, in adolescent idiopathic scoliosis (AIS) and to determine whether assessing would help predict the distinction between progressive and stable AIS at the early stage. METHODS: A retrospective study with a multicentre cohort of 205 AIS was conducted. All AIS underwent a biplanar X-ray between 2013 and 2020. Inclusion criteria were Cobb angle between 10° and 25°; Risser sign lower than 3; age higher than 10 years; and no previous treatment. A 3D spine reconstruction was performed, and the barycentremetry parameters were computed, i.e., the center of mass position at the apex and the axial torque at the apex, the upper and lower junction. A severity index, helping to distinguish stable and progressive AIS, was computed on the first radiograph, and weighted according to these parameters. A clinical and radiographic monitoring determined if AIS were classified such a stable or progressive scoliosis. RESULTS: One hundred and sixty-two AIS were included (i.e., 87 were classified as stable and 75 as progressive). The apex center of mass position was different between the stable and progressive AIS groups (6 mm, SD = 4 mm for the whole cohort; 5 mm, SD = 4 mm for stable AIS versus 7 mm, SD = 4 mm for progressive AIS; p = 0.02). In AIS thoracic, the specificity and positive predictive value of the severity index increased by 19% and 16%, respectively, by adding the apex vertebral axial torque. CONCLUSION: Early assessment of the external envelope from biplanar X-ray reconstruction of idiopathic scoliosis showed that the apex centre of mass position was significantly different between progressive and stable scoliosis. The inclusion of the axial torque of the apex vertebra in the severity index is promising to help the clinician distinguish between stable and progressive thoracic AIS at an early stage. LEVEL OF EVIDENCE: II - Prognostic studies.

Targeting long non-coding RNA H19 in Subchondral Bone Osteocytes Alleviates Cartilage Degradation in Osteoarthritis.

INTRODUCTION: Emerging evidence suggests long non-coding RNA (lncRNA) H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biological function of H19 in OA subchondral bone remodeling and OA progression. METHODS: Clinical joint samples and OA animal models induced by medial meniscus destabilization (DMM) surgery were used to verify the causal relationship between osteocyte H19 and OA subchondral bone and cartilage changes. MLO-Y4 osteocyte cells subjected to fluid shear stress were used to verify the mechanism underlying H19-mediated mechano-response. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal-organic framework (MMOF) nanoparticles in order to develop a site-specific delivery method for targeting osteocyte H19 for OA treatment. RESULTS: Both clinical OA subchondral bone and wildtype mice with DMM-induced OA exhibit aberrant higher subchondral bone mass with more H19 expressing osteocytes. On the contrary, osteocyte-specific deletion of H19 mice is less vulnerable to DMM-induced OA phenotype. In MLO-Y4 cells, H19-mediated osteocyte mechano-response through PI3K/AKT/GSK3 signals activation by EZH2-induced H3K27me3 regulation on PP2A inhibition. Targeted inhibition of H19 (using ASO-loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype. DISCUSSION: In summary, our results provide new evidence that the elevated H19 expression in osteocytes may contribute to aberrant subchondral bone remodeling and OA progression. H19 appears to be required for the osteocyte response to mechanical stimulation, and targeting H19 represents a new promising approach for OA treatment.

Distinguishing risk of curve progression in adolescent idiopathic scoliosis with bone microarchitecture phenotyping: a 6-year longitudinal study.

Low bone mineral density and impaired bone quality have been shown to be important prognostic factors for curve progression in adolescent idiopathic scoliosis (AIS). There is no evidence-based integrative interpretation method to analyze high-resolution peripheral quantitative computed tomography (HR-pQCT) data in AIS. This study aimed to (1) utilize unsupervised machine learning to cluster bone microarchitecture phenotypes on HR-pQCT parameters in girls with AIS, (2) assess the phenotypes' risk of curve progression and progression to surgical threshold at skeletal maturity (primary cohort), and (3) investigate risk of curve progression in a separate cohort of girls with mild AIS whose curve severity did not reach bracing threshold at recruitment (secondary cohort). Patients were followed up prospectively for 6.22 ± 0.33 years in the primary cohort (n = 101). Three bone microarchitecture phenotypes were clustered by fuzzy C-means at time of peripubertal peak height velocity (PHV). Phenotype 1 had normal bone characteristics. Phenotype 2 was characterized by low bone volume and high cortical bone density, and phenotype 3 had low cortical and trabecular bone density and impaired trabecular microarchitecture. The difference in bone quality among the phenotypes was significant at peripubertal PHV and continued to skeletal maturity. Phenotype 3 had significantly increased risk of curve progression to surgical threshold at skeletal maturity (odd ratio [OR] = 4.88; 95% CI, 1.03-28.63). In the secondary cohort (n = 106), both phenotype 2 (adjusted OR = 5.39; 95% CI, 1.47-22.76) and phenotype 3 (adjusted OR = 3.67; 95% CI, 1.05-14.29) had increased risk of curve progression ≥6° with mean follow-up of 3.03 ± 0.16 years. In conclusion, 3 distinct bone microarchitecture phenotypes could be clustered by unsupervised machine learning on HR-pQCT-generated bone parameters at peripubertal PHV in AIS. The bone quality reflected by these phenotypes was found to have significant differentiating risk of curve progression and progression to surgical threshold at skeletal maturity in AIS.

Adolescent idiopathic scoliosis (AIS) is an abnormal spinal curvature that commonly presents during puberty growth. Evidence has shown that low bone mineral density and impaired bone quality are important risk factors for curve progression in AIS. High-resolution peripheral quantitative computed tomography (HR-pQCT) has improved our understanding of bone quality in AIS. It generates a large amount of quantitative and qualitative bone parameters from a single measurement, but the data are not easy for clinicians to interpret and analyze. This study enrolled girls with AIS and used an unsupervised machine-learning model to analyze their HR-pQCT data at the first clinic visit. The model clustered the patients into 3 bone microarchitecture phenotypes (ie, phenotype 1: normal; phenotype 2: low bone volume and high cortical bone density; and phenotype 3: low cortical and trabecular bone density and impaired trabecular microarchitecture). They were longitudinally followed up for 6 years until skeletal maturity. We observed the 3 phenotypes were persistent and phenotype 3 had a significantly increased risk of curve progression to severity that requires invasive spinal surgery (odds ratio = 4.88, p = .029). The difference in bone quality reflected by these 3 distinct phenotypes could aid clinicians to differentiate risk of curve progression and surgery at early stages of AIS.

Assessment of malalignment at early stage in adolescent idiopathic scoliosis: a longitudinal cohort study.

INTRODUCTION: Our objective was to assess abnormalities of the odontoid-hip axis (OD-HA) angle in a mild scoliotic population to determine whether screening for malalignment would help predict the distinction between progressive and stable adolescent idiopathic scoliosis (AIS) at early stage. MATERIALS AND METHODS: All patients (non-scoliotic and AIS) underwent a biplanar X-ray between 2013 and 2020. In AIS, inclusion criteria were Cobb angle between 10° and 25°; Risser sign lower than 3; age higher than 10 years; and no previous treatment. A 3D spine reconstruction was performed, and the OD-HA was computed automatically. A reference corridor for OD-HA values in non-scoliotic subjects was calculated as the range [5th-95th percentiles]. A severity index, helping to distinguish stable and progressive AIS, was calculated and weighted according to the OD-HA value. RESULTS: Eighty-three non-scoliotic and 205 AIS were included. The mean coronal and sagittal OD-HA angles in the non-scoliotic group were 0.2° and -2.5°, whereas in AIS values were 0.3° and -0.8°, respectively. For coronal and sagittal OD-HA, 27.5% and 26.8% of AIS were outside the reference corridor compared with 10.8% in non-scoliotic (OR = 3.1 and 3). Adding to the severity index a weighting factor based on coronal OD-HA, for thoracic scoliosis, improved the positive predictive value by 9% and the specificity by 13%. CONCLUSION: Analysis of OD-HA suggests that AIS patients are almost three times more likely to have malalignment compared with a non-scoliotic population. Furthermore, analysis of coronal OD-HA is promising to help the clinician distinguish between stable and progressive thoracic scoliosis.

Clinical Outcomes of 111 Patients with Early Onset Idiopathic Scoliosis (EOIS) Receiving Brace Treatment: A Longitudinal Retrospective Cohort Study.

Introduction: Bracing is one of the first-line treatment for early-onset idiopathic scoliosis (EOIS) to control curves from progression. This study aimed to explore the determinants that govern bracing effectiveness in EOIS. Methods: One hundred and eleven patients with EOIS (mean age of 8.6 ± 1.25 at diagnosis) received bracing treatment and had a final follow-up beyond skeletal maturity were identified from records between 1988 and 2021. Demographic data and clinical features of spinal curvature were obtained for correlation analyses to determine the associations between curve outcomes and clinical features. Results: Most patients were female (85.6%) and had a major curve on the left side (67%). The mean baseline Cobb angle of major curves was 21.73 ± 7.92°, with a mean Cobb angle progression of 18.05 ± 19.11°. The average bracing duration was 5.3 ± 1.9 years. Only 26 (23.4%) of them underwent surgery. The final Cobb angle and curve progression at the final follow-up with a Cobb angle of ≥50° were positively correlated with the initial Cobb angle (r = 0.206 and r = 0.313, respectively) and negatively correlated with maturity parameters. The lumbar curve type was found to correlate with a smaller final Cobb angle. Conclusions: The majority of patients had a final Cobb angle < 50°, which was considered a successful bracing outcome. The final Cobb angle correlated with the initial Cobb angle and curve types observed in EOIS.

Monitoring of Curve Progression in Patients with Adolescent Idiopathic Scoliosis Using 3-D Ultrasound.

OBJECTIVE: The aim of the work described here was to determine whether 3-D ultrasound can provide results comparable to those of conventional X-ray examination in assessing curve progression in patients with adolescent idiopathic scoliosis (AIS). METHODS: One hundred thirty-six participants with AIS (42 males and 94 females; age range: 10-18 y, mean age: 14.1 ± 1.9 y) with scoliosis of different severity (Cobb angle range: 10º- 85º, mean: of 24.3 ± 14.4º) were included. Each participant underwent biplanar low-dose X-ray EOS and 3-D ultrasound system scanning with the same posture on the same date. Participants underwent the second assessment at routine clinical follow-up. Manual measurements of scoliotic curvature on ultrasound coronal projection images and posterior-anterior radiographs were expressed as the ultrasound curve angle (UCA) and radiographic Cobb angle (RCA), respectively. RCA and UCA increments ≥5º represented a scoliosis progression detected by X-ray assessment and 3-D ultrasound assessment, respectively. RESULTS: The sensitivity and specificity of UCA measurement in detecting scoliosis progression were 0.93 and 0.90, respectively. The negative likelihood ratio of the diagnostic test for scoliosis progression by the 3-D ultrasound imaging system was 0.08. CONCLUSION: The 3-D ultrasound imaging method is a valid technique for detecting coronal curve progression as compared with conventional radiography in follow-up of AIS. Substituting conventional radiography with 3-D ultrasound is effective in reducing the radiation dose to which AIS patients are exposed during their follow-up examinations.

Handgrip strength assessment at baseline in addition to bone parameters could potentially predict the risk of curve progression in adolescent idiopathic scoliosis.

Introduction: Adolescent idiopathic scoliosis (AIS) is characterized by deranged bone and muscle qualities, which are important prognostic factors for curve progression. This retrospective case-control study aims to investigate whether the baseline muscle parameters, in addition to the bone parameters, could predict curve progression in AIS. Methods: The study included a cohort of 126 female patients diagnosed with AIS who were between the ages of 12 and 14 years old at their initial clinical visit. These patients were longitudinally followed up every 6 months (average 4.08 years) until they reached skeletal maturity. The records of these patients were thoroughly reviewed as part of the study. The participants were categorized into two sub-groups: the progressive AIS group (increase in Cobb angle of ≥6°) and the stable AIS group (increase in Cobb angle <6°). Clinical and radiological assessments were conducted on each group. Results: Cobb angle increase of ≥6° was observed in 44 AIS patients (34.9%) prior to skeletal maturity. A progressive AIS was associated with decreased skeletal maturity and weight, lower trunk lean mass (5.7%, p = 0.027) and arm lean mass (8.9%, p < 0.050), weaker dominant handgrip strength (8.8%, p = 0.027), deranged cortical compartment [lower volumetric bone mineral density (vBMD) by 6.5%, p = 0.002], and lower bone mechanical properties [stiffness and estimated failure load lowered by 13.2% (p = 0.005) and 12.5% (p = 0.004)]. The best cut-off threshold of maximum dominant handgrip strength is 19.75 kg for distinguishing progressive AIS from stable AIS (75% sensitivity and 52.4% specificity, p = 0.011). Discussion: Patients with progressive AIS had poorer muscle and bone parameters than patients with stable AIS. The implementation of a cut-off threshold in the baseline dominant handgrip strength could potentially be used as an additional predictor, in addition to bone parameters, for identifying individuals with AIS who are at higher risk of experiencing curve progression.

Genetic insight into the putative causal proteins and druggable targets of osteoporosis: a large-scale proteome-wide mendelian randomization study.

Background: Osteoporosis is a major causative factor of the global burden of disease and disability, characterized by low bone mineral density (BMD) and high risks of fracture. We aimed to identify putative causal proteins and druggable targets of osteoporosis. Methods: This study utilized the largest GWAS summary statistics on plasma proteins and estimated heel BMD (eBMD) to identify causal proteins of osteoporosis by mendelian randomization (MR) analysis. Different GWAS datasets were used to validate the results. Multiple sensitivity analyses were conducted to evaluate the robustness of primary MR findings. We have also performed an enrichment analysis for the identified causal proteins and evaluated their druggability. Results: After Bonferroni correction, 67 proteins were identified to be causally associated with estimated BMD (eBMD) (p < 4 × 10-5). We further replicated 38 of the 67 proteins to be associated with total body BMD, lumbar spine BMD, femoral neck BMD as well as fractures, such as RSPO3, IDUA, SMOC2, and LRP4. The findings were supported by sensitivity analyses. Enrichment analysis identified multiple Gene Ontology items, including collagen-containing extracellular matrix (GO:0062023, p = 1.6 × 10-10), collagen binding (GO:0005518, p = 8.6 × 10-5), and extracellular matrix structural constituent (GO:0005201, p = 2.7 × 10-5). Conclusion: The study identified novel putative causal proteins for osteoporosis which may serve as potential early screening biomarkers and druggable targets. Furthermore, the role of plasma proteins involved in collagen binding and extracellular matrix in the development of osteoporosis was highlighted. Further studies are warranted to validate our findings and investigate the underlying mechanism.

More Prevalent and Severe Low Bone-Mineral Density in Boys with Severe Adolescent Idiopathic Scoliosis Than Girls: A Retrospective Study of 798 Surgical Patients.

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.

Patients with Adolescent Idiopathic Scoliosis Have Higher Metabolic Cost during High-Intensity Interval Training.

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.

Abnormal morphological features of osteocyte lacunae in adolescent idiopathic scoliosis: A large-scale assessment by ultra-high-resolution micro-computed tomography.

AIM: Abnormal osteocyte lacunar morphology in adolescent idiopathic scoliosis (AIS) has been reported while the results were limited by the number of osteocyte lacunae being quantified. The present study aimed to validate previous findings through (a) comparing morphological features of osteocyte lacunae between AIS patients and controls in spine and ilium using a large-scale assessment, and (b) investigating whether there is an association between the acquired morphological features of osteocyte lacunae and disease severity in AIS. METHOD: Trabecular bone tissue of the facet joint of human vertebrae on both concave and convex sides at the apex of the scoliotic curve were collected from 4 AIS and 5 congenital scoliosis (CS) patients, and also at the same anatomic site from 3 non-scoliosis (NS) subjects intraoperatively. Trabecular bone tissue from ilium was obtained from 12 AIS vs 9 NS subjects during surgery. Osteocyte lacunae were assessed using ultra-high-resolution micro-computed tomography. Clinical information such as age, body mass index (BMI) and radiological Cobb angle of the major curve were collected. RESULTS: There was no significant difference between density of osteocyte lacuna and bone volume fraction (BV/TV) between groups. A total of 230,076 and 78,758 osteocyte lacunae from facet joints of apical vertebra of scoliotic curve and iliac bone were included in the analysis, respectively. In facet joint bone biopsies, lacunar stretch (Lc.St) was higher, and lacunar equancy (Lc.Eq), lacunar oblateness (Lc.Ob), and lacunar sphericity (Lc.Sr) were lower in AIS and CS groups when compared with NS group. CA side was associated with higher Lc.St when compared with CX side. In iliac bone biopsies, Lc.Ob was higher and lacunar surface area (Lc.S) was lower in AIS group than NS group. Median values of Lc.St, Lc.Eq and Lc.Sr were significantly associated with radiological Cobb angle with adjustment for age and BMI (R-squared: 0.576, 0.558 and 0.543, respectively). CONCLUSIONS: This large-scale assessment of osteocyte lacunae confirms that AIS osteocyte lacunae are more oblate in iliac bone that is less influenced by asymmetric loading of the deformed spine than the vertebrae. Shape of osteocyte lacunae in iliac bone is associated with radiological Cobb angle of the major curve in AIS patients, suggesting the likelihood of systemic abnormal osteocyte morphology in AIS. Osteocyte lacunae from concave side of scoliotic curves were more stretched in both AIS and CS groups, which is likely secondary to asymmetric mechanical loading.

Sirt3 mediates the benefits of exercise on bone in aged mice.

Exercise in later life is important for bone health and delays the progression of osteoporotic bone loss. Osteocytes are the major bone cells responsible for transforming mechanical stimuli into cellular signals through their highly specialized lacunocanalicular networks (LCN). Osteocyte activity and LCN degenerate with aging, thus might impair the effectiveness of exercise on bone health; however, the underlying mechanism and clinical implications remain elusive. Herein, we showed that deletion of Sirt3 in osteocytes could impair the formation of osteocyte dendritic processes and inhibit bone gain in response to exercise in vivo. Mechanistic studies revealed that Sirt3 regulates E11/gp38 through the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway. Additionally, the Sirt3 activator honokiol enhanced the sensitivity of osteocytes to fluid shear stress in vitro, and intraperitoneal injection of honokiol reduced bone loss in aged mice in a dose-dependent manner. Collectively, Sirt3 in osteocytes regulates bone mass and mechanical responses through the regulation of E11/gp38. Therefore, targeting Sirt3 could be a novel therapeutic strategy to prevent age-related bone loss and augment the benefits of exercise on the senescent skeleton.

Spine slenderness is not an early sign of progression in adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of the spine. Spine slenderness, which represents its potential instability to buckling under compressive loads, was shown to be higher in AIS patients than non-scoliotic subjects, but it is not clear at what stage of the progression this difference appeared, nor if slenderness could be used as an early sign of progression. In this study, we hypothesized that slenderness could be an early sign of progression. One-hundred thirty-eight patients and 93 non-scoliotic subjects were included. They underwent standing biplanar radiography and 3D reconstruction of the spine, which allowed computing vertebra and disc slenderness ratio. Then, patients were followed until progression of the deformity or skeletal maturity (stable patients). Vertebral slenderness ratio in AIS patients varied between 2.9 [2.7; 3.0] (T9) and 3.4 [3.2; 3.6] (T1), while disc slenderness ranged from 0.6 [0.6; 0.7] at T6-T7 to 1.2 [1.1; 1.3] at L4-L5. Slenderness ratio increased with age, while disc slenderness tended to decrease with age and Cobb angle. Slenderness was similar between progressive and stable patients, and also between patients and non-scoliotic subjects. In conclusion, spinal slenderness does not appear to be an early sign of progression. Further studies should analyse the development of slenderness during growth, and how it could be affected by non-operative treatment.

Which interventions may improve bracing compliance in adolescent idiopathic scoliosis? A systematic review and meta-analysis.

This review aimed to systematically review and meta-analyze the effects of interventions in improving bracing compliance among adolescent idiopathic scoliosis (AIS) patients. Eight databases were searched from their inception to April 2022. The eligibility criteria included controlled studies that used any type of intervention to enhance bracing compliance in braced AIS patients. Two researchers independently screened articles and extracted data based on the PICO (participant, intervention, comparator, and outcome) framework. Quality appraisal of included studies was performed using GRADE (overall assessment), and the risk of bias was assessed with Cochrane RoB Tool 2 for randomized controlled trials (RCT) and ROBINS-I for non-RCT studies. The primary outcome was bracing compliance and secondary outcomes included Cobb Angle and measurements for quality of life. Six eligible studies involving 523 participants were included. All studies were evaluated as low or very low quality with a high risk of bias. Four types of interventions were identified, including sensor monitoring (n = 2, RCTs), auto-adjusted brace (n = 1, RCT), more intensive or collaborated medical care (n = 2), and psychosocial intervention (n = 1). A meta-analysis of 215 patients from the three RCTs suggested that the compliance-enhancing intervention group had 2.92 more bracing hours per day than the usual care control (95%CI [1.12, 4.72], P = 0.001). In subgroup analysis, sensor monitoring significantly improved bracing wearing quantity compared to usual care (3.47 hours/day, 95%CI [1.48, 5.47], P = 0.001), while other aforementioned interventions did not show a significant superiority. Compliance-enhancing interventions may be favorable in preventing curve progression and promoting quality of life, but the improvements cannot be clarified according to limited evidence. In conclusion, although the results of this study suggested that sensor monitoring may be the most promising approach, limited high-quality evidence precludes reliable conclusions. Future well-designed RCTs are required to confirm the actual benefit of compliance-improving interventions in clinical practice.

Morphological changes of Intervertebral Disc detectable by T2-weighted MRI and its correlation with curve severity in Adolescent Idiopathic Scoliosis.

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.

Statistical changes of lung morphology in patients with adolescent idiopathic scoliosis after spinal fusion surgery-a prospective nonrandomized study based on low-dose biplanar X-ray imaging.

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 cm2; P<0.001) but without continuous increase at 1Y-FU (125.1 vs. 124.5 cm2; P=0.084), whereas right lung area showed a slight but insignificant interval increase (median: 143.8, 146.5, 148.4 cm2 at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05). At lateral view, the increase in left lung area was slight without statistically difference (median: 175.8, 178.4, 182.5 cm2 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 cm2 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 P<0.05), while preoperative right lung height was not significantly different from postoperative and 1Y-FU value (all P>0.05). 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.

An analysis on the determinants of head to pelvic balance in a Chinese adult population.

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<0.01, respectively), sagittal OD-HA showed increment from 20s to 80s (-1.3° to 0.8° for female, -0.3° to 1.5° for male) and a significant difference between male and female from 20 to 69 years old. Further analysis showed that sex, weight, TK, PT, SVA, TPA and ODI were determinants of OD-HA. Conclusions: 3D OD-HA angle showed physiological stability with little variability from young to elderly adults, with SD of 2.45° and 1.06° in sagittal and coronal planes, respectively. OD-HA angle confirms the hypothesis that the head tends to remain above the pelvis in a small cone of stability. This study provides an analysis of the determinants of OD-HA and the reference range of the head-pelvis balance in each decade and gender based on a large-scale asymptomatic population.

Global Alignment and Proportion (GAP) score in asymptomatic individuals: is it universal?

BACKGROUND: 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. PURPOSE: 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. STUDY DESIGN: A prospective cross-sectional radiographic study. PATIENTS SAMPLE: 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. OUTCOME MEASURES: 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. METHODS: Subjects were divided into four groups: Group 1M: male subjects <60 years old; Group 1F: female subjects <60 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. RESULTS: 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. CONCLUSIONS: 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.

Biological effect of dysregulated LBX1 on adolescent idiopathic scoliosis through modulating muscle carbohydrate metabolism.

BACKGROUND CONTEXT: 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. PURPOSE: 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. STUDY DESIGN: This is a cross-sectional study using clinical data and biological samples followed by basic study using a cellular model. PATIENT SAMPLE: 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). OUTCOME MEASURES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Semi-automatic ultrasound curve angle measurement for adolescent idiopathic scoliosis.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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 OF EVIDENCE: Level III.