Curve Progression in Adolescent Idiopathic Scoliosis With a Minimum of 2 Years' Follow-up After Completed Brace Weaning With Reference to the SRS Standardized Criteria.

STUDY DESIGN: A retrospective study. OBJECTIVES: To investigate curve evolution after brace weaning in adolescent idiopathic scoliosis (AIS) with reference to the Scoliosis Research Society (SRS) criteria. SUMMARY OF BACKGROUND DATA: Previous studies mainly focused on curve evolution during bracing in AIS. However, curve progression after brace weaning was not well addressed. METHODS: Braced AIS girls followed up for at least 2 years after brace weaning were reviewed. All patients had radiographs at initial visit, brace weaning, 6 months, 1 year, and 2 years after brace weaning, and last follow-up. Curve progression after brace weaning was separately defined as increase in Cobb angle >5 degrees and curve magnitude >45 degrees. The predictors for curve progression were identified using the independent t test. RESULTS: 200 AIS girls were reviewed. The average duration of follow-up after brace weaning was 51.4 ± 25.6 months. Compared with brace weaning, at 6 months, 1 year, 2 years and last follow-up after brace weaning, 50 (25.0%), 60 (30.0%), 93 (46.5%), and 87 (43.5%) patients, respectively, had curve progression >5 degrees; 0 (0%), 0 (0%), 2 (1%), and 2 (1%) patients, respectively, had surgery recommended; among those with Cobb angle ≤40 degrees at brace weaning, 7 (4.0%), 11 (6.3%), 16 (9.2%), and 18 (10.3%) patients, respectively, had Cobb angle >45 degrees; the mean progression magnitudes were 2.6 ± 5.8, 3.5 ± 5.8, 5.1 ± 6.5, and 5.4 ± 7.4 degrees, respectively; and the mean progression rates were 0.34 ± 0.83, 0.16 ± 0.56, 0.13 ± 0.39, and 0.006 ± 0.28 degrees/month, respectively. Cobb angle at brace weaning was associated with increase in Cobb angle >5 degrees (p = .033) and curve magnitude >45 degrees (p < .001) after brace weaning. CONCLUSIONS: Curve progression after brace weaning is observed in 43.5% AIS patients. The highest risk occurs within 6 months after brace weaning whereas Cobb angle remains stable after 2 years' follow-up. High Cobb angle at brace weaning indicates high risk of curve progression after brace weaning. LEVEL OF EVIDENCE: Level III.

A validation study on the traditional Chinese version of Spinal Appearance Questionnaire for adolescent idiopathic scoliosis.

PURPOSE: "Simplified Chinese" version of Spinal Appearance Questionnaire (SC-SAQ) for patients with adolescent idiopathic scoliosis (AIS) was available but did not fit for communities using "Traditional Chinese" as their primary language. We developed a traditional Chinese version of SAQ (TC-SAQ) and evaluated its reliability and validity. METHODS: TC-SAQ was administered to 112 AIS patients, of which 101 bilingual (English and Chinese) patients completed E-SAQ and the traditional Chinese version of Scoliosis Research Society-22 questionnaire (TC-SRS-22). Internal consistency and test-retest reliability were evaluated. Concurrent validity was evaluated by comparing TC-SAQ score with E-SAQ score, and convergent validity by comparing TC-SAQ score with TC-SRS-22 self-image domain score, and discriminant validity by analyzing the relationship between TC-SAQ score and patients' characteristics. RESULTS: Internal consistency of individual TC-SAQ domain was high (Cronbach's α = 0.785 to 0.940), except for general (Cronbach's α = 0.665) and shoulders (Cronbach's α = 0.421) domain. Test-retest reliability of TC-SAQ was good (ICCs of each domain from 0.798 to 0.865). Concurrent validity demonstrated an excellent correlation between TC-SAQ and E-SAQ scores (r = 0.820 to 0.954, P < 0.0001 for all domains). Correlation between TC-SAQ domains and TC-SRS-22 self-image domain was weak to moderate. TC-SAQ total score and individual domain scores (except waist and chest domains) were positively correlated to major curve magnitude. CONCLUSIONS: TC-SAQ had good internal consistency and test-retest reliability. Concurrent validity evaluated against the original English version was excellent. TC-SAQ was both reliable and valid for clinical use for AIS patients using traditional Chinese as their primary language.

Initial Cobb angle reduction velocity following bracing as a new predictor for curve progression in adolescent idiopathic scoliosis.

PURPOSE: The initial correction rate (ICR) has been widely used as a predictor for curve progression in adolescent idiopathic scoliosis (AIS) undergoing bracing treatment. We proposed a new parameter, the initial Cobb angle reduction velocity (ARV), for prediction of curve progression. The purpose of this study was to identify whether the initial ARV was a more effective predictor than ICR for curve progression in AIS patients undergoing brace treatment, and to evaluate the ideal cut-off point of initial ARV for prediction of curve progression. METHODS: This was a retrospective cohort study on AIS girls receiving standardized bracing treatment regularly followed up every 3-6 months. Standardized SRS criteria for bracing study were utilized in the case selection. The demographic data, maturity status and Cobb angle of each visit were recorded. The initial ARV and ICR were identified. Patients were divided into progressive (≥6°) and non-progressive (<6°) groups based on their final bracing outcome. Differences between two groups were identified and logistic regression analysis was applied to compare the predictive values of initial ARV and ICR for curve progression during bracing treatment. RESULTS: Seventy-six patients were included in the non-progressive group and 19 in the progressive group. Significant differences between non-progressive and progressive groups were found in terms of initial ARV (12.8 ± 21.4°/year vs -5.4 ± 15.2°/year, P = 0.001) and ICR (12.1 ± 20.7 % vs -5.8 ± 18.0 %, P = 0.001). The logistic regression analysis revealed that age at initial visit (OR 1.742, P = 0.043) and initial ARV (OR 1.057, P = 0.002) had higher predictive values than ICR (P = 0.601) for curve progression in braced AIS girls. The ideal cut-off point of initial ARV was 10°/year (OR 8.959, P = 0.005) for the prediction of curve progression. CONCLUSIONS: The initial Cobb angle reduction velocity serves as a better predictor for curve progression than initial correction rate in braced AIS patients with follow-up interval of 3-6 months. At the second visit following bracing prescription, those AIS patients with reduction velocity in Cobb angle lower than 10°/year have significantly higher risk of curve progression.

Phytomolecule icaritin incorporated PLGA/TCP scaffold for steroid-associated osteonecrosis: Proof-of-concept for prevention of hip joint collapse in bipedal emus and mechanistic study in quadrupedal rabbits.

Steroid-associated osteonecrosis (SAON) may lead to joint collapse and subsequent joint replacement. Poly lactic-co-glycolic acid/tricalcium phosphate (P/T) scaffold providing sustained release of icaritin (a metabolite of Epimedium-derived flavonoids) was investigated as a bone defect filler after surgical core-decompression (CD) to prevent femoral head collapse in a bipedal SAON animal model using emu (a large flightless bird). The underlying mechanism on SAON was evaluated using a well-established quadrupedal rabbit model. Fifteen emus were established with SAON, and CD was performed along the femoral neck for the efficacy study. In this CD bone defect, a P/T scaffold with icaritin (P/T/I group) or without icaritin (P/T group) was implanted while no scaffold implantation was used as a control. For the mechanistic study in rabbits, the effects of icaritin and composite scaffolds on bone mesenchymal stem cells (BMSCs) recruitment, osteogenesis, and anti-adipogenesis were evaluated. Our efficacy study showed that P/T/I group had the significantly lowest incidence of femoral head collapse, better preserved cartilage and mechanical properties supported by more new bone formation within the bone tunnel. For the mechanistic study, our in vitro tests suggested that icaritin enhanced the expression of osteogenesis related genes COL1α, osteocalcin, RUNX2, and BMP-2 while inhibited adipogenesis related genes C/EBP-ß, PPAR-γ, and aP2 of rabbit BMSCs. Both P/T and P/T/I scaffolds were demonstrated to recruit BMSCs both in vitro and in vivo but a higher expression of migration related gene VCAM1 was only found in P/T/I group in vitro. In conclusion, both efficacy and mechanistic studies show the potential of a bioactive composite porous P/T scaffold incorporating icaritin to enhance bone defect repair after surgical CD and prevent femoral head collapse in a bipedal SAON emu model.

Abnormal response of the proliferation and differentiation of growth plate chondrocytes to melatonin in adolescent idiopathic scoliosis.

Abnormalities in the melatonin signaling pathway and the involvement of melatonin receptor MT2 have been reported in patients with adolescent idiopathic scoliosis (AIS). Whether these abnormalities were involved in the systemic abnormal skeletal growth in AIS during the peripubertal period remain unknown. In this cross-sectional case-control study, growth plate chondrocytes (GPCs) were cultured from twenty AIS and ten normal control subjects. Although the MT2 receptor was identified in GPCs from both AIS and controls, its mRNA expression was significantly lower in AIS patients than the controls. GPCs were cultured in the presence of either the vehicle or various concentrations of melatonin, with or without the selective MT2 melatonin receptor antagonist 4-P-PDOT (10 µM). Then the cell viability and the mRNA expression of collagen type X (COLX) and alkaline phosphatase (ALP) were assessed by MTT and qPCR, respectively. In the control GPCs, melatonin at the concentrations of 1, 100 nM and 10 µM significantly reduced the population of viable cells, and the mRNA level of COLX and ALP compared to the vehicle. Similar changes were not observed in the presence of 4-P-PDOT. Further, neither proliferation nor differentiation of GPCs from AIS patients was affected by the melatonin treatment. These findings support the presence of a functional abnormality of the melatonin signaling pathway in AIS GPCs, which might be associated with the abnormal endochondral ossification in AIS patients.

A prospective randomized controlled study on the treatment outcome of SpineCor brace versus rigid brace for adolescent idiopathic scoliosis with follow-up according to the SRS standardized criteria.

PURPOSE: SpineCor is a relatively innovative brace for non-operative treatment of adolescent idiopathic scoliosis (AIS). However, the effectiveness of SpineCor still remains controversial. The objective of the current study was to compare the treatment outcomes of SpineCor brace with that of rigid brace following the standardized Scoliosis Research Society (SRS) criteria on AIS brace study. METHODS: Females subjects with AIS and aged 10-14 were randomly allocated into two groups undergoing treatment of SpineCor (S Group, n = 20) or rigid brace (R Group, n = 18). During SpineCor treatment, patients who had curve progression of >5° would be required to switch to rigid brace treatment. The effectiveness of the two brace treatments was assessed using the SRS standardized criteria. RESULTS: Before skeletal maturity, 7 (35.0%) patients in the S Group and 1 (5.6%) patient in the R Group had curve progression >5° (P = 0.026). At skeletal maturity, 5 of the 7 (71.4%) patients who failed with SpineCor bracing showed control from further progression by changing to rigid bracing. At the latest follow-up with a mean duration of 45.1 months after skeletally maturity, 29.4% of patients who were successfully treated by rigid brace showed further curve progression beyond skeletal maturity, versus 38.5% of patients in the SpineCor group (P > 0.05). For both groups, the primary curves were slightly improved at the time of brace weaning, but additionally increased at the latest follow-up, with a rate of 1.5° per year for post-maturity progression. CONCLUSIONS: Curve progression rate was found to be significantly higher in the SpineCor group when compared with the rigid brace group. Changing to rigid bracing could control further curve progression for majority of patients who previously failed with SpineCor bracing. For both SpineCor and rigid brace treatments, 30-40% of patients who were originally successfully treated by bracing would exhibit further curve progression beyond skeletal maturity. The post-maturity progression rate was found to be 1.5° per year in the current study, which was relatively greater than those reported before.

Bone structural and mechanical indices in Adolescent Idiopathic Scoliosis evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT).

Adolescent Idiopathic Scoliosis (AIS) is associated with systemic low bone mass. It could persist into adulthood and was shown to be an important prognostic factor for curve progression in AIS. Previous studies were confined to areal bone mineral density (aBMD) measured by Dual-energy X-ray Absorptiometry (DXA) which was a two-dimensional measurement for a three-dimensional structure. This conventional measurement was inadequate to evaluate volumetric bone density and bone quality which are important determinants for bone strength and bone health status as defined in the 2000 NIH consensus statement. High-resolution peripheral quantitative computed tomography (HR-pQCT) was therefore used in this study for three-dimensional evaluation of volumetric bone mineral density and bone micro-architecture as well as estimation of bone strength. In this study, 214 newly diagnosed AIS girls and 187 age and gender-matched normal control aged between 11 and 13years old were recruited for HR-pQCT evaluations on bone geometry, trabecular bone micro-architecture and volumetric BMD (vBMD) at the non-dominant distal radius. We demonstrated that AIS was associated with lower Cortical Bone Area, Cortical Bone vBMD, Trabecular Number and greater Trabecular Separation. With multivariate linear regression analysis and after adjustment for age, dietary calcium intake and physical activity level, the association of AIS with lower Cortical Bone vBMD, lower Trabecular Number and greater Trabecular Separation remained statistically significant. The findings of this study indicated that AIS was associated with an abnormal bone quality profile suggestive of alteration in endocortical modeling, derangement in trabecular bone structure and disturbance in bone mineralization. The cause for these changes and how they are related to the etiopathogenesis of AIS warrant further studies.

Abnormal bone quality versus low bone mineral density in adolescent idiopathic scoliosis: a case-control study with in vivo high-resolution peripheral quantitative computed tomography.

BACKGROUND CONTEXT: Adolescent idiopathic scoliosis (AIS) is associated with low bone mass that could persist into early adulthood and is an important prognostic factor for curve progression. Previous studies were confined to areal bone mineral density measurement that was a two-dimensional investigation for a three-dimensional structure. Evaluation of volumetric BMD (vBMD) and other bone quality parameters are important for gaining in-depth understanding of the etiopathogenesis of AIS. PURPOSE: The objective of this study was to carry out direct in vivo measurement of bone quality in AIS using high-resolution peripheral quantitative computed tomography (HR-pQCT) and compare the correlation of bone quality with osteopenia between AIS and control subjects. STUDY DESIGN/SETTING: A case-control study. PATIENT SAMPLE: Newly diagnosed AIS girls (n=112) and non-AIS girls (n=115) between 11 and 13 years. OUTCOME MEASURES: Areal bone mineral density of bilateral femoral necks and HR-pQCT of the nondominant distal radius were performed. METHODS: Areal bone mineral density of femoral necks was measured by dual-energy X-ray absorptiometry. Subjects were classified into the osteopenic (Z score less than or equal to -1) and nonosteopenic (Z score more than -1) groups. Bone quality parameters, including bone morphometry, trabecular bone microarchitecture, and vBMD, were measured by HR-pQCT (XtremeCT; Scanco Medical, Zurich, Switzerland). RESULTS: In AIS, the osteopenic group had lower measurements in cortical area, cortical thickness, average vBMD, compact bone vBMD, trabecular vBMD, trabecular bone volume to tissue volume ratio, and trabecular thickness compared with nonosteopenic AIS subjects. In contrast, among the non-AIS controls, the osteopenic group had lower measurements only in bone morphometry, average vBMD, and compact bone vBMD but not in trabecular vBMD and all other trabecular bone microarchitecture parameters. CONCLUSIONS: This is the first study using HR-pQCT to compare the correlation of bone quality with osteopenia in AIS and non-AIS subjects. It provides new insights and highlights the unique bone quality profile with predominant changes in the trabecular compartment in association with osteopenia being notably only detected in the AIS subjects. Further studies in this area are warranted for defining the metabolic nature and biomechanical sequelae of derangement in bone mass and bone quality and their roles in the etiopathogenesis of AIS.

Pathomorphological changes of bone marrow adipocytes in process of steroid-associated osteonecrosis.

OBJECTIVE: The role of extravascular fat deposition in pathogenesis of steroid-associated osteonecrosis (ON) still remains unclear. This study aimed to explore the pathomorphological changes of bone marrow adipocytes over time in a rabbit ON model. METHODS: Thirty-two adult rabbits were divided into control group (n=16) and steroid group (n=16). Rabbits in the steroid group were injected with venous lipopolysaccharide once and intramuscular methylprednisolone trice to induce ON. Rabbits in the control group were treated with normal saline of equal volume. 2 weeks (early stage; n=8) and 4 weeks (late stage; n=8) after the last steroid injection, animals were sacrificed, and bilateral femora were harvested. The density, diameter and area of bone marrow adipocytes were determined by histomorphometry, and ON was evaluated histopathologically. RESULTS: The adipocyte density in steroid group increased by 67.1% and 54.4% at week 2 and week 4, respectively, when compared with control group, but there was no significant difference between week 2 and week 4. The adipocyte diameter in the steroid group at week 4 was significantly larger than that in the control group, but the adipocyte diameter in the steroid group at week 2 was slightly smaller than that in the control group. The adipocyte area in the steroid group increased by 44% and 83.4% at week 2 and week 4, respectively, when compared with the control group, and the adipocyte area in the steroid group at week 4 was markedly larger than that at week 2. In the control group, there were a largest number of adipocytes with 40-50 µm in diameter. When compared with the control group, most of increased adipocytes in the steroid group at week 2 were 30-40 µm in diameter, and those at week 4 were 50-60 µm in diameter. In the steroid group, histopathological examination showed ON was found in 25% (2/8) of rabbits at week 2 and 87.5% (7/8) of rabbits at week 4. CONCLUSION: In the process of ON, extravascular fat deposition is characterized by increased small adipocytes at the early stage and hypertrophy of adipocytes at the late stage.

PICK1 and ICA69 control insulin granule trafficking and their deficiencies lead to impaired glucose tolerance.

Diabetes is a metabolic disorder characterized by hyperglycemia. Insulin, which is secreted by pancreatic beta cells, is recognized as the critical regulator of blood glucose, but the molecular machinery responsible for insulin trafficking remains poorly defined. In particular, the roles of cytosolic factors that govern the formation and maturation of insulin granules are unclear. Here we report that PICK1 and ICA69, two cytosolic lipid-binding proteins, formed heteromeric BAR-domain complexes that associated with insulin granules at different stages of their maturation. PICK1-ICA69 heteromeric complexes associated with immature secretory granules near the trans-Golgi network (TGN). A brief treatment of Brefeldin A, which blocks vesicle budding from the Golgi, increased the amount of PICK1 and ICA69 at TGN. On the other hand, mature secretory granules were associated with PICK1 only, not ICA69. PICK1 deficiency in mice caused the complete loss of ICA69 and led to increased food and water intake but lower body weight. Glucose tolerance tests demonstrated that these mutant mice had high blood glucose, a consequence of insufficient insulin. Importantly, while the total insulin level was reduced in PICK1-deficient beta cells, proinsulin was increased. Lastly, ICA69 knockout mice also displayed similar phenotype as the mice deficient in PICK1. Together, our results indicate that PICK1 and ICA69 are key regulators of the formation and maturation of insulin granules.

Abnormal Skeletal Growth in Adolescent Idiopathic Scoliosis Is Associated with Abnormal Quantitative Expression of Melatonin Receptor, MT2.

The defect of the melatonin signaling pathway has been proposed to be one of the key etiopathogenic factors in adolescent idiopathic scoliosis (AIS). A previous report showed that melatonin receptor, MT2, was undetectable in some AIS girls. The present study aimed to investigate whether the abnormal MT2 expression in AIS is quantitative or qualitative. Cultured osteoblasts were obtained from 41 AIS girls and nine normal controls. Semi-quantification of protein expression by Western blot and mRNA expression by TaqMan real-time PCR for both MT1 and MT2 were performed. Anthropometric parameters were also compared and correlated with the protein expression and mRNA expression of the receptors. The results showed significantly lower protein and mRNA expression of MT2 in AIS girls compared with that in normal controls (p = 0.02 and p = 0.019, respectively). No differences were found in the expression of MT1. When dichotomizing the AIS girls according to their MT2 expression, the group with low expression was found to have a significantly longer arm span (p = 0.036). The results of this study showed for the first time a quantitative change of MT2 in AIS that was also correlated with abnormal arm span as part of abnormal systemic skeletal growth.

Quantitative ultrasound for predicting curve progression in adolescent idiopathic scoliosis: a prospective cohort study of 294 cases followed-up beyond skeletal maturity.

Adolescent idiopathic scoliosis (AIS) is prevalent among adolescents and can carry significant morbidities. We evaluated the use of quantitative ultrasound (QUS) for predicting curve progression in patients with AIS. We recruited 294 girls with AIS at a mean age of 13.4 years, and they were prospectively followed beyond skeletal maturity for curve progression. We recorded 3 calcaneal QUS measurements at baseline, namely broadband ultrasound attenuation (BUA), velocity of sound (VOS), and stiffness index (SI). Logistic regression analysis indicated that SI, age, menarchal status, and Cobb angle were significant prognostic factors to be included in the final prediction model. The adjusted odds ratio of curve progression for Z-score of SI≦0 was 2.00 (95% CI: 1.08-3.71). The area under the ROC curve was 0.831 (95% CI: 0.785-0.877). The results of this study indicate that SI was an independent and significant prognostic factor for AIS and could be considered in addition to other prognostic factors when estimating the risk for curve progression and planning treatment for patients with AIS.

Abnormal skeletal growth patterns in adolescent idiopathic scoliosis--a longitudinal study until skeletal maturity.

STUDY DESIGN: A cross-sectional and prospective longitudinal study on the anthropometric parameters and growth pattern of girls with adolescent idiopathic scoliosis (AIS). OBJECTIVE: To investigate the growth pattern of girls with AIS with different severities, using cross-sectional and prospective longitudinal data set in comparison with age-matched healthy controls. SUMMARY OF BACKGROUND DATA: AIS occurs in children during their pubertal growth spurt. Although there is no clear consensus on the difference in body height between girls with AIS and healthy controls, it is generally thought that the development and curve progression in girls with AIS is closely associated with their growth rate. There is no concrete prospective longitudinal study to document clearly the growth pattern and growth rate of subjects with AIS . METHODS: A total of 611 girls with AIS and 296 healthy age-matched controls were included in the study and among them, 194 girls with AIS and 116 healthy controls were followed up until skeletal maturity. The girls with AIS were grouped into moderate (AIS20) and severe curve (AIS40) groups on the basis of maximum curve magnitude at skeletal maturity. Clinical data and detailed anthropometric parameters were recorded. In the cross-sectional analysis, the groups of subjects were compared within different age groups (from the age of 12-16 yr). In the longitudinal study, linear mixed modeling with respect to age or years since menarche was employed to formulate the growth trajectory of different anthropometric parameters. RESULTS: In the cross-sectional analysis, the girls with AIS were generally taller, with longer arm span and lower body mass index than the healthy controls. The girls with AIS40 were found to be significantly shorter in height (P = 0.006) and arm span (P = 0.025) at the age of 12 years but caught up and overtook the control group at the age of 14 to 16 years. In the longitudinal study, the average growth rate of arm span in girls with AIS40 was significantly higher than that in girls with AIS20 (> 30%) (P = 0.004) and controls (> 70%) (P = 0.0004). The age of menarche of girls with AIS40 was significantly delayed by 5.9 months and 3.8 months when compared with the control group and girls with AIS20, respectively (P < 0.05). CONCLUSION: The growth patterns of girls with AIS with confirmed curve severities were significantly different from healthy age-matched controls. Girls with severe AIS had delayed menarche with faster skeletal growth rate during the age of 12 to 16 years. Monitoring the rate of change of arm span of girls with AIS could be an important additional clinical parameter in helping predict curve severity in girls with AIS.

Genetic epidemiology and heritability of AIS: A study of 415 Chinese female patients.

Recent familial segregation studies supported a multifactorial genetic model for the etiology of adolescent idiopathic scoliosis (AIS). However, the extent of quantitative genetic effects, such as heritability, have not been fully evaluated. This genetic epidemiology study examined the sibling recurrent risk and heritability of AIS in first-degree relatives of 415 Chinese female patients, which is up to now the largest cohort. They were first diagnosed by community screening program and compared to 203 age-matched normal controls. Out of the total 531 sibs of AIS cases, 94 sibs had scoliosis (sibling recurrence risk = 17.7%). The prevalence of AIS among male and female sibs of an index case were 11.5% (95% CI = 7.5-15.5) and 23.0% (95% CI = 18.1-27.9), respectively. Female sibs of an index case had an increased risk of 8.9-fold (95% CI = 3.2-34.4) for developing AIS. These recurrent risks were significantly higher than the risk in the control group (p < 0.0001). Overall, heritability was estimated to be 87.5 ± 11.1%. The results confirmed the prevailing impression of strong genetic influence on the risk of AIS. Here we provided a large-scale study for the genetic aggregation estimates in an Asian population for the first time. The finding also positioned AIS among other common disease or complex traits with a high heritability.

Abnormal leptin bioavailability in adolescent idiopathic scoliosis: an important new finding.

STUDY DESIGN: This was a cross-sectional study. OBJECTIVE: The present study aimed to explore the differences in leptin bioavailability between adolescent idiopathic scoliosis (AIS) and healthy age-matched girls in a Chinese Han population. SUMMARY OF BACKGROUND DATA: AIS is a common spinal deformity mainly occurring in girls during the peripubertal period. The development of scoliosis is related to relative anterior spinal overgrowth. AIS girls also have associated lower body mass index (BMI) and lower bone mineral status. Leptin, together with soluble leptin receptor (sOB-R), was shown to play an important role in the regulation of bone and energy metabolism in children. It was hypothesized that leptin and sOB-R are abnormal and associated with deranged growth and anthropometric phenotypes in AIS girls. METHODS: Serum leptin and sOB-R were measured together with documentation of anthropometric parameters and clinical data in 95 AIS girls and 46 healthy matched controls (age 11-16 years). Serum leptin and sOB-R concentrations were measured by enzyme-linked immunosorbent assay and correlated with the different measured parameters. RESULTS: AIS girls had significantly lower BMI and longer arm span than healthy controls. AIS girls were found to have significantly higher sOB-R levels and lower free leptin index (FLI) after adjusting for age and body weight in multivariate regression analysis. Significant correlation was found between sOB-R, FLI, and curve severity in AIS girls. CONCLUSION: This is the first study demonstrating the presence of abnormal leptin bioavailability in AIS girls that might play an important role in the etiopathogenesis of AIS. Further investigation is required to provide a better understanding of the underlying mechanisms, with the aim to explore the potential clinical application as a biomarker for predicting curve initiation or progression in AIS.

Restoration of longitudinal growth by bioengineered cartilage pellet in physeal injury is not affected by low intensity pulsed ultrasound.

Physeal fracture is a common pediatric fracture that would result in premature physeal closure in long bones, and there is currently no gold standard for its management. In this study, we investigated the application of a Bioengineered Cartilage Pellet (BCP) in repairing a rabbit physeal fracture model, and the possible effects of Low Intensity Pulsed Ultrasound (LIPUS) treatment. Rabbits with physeal fracture created were assigned to the NC group (no BCP, no LIPUS), GC group (BCP, no LIPUS), and GT group (BCP and LIPUS). Femoral lengths and cartilage area were assessed at 4, 8, and 16 weeks post-defect. After transplantation, the BCP showed continuous growth in the host and demonstrated resemblance to a natural growth plate. The GC group showed 34.1, 32.1, and 41.1% advantage in lengthening over the NC group and the GT group showed 51.1, 41.6, and 26.9% improved lengthening than the NC group, at 4 (p = 0.203), 8 (p = 0.543) and 16 weeks (p = 0.049), respectively. Cartilage area was shown to be significantly higher in GC and GT group compared to NC group (p < 0.05). No significant difference was found between GC and GT group. Femoral longitudinal growth was shown to be improved by the BCP, however no additional enhancement effect was shown to be provided by LIPUS.

Use of allogeneic scaffold-free chondrocyte pellet in repair of osteochondral defect in a rabbit model.

Cell-based therapies are currently being used in treating osteochondral defect (OCD), but technical advances are needed to tackle the problems of scaffold and grafting technique. This study aimed to test the potential of allogeneic scaffold-free bioengineered chondrocyte pellet (BCP) in treating OCD. BCP was fabricated from rabbit costal cartilage and implanted into 3 mm × 3 mm OCD in medial femoral condyle of 20 rabbits. Samples were harvested at 2, 4, 8, and 16 weeks for histology, histological scoring and histomorphometric analysis. At treated side, cartilage score was significantly better at week 4 (p = 0.027), and cartilage thickness measured in histomorphometric analysis was significantly thicker at week 4 (p = 0.028) and week 16 (p = 0.028) compared to the empty controls. At treated side, bone score remained significantly lower from week 8 onwards (p = 0.024 at week 8, p = 0.02 at week 16) whereas bone area was significantly smaller from week 4 onwards compared to the empty controls (p = 0.028 at week 4, 8, 16). No immunorejection was observed throughout the experiment. The results demonstrated that the BCP enhanced cartilage repair at early stage. Press-fitting of allogeneic BCP was a simple method for OCD repair without immunorejection. Further optimization of the treatment is required before clinical application.

Impaired bone healing pattern in mice with ovariectomy-induced osteoporosis: A drill-hole defect model.

OBJECTIVE: To establish a drill-hole defect model in osteoporotic mouse femur by comparing temporal cortical bone healing pattern between OVX-induced osteoporotic bone and sham-operated bone. METHODS: 3-month-old female C57BL/6 mice were randomly divided into an ovariectomy group (OVX) and a sham-operated group (Sham). At 6 weeks post-surgery, 7 mice from each group were sacrificed to examine the distal femur and femoral shaft by both micro-CT and mechanical testing for confirming established osteoporosis induced by OVX. In the remaining mice, a cortical bone defect 0.8mm in diameter was created on the mid-diaphysis of the right femur. The local repair process at days 0, 3, 7, 10, 14 and 21 after creation of the drill-hole was in vivo monitored by high-resolution micro-CT scanning. At each time point, each animal was scanned four times and was removed from the scanner between scans to determine reproducibility. Mice were sacrificed at each time point (n=12 at days 0, 3, 7, 10 and 14; n=20 at day 21). Before sacrifice, sera were collected to examine expression of bone formation marker P1NP (procollagen type I N-terminal propeptide) and bone resorption marker CTX (C-terminal telopeptide of type I collagen). After sacrifice, callus samples were collected and subjected to the following analyses: micro-CT-based angiography; histological examination; immunohistochemical staining to determine estrogen receptor expression; quantitative real-time PCR analysis of collagen type I, collagen type II, collagen type X, osteocalcin, tartrate-resistant acid phosphatase, estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) gene expression; and three-point mechanical testing. RESULTS: At 6 weeks post-surgery, OVX mice had significantly lower bone mass, impaired bone micro architecture and compromised mechanical properties compared to the Sham mice. In vivo micro-CT analysis revealed that the bone volume fraction in the defect region was significantly lower in the OVX group from day 10 to day 21 post-injury as compared to the Sham group, and was significantly lower in the intra-medulla region in the OVX group from day 7 to day 14 as compared to the Sham group, consistent with the histological data. Analysis of bone biochemical markers indicated that circulating P1NP levels normalized by baseline in the OVX mice were significantly lower than in the Sham mice from day 7 to day 10, and that temporal expression of circulating CTX levels normalized by baseline was also lower in the OVX mice as compared to the Sham mice. These results were consistent with quantitative real-time PCR analysis. ER alpha mRNA expression was significantly lower in the OVX mice, whereas ER beta mRNA expression was significantly higher in the OVX mice as compared to the Sham mice at all time points examined, consistent with immunohistochemical staining. The restoration of femoral mechanical property, determined based on ultimate load and energy-to-failure, was significantly lower in the OVX mice than in the Sham mice. In addition, in vivo micro-CT scanning for quantifying new bone formation in the defect site was highly reproducible in this model. CONCLUSION: The bone healing of the drill-hole defect was impaired in mice with OVX-induced osteoporosis. The present study provides a model to investigate the functional role of specific gene in osteoporotic bone healing and may facilitate development of novel therapeutic strategies for promoting osteoporotic bone healing.

Low-intensity pulsed ultrasound enhances posterior spinal fusion implanted with mesenchymal stem cells-calcium phosphate composite without bone grafting.

STUDY DESIGN: Experimental study on the effect of low-intensity pulsed ultrasound (LIPUS) on rabbit spinal fusion with mesenchymal stem cell (MSC)-derived osteogenic cells and bioceramic composite. OBJECTIVE: To investigate the efficacy of LIPUS in enhancing fusion rate and bone formation with porous tricalcium phosphate (TCP) bioceramic scaffold impregnated with MSCs without any bone grafts. SUMMARY OF BACKGROUND DATA: The goal of spinal fusion in the corrective spinal surgery for spinal deformities is to achieve solid bony fusion between selected vertebral segments. Previous studies with bone morphogenetic proteins and genetically manipulated materials revealed significant difficulties in actual clinical application. Alternative such as LIPUS has been shown to be effective in enhancing healing of fracture and nonunion clinically. Its potential for enhancing spinal fusion warrants further in-depth study. METHODS: Posterolateral intertransverse processes spinal fusion at the L5 and L6 levels were evaluated in New Zealand white rabbit model. The animals were divided into three groups with (A) TCP alone, (B) TCP with differentiated MSCs, and (C) TCP with differentiated MSCs and LIPUS treatment. At week 7 postoperation, manual palpation, peripheral quantitative computed tomography, and histomorphometric assessments were performed. RESULTS: At week 7 postoperation, a statistically significant increase in clinical fusion by manual palpation was observed in group C animals treated with LIPUS (86%) in comparing with groups A (0%) and B (14%) without LIPUS. With peripheral quantitative computed tomographic analysis, the bone volume of group C fusion mass was significantly larger than the other two groups. Group C fusion also had better osteointegration length between host bone and implanted composite and more new bone formed in the TCP implants. Importantly, all the group C animals had osteochondral bridging--early stage of bony fusion histologically. Endochondral ossification was observed at the junction between the cartilaginous and osseous tissues at the intertransverse processes area. Quantitative analysis showed that the fusion mass in group C had significantly smaller gap and larger area of cartilaginous tissue between the transverse processes. CONCLUSION: The present study showed that the combination of synthetic biomaterials, autologous differentiated MSCs, and LIPUS could promote clinical fusion in rabbit posterior spinal fusion model. The mechanism was likely to be mediated through better osteointegration between the host bone and implanted materials and enhanced endochondral ossification at the fusion site.

Abnormal bone quality in adolescent idiopathic scoliosis: a case-control study on 635 subjects and 269 normal controls with bone densitometry and quantitative ultrasound.

STUDY DESIGN: A case-control study comparing bone quality in Adolescent Idiopathic Scoliosis (AIS) with normal controls. OBJECTIVE: To evaluate bone quality with quantitative ultrasound (QUS) in AIS and normal controls so as to detect any derangement in bone quality among AIS subjects. SUMMARY OF BACKGROUND DATA: AIS is characterized by complex spinal deformities. Despite its high prevalence and clinical impact in adolescents, etiology of AIS remains unknown but one possible mechanism is related to derangement of bony mechanical stability, as quantified by bone mineral density (BMD) and bone quality. AIS is known for its association with osteopenia, but little is known about the bone quality in AIS. With technological advancement, QUS can provide objective measurement of bone quality. In this study, we sought to compare bone quality in AIS with normal controls using QUS in addition to the conventional BMD measurement. METHODS: Six hundred thirty-five AIS girls and 269 age-matched normal girls were investigated. Broadband ultrasound attenuation (BUA), velocity of sound (VOS), and stiffness index (SI) were measured over the nondominant calcaneus using QUS. The results were correlated with anthropometric measurement, radiologic assessment, and BMD of both hips. RESULTS: The z-score of BMD at the femoral neck of AIS subjects (-0.47 ± 0.97) was significantly lower than that of normal controls (-0.12 ± 1.01, P < 0.001). Crude comparison showed that BUA, VOS, and SI of AIS group were 3.8% (P < 0.01), 0.5% (P = 0.042), and 6.9% (P < 0.01) lower than controls, respectively. After controlling confounding from maturity, body weight, body height, and BMD with multiple linear regression analysis for both mild (Cobb's angle ≤ 25°) and severe (Cobb's angle > 25°) curves, BUA and SI were found to be statistically significantly lower in AIS as compared with controls (P < 0.05). CONCLUSION: In addition to higher prevalence of osteopenia, AIS patients were also found to have deranged bone quality. These might contribute to the etiopathogenesis of spinal deformities in AIS.