Resumo: Proposição: Avaliar a resposta tecidual ao enxerto xenógeno inorgânico de osso bovino, por meio de análise histomorfológica e histomorfométrica. Material e método: O enxerto foi obtido da costela de boi resfriada após 8 horas de sacrifício do animal e processado da seguinte maneira: imersão por 60 minutos em água oxigenada a temperatura ambiente, com trocas a cada 15 minutos; imersão em água oxigenada aquecida, a uma temperatura de 100ºC, por 30 segundos e resfriamento imediato com água destilada a uma temperatura variando de 6º a 8ºC; enxague em água destilada corrente por 6 horas; imersão em álcool 70º, 90º e 100º, respectivamente, sendo 15 minutos em cada álcool; esterilização em autoclave. Em seguida, 10 coelhos brancos (Nova Zelândia) foram utilizados, originando dois grupos: Grupo I - enxerto inserido no pavilhão auricular e Grupo II - enxerto inserido e fixado em tíbia. Decorridos 180 dias, foi realizado sacrifício dos animais por injeção excessiva de anestésico. Resultados: No Grupo I, o enxerto apresentou-se em íntimo contato com tecido subcutâneo. No Grupo II, o enxerto apresentou-se em justaposição com o leito ósseo receptor. E nos dois grupos havia espaços medulares preenchidos por medula óssea ativa e osso neoformado, além da ausência de osteócitos no osso bovino e presença destas células no osso neoformado, próximo aos espaços medulares. Conclusão: Em razão dos resultados obtidos o enxerto xenógeno inorgânico de osso bovino demonstrou biocompatibilidade, capacidade osteocondutora e discreta perda de volume, preenchendo requisitos importantes do material ideal para reconstrução óssea. / Abstract: Objective: To evaluate tissue response to inorganic bovine bone xenograft by histomorphological and histomorphometrical analyses. Material and methods: The bone grafts was obtained from cooled bovine rib 8 hours after slaughtering and were processed as follows: 60-minute immersion in hydrogen peroxide at room temperature, with changes at 15-minute intervals; 30-second immersion in hydrogen peroxide at 100ºC; immediate cooling with distilled water at temperatures ranging from 6º to 8ºC; rinsing in running distilled water for 6 hours; immersion in alcohol grades of 70º, 90º and 100ºGL (15-minute in each solution); autoclaving. Thereafter, 10 white New Zealand rabbits were distributed into two groups: Group I - graft inserted in the ear pavilion and Group II - graft inserted and fixed in the tibia. After 180 days, the animals were sacrificed by anesthetic overdose. Results: In Group I, the graft was in intimate contact with the subcutaneous tissue, while in Group II the graft was juxtaposed to the recipient site. Both groups presented medullar spaces filled with active bone marrow and newly formed bone. In addition, osteocytes were absent in the bovine bone graft and present in the newly formed bone, close to the medullar spaces. Conclusion: From the obtained results, the inorganic bovine bone xenograft showed biocompatibility. / Orientador: Wilson Roberto Poi / Coorientador: Idelmo Rangel Garcia Júnior / Banca: Osvaldo Magro Filho / Banca: Roberta Okamoto / Banca: José Luiz Rodrigues Leles / Banca: Eleonor Álvaro Garbin Júnior / Doutor

Mechanotransduction is a process by which cells sense and convert mechanical loads into biochemical signals and transcriptional changes. This process is particularly critical in bone, a metabolically active tissue that continously remodels and adapts to mechanical loads in its local environment. Osteocytes are the most prevalent bone cell type and are responsible for coordinating skeletal adaptation. Recently, the loss of primary cilia, nonmotile antenna-like cellular structures, has been attributed to causing defects in skeletal development and loading-induced bone formation. While primary cilia have been implicated in osteocyte mechanotransduction, the molecular mechanism associated with this process is not understood. In this thesis, we demonstrate that the osteocyte primary cilium forms a microdomain that mediates osteogenic responses to mechanical loads. In the first study, we build a genetically encoded primary cilium-localized calcium biosensor and characterize ciliary calcium mobilization in response to mechanical loading with unprecedented sensitivity. Next, we apply similar techniques to monitor levels of another second messenger, cyclic AMP (cAMP), and are the first to demonstrate that the primary cilium segregates ciliary cAMP from the cytosol. In the third study, we link loading-induced bone formation in vivo to adenylyl cyclase 6 enzyme function, a component of the primary cilium-mediated mechanotransduction mechanism. Collectively, this thesis elucidates how osteocyte primary cilia convert mechanical stimuli into osteogenic responses at the molecular and tissue levels and characterizes the primary cilium as a microdomain that serves as a biochemical and mechanical signaling nexus. Improvements in our understanding of primary cilia-regulated mechanotransduction will advance research efforts in the bone, tissue engineering, and mechanobiology communities.

Osteoporosis is a major metabolic bone disease that causes reduced bone mass, deteriorated bone microstructural and increased fracture risk. In clinical practice, the gold standard to examine bone quality and evaluate fracture risk is using dual energy X-ray absorptiometry through measurements of areal bone mineral density (aBMD). However, it has been well accepted that in addition to aBMD, bone geometry, microstructure and material properties also play important roles in determining overall bone mechanical competence, which is directly related to fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) has the capability to image three-dimensional (3D) bone microstructures in vivo and provide quantitative measurements of bone mineral density as well as cortical and trabecular microstructure. Based on the HR-pQCT images, micro finite element (µFE) models can be constructed to directly estimate bone strength. HR-pQCT has become a widely used imaging tool in clinical research to evaluate the effect of aging, drug treatment, and metabolic bone disease on bone quality. The work in this thesis focuses on evaluating the accuracy and capability of HR-pQCT in quantifying microstructural properties of human radius and tibia bone, exploring its prediction power of whole bone strength and discussing potential applications in clinical studies. In this thesis, we quantified the accuracy of the standard HR-pQCT microstructural measurements of human distal radius and tibia through comparisons with gold standard µCT-based morphological measures. The results showed that the BV/TVd, Tb.N*, Tb.Th and Tb.Sp from HR-pQCT were significantly and highly correlated with those from gold-standard µCT measurements. Strong correlations between the HR-pQCT µFE predictions and direct mechanical testing measures suggest that HR-pQCT µFE is a robust method to determine bone mechanical properties. In a clinical setting, standard HR-pQCT scans are performed on the non-dominant wrist (usually the left) and the corresponding tibia. However, the contralateral side is selected for scanned when there is a fracture the non-dominant wrist. It remains unclear whether the dominant side is representative of the non-dominant side and how much error it will bring into a study where subjects include mixed scans of both sides. In this thesis, we applied HR-pQCT and µCT based morphological and mechanical measurements to characterize the symmetric nature of distal radius and tibia. We found that the right radius tend to be larger than the left radius. However, at the tibia, the bone size was found to be similar between left and right. By micro computed tomography (µCT), microstructural parameters such as BV/TV were also found to be larger at the right radius, while no difference was found at the tibia. Trabecular number, trabecular thickness, trabecular separation and cortical thickness were not different between left and right radius. µFE analyses demonstrated that stiffness and strength of right radius were significantly higher than left radius, while there was no difference at the tibia. The standard clinical region of interest HR-pQCT is recommended by the manufacturer; however, it is not clear whether a segment HR-pQCT scan is representative of whole bone mechanical properties. Therefore we quantified the associations of microstructural and mechanical measurements of the radius and tibia segments with whole bone stiffness and examined if we can improve the correlation when we select a different region. The microstructural and mechanical measurements at the two regions next to the standard HR-pQCT segment (proximal and distal) were also examined. The results showed that the bone microstructure from proximal and distal sections is highly correlated to standard region at both distal radius and tibia. The mechanical properties of the three segments were strongly correlated with overall bone mechanical properties. The microstructural measurements at the most distal section were correlated with whole bone stiffness better compared to those from standard and proximal regions. DXA is incapable of discriminating patients with wrist fracture from those without. In this study, we examined the microstructural and mechanical properties in patients with and without wrist fracture through HR-pQCT based analyses. We demonstrated that wrist fracture patients had lower plate and rod bone volume fraction, less plate and rod trabecular number, thinner cortex and lower whole bone stiffness and strength, compared to healthy controls. Failure analyses also depicted significantly lower trabecular plate compression and tension failure fraction in wrist fracture patients.

Troodontidae is an important dinosaur taxon that closely resembles birds in both morphology and biology. The evolution of troodontids is crucial for understanding evolutionary transitions between non-avialan theropods and avialans. Despite the recent discovery of several troodontid taxa across the world and many new studies of coelurosaurian relationships, an overall survey of morphological variation in troodontids and a comprehensive analysis of ingroup troodontid relationships have yet to be accomplished. In the first four chapters of this dissertation, the osteology of two new troodontid taxa and two closely related paravians are described in detail. These descriptions are based on new specimens recovered from the Mesozoic of China and Mongolia. These new taxa include the basal dromaeosaurid Microraptor zhaoianus, the basal avialan Anchiornis huxleyi, a new troodontid taxon represented by IGM 100/1323, and a second new troodontid taxon represented by IGM 100/1126 and IGM 100/3500. These paravian taxa are all small-sized, with a basal paravian body plan resembling Archaeopteryx, yet they represent members of all three major paravian lineages (Troodontidae, Dromaeosauridae and Avialae), and support the traditionally recognized paravian interrelationships. Osteological description of Microraptor zhaoianus is based on an excellently preserved new specimen BMNHC PH881. This specimen preserves significant morphological details that are not present, or are poorly preserved, in the other Microraptor specimens, including aspects of the skull, rib cage, and humerus. These new characters corroborate Microraptor as a member of the Dromaeosauridae and support the close relationship of troodontids with dromaeosaurids. Four new specimens (PKUVP 1068; BMNHC PH804, BMNHC PH822 and BMNHC PH823) of Anchiornis huxleyi reveal new osteological details of this important paravian taxon. Anchiornis huxleyi shares derived features with avialans, but it lacks derived deinonychosaurian characteristics such as a laterally exposed splenial and a specialized raptorial pedal digit II. IGM 100/1323 represents a new troodontid taxon from the Late Cretaceous Djadokhta Formation of Mongolia, diagnosed from other troodontids by the absence of the lateral groove on the dentary, a posteriorly curved pterygoid flange, a distinct spike-like process on the ischium, and elongate chevrons. Despite generally having a basal paravian body plan, IGM 100/1323 displays many derived troodontid features. IGM 100/1126 and IGM 100/3500 represent another new Late Cretaceous troodontid taxon from the Djadokhta-Formation-like rocks at Ukhaa Tolgod, Mongolia. It is unique and distinct from other troodontids in having closely packed peg-like teeth, a twisted suborbital process of the jugal, a quadratojugal with a crescentic ascending process that braces the quadrate posteriorly, reduction of the basal tubera, and presence of a posterior fossa on the proximal fibula. This new taxon is morphologically more derived than Early Cretaceous troodontids but is more primitive than other Late Cretaceous troodontids. A new and comprehensive phylogenetic analysis of coelurosaurian theropods, focusing on troodontids is presented in Chapter 5. This is an updated version of the Theropod Working Group (TWiG) analysis (2015.1). This new analysis incorporates new paravian taxa and new characters, most of which are relevant to paravians, especially the troodontids that are the focus of this dissertation. The new phylogenetic analysis agrees with previous studies on the general relationships of coelurosaurians, yet some important differences from previous TWiG analyses are present in paravians, including: 1), the Jianchang paravians are recovered as basal avialans; 2), Late Cretaceous troodontids form a monophyletic group; and 3), Jinfengopteryginae is not monophyletic.

Progressive bone loss and weakening bone strength associated with aging predispose the elderly population to osteoporosis and millions of costly fragility fractures. Micro finite element (µFE) analysis based on clinical high-resolution skeletal imaging provides an accurate computational solution to assessing the mechanical properties of bone, which can be used as the dominant factors for fracture risk. However, the current µFE analysis technique is impractical for clinical use due to its prohibitive computational costs, which result from the “voxel-to-element” approach of modeling human bone regardless of its microstructural pattern. I developed a novel plate-rod microstructural modeling technique for highly efficient patient-specific µFE analysis and translated it to clinical research for the assessment of bone strength in osteoporosis and fragility fractures. Trabecular microstructure is composed of interconnected plate-like and rod-like trabeculae. Instead of converting every image voxel directly into an element, the plate-rod modeling approach created mechanical characterization for every individual trabecular plate and rod. The validation studies demonstrated that the PR model was able to reproduce the morphology and mechanical behavior of the original trabecular microstructure, while reducing the size of the µFE model and improving the efficiency of µFE simulations. First, the PR models of trabecular bone were developed based on high-resolution micro computed tomography (µCT), and evaluated in comparison with computational gold standard-voxel µFE models and experimental gold standard-mechanical testing for estimating Young’s modulus and yield strength of human trabecular bone. Results suggested that PR model predictions of the trabecular bone mechanical properties were strongly correlated with voxel models and mechanical testing results. Moreover, the PR models were indistinguishable from the corresponding voxel models constructed from the same images in the prediction of trabecular bone Young’s modulus and yield strength. In addition, PR model nonlinear µFE analyses resulted in over 200-fold reduction in computation time compared with voxel model µFE analyses. In the effort of studying the heterogeneous bone mineralization in trabecular plates and rods, I developed an individual trabecula mineralization (ITM) analysis technique that allows quantification of the tissue mineral density of each individual trabecular plate and rod. By examining the variation of mineral density with trabecular types and orientations, it was found that trabecular plates were higher mineralized than trabecular rods. Furthermore, trabecular plate mineral density varied with trabecular orientation, increasing from the longitudinal direction to the transverse direction. ITM provided measurement of mineral density of each trabecular plate and rod, which was converted to trabecula-specific tissue modulus and used in the PR models to incorporate mineral heterogeneity in µFE simulations. Results suggested that heterogeneous PR models did not differ from the homogeneous PR models or specimen-specific PR models in their predictions of apparent Young’s modulus and yield strength of the human trabecular bone specimens from non-diseased donors. Based on the trabecular bone PR model, a whole bone PR model was developed for assessing whole bone mechanical strength at the distal radius and the distal tibia from high-resolution peripheral quantitative computed tomography (HR-pQCT). The accuracy of the whole bone PR model was evaluated on human cadaver radius and tibia specimens which were imaged using HR-pQCT and µCT, respectively, and tested to failure. The whole bone stiffness and yield load of the radius and tibia segments predicted by HR-pQCT PR models were strongly correlated with those predicted by corresponding HR-pQCT voxel models, µCT voxel models, and mechanical testing measurements. The PR models µFE results were indistinguishable from the voxel models constructed from the same HR-pQCT images. Moreover, the PR models significantly reduced the computational time for nonlinear µFE assessment of whole bone strength. After evaluating the accuracy and efficiency of the newly developed whole bone PR model, it was employed in a clinical study aimed at characterizing the abnormalities of trabecular plate and rod microstructure, cortical bone, and whole bone mechanical properties in postmenopausal women with vertebral fractures. Women with vertebral fractures had thinner cortical bone, and larger trabecular area compared to their non-fractured peers. ITS analyses suggested vertebral fracture subjects had deteriorated trabecular microstructure, evidenced by fewer trabecular plates, less axially aligned trabeculae and less trabecular connectivity at both radius and tibia. These microstructural deficits translated into reduced whole bone stiffness and yield load at radius and tibia as predicted by PR model nonlinear µFE simulation. More importantly, logistic regression indicated that whole bone yield load was effective in discriminating the vertebral fracture subjects from the non-fractured controls.

Primary cilia are sensory organelles that facilitate early skeletal development, as well as maintenance and adaptation of bone later in life. These solitary, immotile organelles are known to be involved in cell differentiation, proliferation, and mechanotransduction, a process by which cells sense and covert external physical stimuli into intracellular biochemical signals. Bone is a metabolically active tissue that continuously recruits osteogenic precursors and relies on osteocytes, the sensory cells of bone, to coordinate skeletal maintenance. Overall bone quality is dependent on the integrity of the initial structure formed, as well as this organ’s ability to adapt to physical loads. Proper differentiation and controlled proliferation of osteogenic progenitors are critical to the initial formation of the skeleton, while osteocyte mechanotransduction is essential for adaptation of developed bone. These phenomena rely on primary cilia, but little is known about the origin of osteogenic precursors and the ciliary mechanisms that promote osteogenesis. In this thesis, we first characterize an osteochondroprogenitor (OCP) population that rapidly and extensively populates skeletal tissues during juvenile skeletal development (Chapter 2). We also demonstrate that the primary cilium is critical for these cells to differentiate and contribute to skeletogenesis. We then show this OCP population is required for adult bone adaptation and is mechanoresponsive (Chapter 3). Again, we demonstrate that primary cilia are necessary for these OCPs to sense physical stimuli and differentiate into active bone-forming cells. Finally, we identify a novel link between ciliary calcium and cAMP dynamics in the osteocyte primary cilium (Chapter 4). Specifically, we show that a calcium channel (TRPV4) and adenylyl cyclases, which produce cAMP, bind calcium to mediate calcium entry and cAMP production, respectively, and these phenomena are critical to fluid flow-induced osteogenesis. Collectively, our results demonstrate that an easily extracted progenitor population is pre-programmed towards an osteogenic fate and extensively contributes to bone generation through primary cilium-mediated mechanisms at multiple stages of life. Furthermore, we identified ciliary proteins that are potentially unique to the osteocyte and can be manipulated to encourage osteogenesis by tuning calcium/ cAMP dynamics. For these reasons, we propose that this OCP population and their primary cilia, as well as osteocyte ciliary proteins that coordinate calcium/ cAMP dynamics, are attractive therapeutic targets to encourage bone regeneration.

Osteoporosis is a devastating condition characterized by decreased bone mass, and affects over 50% of the population over 50 years old. Progression of osteoporosis results in significantly heightened risk of fracture leading to loss of mobility, prolonged rehabilitation, and even mortality due to extended hospitalization. Current therapeutic options exist to combat low bone mass, but these treatments are being met with increasing concern as reports emerge of atypical fractures and necrosis. Thus, new therapeutic strategies are required. Bone is highly dynamic, and it has long been known that physical load is a potent stimulus of bone formation. Despite this, none of the current treatments for bone disease leverage the inherent mechanosensitivity of bone – the ability of bone cells to sense and respond to mechanical forces such as exercise. One potential therapeutic target is the primary cilium. Primary cilia are solitary antenna-like organelles, and over the last 20 years have been identified as a critical cellular mechanosensor. Primary cilia and cell mechanotransduction are critical to the function of numerous cells and tissues. Thus, understanding primary cilia-mediated mechanotransduction has potential applications in treating kidney and liver disease, atherosclerosis, osteoarthritis, and even certain cancers. Previous work from our group has demonstrated that disruption of the cilium impairs bone cell mechanosensitivity, resulting in abrogated whole bone adaptation in response to physical load. In this thesis we examine the potential of targeting the primary cilium to enhance bone cell mechanosensitivity and promote whole bone formation. First, we demonstrate the pharmacologically increasing primary cilia length significantly enhances cell mechanotransduction. Next, we expand our list of candidate compounds to manipulate ciliogenesis through the use of high-throughput drug screening. We developed an automated platform for culturing, staining, imaging, and analyzing nearly 7000 small molecules with known biologic activity, and classify them based on mechanism of action. One of these compounds is then used in a co-culture model to study the effects of manipulating osteocyte primary cilia-mediated mechanosensing on pro-osteogenic paracrine signaling to promote the activity of bone-forming osteoblasts and osteogenic differentiation of mesenchymal stem cells. Finally, we translate our in vitro findings into an in vivo model of load-induced bone formation using the same compound to enhance cell mechanotransduction. We demonstrate that we can sensitize bones to mechanical stimulation to enhance load-induced bone formation in healthy and osteoporotic animals, with minimal adverse effects. Together, this work demonstrates the therapeutic potential and viability of targeting primary cilia-mediated mechanotransduction for treating bone diseases.

Life relies on the integration of external environmental stimuli and internal signals to balance fluctuations in nutrient availability to achieve homeostasis. Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, FGF23 and osteocalcin, which regulate kidney function and glucose homeostasis, respectively. These findings have raised the question of whether other bone-derived hormones exist and what their potential functions are. Here we identify, through molecular and genetic analyses in mice, lipocalin 2 (LCN2) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrate that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived LCN2 inhibits food intake. LCN2 crosses the blood–brain barrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathway. These results identify LCN2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and show that the control of appetite is an endocrine function of bone. Furthermore, we show that serum LCN2 levels correlate with insulin levels and β-cell function, indices of healthy glucose metabolism, in genetic and diet-induced mouse models of obesity and in obese, healthy or pre-diabetic patients. However, LCN2 serum levels also correlate with body mass index (BMI) and insulin resistance in the same patients; and are increased in obese mice. To dissect this apparent discrepancy, we examined LCN2 effects in hyperphagia and β -cell function mouse models of obesity or β -cell destruction. Silencing Lcn2 expression increases hyperphagia, fat and body weight and worsens β -cell function and general metabolic dysfunction in obese, leptin receptor-deficient mice. Conversely, LCN2 increases β-cell numbers and promotes β-cell function after streptozotocin-induced β -cell failure by (STZ) and acts as a growth factor necessary for β -cell adaptation to higher metabolic load in mice. These results support a protective role for LCN2 in obesity-induced glucose intolerance and insulin resistance that stem from its ability to decrease food intake and promote adaptive β-cell proliferation.

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

Chan Chun Wai. / "August 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references. / 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 Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.