Vivian Wing-Yin Hung

Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis.

Study Design. A genetic association study to comprehensively investigate variations of melatonin receptor 1B gene polymorphism by a set of tagging single nucleotide polymorphisms (tagSNPs) derived from the International Hapmap project. Objectives. To determine whether melatonin receptor 1B (MTNR1B) gene polymorphisms are associated with the predisposition and/or disease severity of adolescent idiopathic scoliosis (AIS). Summary of Background Data. Linkage studies suggested a genetic predisposition for AIS. In addition, evidence showed that AIS might be related to melatonin deficiency and dysfunction of melatonin signaling pathway. Locating in one of the chromosomal regions linked to AIS, MTNR1B gene is a potential candidate gene for AIS. Methods. This study was carried out in 2-stage case-control analysis: 1) initial screening (472 cases and 304 controls) and 2) separate replication test (342 cases and 347 controls) to confirm results in the screening. In the first screening stage, 5 tagSNPs were selected to cover most of the genetic variation in the MTNR1B gene. In the second stage, SNPs showing association in the screening stage were studied in a separate replication sample set to confirm the association. Genotyping was performed by PCR-RFLP. Results. The first stage showed a putative association between rs4753426 and AIS, which was confirmed in the replication sample set. By meta-analysis, the frequency of C allele of this SNP locating in the promoter was significantly higher in the cases than controls (P = 0.006 aftermeta-analysis). Subjects with the CC genotype had an odds ratio of 1.29 for AIS. Another SNP rs741837 in promoter region, being moderate linkage disequilibrium with rs4753426, was also marginally associated with AIS. Conclusion. Polymorphisms of the promoter of MTNR1B gene were associated with AIS, but not with the curve severity in AIS patients. This suggested that MTNR1B was an AIS predisposition gene.

A Relook Into the Association of the Estrogen Receptor α Gene (PvuII, XbaI) and Adolescent Idiopathic Scoliosis : A Study of 540 Chinese Cases

Study Design. A genetic association study of estrogen receptor-α gene (ESR1) with adolescent idiopathic scoliosis (AIS) in Chinese. Objectives. To investigate whether: 1) PvuII and XbaI polymorphisms in ESR1 are predisposition factor for AIS and 2) these polymorphisms correlate with the severity of curvature in AIS. Summary of Background Data. A common single nucleotide polymorphism (SNP) in ESR1 (XbaI) was found to be associated with curve severity in Japanese AIS patients recently. The role of ESR1 as a predisposition gene using a case-control design in other ethnic groups is required to confirm the previous associations. Methods. A total of 540 Chinese AIS girls with Cobb angle above 20° were recruited as cases together with 260 healthy controls. The effect of ESR1 SNPs on severity of scoliosis was analyzed in a subgroup of AIS patients (n = 364) followed up until skeletal maturity with the maximum Cobb angle recorded. Two SNPs in ESR1 were genotyped by PCR-restriction fragment length polymorphism in all subjects. Results. The allelic frequency of X allele was 23% in both case and control groups. The P allele was found at allelic frequency of 40% and 36% in the case and control groups, respectively. No association between the two ESR1 SNPs and the occurrence of AIS by both genotype and haplotype analysis could be established, suggesting that both SNPs were not predisposition alleles for AIS. AIS patients with different genotypes showed no difference in the maximum Cobb angle. No association was found between the genotype and anthropometric measurements in AIS patients. Conclusion. The previously reported association with curve severity could not be replicated in our large series of Chinese AIS patients. The current study also did not show any association of the 2 SNPs with increased risk of having AIS.

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 (Cobbs angle ⩽ 25°) and severe (Cobbs 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.

Bone Microarchitecture Assessment by High-Resolution Peripheral Quantitative Computed Tomography in Patients with Systemic Lupus Erythematosus Taking Corticosteroids

Objective. We assessed the relationship between vertebral fracture and bone microarchitecture in patients with systemic lupus erythematosus (SLE) on chronic corticosteroid therapy using high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods. Fifty-nine Chinese women with SLE taking corticosteroid were selected to participate in a cross-sectional study. Vertebral fracture was confirmed semiquantitatively by lateral radiographs of the thoracic and lumbar spine. Density and microarchitecture at the distal radius were measured with HR-pQCT. Areal bone mineral density (aBMD) at hip and lumbar spine was measured by dual-energy x-ray absorptiometry (DEXA). Results. Twelve patients had vertebral fractures. The aBMD of spine or hip did not differ between those with and without vertebral fractures. Measures by HR-pQCT revealed that patients with vertebral fractures had significantly lower level of average bone density (p = 0.007), cortical bone density (p = 0.029), trabecular bone density (p = 0.024), trabecular bone volume to tissue volume (p = 0.023), and trabecular thickness (p = 0.011) than those without vertebral fractures. Independent explanatory variables associated with higher risk of vertebral fractures were older age (p = 0.013) and lower average cortical bone density (p = 0.029). Conclusion. Vertebral fracture in patients with SLE on chronic corticosteroid treatment was associated with alterations of bone density and microarchitectures measured by HR-pQCT and DEXA. However, alterations were more pronounced in measurements by HR-pQCT. Low cortical bone density and old age were significant predictors of vertebral fracture risk.

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.

Alterations of Bone Density, Microstructure, and Strength of the Distal Radius in Male Patients With Rheumatoid Arthritis: A Case-Control Study With HR-pQCT

In this cross‐sectional study, we investigated volumetric bone mineral density (vBMD), bone microstructure, and biomechanical competence of the distal radius in male patients with rheumatoid arthritis (RA). The study cohort comprised 50 male RA patients of average age of 61.1 years and 50 age‐matched healthy males. Areal BMD (aBMD) of the hip, lumbar spine, and distal radius was measured by dual‐energy X‐ray absorptiometry. High‐resolution peripheral quantitative computed tomography (HR‐pQCT) of the distal radius provided measures of cortical and trabecular vBMD, microstructure, and biomechanical indices. aBMD of the hip but not the lumbar spine or ultradistal radius was significantly lower in RA patients than controls after adjustment for body weight. Total, cortical, and trabecular vBMD at the distal radius were, on average, –3.9% to –23.2% significantly lower in RA patients, and these differences were not affected by adjustment for body weight, testosterone level, or aBMD at the ultradistal radius. Trabecular microstructure indices were, on average, –8.1% (trabecular number) to 28.7% (trabecular network inhomogeneity) significantly inferior, whereas cortical pore volume and cortical porosity index were, on average, 80.3% and 63.9%, respectively, significantly higher in RA patients. RA patients also had significantly lower whole‐bone stiffness, modulus, and failure load, with lower and more unevenly distributed cortical and trabecular stress. Density and microstructure indices significantly correlated with disease activity, severity, and levels of pro‐inflammatory cytokines (interleukin [IL] 12p70, tumor necrosis factor, IL‐6 and IL‐1β). Ten RA patients had focal periosteal bone apposition most prominent at the ulnovolar aspect of the distal radius. These patients had shorter disease duration and significantly higher cortical porosity. In conclusion, HR‐pQCT reveals significant alterations of bone density, microstructure, and strength of the distal radius in male RA patients and provides new insight into the microstructural basis of bone fragility accompanying chronic inflammation.

Repair of Bone Erosion in Rheumatoid Arthritis by Denosumab: A High-Resolution Peripheral Quantitative Computed Tomography Study

To compare the bone healing effects of denosumab and alendronate in female rheumatoid arthritis (RA) patients by high‐resolution peripheral quantitative computed tomography.

Impaired bone healing in rabbits with steroid-induced osteonecrosis

Corticosteroids are prescribed for the treatment of many medical conditions and their adverse effects on bone, including steroid-associated osteoporosis and osteonecrosis, are well documented. Core decompression is performed to treat osteonecrosis, but the results are variable. As steroids may affect bone turnover, this study was designed to investigate bone healing within a bone tunnel after core decompression in an experimental model of steroid-associated osteonecrosis. A total of five 28-week-old New Zealand rabbits were used to establish a model of steroid-induced osteonecrosis and another five rabbits served as controls. Two weeks after the induction of osteonecrosis, core decompression was performed by creating a bone tunnel 3 mm in diameter in both distal femora of each rabbit in both the experimental osteonecrosis and control groups. An in vivo micro-CT scanner was used to monitor healing within the bone tunnel at four, eight and 12 weeks postoperatively. At week 12, the animals were killed for histological and biomechanical analysis. In the osteonecrosis group all measurements of bone healing and maturation were lower compared with the control group. Impaired osteogenesis and remodelling within the bone tunnel was demonstrated in the steroid-induced osteonecrosis, accompanied by inferior mechanical properties of the bone. We have confirmed impaired bone healing in a model of bone defects in rabbits with pulsed administration of corticosteroids. This finding may be important in the development of strategies for treatment to improve the prognosis of fracture healing or the repair of bone defects in patients receiving steroid treatment.

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.