Introduction. The etiology of adolescent idiopathic scoliosis (AIS) is largely unknown. AIS was well-documented to be associated with low bone mineral density (BMD) and abnormal bone quality. We hypothesized that bone matrix mineralization is abnormally low in AIS and that the abnormality could lead to the observed osteopenia and abnormal bone quality that might contribute to the etiopathogenesis of AIS. / Objectives. 1. To verify the abnormal bone mass and bone quality in AIS Vs normal matched controls 2. To study the bone matrix mineralization status, micro-architecture and mechanical property in AIS Vs controls 3. To study the cellular and molecular characterization of bone formation and resorption in AIS Vs controls 4. To study the possible association of abnormal bone quality with the curve progression / Methods. 1. The case-control study in Chapter 3 included 257 AIS and 187 age- and gender-matched normal controls. BMD and bone quality were measured with dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) in vivo. 2. Chapter 4 studied iliac crest bone biopsies from 28 AIS and 9 controls. Bone mineral status was measured with DXA, micro-computed tomography (micro-CT) and energy dispersive X-ray spectroscopy; bone micro-architecture and mechanical property were measured with micro-CT, individual trabeculae segmentation analysis and finite element analysis (FEA). 3. Chapter 5 included 46 AIS and 23 controls. The mRNA expression of the bone tissue and primary osteoblastic and osteoclastic activities related to bone mineralization were studied. 4. Chapter 6 included 82 AIS patients. Bone quality was measured with HR-pQCT in vivo at baseline. Comparison was made between the stable and the progressive patients followed for more than 1.5 years after skeletal maturity. / Results. 1. In Chapter 3, both osteopenic and non-osteopenic AIS had lower areal BMD (aBMD) and trabecular and cortical volumetric BMD (vBMD) than their matched normal controls, with the non-osteopenic AIS reaching statistical significance (P<0.05). Osteopenic AIS had larger cortical perimeter and trabecular area than the osteopenic controls after adjustments of confounding factors (P<0.05); non-osteopenic AIS had significantly lower cortical area, thickness and vBMD than the non-osteopenic controls (P<0.05), and marginally significant cortical area and thickness after adjustments. 2. In Chapter 4, AIS had lower bone calcium content (Ca/C ratio) in trabecular bone than controls (P<0.05); moreover, AIS had significantly lower trabeculae rod number and thickness and mechanical property (P<0.05). Osteopenic AIS had significantly lower rod and plate micro-architecture (P<0.05) and 11.3% of decline of FEA mechanical property than non-osteopenic AIS. 3. In Chapter 5, AIS had lower expression of osteogenic markers (ALP and RUNX2) (P=0.009-0.132) and higher expression of extracellular matrix markers (COL1 and BGLAP) (P =0.109-0.132) in bone formation, and higher expression of bone resorption markers (TRAP and CTSK) (P =0.045-0.100). AIS also showed lower osteogenic differentiation potential and calcium nodule formation ability than controls. Within the subgroups, osteopenic AIS showed lower osteoblastic differentiation (P=0.009) and 41.8% decline of calcium formation abilities (P =0.186). The primary osteoblasts from the osteopenic AIS had higher pro-osteoclastogenic potential (P =0.034) and higher osteoclastogenic differentiation potential on osteoclasts. 4. In Chapter 6, progressive AIS had significantly lower aBMD, total vBMD and lower cortical area and thickness after adjustments (P<0.05). The predictive model showed that bone quality model was more predictive than the aBMD model which was more predictive than the basic model on curve progression. / Discussions The present study verified all the AIS had lower BMD and abnormal bone quality. It provided a direct evidence of lower calcium content in AIS which might contribute to the observed lower BMD. Therefore, these abnormalities in AIS could represent a spectrum of severity which is labeled as osteopenic or non-osteopenic with DXA and partly explained by the cellular and molecular studies. The longitudinal study showed AIS with poorer bone quality have significantly higher probability of curve progression. In summary, the present findings supported and confirmed our proposed hypothesis. / 引言：有研究提示AIS低骨量與骨質量異常與病因學有關。我們推測，AIS的骨基質礦化可能異常降低，進而導致低骨量和異常骨質量發生，這可能與AIS病因学有關。 / 目的：1. 驗證AIS的低骨量及骨質量異常 2. 调查AIS骨基質礦化、骨微結構和機械性能狀態 3. 研究AIS關於骨礦化的細胞分子功能 4. 探讨AIS骨質量與側彎進展間的關聯 / 方法：1. 通過雙能吸收儀和高分辨率外周定量CT比较低骨量和非低骨量AIS与其正常對照間骨密度和骨質量的差异 2. 通過雙能吸收儀、顯微CT和掃描電鏡與能量色散光譜儀檢測骨礦物質含量，及顯微CT、骨小梁個體分割和有限元分析法檢測骨微結構和力學性能，比較AIS和正常對照及AIS亞組間的差異。3. 通過檢測與骨礦化相關的mRNA，和原代成骨和破骨細胞培養，比較AIS和正常對照及AIS亞組間的差異。4. 通過高分辨率外周定量CT縱向隨診AIS患者，比較進展組和穩定組間骨質量差異。 / 結果：1. 低骨量和非低骨量AIS均比正常對照組骨密度和骨質量降低。2. AIS骨鈣含量降低，骨微結構和機械性能顯著異常。3. AIS骨形成標記物降低、骨吸收標記物升高，成骨分化潛能降低。低骨量AIS比非低骨量AIS成骨細胞分化能力降低和親破骨分化潛能升高。4. 側彎進展AIS骨密度和骨質量顯著異常。 / 討論：本研究結果支持我們的假設：AIS骨基質礦化異常，導致低骨量和異常骨質量，提示與AIS發病機理相關聯。 / Wang, Zhiwei. / Thesis Ph.D. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 243-261). / Abstracts also in Chinese; appendixes includes Chinese. / Title from PDF title page (viewed on 09, September, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Yim, Po Yee Annie. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 166-219). / Abstracts in English and Chinese. / Acknowledgements --- p.ii / Abstract --- p.iv / Abbreviations --- p.xi / Table of Content --- p.xiii / List of Figures --- p.xviii / List of Tables --- p.xxi / Major Conference Presentations --- p.xxiii / Publication in Preparation --- p.xxvi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General Overview of Adolescent Idiopathic Scoliosis (AIS) --- p.2 / Chapter 1.2 --- Natural History --- p.3 / Chapter 1.3 --- Current Treatments --- p.5 / Chapter 1.3.1 --- Non-operative Treatments --- p.5 / Chapter 1.3.2 --- Surgical Treatments --- p.6 / Chapter 1.4 --- Current Hypothesis on the Etiology of AIS --- p.8 / Chapter 1.4.1 --- Genetic Factors --- p.8 / Chapter 1.4.2 --- Neuromuscular Impairment --- p.10 / Chapter 1.4.3 --- Abnormalities in Skeletal Development --- p.11 / Chapter 1.4.4 --- Metabolic Dysfunction --- p.12 / Chapter 1.4.4.1 --- Lower Bone Mineral Density --- p.12 / Chapter 1.4.4.2 --- Delayed Sexual Maturity --- p.14 / Chapter 1.4.4.3 --- Hormonal Dysfunction --- p.14 / Chapter 1.5 --- Skeletal arid Spinal Growth in AIS --- p.16 / Chapter 1.5.1 --- Abnormal Growth during Puberty --- p.16 / Chapter 1.5.2 --- Growth Pattern --- p.17 / Chapter 1.5.3 --- Disproportional Growth in AIS --- p.18 / Chapter 1.5.4 --- Asymmetric Growth --- p.20 / Chapter 1.6 --- Melatonin and its Receptor --- p.22 / Chapter 1.6.1 --- Introduction --- p.22 / Chapter 1.6.2 --- Melatonin Receptor --- p.24 / Chapter 1.6.3 --- Melatonin's Role in t h e Skeletal System --- p.25 / Chapter 1.6.4 --- Melatonin-Deficient Scoliotic Animal Model --- p.27 / Chapter 1.6.5 --- Melatonin and AIS --- p.29 / Chapter 1.6.5.1 --- Melatonin Level in AIS --- p.30 / Chapter 1.6.5.2 --- Melatonin Receptor in AIS --- p.30 / Chapter Chapter 2 --- Hypothesis and Objectives --- p.39 / Chapter 2.1 --- Study Hypothesis --- p.40 / Chapter 2.2 --- Objectives --- p.41 / Chapter Chapter 3 --- Abnormal skeletal growth patterns in adolescent idiopathic scoliosis - A longitudinal study till skeletal maturity --- p.42 / Chapter 3.1 --- Introduction --- p.43 / Chapter 3.2 --- Methodology --- p.44 / Chapter 3.2.1 --- Recruitments of Subjects --- p.44 / Chapter 3.2.1.1 --- Patients with AIS --- p.44 / Chapter 3.2.1.2 --- Normal Controls --- p.44 / Chapter 3.2.1.3 --- Patients Consents --- p.45 / Chapter 3.2.2 --- Anthropometric Measurements --- p.45 / Chapter 3.2.3 --- Data Analysis --- p.46 / Chapter 3.2.3.1 --- Cross-sectional Study --- p.46 / Chapter 3.2.3.2 --- Longitudinal Study --- p.46 / Chapter 3.3 --- Results --- p.47 / Chapter 3.3.1 --- Cross-sectional Study of Anthropometric Measurements --- p.47 / Chapter 3.3.2 --- Longitudinal Study of Anthropometric Measurements --- p.48 / Chapter 3.3.2.1 --- Comparison Adjusted for Chronological Age --- p.49 / Chapter 3.3.2.2 --- Comparison Along Year Since Menarche (YSM) --- p.49 / Chapter 3.4 --- Discussion --- p.51 / Chapter Chapter 4 --- Establishment of a Melatonin-Deficierit Induced Scoliotic Model with Locally Bred Chicken --- p.63 / Chapter 4.1 --- Introduction --- p.64 / Chapter 4.2 --- Methodology --- p.67 / Chapter 4.2.1 --- Animals --- p.67 / Chapter 4.2.2 --- Materials and Reagents --- p.67 / Chapter 4.2.3 --- Pinealectomy --- p.68 / Chapter 4.2.4 --- Confirmation of Pineal Gland Removal --- p.69 / Chapter 4.2.5 --- Development of Scoliosis --- p.69 / Chapter 4.2.6 --- Measurement of Long Bone Growth --- p.70 / Chapter 4.2.7 --- Measurement of Weight --- p.71 / Chapter 4.2.8 --- Measurement of Bone Mineral Density (BMD) --- p.71 / Chapter 4.2.8.1 --- Micro Computed Tomography (MicroCT) --- p.71 / Chapter 4.2.8.2 --- Image Processing and Evaluation of BMD --- p.71 / Chapter 4.2.9 --- Data Analysis --- p.72 / Chapter 4.2.9.1 --- Measurements of Long Bone Growth and Weight --- p.72 / Chapter 4.2.9.2 --- Bone Mineral Density --- p.72 / Chapter 4.3 --- Results --- p.73 / Chapter 4.3.1 --- Confirmation of Pineal Gland Removal --- p.73 / Chapter 4.3.2 --- Occurrence of Scoliosis --- p.73 / Chapter 4.3.3 --- Measurements of Long Bone and Weight --- p.74 / Chapter 4.3.4 --- Measurement of Bone Mineral Density --- p.75 / Chapter 4.4 --- Discussion --- p.76 / Chapter Chapter 5 --- Expression of Melatonin Receptor in AIS and Control --- p.102 / Chapter 5.1 --- Introduction --- p.103 / Chapter 5.2 --- Methodology --- p.105 / Chapter 5.2.1 --- Subjects Recruitments --- p.105 / Chapter 5.2.2 --- Cell Isolation --- p.106 / Chapter 5.2.2.1 --- Bone Biopsies for Osteoblasts Isolation --- p.106 / Chapter 5.2.2.2 --- Materials and Reagents --- p.106 / Chapter 5.2.2.3 --- Isolation of Osteoblasts from Bone Biopsies --- p.107 / Chapter 5.2.3 --- Expression Level and Pattern of Melatonin Receptors 1A and IB --- p.108 / Chapter 5.2.3.1 --- Materials and Reagents --- p.108 / Chapter 5.2.3.2 --- Validation of Specificities of Antibodies by Co-immunoprecipitation --- p.113 / Chapter 5.2.3.3 --- Quantification of Protein Expression of Melatonin Receptors in Osteoblasts --- p.115 / Chapter 5.2.3.4 --- Quantification of mRNA Expression of Melatonin Receptor in Osteoblast --- p.117 / Chapter 5.2.3.5 --- Localization of Melatonin Receptor 1A and IB by Immunofluorescence Staining --- p.119 / Chapter 5.2.4 --- Evaluation and Correlation of Clinical Phenotypes with Melatonin Receptor Expression --- p.120 / Chapter 5.2.5 --- Data Analysis --- p.120 / Chapter 5.3 --- Results --- p.121 / Chapter 5.3.1 --- Protein Expression of Melatonin Receptor 1A and IB --- p.121 / Chapter 5.3.2 --- mRNA Expression of Melatonin Receptor 1A and IB --- p.121 / Chapter 5.3.3 --- Localization of Melatonin Receptors 1A and IB --- p.122 / Chapter 5.3.4 --- Evaluation and Correlation of Clinical Phenotypes with Melatonin Receptor Expression --- p.123 / Chapter 5.4 --- Discussion --- p.124 / Chapter Chapter 6 --- Summary and Overall Discussion --- p.152 / Chapter 6.1 --- Study Flowchart --- p.153 / Chapter 6.2 --- Summary and Discussion --- p.159 / Chapter 6.3 --- Limitations and Further Studies --- p.163 / Bibliography --- p.166

Cheung Siu-king. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves [103-113]). / Abstracts in English and Chinese. / ACKNOWLEDGMENT --- p.i / TABLE OF CONTENTS --- p.ii / LIST OF ABBREVIATIONS --- p.vi / LIST OF TABLES --- p.vi / LIST OF FIGURES --- p.ix / ABSTRACT (ENGLISH VERSION) --- p.x / ABSTRACT (CHINESE VERSION) --- p.xii / Chapter 1. --- INTRODUCTION --- p.1 / Chapter 1.1. --- ADOLESCENT IDIOPATHIC SCOLIOSIS --- p.1 / Chapter 1.1.1. --- prevalence and geographic patterns of ais --- p.1 / Chapter 1.1.2. --- CLINICAL ASPECTS OF AIS --- p.3 / Chapter 1.1.3. --- ETIOLOGY OF AIS --- p.8 / Chapter 1.2. --- OBJECTIVES OF THIS STUDY --- p.24 / Chapter 2. --- SUBJECTS AND METHODS --- p.25 / Chapter 2.1. --- STUDY DESIGN --- p.25 / Chapter 2.2. --- SUBJECTS RECRUITMENT --- p.25 / Chapter 2.2.1. --- ais subjects --- p.25 / Chapter 2.2.2. --- control subjects --- p.25 / Chapter 2.2.3. --- GROUPING ACCORDING TO THE CHRONOLOGICAL AGE --- p.26 / Chapter 2.2.4. --- informed Consent --- p.26 / Chapter 2.2.5. --- EVALUATION OF COBB'S ANGLE --- p.26 / Chapter 2.3. --- ANTHROPOMETRIC ASSESSMENTS --- p.26 / Chapter 2.4. --- BMD MEASUREMENTS --- p.28 / Chapter 2.4.1. --- measured by dexa --- p.28 / Chapter 2.4.2. --- measured by pqct --- p.30 / Chapter 2.5. --- BONE FORMATION MARKER ： BALP --- p.32 / Chapter 2.5.1. --- SERUM COLLECTION --- p.32 / Chapter 2.5.2. --- ABBOTT METHODS FOR SERUM ALP ACTIVITY --- p.32 / Chapter 2.6. --- BONE RESORPTION MARKER ： DPD --- p.34 / Chapter 2.6.1. --- PYRILINK-D KITS REAGENT --- p.34 / Chapter 2.6.2. --- CREATININE ASSAY --- p.34 / Chapter 2.7. --- GENETIC MARKER - POLYMORPHISM OF ESTROGEN RECEPTOR GENE --- p.38 / Chapter 2.7.1. --- DIGESTION OF PERIPHERAL BLOOD CELLS --- p.38 / Chapter 2.7.2. --- QUANTITATION OF DNA --- p.39 / Chapter 2.7.3. --- CONFIRMATION OF INTEGRITY OF DNA --- p.39 / Chapter 2.7.4. --- POLYMERASE CHAIN REACTION (PCR) --- p.39 / Chapter 2.7.5. --- REACTION BUFFER --- p.39 / Chapter 2.8. --- STATISTICS --- p.45 / Chapter 3. --- RESULTS --- p.46 / Chapter 3 .1 --- SUBJECT DISTRIBUTION OF AIS AND NORMAL CONTROL --- p.46 / Chapter 3.1.1. --- "mean ages of menarche, breast development and pubic hair development" --- p.47 / Chapter 3.1.2. --- "PUBERTAL STATUES OF DIFFERENT AGE GROUPS EVALUATED BY MENARCHE, BREAST DEVELOPMENT AND PUBIC HAIR DEVELOPMENT" --- p.48 / Chapter 3.2. --- ANTHROPOMETRIC ASSESSMENTS --- p.49 / Chapter 3.2.1. --- OVERALL REVIEW OF ANTHROPOMETRIC ASSESSMENTS --- p.49 / Chapter 3.2.2. --- ANTHROPOMETRIC ASSESSMENTS ACCORDING TO THE CHRONOLOGICAL AGE --- p.50 / Chapter 3.3. --- BMD PROFILE OF AIS PATIENTS --- p.51 / Chapter 3.3.1. --- ABMD MEASURED BY DEXA (OVERALL REVIEW) --- p.51 / Chapter 3.3.2. --- ABMD IN DIFFERENT AGE GROUPS --- p.52 / Chapter 3.3.3. --- VBMD MEASURED BY PQCT (OVERALL REVIEW) --- p.52 / Chapter 3.3.4. --- VBMD IN DIFFERENT AGE GROUPS --- p.53 / Chapter 3.3.5. --- PREVALENCE OF OSTEOPENIA IN AIS PATIENTS --- p.53 / Chapter 3.3.6. --- SYMMETRY OF BILATERAL PROXIMAL FEMUR AND DISTAL TIBIA … --- p.54 / Chapter 3.3.7. --- CORRELATION OF ABMD AND VBMD WITH ANTHROPOMETRIC PARAMETERS AND SPINAL DEFORMITY --- p.54 / Chapter 3.4. --- BONE FORMATION MARKER- BALP --- p.55 / Chapter 3.5. --- BONE RESORPTION MARKER -DPD --- p.56 / Chapter 3.6. --- GENETIC MARKER -ESTROGEN RECEPTOR GENE --- p.57 / Chapter 4 --- DISCUSSION…… --- p.84 / Chapter 4.1 --- BONE MINERAL DENSITY OF AIS PATIENTS --- p.84 / Chapter 4.2 --- ANTHROPOMETRIC MEASUREMENTS --- p.89 / Chapter 4.3 --- BONE BIOCHEMICAL TURNOVER MARKER --- p.91 / Chapter 4.4 --- GENETIC MARKER - ER GENE --- p.97 / Chapter 4.4.1 --- OSTEOPORTIC CANDIDATE GENE- ER GENE --- p.98 / Chapter 4.4.2 --- NO CORRELATION BETWEEN ER GENE AND AIS --- p.99 / Chapter 4.5 --- SUMMARY --- p.100 / Chapter 5. --- CONCLUSION --- p.101 / BIBLIOGRAPHY --- p.XIV / APPENDIX --- p.XXV

青少年特發性脊柱側凸(Adolescent Idiopathic Scoliosis, AIS) 是一種脊柱三維結構性畸形，其病因至今未明。它主要出現於11-13歲的青少年女性，其發病率為4%。由於目前此病的臨床治療效果未能盡如人意，因此必須明確其發病機制，以便能夠制定更有效的治療方案及預防措施。 / 既往有研究指出30%AIS患者存在系統性骨密度減低，且已證實骨密度的減少能夠預測其病情進展的情況。之前的研究主要通過傳統的雙能量X光骨質密度吸收儀（DXA）檢測骨密度，其測量結果僅局限於面積骨密度。然而，三維容積骨密度以及骨質微結構的分析對於深入了解患者的骨質量及其與發病機制的聯繫尤為重要。通過現代影像掃描技術發展，使我們可以通過高分辨率外周骨定量X-線斷層掃描儀（HR-pQCT）進行人體骨品質的無創定量檢測。其參數包括骨形態，容積骨密度以及鬆質骨的微結構。 / 本研究分為兩部分，研究目的為： 1）研究AIS患者與年齡，性別匹配的正常青少年骨品質的差異；2）評估及比較在AIS患者及其對照組中骨品質跟骨密度減少之關係。 / 未經治療AIS 患者214例，正常對照組187例，均為11-13歲的女性。 AIS患者及正常對照組均採用DXA掃描評估股骨頸的面積骨密度。此外，所有參加計劃者通過非優勢側橈骨遠端HR-pQCT 掃描，定量測量其骨形態，容積骨密度以及鬆質骨的微結構。 / 第一部分的結果顯示在校正年齡後AIS患者的皮質骨面積(p=0.048)，皮質骨容積骨密度(p=0.014)及鬆質骨骨小樑數目(p=0.003) 低於對照組，並且存在較高的骨小樑分離度(p=0.006)。通過多元線性回歸分析校正了年齡，鈣攝入量及體育活動後，仍顯示AIS患者皮質骨容積骨密度(p=0.032)及鬆質骨骨小樑數目(p=0.005) 顯著低於對照組，骨小樑分離度（p=0.010）顯著高於對照組。而皮質骨週長的比較則未見顯著差異。皮質骨中骨質量的異常提示AIS患者內皮質成骨時可能存在骨礦堆積障礙。並且這種較低的皮質骨面積及容積骨密度預示著較弱的骨機械強度，從而誘發AIS患者脊柱的不隱定以至畸形。此外，AIS中較少的骨小樑數目反映了骨小樑形成的缺陷，這可能是由於患者存在軟骨內成骨及骨礦化的異常調節。 / 在第二部分，根據DXA測量及計算的Z值，參加者被分為骨量偏低組（Z值≤-1)及正常骨量組（Z值>-1)。研究結果顯示，AIS的骨量偏低組與對照組具有顯著差異。通過骨量偏低組及正常骨量組的比較，結果顯示鬆質骨品質與骨量偏低的關係只存在於AIS組中。本研宄發現，在AIS患者中的骨量偏低組存在鬆質骨容積骨密度，骨體積分數顯著減少及骨小梁變薄。並且結果顯示AIS患者骨小梁模型指數（SMI）較大（p<0.001)，提示骨小梁更接近柱收結構，而先前研究已經證明柱狀結構較板狀結構在力學上更不穩定。通常鬆質骨對於代謝及生物力學的改變更加敏感。骨量偏低的AIS患者松質骨中骨品質的異常改變提示AIS患者可能存在骨代謝功能障礙，從而導致異常的骨形成及重塑。鬆質骨中骨微結構的改變可能會引起骨強度的下降，從而導致脊柱在機械力學上的不穩定及側凸進展。因此本研究的重要臨床意義在於需要形成一個融合了骨品質及骨密度相關指標的複合預測因素，在AIS的臨床治療過程中預測側凸進展。 / 此體內研究首次對AIS患者的骨品質進行了報導。研究結果表明AIS患者存在骨品質異常，並且首次提出骨量下降的AIS患者存在鬆質骨的異常改變。骨品質異常的本質和原因及其在AIS的發病機制中的作用值得進一步研究。 / Adolescent Idiopathic Scoliosis is a three-dimensional spinal deformity of unknown etiology. It occurs mainly in girls between 11 to 13-year-old with a prevalence rate of 4%. This common spinal condition can be associated with significant cosmetic and clinical morbidities in severe cases. Since the treatment for AIS remains unsatisfactory, it is imperative to elucidate the etiopathogenesis of AIS so that effective therapeutic and preventive measures can be devised. Towards this end, Cheng et al. investigated and noted that osteopenia was present in 30% of AIS subjects. Osteopenia was found to be a significant prognostic factor for curve progression in AIS. In previous studies, only Dual energy X-ray Absorptiometry (DXA) was available and the measurement was confined to areal-BMD (aBMD). For in-depth understanding of the bone quality and its link to the etiopathogenesis of AIS, three-dimensional volumetric evaluation of bone mass and measurement of key parameters of bone quality would be important. With the advancement of imaging techniques and the availability of high-resolution pQCT (HR-pQCT), it is now possible to have in vivo measurement of bone quality including Bone Morphometry, Volumetric BMD (vBMD) and Trabecular Bone Micro-architecture in human subjects. / The current study utilized HR-pQCT with the following objectives: 1) to investigate bone quality in AIS vs. age- and sex-matched normal controls and 2) to evaluate and compare the correlation of bone quality with osteopenia between AIS and non-AIS control subjects. / 214 untreated AIS and 187 non-AIS healthy girls between 11-13 years old were recruited. aBMD of bilateral femoral necks was measured by DXA. Bone Morphometry, vBMD and Trabecular Bone Micro-architecture were measured at the non-dominant distal radius using HR-pQCT. / In the first part, our findings demonstrated that AIS was associated with lower Cortical Bone Area (p=0.048), Cortical Bone vBMD (p=0.014), Trabecular Number (p=0.003) and greater Trabecular Separation (p=0.006) after adjustment for age. With multivariate linear regression analysis, after adjusted for age, calcium intake and physical activity levels, the association of AIS with lower Cortical Bone vBMD, (p=0.032), Trabecular Number (p=0.005) and greater Trabecular Separation (p=0.010) remained. In contrast, no difference was found in the Cortical Perimeter between AIS and controls. / The abnormalities in cortical bone quality in AIS suggested the possibility of defects in mineral accretion during endocortical apposition. We speculated that lower Cortical Area and vBMD could be associated with reduced bone mechanical strength thus predisposing to the development or progression of spinal deformity in AIS. Furthermore, the association between AIS and lower Trabecular Number reflected a defect in trabecular formation, which might be due to abnormal regulation and modulation of endochondral ossification and bone mineralization in AIS. / In the second part, subjects were classified into the osteopenic (Z-score≤-1) and non-osteopenic (Z-score>-1) group. Interestingly, we found that osteopenia in AIS was distinctly different from osteopenia in non-AIS controls. Alterations in trabecular bone quality in association with osteopenia were only detected in AIS. Osteopenic AIS was uniquely associated with lower Trabecular Bone vBMD, BV/TV, Trabecular Thickness (all p<0.001) and greater SMI (p=0.008) indicating predominance of rod-like trabeculae when compared with non-osteopenic AIS. / The trabecular compartment is generally more vulnerable and responsive to changes in the metabolic and biomechanical environment. The unique alterations of trabecular bone quality in osteopenic AIS suggested the presence of metabolic dysfunction resulting in abnormal modeling and remodeling processes in AIS. These altered trabecular bone micro-architecture might lead to reduced bone strength thus resulting in mechanical weakness of the spine and subsequent curve progression. Another clinical significance of the present study was the call for developing a composite prognostic factor incorporating both BMD and bone quality parameters for more accurate prediction of curve occurrence and progression in AIS in clinical practice. / In conclusion, this is the first series of in vivo studies evaluating bone quality in AIS. Our findings demonstrated abnormal bone quality in AIS and unique alteration of trabecular bone profile in osteopenic AIS. Further studies are warranted to better define the nature, origin and abnormal metabolic pathways and processes leading to the derangement in bone quality and its link to the etiopathogenesis of AIS. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Yu, Wing Sze. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 122-134). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese; appendixes includes Chinese. / ABSTRACT --- p.i / ABSTRACT (in Chinese) --- p.iv / ACKNOWLEDGEMENT --- p.vi / TABLE OF CONTENTS --- p.vii / LIST OF TABLES --- p.x / LIST OF FIGURES --- p.xi / LIST OF ABBREVIATIONS --- p.xii / Chapter Chapter 1 --- INTRODUCTION --- p.1 / Chapter 1.1. --- General overview of scoliosis --- p.1 / Chapter 1.1.1. --- Classification of scoliosis --- p.1 / Chapter 1.1.2. --- Prevalence of AIS --- p.2 / Chapter 1.2. --- Natural History of AIS --- p.3 / Chapter 1.3. --- Curve progression --- p.4 / Chapter 1.4. --- Current treatment modalities --- p.5 / Chapter 1.5. --- Etiology of AIS --- p.6 / Chapter 1.5.1. --- Bone mass and bone development --- p.9 / Chapter 1.5.2. --- Measurement of bone mineral density --- p.10 / Chapter 1.5.3. --- Osteopenia in AIS --- p.11 / Chapter 1.6. --- Bone quality --- p.13 / Chapter 1.6.1. --- Limitation of two-dimensional BMD measurement by DXA --- p.13 / Chapter 1.6.2. --- Bone quality assessment --- p.14 / Chapter Chapter 2 --- METHODOLOGY --- p.22 / Chapter 2.1. --- Research questions and Objectives --- p.22 / Chapter 2.2. --- Study Design --- p.23 / Chapter 2.2.1. --- Study Flowchart --- p.24 / Chapter 2.3. --- Subject Recruitment --- p.29 / Chapter 2.3.1. --- AIS patients --- p.29 / Chapter 2.3.2. --- Normal Controls --- p.29 / Chapter 2.4. --- Patients Consents --- p.30 / Chapter 2.5. --- Radiological Assessment --- p.30 / Chapter 2.5.1. --- Curve severity --- p.30 / Chapter 2.6. --- Anthropometric and pubertal assessments --- p.31 / Chapter 2.6.1. --- Body weight --- p.31 / Chapter 2.6.2. --- Body height --- p.31 / Chapter 2.6.3. --- Arm span --- p.32 / Chapter 2.6.4. --- Sitting height --- p.32 / Chapter 2.6.5. --- Body mass index --- p.32 / Chapter 2.7. --- Menstrual status and pubertal maturity --- p.33 / Chapter 2.8. --- Dietary calcium intake --- p.33 / Chapter 2.9. --- Physical activities --- p.34 / Chapter 2.10. --- Bone mineral density (BMD) measurements --- p.34 / Chapter 2.10.1. --- Areal BMD measured by Dual energy X-ray Absorptiometry (DXA) --- p.34 / Chapter 2.10.2. --- Definition of osteopenia or low bone mass --- p.35 / Chapter 2.11. --- Bone quality assessment --- p.36 / Chapter 2.11.1. --- Positioning --- p.36 / Chapter 2.11.2. --- Standardization of the Region of Interest (ROI) for Scan Acquisition --- p.36 / Chapter 2.11.3. --- Analysis of the Scan Results --- p.38 / Chapter 2.12. --- Statistical analysis --- p.41 / Chapter Chapter 3 --- RESULTS --- p.55 / Chapter 3.1. --- Subject characteristics --- p.55 / Chapter 3.2. --- Age of menarche, breast development and pubic hair development --- p.55 / Chapter 3.3. --- Anthropometric assessment --- p.55 / Chapter 3.4. --- Dietary calcium intake --- p.56 / Chapter 3.5. --- Physical activities --- p.56 / Chapter 3.6. --- aBMD and prevalence of osteopenia in AIS and controls --- p.56 / Chapter 3.7. --- Comparison of bone quality between AIS and controls --- p.57 / Chapter 3.7.1. --- Bone Morphometry --- p.57 / Chapter 3.7.2. --- Volumetric BMD --- p.58 / Chapter 3.7.3. --- Trabecular Bone Micro-architecture --- p.59 / Chapter 3.7.4. --- Short summary --- p.59 / Chapter 3.8. --- Comparison of bone quality Vs. Osteopenia between AIS and Controls --- p.61 / Chapter 3.8.1. --- Demographic characteristic of osteopenic and non-osteopenic AIS and controls --- p.61 / Chapter 3.8.2. --- Bone quality Vs Osteopenia in AIS and controls --- p.62 / Chapter 3.8.3. --- Short summary --- p.64 / Chapter Chapter 4 --- OVERALL DISCUSSION and CONCLUSION --- p.81 / Chapter 4.1. --- Low bone mineral density in AIS --- p.82 / Chapter 4.2. --- Comparison of bone quality between AIS and controls --- p.83 / Chapter 4.2.1. --- Alterations of Cortical Bone Morphometry and vBMD in AIS --- p.84 / Chapter 4.2.2. --- Lower Trabecular Number and greater Trabecular Separation in AIS --- p.88 / Chapter 4.3. --- Correlation between bone quality and osteopenia in AIS Vs normal controls --- p.90 / Chapter 4.3.1. --- Unique alteration of bone quality of trabecular bone in osteopenic AIS subjects --- p.90 / Chapter 4.3.2. --- Effect of the alterations in trabecular bone quality on bone strength in osteopenic AIS and its possible relationship with curve progression --- p.92 / Chapter 4.4. --- Justification of the Methodology --- p.95 / Chapter 4.4.1. --- Site of BMD measurement --- p.95 / Chapter 4.5. --- Summary and clinical significance --- p.97 / Chapter 4.6. --- Limitations and further studies --- p.99 / APPENDIX --- p.101 / BIBLIOGRAPHY --- p.122 / CONFERENCES AND PUBLICATIONS --- p.136

Hung Wing Yin Vivian. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 128-142). / Abstracts in English and Chinese ; appendix in Chinese. / ABSTRACT --- p.i / ABSTRACT (in Chinese) --- p.iv / ACKNOWLEDGMENT --- p.vii / TABLE OF CONTENTS --- p.viii / LIST OF TABLES --- p.xiv / LIST OF FIGURES --- p.xvi / LIST OF ABBREVIATIONS --- p.xix / Chapter I. --- INTRODUCTION --- p.1 / Chapter 1.1. --- Scoliosis --- p.1 / Chapter 1.1.1. --- Classification of scoliosis --- p.1 / Chapter 1.1.2. --- Idiopathic scoliosis --- p.1 / Chapter 1.1.3. --- Clinical examination --- p.2 / Chapter 1.1.4. --- Curve pattern --- p.2 / Chapter 1.2. --- Etiology of AIS --- p.3 / Chapter 1.2.1. --- Prevalence of AIS --- p.5 / Chapter 1.2.2. --- Anthropometric Measurement in AIS --- p.5 / Chapter 1.2.3. --- Bone mass --- p.6 / Chapter 1.2.4. --- Bone mineral density measurements --- p.6 / Chapter 1.2.5. --- Osteopenia in AIS --- p.7 / Chapter 1.3. --- Natural history ofAIS --- p.8 / Chapter 1.3.1. --- Curve progression --- p.9 / Chapter 1.3.2. --- Treatment of scoliosis --- p.11 / Chapter 1.4. --- Research questions --- p.12 / Chapter 1.5. --- Objectives --- p.13 / Chapter II. --- METHODOLOGY --- p.20 / Chapter 2.1 --- Study Design --- p.20 / Chapter 2.2 --- Subject recruitment --- p.20 / Chapter 2.2.1 --- AIS patients --- p.20 / Chapter 2.2.2 --- Inclusion criteria --- p.20 / Chapter 2.2.3 --- Exclusion criteria --- p.20 / Chapter 2.2.4 --- Informed consent --- p.21 / Chapter 2.3 --- Grouping for chronological age --- p.21 / Chapter 2.4 --- Radiography assessments --- p.21 / Chapter 2.4.1 --- Cobb angle measurement --- p.21 / Chapter 2.4.2 --- Curve pattern --- p.22 / Chapter 2.4.3 --- Risser grade --- p.22 / Chapter 2.5 --- Definition of curve progression --- p.22 / Chapter 2.6 --- Bone mineral density (BMD) measurements --- p.23 / Chapter 2.6.1 --- Dual energy X-ray Absorptiometry (DXA) --- p.23 / Chapter 2.6.2 --- Peripheral quantitative computed tomography (pQCT) --- p.24 / Chapter 2.6.3 --- Definition of osteopenia or low bone mass --- p.24 / Chapter 2.7 --- Anthropometric measurements --- p.25 / Chapter 2.7.1 --- Body height --- p.25 / Chapter 2.7.2 --- Body weight --- p.26 / Chapter 2.7.3 --- Arm span --- p.26 / Chapter 2.7.4 --- Sitting height --- p.27 / Chapter 2.8 --- Family history --- p.27 / Chapter 2.9 --- Menstrual status --- p.27 / Chapter 2.10 --- Medication and fracture history --- p.27 / Chapter 2.11 --- Statistical analysis --- p.27 / Chapter 2.11.1 --- Sample size power calculation --- p.28 / Chapter 2.11.2 --- Student t test --- p.28 / Chapter 2.11.3 --- Paired t-test --- p.28 / Chapter 2.11.4 --- Predicting the incidence of curve progression --- p.28 / Chapter 2.11.4.1 --- Predictive outcome --- p.28 / Chapter 2.11.4.2 --- Potential risk factors --- p.28 / Chapter 2.11.4.3 --- Coding system for categorical variables --- p.29 / Chapter 2.11.4.4 --- Univariate analysis --- p.30 / Chapter 2.11.4.5 --- Logistic regression --- p.30 / Chapter 2.11.4.6 --- Receiver operating characteristics (ROC) curves --- p.32 / Chapter III. --- RESULTS --- p.54 / Chapter 3.1 --- Patients Characteristics --- p.54 / Chapter 3.1.1 --- Sample size --- p.54 / Chapter 3.1.2 --- Distribution of patient characteristics --- p.54 / Chapter 3.1.3 --- Drop out --- p.54 / Chapter 3.1.4 --- Prevalence of osteopenia (BMDage-adjusted ≤ -1) and low bone mass (BMCage-adjusted ≤ -1) --- p.55 / Chapter 3.1.5 --- Comparison between the BMD of the bilateral hip and tibia --- p.55 / Chapter 3.2 --- Comparison of AIS patients with osteopenia and with normal bone status --- p.55 / Chapter 3.3 --- Univariate analysis --- p.56 / Chapter 3.3.1 --- Growth related factors --- p.56 / Chapter 3.3.2 --- "Skeletal related parameters (areal BMD, volumetric BMD and BMC)" --- p.56 / Chapter 3.3.2.1 --- DXA lumbar spine --- p.56 / Chapter 3.3.2.2 --- DXA proximal femur at the convex-side hip --- p.56 / Chapter 3.3.2.3 --- DXA proximal femur at the concave-side hip --- p.57 / Chapter 3.3.2.4 --- pQCT at non-dominant distal radius --- p.57 / Chapter 3.3.2.5 --- pQCT - vBMD at convex-side distal tibia --- p.57 / Chapter 3.3.2.6 --- pQCT - vBMD at concave-side distal tibia --- p.58 / Chapter 3.3.3 --- Curve related factors --- p.58 / Chapter 3.3.4 --- Anthropometrics parameters --- p.58 / Chapter 3.3.5 --- Family history --- p.58 / Chapter 3.3.6 --- Summary of univariate analysis --- p.59 / Chapter 3.4 --- Logistic regression model (single factor) --- p.59 / Chapter 3.5 --- Logistic regression model (multiple factors) --- p.60 / Chapter 3.5.1 --- BMD inclusive model --- p.60 / Chapter 3.5.2 --- BMC inclusive model --- p.61 / Chapter 3.5.3 --- Conventional model --- p.63 / Chapter 3.6 --- ROC curve --- p.63 / Chapter 3.6.1 --- BMD inclusive model --- p.64 / Chapter 3.6.2 --- Conventional model --- p.64 / Chapter 3.7 --- Predictive equation obtained from different logistic regression models --- p.64 / Chapter 3.7.1 --- BMD inclusive model --- p.65 / Chapter 3.7.2 --- Conventional model --- p.65 / Chapter IV. --- DISCUSSION --- p.105 / Chapter 4.1 --- Prognostic factors for curve progression --- p.105 / Chapter 4.1.1 --- Well-known prognostic factors --- p.105 / Chapter 4.1.1.1 --- Growth-related factors --- p.106 / Chapter 4.1.1.2 --- Initial curve magnitude --- p.107 / Chapter 4.1.2 --- A new predictor 一 Osteopenia --- p.107 / Chapter 4.2 --- Non-significant prognostic factors for curve progression --- p.109 / Chapter 4.2.1 --- Anthropometric parameters --- p.109 / Chapter 4.2.2 --- Family History --- p.110 / Chapter 4.2.3 --- Curve pattern --- p.110 / Chapter 4.3 --- Predictive model --- p.111 / Chapter 4.4 --- Comparison of predictive models between BMD inclusive model and conventional model derived from our population --- p.115 / Chapter 4.5 --- Possible relationship between osteopenia and etiopathogensis of AIS --- p.116 / Chapter 4.6 --- Axial measurement has a better predictive power in curve progression than peripheral measurement --- p.117 / Chapter 4.7 --- Discordance of BMD in bilateral hips --- p.118 / Chapter 4.8 --- Method justifications --- p.119 / Chapter 4.8.1 --- Definition of curve progression --- p.119 / Chapter 4.8.2 --- Incidence of progression as the outcome of prediction --- p.119 / Chapter 4.8.3 --- Selection on bone densitometers --- p.119 / Chapter 4.9 --- Clinical significance --- p.121 / Chapter 4.10 --- Limitations and Future Studies --- p.122 / Chapter 4.10.1 --- Limited follow-up time --- p.122 / Chapter 4.10.2 --- No defined cutoff value for 226}0´ببosteopenia 226}0ح or low BMC in paediatric area --- p.122 / Chapter 4.10.3 --- Predictive model could only applied in local population --- p.122 / Chapter 4.10.4 --- Intrinsic error in Risser grade measurement --- p.123 / Chapter 4.10.5 --- Further studies --- p.123 / Chapter 4.10.5.1 --- Validation of the newly developed predictive model --- p.123 / Chapter 4.10.5.2 --- Possible intervention of osteopenia --- p.124 / Chapter 4.10.5.3 --- Long term follow-up BMD measurements and fracture risk in AIS patients --- p.124 / Chapter 4.10.5.4 --- Discordance of bilateral hips BMD contributed by the shift of center of gravity --- p.125 / Chapter 4.10.5.5 --- Axial QCT can be an alternative method in assessing BMDin scoliotic patients --- p.125 / Chapter V. --- CONCLUSION --- p.126 / Chapter VI. --- APPENDIX --- p.127 / Chapter VII. --- BIBLIOGRAPHY --- p.128 / Chapter VIII. --- CONFERENCE PUBLICATIONS --- p.142

青少年特發性脊柱側凸(Adolescent idiopathic scoliosis , AIS)是一種複雜的脊柱三維畸形，常見於10-16 歲處於生長發育高峰期的青少年女性。儘管AIS 發生率較高並且臨床影響較大，但是到目前為止其病因未明。在眾多關於AIS 病因學的假設和理論研究中，普遍認為低骨密度是AIS 的一個重要影響因素。然而近年來對於AIS 患者低骨密度研究不足，其潛在的機制尚不明確。我們之前初步的組織學研究發現，AIS 患者的松質骨中成骨細胞功能下降，此研究為AIS中存在骨礦化異常提供了初步依據。 / 骨橋蛋白是骨組織中一種重要的非膠原細胞外基質蛋白，其在骨礦化過程中起著重要作用。近期的研究報導AIS 患者血漿中骨橋蛋白水準高於年齡匹配的正常對照。因此本研究假設AIS 患者血漿及骨組織中骨橋蛋白高於正常對照，并可能影響了骨基質的礦化，從而導致低骨密度。 / 本系列研究的第一部分旨在通過外周定量電腦斷層掃描（pQCT）明確AIS患者中皮質骨密度及松質骨密度是否均低於正常對照。pQCT 可以準確地三維評估皮質骨密度，松質骨密度及其他骨品質的相關參數。採用雙能X 線骨密度儀（DXA）測量受試者的非優勢側近端股骨面積骨密度（包括股骨頸，Ward’s 三角及大轉子）。而採用pQCT 測量受試者非優勢側橈骨遠端容積骨密度，包括皮質骨密度及松質骨密度。結果顯示AIS 患者面積骨密度，皮質骨密度及松質骨密度在不同年齡段和月經時間分組中均低於正常對照。並且AIS 與正常對照皮質骨密度的差異隨著年齡增長越來越大，而松質骨密度差異則隨著年齡增長越來越小。 / 第二部分通過顯微CT 及組織形態測定研究AIS 及正常骨組織的骨礦化及骨微結構。採用顯微CT 檢測骨組織的三維結構參數，包括材料骨密度及骨微結構。未脫鈣骨組織的切片通過Goldner’s 染色進行組織形態學測量。結果顯示AIS患者的骨體積分數，骨小梁數目，骨小梁厚度及結構模型指數與正常對照之間均無顯著差異，而材料骨密度顯著低於正常對照。組織形態學分析結果顯示AIS中低礦化骨顯著多於正常對照。 / 第三部分旨在研究AIS 及正常對照血漿中骨橋蛋白水準及其與骨密度的關係。採用酶聯吸附免疫法測量AIS 患者及年齡匹配的正常對照血漿中的骨橋蛋白水準。血漿骨橋蛋白水準與骨密度的關係採用多元回歸分析。研究結果顯示AIS 患者及正常對照血漿骨橋蛋白水平均與年齡及月經時間呈負相關。AIS 患者的血漿骨橋蛋白水準顯著高於正常對照，並且與松質骨密度呈顯著負相關。 / 本研究第四部分旨在探討骨組織中的骨橋蛋白表達與骨形態學及骨礦化指標在AIS 及正常對照中的關係。骨組織中骨橋蛋白的表達採用半定量免疫組織化學法評估。研究結果顯示在AIS 中血漿骨橋蛋白水準與骨組織中骨橋蛋白的表達呈正相關。且AIS 骨組織中骨橋蛋白的表達也顯著高於正常對照。進一步的研究發現骨組織中骨橋蛋白的表達與材料骨密度呈負相關，而與低礦化骨量呈正相關。 / 本研究明確了AIS 中骨礦化水準低於正常對照，進一步證明AIS 患者中的皮質骨及松質骨密度下降可能與骨礦化的調控異常有關。本研究發現的骨橋蛋白與低骨密度及低骨礦化水準的關係，可以推測AIS 患者中異常升高的骨橋蛋白水準可能在骨礦獲取的調解中起重要作用。本系列研究提供證據支援AIS 患者中骨橋蛋白的異常表達可能影響了骨基質的礦化，從而導致低骨密度。本研究為AIS 中低骨密度可能的機制提供了全新的見解，並可能進一步解釋AIS 的發病機理及其發生，發展。 / Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine occurring most commonly in girls between ages 10-16 during the pubertal growth spurt. Despite its high prevalence and clinical impact, etiology of AIS remains largely unknown. Among the number of proposed hypothesis and observations on the etiopathogenesis of AIS, low bone mineral density (BMD) is one of the most reported factor (Cheng et al. 1999; Hung et al. 2005; Cheung et al. 2006; Hui et al. 2011). However, the underlying mechanism of low BMD in AIS has not been sufficiently studied scientifically and its link to the etiopathogenesis is still not clear. From a previous pilot study, our group has reported the histological features of reduced osteoblastic activity in bone biopsy specimens obtained from AIS subjects intraoperatively, thus providing the early evidence of abnormal bone mineral acquisition and mineralization (Cheng et al. 2001). / Osteopontin (OPN) has been recognized as one the major non-collagen extracellular matrix proteins in bone and plays an important role in bone mineralization. Recent report suggested that AIS patients have higher OPN level than normal controls (Moreau et al. 2009). It was hypothesized that the low BMD in AIS is associated with abnormal bone matrix mineralization which may be related to abnormal expression of OPN in the plasma and at tissue level. / In this series of studies, the first part aimed to investigate the differential cortical and trabecular bone mineral density of AIS Vs normal controls. The non-dominant proximal femur areal BMD (aBMD) (femoral neck, Ward’s triangle and greater trochanter) of the subjects were measured with dual-energy x-ray absorptiometry (DXA). The volumetric bone mineral density (vBMD) in non-dominant distal radius was measured with peripheral quantitative computed tomography (pQCT) that allows accurate three dimensional assessment of the cortical and trabecular bone mineral density and other parameters of bone quality. AIS was found to have lower aBMDs, trabecular BMD (TBMD) and cortical BMD (CBMD) in different age groups and year since menarche (YSM) groups. Furthermore, the percentage difference of CBMD between AIS and controls was increased with age while a decreasing trend was observed in the TBMD. / The second part of the study investigated the bone mineralization and bone micro-architecture with micro-computed tomography (micro-CT) and histomorphometry study of bone biopsies obtained from AIS and normal controls. Three-dimensional structural parameters including material bone mineral density (mBMD) and bone architecture were evaluated by micro-CT. Bone histomorphometry was assessed by undecalcified sectioning with Goldner’s trichrome staining. mBMD of trabecular bone in AIS was found to be significantly lower than the normal control while no difference could be demonstrated in BV/TV, Tb.N, Tb.Th and SMI measurement between the two groups. It was also shown that the percentage of low-mineralized bone in AIS was significantly higher than that in normal controls. / The third part aimed to study the plasma OPN level and its association with the BMD in AIS Vs normal controls. Plasma OPN level in AIS and age-matched controls was measured by ELISA. With multivariate regression analysis, the plasma OPN level was found to be negatively correlated with Age and YSM in both AIS and normal controls. In addition, the plasma OPN level in AIS was significantly higher and correlated with the low trabecular BMD. / The fourth part of the study investigated the OPN expression in bone tissues level and its association with histomorphometric bone mineralization and bone micro-architectural parameters in AIS Vs normal controls. OPN expression in bone biopsy was semi-quantified by immunohistochemistry. It was found that the bone tissue OPN level was significantly higher in AIS and also positively correlated with plasma OPN level. In addition, in this pilot study, we found the trend that OPN expression in trabecular bone was negatively associated with mBMD, and positively with the percentage of low-mineralized bone. / The present study showed that AIS had lower bone mineralization than normal controls. The low cortical and trabecular BMD found in AIS is likely to be resulting from abnormal regulation of bone mineralization. The association of OPN with abnormal BMD and bone mineralization further suggested that abnormal OPN level might play an important role in affecting the bone mineral acquisition in AIS. All of these findings strongly supported the hypothesis that the low BMD in AIS is associated with abnormal bone matrix mineralization which could be related to abnormal expression of OPN. This study provided important additional insight into the possible mechanism of lower bone mineral density that might be linked to theetiopathogenesis, development and progression of the spinal deformity in AIS. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Sun, Guangquan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 143-160). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract and appendix A also in Chinese. / THE CHINESE UNIVERSITY OF HONG KONG --- p.I / ACKNOWLEDGEMENTS --- p.II / ABSTRACT --- p.IV / ABBREVIATION --- p.XI / TABLE OF CONTENTS --- p.XIII / LIST OF TABLES --- p.XVII / LIST OF FIGURES --- p.XIX / LIST OF PUBLICATIONS --- p.XXI / Chapter CHAPTER 1 --- STUDY BACKGROUND --- p.1 / Chapter 1.1 --- GENERAL OVERVIEW OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS) --- p.2 / Chapter 1.1.1 --- NATURAL HISTORY --- p.4 / Chapter 1.1.2 --- CURRENT TREATMENTS --- p.6 / Chapter 1.1.2.1 --- Observation --- p.7 / Chapter 1.1.2.2 --- Bracing --- p.7 / Chapter 1.1.2.3 --- Surgical treatments --- p.9 / Chapter 1.1.3 --- CURRENT HYPOTHESIS ON THE ETIOLOGY OF AIS --- p.11 / Chapter 1.1.3.1 --- Genetic factors --- p.12 / Chapter 1.1.3.2 --- Neuromuscular impairment --- p.14 / Chapter 1.1.3.3 --- Abnormalities in skeletal development --- p.16 / Chapter 1.1.3.4 --- Low bone mineral density in AIS --- p.16 / Chapter 1.2 --- BONE MINERALIZATION --- p.18 / Chapter 1.2.1 --- Overview of bone mineralization --- p.18 / Chapter 1.2.2 --- Bone modeling --- p.18 / Chapter 1.2.3 --- Bone remodeling --- p.19 / Chapter 1.2.4 --- Factors affecting bone mineralization --- p.21 / Chapter 1.3 --- OSTEOPONTIN --- p.23 / Chapter 1.3.1 --- Structure of osteopontin --- p.23 / Chapter 1.3.2 --- Osteopontin - cellular and tissue distribution --- p.24 / Chapter 1.3.3 --- Osteopontin functions --- p.25 / Chapter 1.3.4 --- Osteopontin functions in bone --- p.25 / Chapter 1.3.5 --- Osteopontin and bone mineral density in human --- p.29 / Chapter CHAPTER 2 --- STUDY HYPOTHESIS AND PLAN --- p.31 / Chapter 2.1 --- INTRODUCTION --- p.32 / Chapter 2.2 --- HYPOTHESIS --- p.33 / Chapter 2.3 --- OBJECTIVES --- p.34 / Chapter 2.4 --- STUDY PLAN --- p.34 / Chapter CHAPTER 3 --- LOW BONE MINERAL DENSITY IN ADOLESCENT IDIOPATHIC SCOLIOSIS - AREAL VS VOLUMETRIC, CORTICAL VS TRABECULAR BONE MINERAL DENSITY --- p.36 / Chapter 3.1 --- INTRODUCTION --- p.37 / Chapter 3.2 --- SUBJECTS AND METHODS --- p.39 / Chapter 3.2.1 --- Subjects --- p.39 / Chapter 3.2.2 --- BMD Measurement --- p.40 / Chapter 3.2.3 --- Statistical Analysis --- p.41 / Chapter 3.3 --- RESULTS --- p.42 / Chapter 3.3.1 --- aBMD of AIS and normal controls by age groups --- p.42 / Chapter 3.3.2 --- TBMD and CBMD in AIS and normal controls by age groups --- p.42 / Chapter 3.3.3 --- aBMD in AIS and normal controls by year since menarche --- p.43 / Chapter 3.3.4 --- TBMD and CBMD in AIS and normal controls by year since menarche --- p.43 / Chapter 3.3.5 --- Correlation between CBMD & TBMD and chronological age or year since menarche --- p.44 / Chapter 3.3.6 --- Comparisons adjusted for chronological age or year since menarche --- p.44 / Chapter 3.4 --- DISCUSSION --- p.45 / Chapter 3.5 --- TABLES AND FIGURES --- p.50 / Chapter CHAPTER 4 --- ABNORMAL BONE MATRIX MINERALIZATION AND BONE MICROARCHITECTURE IN ADOLESCENT IDIOPATHIC SCOLIOSIS - A HISTOMORPHOMETRIC AND MICRO-CT STUDY --- p.60 / Chapter 4.1 --- INTRODUCTION --- p.61 / Chapter 4.2 --- SUBJECTS AND METHODS --- p.62 / Chapter 4.2.1 --- Subjects --- p.62 / Chapter 4.2.2 --- Micro-computed tomography --- p.63 / Chapter 4.2.3 --- Bone histomorphometry --- p.64 / Chapter 4.2.4 --- Statistical analysis --- p.68 / Chapter 4.3 --- RESULTS --- p.68 / Chapter 4.3.1 --- Results of micro-CT analysis --- p.68 / Chapter 4.3.2 --- Results of histomorphometric analysis --- p.69 / Chapter 4.3.3 --- Relationship of mBMD and percentage of low-mineralized bone --- p.69 / Chapter 4.4 --- DISCUSSION --- p.70 / Chapter 4.5 --- TABLES AND FIGURES --- p.74 / Chapter CHAPTER 5 --- PLASMA OSTEOPONTIN LEVEL AND ITS ASSOCIATION WITH BONE MINERAL DENSITY IN ADOLESCENT IDIOPATHIC SCOLIOSIS --- p.82 / Chapter 5.1 --- INTRODUCTION --- p.83 / Chapter 5.2 --- SUBJECTS AND METHODS --- p.84 / Chapter 5.2.1 --- Subjects --- p.84 / Chapter 5.2.2 --- Anthropometric assessment --- p.84 / Chapter 5.2.3 --- Plasma osteopontin measurement --- p.85 / Chapter 5.2.4 --- BMD Measurement --- p.86 / Chapter 5.2.5 --- Statistical Analysis --- p.86 / Chapter 5.3 --- RESULTS --- p.86 / Chapter 5.3.1 --- Comparison of anthropometric parameters between AIS and controls --- p.86 / Chapter 5.3.2 --- Correlation between OPN plasma level with age or YSM in AIS and controls --- p.87 / Chapter 5.3.3 --- Comparison of OPN plasma level between AIS and controls --- p.87 / Chapter 5.3.4 --- Correlation between OPN plasma level and curve severity in AIS --- p.87 / Chapter 5.3.5 --- Relationship between OPN plasma level and vBMD --- p.88 / Chapter 5.4 --- DISCUSSION --- p.88 / Chapter 5.5 --- TABLES AND FIGURES --- p.94 / Chapter CHAPTER 6 --- OSTEOPONTIN EXPRESSION IN BONE TISSUE AND ITS ASSOCIATION WITH BONE MATRIX MINERALIZATION IN ADOLESCENT IDIOPATHIC SCOLIOSIS - A PILOT STUDY --- p.102 / Chapter 6.1 --- INTRODUCTION --- p.103 / Chapter 6.2 --- SUBJECTS AND METHODS --- p.104 / Chapter 6.2.1 --- Subjects --- p.104 / Chapter 6.2.2 --- Micro-computed tomography --- p.104 / Chapter 6.2.3 --- Bone histomorphometry --- p.104 / Chapter 6.2.4 --- Semi-quantification of OPN expression in bone biopsy by immunohistochemistry --- p.105 / Chapter 6.2.5 --- Plasma osteopontin measurement --- p.107 / Chapter 6.2.6 --- Statistical Analysis --- p.108 / Chapter 6.3 --- RESULTS --- p.108 / Chapter 6.3.1 --- Comparison of anthropometric parameters between AIS and control subjects --- p.108 / Chapter 6.3.2 --- Comparison of OPN expression detected by immunohistochemistry in bone biopsy between AIS and control groups --- p.108 / Chapter 6.3.3 --- Comparison of histomorphometric and micro-CT results between AIS and control groups --- p.109 / Chapter 6.3.4 --- Relationship between plasma OPN level and OPN expression in bone biopsy --- p.109 / Chapter 6.3.5 --- Relationship between percentage of low-mineralized bone and OPN expression in bone biopsy --- p.109 / Chapter 6.3.6 --- Relationship between material bone mineral density and OPN expression in bone biopsy --- p.110 / Chapter 6.4 --- DISCUSSION --- p.110 / Chapter 6.5 --- TABLES AND FIGURES --- p.114 / Chapter CHAPTER 7 --- SUMMARY STUDY FLOWCHART, OVERALL DISCUSSION, CONCLUSIONS, LIMITATIONS AND FURTHER STUDIES --- p.119 / Chapter 7.1 --- SUMMARY OF THE STUDY FLOW CHART WITH KEY FINDINGS --- p.120 / Chapter 7.2 --- OVERALL DISCUSSION --- p.125 / Chapter 7.2.1 --- The novel findings on bone mineralization abnormality in AIS in this study --- p.125 / Chapter 7.2.2 --- OPN is a key modulator in AIS --- p.128 / Chapter 7.3 --- OVERALL CONCLUSIONS --- p.130 / Chapter 7.4 --- LIMITATION OF THIS STUDY AND FUTURE RESEARCH --- p.131 / Chapter APPENDIX A. --- CONSENT FORM OF AIS RESEARCH --- p.135 / Chapter APPENDIX B. --- CONSENT FORM OF BONE BIOPSY COLLECTION --- p.137 / Chapter APPENDIX C. --- MATERIALS AND REAGENTS INFORMATION AND PROTOCOL FOR SOLUTIONS PREPARATION --- p.138 / BIBLIOGRAPHY --- p.143

Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional structural spine deformity with lateral curve and vertebral rotation occurring predominantly in adolescent girls during the peri-pubertal period. The prevalence of AIS is nearly 4% in Hong Kong and 2-3% worldwide. AIS without treatment or with improper treatment may deteriorate progressively and lead to significant cosmetic problems and functional disabilities. In severe cases, increased mortality rate can result from the associated early onset of cardiopulmonary failure. Up to now, the treatment of the AIS is basically passive through bracing and corrective spinal surgery. The current protocol of treatment is not totally satisfactory since the curve may continue to progress with brace treatment and corrective surgery is associated with major surgery and permanent fusion of parts of the spine. This is due to the fact that one is still uncertain about the etiology of AIS and therefore cannot directly treat the AIS. Among the different proposed etiology of AIS, the role of abnormal skeletal growth and development during peri-pubertal period has been one of the main focuses in addition to genetic predisposition in the development of AIS. / It has been well established that girls with idiopathic scoliosis have a tendency to be taller and more slender than their peers. Recently, it has been shown that the trabecular bone mineral density at the spine, hip, and peripheral bones of AIS girls was lower than their healthy peers. Studies from our center have also demonstrated growth discrepancy between anterior and posterior vertebral column using magnetic resonance imaging (MRI) technique. The vertebral bodies were shown to be slender in AIS patients than that in normal controls. The observation pointed to a disproportionate growth of the anterior and posterior spinal column resulting from imbalance in endochondral and membranous ossification. The present study hypothesizes that the abnormality of skeletal growth could be a systemic problem affected by both endochondral ossification and membranous ossification. The degree of abnormal growth could vary with different curve severities. The concurrent finding of abnormal skeletal growth and osteopenia could be related to certain underlying abnormal genetic factors affecting the etiopathogenesis of AIS. The hypothesis leads to the following objectives: (1) To study the anthropometric measurements and the related changes in AIS girls with different curve severity; (2) To document the presence of abnormal systemic growth through endochondral ossification; (3) To document the presence of abnormal membranous ossification through studies of the morphology and bone mineral density of the midshaft of the appendicular skeleton and the skull; (4) To study the association of occurrence of AIS and its related phenotypes with the genes associated with growth and osteopenia. (Abstract shortened by UMI.) / by Yeung Hiu-Yan. / "January 2006." / Adviser: Jack C. Y. Cheng. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6301. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 206-227). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

by Tang Shengping. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 217-244). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Man, Chi Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 141-184). / Abstract also in Chinese. / Acknowledgements --- p.ii / Abstract --- p.iv / Abbreviations --- p.xi / List of Tables --- p.xviii / List of Figures --- p.xx / Major Conference Presentations --- p.xxii / Publications in Preparation --- p.xxiv / Study Flowchart --- p.xxv / Chapter Chapter 1 --- Study Background --- p.1 / Chapter 1. --- Introduction --- p.2 / Chapter 1.1. --- General Overview of Adolescent Idiopathic Scoliosis (AIS) --- p.2 / Chapter 1.2. --- Natural History --- p.3 / Chapter 1.3. --- Current Treatments --- p.5 / Chapter 1.4. --- Additional Phenotypes Abnormalities --- p.9 / Chapter 1.5. --- Bone Modeling and Remodeling in Adolescents --- p.14 / Chapter 1.6. --- Bone Development --- p.15 / Chapter 1.7. --- Bone (re)modeling by osteoclasts and osteoblasts --- p.17 / Chapter 1.8. --- Factors Affecting Osteoblasts Regulation --- p.19 / Chapter 1.9. --- Current Hypothesis on the Etiology of AIS --- p.21 / Chapter 1.10. --- Melatonin --- p.26 / Chapter Chapter 2 --- Hypothesis and Objectives --- p.47 / Chapter 2. --- Hypothesis and Objectives --- p.48 / Chapter 2.1. --- Study Hypothesis --- p.48 / Chapter 2.2. --- Objectives --- p.48 / Chapter Chapter 3 --- Study on the Anthropometric Parameters and Bone Geometry of Girls with Severe AIS --- p.49 / Chapter 3.1. --- Introduction --- p.50 / Chapter 3.2. --- Methodology --- p.51 / Chapter 3.2.1. --- Recruitment of Subjects --- p.51 / Chapter 3.2.2. --- Evaluation of Curve Severity of Scoliosis --- p.52 / Chapter 3.2.3. --- Anthropometric Measurements --- p.53 / Chapter 3.2.4. --- Measurements of BMD --- p.53 / Chapter 3.2.5. --- Data Analysis --- p.54 / Chapter 3.3. --- Results --- p.55 / Chapter 3.3.1. --- Anthropometry --- p.55 / Chapter 3.3.2. --- BMD of Femoral Neck and Midshaft of Radius --- p.56 / Chapter 3.4. --- Discussion --- p.57 / Chapter Chapter 4 --- Response of Osteoblasts to Melatonin in AIS Girls In vitro Study --- p.69 / Chapter 4.1. --- Introduction --- p.70 / Chapter 4.2. --- Methodology --- p.72 / Chapter 4.2.1. --- Subjects Recruitments --- p.72 / Chapter 4.2.2. --- Cell Isolation --- p.73 / Chapter 4.2.3. --- Effect of Melatonin on Proliferation and Differentiation of AIS Osteoblasts --- p.76 / Chapter 4.2.4. --- Data Analysis --- p.79 / Chapter 4.3. --- Results --- p.80 / Chapter 4.3.1. --- Isolated Osteoblasts from Normal Human and AIS Patients --- p.80 / Chapter 4.3.2. --- Effect of Melatonin on Osteoblasts Proliferation --- p.80 / Chapter 4.3.3. --- Effect of Melatonin on Cell Differentiation --- p.81 / Chapter 4.4. --- Discussion --- p.83 / Chapter Chapter 5 --- Expression of MT1 and MT2 receptors in AIS Osteoblasts --- p.101 / Chapter 5.1. --- Introduction --- p.102 / Chapter 5.2. --- Methodology --- p.104 / Chapter 5.2.1. --- Osteoblast Samples --- p.104 / Chapter 5.2.2. --- Protein Expression of Melatonin Receptors in AIS Osteoblasts. --- p.105 / Chapter 5.2.3. --- Genotyping of MT2 receptors by Restriction Fragment Length Polymorphism (RFLP) --- p.109 / Chapter 5.2.4. --- Clinical Evaluations of the AIS Patients --- p.110 / Chapter 5.2.5. --- Data Analysis --- p.110 / Chapter 5.3. --- Results --- p.111 / Chapter 5.3.1. --- Semi quantification of Melatonin Receptors in AIS Osteoblasts 111 --- p.111 / Chapter 5.3.2. --- RFLP --- p.112 / Chapter 5.3.3. --- Functional Response Between the Different AIS Groups --- p.112 / Chapter 5.3.4. --- Correlation of the Clinical Phenotypes with the Different AIS Subgroups --- p.114 / Chapter 5.4. --- Discussion --- p.115 / Chapter Chapter 6 --- Summary and Conclusion --- p.132 / Chapter 6.1. --- Summary and Discussion --- p.133 / Chapter 6.2. --- Limitations and Further Studies --- p.136 / Chapter 6.3. --- Conclusion --- p.138 / Bibliography --- p.141 / Appendix I --- p.185 / Appendix II --- p.186 / Appeddix III --- p.187 / Appendix IV --- p.188 / Appendix V --- p.189 / Appendix VI --- p.190