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Osteoporosis is a widespread problem and a major public health challenge, with one in two women and one in five men over the age of 50 years expected to experience an osteoporotic fracture. Various factors contribute to an increased risk of disease including female gender, Caucasian ethnicity, age, physical inactivity, inadequate status of calcium and vitamin D, excessive alcohol intake and smoking. In recent years convincing evidence has emerged linking low B-vitamins, the related metabolite homocysteine (Hcy), and a common polymorphism in folate metabolism (the MTHFR 677C~T polymorphism) with low bone mineral density (BMD) and an increased fracture risk. Patients with coeliac disease (CD), a common autoimmune inflammatory condition characterised by intestinal damage due to gluten consumption, are at increased risk both of osteoporosis and inadequate B-vitamin status. The aim of this thesis was to investigate the role of the B-vitamins, Hcy and the MTHFR 677C~T polymorphism in bone health and disease, including an evaluation of the potential protective role of Bvitamin supplementation in the maintenance of BMD in CD patients. The findings within this thesis provide evidence to supplier an association between bone health and biomarkers of B-vitamin status, particularly vitamin B 12 and vitamin B6, and Hcy (women only). Among those with the variant MTHFR 677TT genotype, a low status of riboflavin (women only), and folate, were associated with a 1.8-2.1 times increased risk of osteoporosis. Preliminary findings from the on-going randomised controlled trial (RCT) suggest a beneficial effect of combined folic acid (400 Ilg/d) and vitamin B 12 (10 Ilg/d) supplementation for a 2 year period on BMD, particularly at the spine in male CD patients, but no firm conclusions can be drawn until completion of the trial. In conclusion, the achievement of optimal B-vitamin status may be important for bone health in normal ageing and within CD patients.

Bone fracture, particularly that occurring in osteoporotic conditions, has become a major health issue. Fracture healing is a well-orchestrated regenerative process, the enhancement of which has been one of the major goals in fracture management. Low-magnitude high-frequency vibration (LMHFV) is osteogenic for intact bone and beneficial for limb blood circulation, which implies a potential of enhancement for fracture healing. Three parts of the experiments were conducted in this study to test the hypothesis that LMHFV would accelerate fracture healing by promoting chondrogenesis, endochondral ossification, and remodeling in both normal and osteoporotic bones. / Part I study. Three-month-old female SD rats underwent closed femoral fracture and were randomized into either vibration group (VG-I, 35Hz, 0.3g, 20min/day, 5days/week) or sham-treated control group (CG-I). Femora were harvested at 1, 2 and 4 weeks for micro-CT analysis, histomorphometry, and mechanical testing. Part II study. Osteoporotic model was established in nine-month-old SD rats after three months of inducement following ovariectomy. Similar grouping (VG-II and CG-II) and treatment regimes were performed after fracture, with the femora harvested at 2, 4 and 8 weeks for assessments like those in the Part I study. Part III study. After fracture, 3-month-old female SD rats were grouped (VG-III and CG-III) and treated as in the Part I study. At 1, 2 and 4 weeks, femora were collected for gene quantification (Col-1, Col-2, BMP-2, VEGF, and TGF-beta1) using real-time PCR. Type I and II collagens were located immunochemically in histological sections. / Results of the Part I and II studies demonstrated that LMHFV promoted callus formation (together with chondrogenesis), mineralization (endochondral ossification), and remodeling, which led to faster healing and better mechanical outcomes in both normal and osteoporotic fractures. In molecular level, the effect of LMHFV was reflected by the stimulation of chondrogenesis and osteogenesis related matrix collagen formation and growth factor expression. The molecular data echo Part I and II findings well. This study proved that LMHFV accelerated fracture healing by promoting chondrogenesis, endochondral ossification, and remodeling in both normal and osteoporotic bones, and indicated great potential of its future clinical application on fracture healing. / Shi, Hongfei. / Adviser: Kwok-Sui Leung. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3422. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 180-201). / 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.

Accurate assessment of hip fracture risk is very important to prevent hip fracture and to monitor the effect of a treatment. A subject-specific QCT-based finite element model was constructed to assess hip fracture risk at the critical locations of femur during the single-leg stance and the sideways fall. The aim of this study was to improve the prediction of hip fracture risk by introducing a more proper failure criterion to more accurately describe bone failure mechanism. Hip fracture risk index was defined using the strain energy criterion, which is able to integrally consider information such as stresses, strains and material properties in bone failure. It was found that the femoral neck and the intertrochanteric region have higher fracture risk than other part of the femur, probably owing to the larger content of cancellous bone in these regions. The study results also suggested that women are more prone to hip fracture than men. The effects of different parameters such as age, body height, weight, and BMI on hip fracture risk were also investigated in this study. The findings in this study have a good agreement with those clinical observations reported in the literature. The main contributions from this study include: (1) introducing an algorithm for hip fracture risk assessment at the critical locations of femur using the strain energy criterion and QCT-based finite element modeling, (2) theoretically more reasonable definition of hip fracture risk index based on the strain energy criterion, and (3) a semi-automatic finite element analysis and automatic calculation of hip fracture risk index at the critical locations of femur using in-house developed computer codes. The proposed hip fracture risk index based on the strain energy criterion will be a promising tool for more accurate assessment of hip fracture risk. However, experimental validation should be conducted before its clinical applications. / October 2015

Protein is an important component of bone, but the role of dietary protein intake in osteoporosis remains controversial. The Utah picture-sort food frequency questionnaire was found to produce a useful estimation of usual dietary intake in the elderly. This method of dietary assessment was used in a population-based case-control study to examine the relationship between protein intake and risk of osteoporotic hip fracture in elderly Utah residents. Analyses of risk of hip fracture across increasing quartiles of protein intake were stratified by age-group. Higher protein intake was associated with a reduced risk of hip fracture in men and women aged 50-69 years but did not appear to increase or decrease risk of hip fracture in those aged 70-89 years. The relationship appeared to be modified by age. Modification of protein intake late in life may be a useful means to prevent hip fractures in the elderly.

Introduction Chronic liver disease (CLD) causes more than 1 million deaths every year and remains a pandemic in the last decade affecting more than 600,000 patients in the United States. Previous studies found patients with CLD had increased risk of osteoporosis, so fractures were inferred to be complications of this condition. The aim of this meta-analysis is to summarize the best evidence that correlates CLD patients and the risk to develop osteoporotic fractures versus control patients without CLD. Methods A review of the literature using MEDLINE and EMBASE database was performed during December 2017. We included cross-sectional and cohort studies that reported relative risks (RR), odds ratios (OR) and hazard ratios (HR) comparing the risk of developing osteoporotic fractures among patients with CLD versus patients without CLD. Pooled OR and 95% confidence interval (CI) were calculated using generic inverse- variance method. The Newcastle-Ottawa scale was used to determine the quality of the studies. Effect estimates from the individual study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. Results After the review of the literature, seven studies fulfilled the eligibility criteria established during the analysis. Significant association was found between CLD and osteoporotic fractures with a pooled OR of 2.13 (95% CI, 1.79 - 2.52). High heterogeneity among the studies was found (I2=88.5). No publication bias was found using Egger regression test (p=0.44). Conclusion We found a significant association between CLD and the risk of developing osteoporotic fractures. The calculated risk was 2.13 times higher for patients with CLD when compared with controls. The results showed high heterogeneity but no publication bias. More prospective studies are needed to fully understand the mechanisms involved in loss of bone density and osteoporotic fractures in order to improve the morbidity associated with this disease.

Osteoporosis is a disease prevalent in older adults, characterized by increased bone porosity resulting in significant fracture risk. Orthopaedic implants are designed and validated against cadavers from the general ‘healthy’ population, but little is known about their response in osteoporotic bone. Orthopaedic implants can also be developed using synthetic bones, if they have been demonstrated to be representative of healthy bone, and offer a number of advantages. To date, no synthetic femur has been validated for the osteoporotic population. The purpose of this study was to assess novel synthetic femurs for representing this population. Custom jigs were manufactured to test two sets of ten synthetic femurs and five isolated cadaveric femurs in four-point bending, torsion, axial compression, axial failure, and screw pullout, using an Instron mechanical testing machine to record load-displacement data. Statistical significance was found in bending, torsion, and screw pullout between both synthetic sets and cadavers using one-way ANOVA with post-hoc Tukey analysis. In all instances, the synthetic femurs had lower coefficients of variation than natural specimens. Both synthetic and cadaveric femurs were CT scanned prior to testing. The data were used to measure key anatomical details and to develop a series of numerical models of the synthetic bones, using Materialize Mimics® and ABAQUS® software, evaluated using axial and bending data. The model was modified by reducing cortical thickness and modulus in an attempt to make the synthetic model better represent osteoporotic bone. Establishing synthetic femurs as suitable replacements for osteoporotic bone allows for improved orthopaedic implant development. The digital model constructed allows the synthetic to be further analyzed, improving expected response of the synthetic bones. These synthetic bones could provide a foundation for development of effective orthopaedics for this population. / Thesis / Master of Applied Science (MASc) / The considerations and parameters in the design of orthopaedic implants for osteoporotic bone are relatively unknown. Orthopaedic implants can be evaluated with synthetic bones, which offer a number of advantages to natural specimens, assuming they are sufficiently representative of natural bone. No physical synthetic model yet exists that represents an osteoporotic femur. In the present work, synthetic femurs were subjected to bending, torsion, axial compression, and screw pullout and compared to natural osteoporotic specimens. The synthetics were significantly different to natural specimens in bending, torsion, and screw pullout. A numerical model was created, evaluated, and tested in finite element software alongside modified models with reduced modulus and cortical thickness to assess stiffness. Recommendations were made to improve the accuracy of a future synthetic model. The synthetic femurs tested were not representative of osteoporotic femurs, but may be feasible alternatives with minor modifications and could be useful in future orthopaedics design.

O rápido envelhecimento da população brasileira cria um contexto de assistência prolongada e específica a morbidades que tendem a ampliar a duração do tratamento, as incapacidades dos indivíduos, os gastos com exames complementares, internações hospitalares e medicação. Dentro desse contexto, a osteoporose, doença intimamente relacionada com o envelhecimento, pode ter um aumento considerável nos próximos anos. Conhecer quem são os indivíduos em risco de desenvolver a doença é fundamental, uma vez que a fratura, sua mais importante conseqüência clínica, representa gastos elevados com serviços de saúde e está associada à alta taxa de morbidade e mortalidade. O exame indicado pela Organização Mundial da Saúde (OMS) como padrão-ouro para o diagnóstico da osteoporose é o exame de densitometria óssea (DXA), Devidos aos custos e acesso restrito e assim, selecionar candidatos ao exame é uma questão com importantes implicações clínicas e sócioeconômicas. O objetivo deste estudo foi avaliar a validade diagnóstica da radiografia panorâmica para identificação de mulheres na pós-menopausa com baixa massa óssea. Foram utilizados: questionário baseado nos fatores clínicos de risco para osteoporose, exame de densitometria óssea (fêmur, coluna e antebraço), radiografia panorâmica digital e o São Paulo Osteoporosis Risk Index (SAPORI). O estudo é do tipo observacional transversal. Os valores de sensibilidade e especificidade, valor preditivo positivo e negativo foram calculados. A amostra foi constituída por 88 mulheres na pós-menopausa com média de idade de 61 anos. A baixa massa óssea no quadril foi observada em 62 mulheres (70,5%), na coluna em 61(69,3%), no antebraço em 78 (88,6%) e 52 (59,1%) na mandíbula. Fratura após os 50 anos de idade foi observada em 17 mulheres (19,3%) e 37 (42%) relataram ocorrência de queda nos últimos 12 meses. A radiografia panorâmica é um instrumento válido para a identificação de mulheres na pósmenopausa com baixa densidade mineral óssea / The rapid aging of the Brazilian population creates a context of prolonged and specific assistance to morbidities that tend to increase the time of treatment, disabilities and costs related to clinical tests, hospital admissions and medication. Within this context, the osteoporosis, disease closely related to aging, can have a significant burden in the next years. Identifying people at risk to present the disease is essential, once fracture, its main clinical consequence, represents high costs related to health services and is associated to the high rate of morbidity and mortality. The bone densitometry (DXA) is recommended by the World Health Organization as the gold standard test to the osteoporosis diagnosis. Due to the costs associated and restricted access, to select candidates to the exam is an important issue, with clinical and socioeconomic implications. The objective of this study was to evaluate the diagnostic validity of the panoramic radiography to identify women with low bone density. The following were performed: questionnaire based on clinical risk factors for osteoporosis and fragility fracture, bone densitometry (hip, spine and forearm), digital panoramic radiography and the São Paulo Osteoporosis Risk Index (SAPORI). This is a cross-sectional study. The values sensitivity, specificity, positive and negative predictive values were calculated. The sample was constituted of 88 post-menopausal women with an average age of 61 years. Low bone density in the hip was observed in 62 women (70.5%), in the spine in 61 (69.3%), in the forearm in 78 (88.6%) and 52 (59.1%) in the mandible. Fracture after 50 years old was observed in 17 women (19.3%) and 37 (42%) of the sample reported fall in the last 12 months. The panoramic radiography is a valid instrument to identify postmenopausal women with low bone density

O rápido envelhecimento da população brasileira cria um contexto de assistência prolongada e específica a morbidades que tendem a ampliar a duração do tratamento, as incapacidades dos indivíduos, os gastos com exames complementares, internações hospitalares e medicação. Dentro desse contexto, a osteoporose, doença intimamente relacionada com o envelhecimento, pode ter um aumento considerável nos próximos anos. Conhecer quem são os indivíduos em risco de desenvolver a doença é fundamental, uma vez que a fratura, sua mais importante conseqüência clínica, representa gastos elevados com serviços de saúde e está associada à alta taxa de morbidade e mortalidade. O exame indicado pela Organização Mundial da Saúde (OMS) como padrão-ouro para o diagnóstico da osteoporose é o exame de densitometria óssea (DXA), Devidos aos custos e acesso restrito e assim, selecionar candidatos ao exame é uma questão com importantes implicações clínicas e sócioeconômicas. O objetivo deste estudo foi avaliar a validade diagnóstica da radiografia panorâmica para identificação de mulheres na pós-menopausa com baixa massa óssea. Foram utilizados: questionário baseado nos fatores clínicos de risco para osteoporose, exame de densitometria óssea (fêmur, coluna e antebraço), radiografia panorâmica digital e o São Paulo Osteoporosis Risk Index (SAPORI). O estudo é do tipo observacional transversal. Os valores de sensibilidade e especificidade, valor preditivo positivo e negativo foram calculados. A amostra foi constituída por 88 mulheres na pós-menopausa com média de idade de 61 anos. A baixa massa óssea no quadril foi observada em 62 mulheres (70,5%), na coluna em 61(69,3%), no antebraço em 78 (88,6%) e 52 (59,1%) na mandíbula. Fratura após os 50 anos de idade foi observada em 17 mulheres (19,3%) e 37 (42%) relataram ocorrência de queda nos últimos 12 meses. A radiografia panorâmica é um instrumento válido para a identificação de mulheres na pósmenopausa com baixa densidade mineral óssea / The rapid aging of the Brazilian population creates a context of prolonged and specific assistance to morbidities that tend to increase the time of treatment, disabilities and costs related to clinical tests, hospital admissions and medication. Within this context, the osteoporosis, disease closely related to aging, can have a significant burden in the next years. Identifying people at risk to present the disease is essential, once fracture, its main clinical consequence, represents high costs related to health services and is associated to the high rate of morbidity and mortality. The bone densitometry (DXA) is recommended by the World Health Organization as the gold standard test to the osteoporosis diagnosis. Due to the costs associated and restricted access, to select candidates to the exam is an important issue, with clinical and socioeconomic implications. The objective of this study was to evaluate the diagnostic validity of the panoramic radiography to identify women with low bone density. The following were performed: questionnaire based on clinical risk factors for osteoporosis and fragility fracture, bone densitometry (hip, spine and forearm), digital panoramic radiography and the São Paulo Osteoporosis Risk Index (SAPORI). This is a cross-sectional study. The values sensitivity, specificity, positive and negative predictive values were calculated. The sample was constituted of 88 post-menopausal women with an average age of 61 years. Low bone density in the hip was observed in 62 women (70.5%), in the spine in 61 (69.3%), in the forearm in 78 (88.6%) and 52 (59.1%) in the mandible. Fracture after 50 years old was observed in 17 women (19.3%) and 37 (42%) of the sample reported fall in the last 12 months. The panoramic radiography is a valid instrument to identify postmenopausal women with low bone density

The management of significant bone defects, delayed and non-union of fractures can be extremely challenging. Development of specific treatment is hindered by an absence of information regarding the molecular events which regulate these processes. In this thesis, a bilateral cancellous bone defect model of the femur and tibia was developed in a rodent and the spatiotemporal profile of TGF-β, BMP 2 and 7, Smads 1, 4 and 5 characterised. Next, the capability of acid solution to augment healing was tested in both a bone defect and in a closed femoral fracture model. Finally, a long term oestrogen deficiency (OVX) rat model of postmenopausal osteoporosis was characterised and the spatiotemporal profiles of IGF-1, IGFR-1, MMP-1, MMP-3, MMP-9, MMP-13, TIMP-1, TIMP-2, BMP-2, BMP-4, BMP-7, TGF-β, Smad4, Smad7, VEGF, Flt-1, Ihh and FGF-2 were compared in femoral osteotomies between OVX and Sham groups. The bilateral cancellous defect model was successfully created with a number of advantages with which to recommend its use in future studies. TGF-β, BMP 2 and 7, Smads 1, 4 and 5 had characteristic spatiotemporal profiles during cancellous bone defect healing suggesting that they have a regulatory role. The results of the acid study were inconclusive and problems with substance delivery and maintenance at the desired site need to be addressed in the future to fully test this hypothesis. No significant differences were detected on histology or three-point mechanical testing between the fracture calluses of acid and control groups. In the final study, OVX rats after six months had significantly increased weight and decreased bone mineral density compared to their sham counterparts. A histological delay in osteotomy healing was observed in the OVX group but no significant differences on tensile testing were seen between OVX and Sham groups up to six weeks. Immunohistochemistry revealed that delayed healing may be due to the down-regulation of IGF-1, BMP-2, 4, and 7 and the up-regulation of MMP-3 in OVX compared to Sham groups. In conclusion, the results of this thesis give some insight into the molecular biology of bone defects and osteoporotic fractures. This information may also be useful in the development of specific treatments aimed at augmenting healing in bone defects and osteoporotic fractures.