Elisa M S Tam

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.

A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups

Background Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). Methods Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. Results We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10–43 for rs11190870, and P=2.94×10–48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. Conclusions Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.

Are volumetric bone mineral density and bone micro-architecture associated with leptin and soluble leptin receptor levels in adolescent idiopathic scoliosis?--A case-control study.

Background Adolescent idiopathic scoliosis (AIS) is associated with low bone mineral density (BMD). The underlying etiology and how it may relate to the development of osteopenia remains unknown. Leptin has been postulated as one of the etiologic factors of AIS because of its profound effects on bone metabolism and pubertal growth. Its modulator, soluble leptin receptor (sOB-R), may affect leptin bioavailability and signaling. This study aimed to investigate whether serum leptin and sOB-R levels may be associated with bone quality, and whether these relationships may differ between young adolescent girls with and without AIS. Methods This was a case-control study involving 94 newly diagnosed AIS girls (Cobb angle 12–48°) aged 12 to 14 years old and 87 age and gender-matched normal controls. Subjects with BMI>23.0 Kg/m2 were excluded. Anthropometric measurements including body weight, height, arm span and sitting height were taken. Serum total leptin and sOB-R were assayed with ELISA. Non-dominant distal radius was scanned with High Resolution pQCT for assessing bone quality in terms of bone morphometry, volumetric BMD (vBMD) and trabecular bone micro-architecture. Results Compared with normal controls, AIS girls had numerically higher sOB-R (p = 0.006), lower average vBMD (p = 0.048), lower cortical vBMD (p = 0.029), higher cortical bone perimeter (p = 0.014) and higher trabecular area (p = 0.027), but none remained statistically significant after the Hochberg-Benjamini procedure. Correlation analysis on serum leptin level indicated that distinctive correlations with trabecular bone parameters occurred only in AIS. Conclusion This study showed that bone quality in AIS girls was deranged as compared with controls. In addition, the distinct differences in correlation pattern between leptin and trabecular bone parameters indicated possible abnormalities in bone metabolism and dysfunction of the leptin signaling pathway in AIS.

Lower Muscle Mass and Body Fat in Adolescent Idiopathic Scoliosis Are Associated With Abnormal Leptin Bioavailability.

Study Design. This was a case-control study. Objective. This study aimed to investigate the body composition and its correlation with leptin and soluble leptin receptor (sOB-R) levels in girls with adolescent idiopathic scoliosis (AIS) and compared with healthy controls. Summary of Background Data. Patients with AIS are associated with lower body weight, taller stature, lower body mass index (BMI), and deranged bone quality. Despite the widely reported lower BMI and body weight in girls with AIS, the body composition of these patients was not thoroughly studied with sufficient sample size. Leptin is an important factor in regulating energy and bone metabolism, and has been postulated as one of the etiologic factors of AIS. Methods. One hundred forty-eight AIS and 116 control girls aged 12 to 14 were recruited. Body composition was measured with bioelectrical impedance analysis. Caloric intake and physical activity level were assessed by food frequency and Baecke questionnaires respectively. Serum total leptin and sOB-R levels were measured with enzyme-linked immunosorbent assay, and free leptin index was calculated. Results. AIS girls had lower body weight and BMI, other anthropometric and sexual maturity parameters were comparable with controls. There were no difference in caloric intake and physical activity levels. After adjustment for physical activity level, AIS girls had lower skeletal muscle mass, lower body fat, and %body fat. Higher sOB-R and lower free leptin index were found in AIS girls after adjusted for age and body weight. Weaker correlations between serum total leptin, FLI, and body composition parameters were observed in AIS girls. Conclusion. Results suggested that the lower body weight in AIS girls was contributed by both lower skeletal muscle mass and lower body fat. Altered leptin bioavailability also exists in AIS girls and could lead to lower body weight, lower BMI, and abnormal body composition that were manifested in AIS simultaneously. Level of Evidence: 4

Bone Metabolism in AIS

Adolescent idiopathic scoliosis (AIS) occurs in children during their pubertal growth spurt. Rapid skeletal growth and abnormal anthropometric parameters are associated with the development and progression of scoliotic curves, with the curves stabilized when skeletal maturity is reached. Systemic osteopenia affecting multiple skeletal sites, defined as bone mineral density (BMD) of Z-score ≤ −1 with reference to the age and ethnic-matched population, was found by dual-energy X-ray absorptiometry (DXA) in over 30% of the AIS patients. The osteopenia could persist into adulthood, thus predisposing the AIS patients to osteoporosis and other related complications in later life. Osteopenia in AIS was shown to be an important prognostic factor for curve progression. Recent studies with advanced high-resolution peripheral quantitative computed tomography (HR-pQCT) revealed significant alterations in systemic bone geometry, micro-architecture, volumetric BMD, and mechanical bone strength (finite element analysis) in addition to osteopenia in AIS. Serological and cellular functional studies supported the presence of abnormal bone formation and resorption that might have contributed to the abnormal bone qualities and bone strength which could be linked to the etiopathogenesis of AIS. Physical activities, calcium and vitamin D intake, and genetics are important factors affecting bone mass in AIS. Recent RCT studies on whole-body vibration therapy and supplement therapy with calcium and vitamin D have shown to improve low bone mass in AIS significantly. A better understanding on the possible association between bone qualities and curve progression will shed light on future development of novel prognostic biomarkers and therapeutic strategies in AIS.