Sweden and Norway have the worldwide highest incidence of osteoporotic fractures. As these fractures constitute a tremendous and growing problem, primary prevention is of great importance. The principal causes of an osteoporotic fracture are a fall and a fragile skeleton. The aim of the studies reported in these papers was therefore to determine the genetic and environmental influences on fractures and the genetic influence on the two main reasons to the emergence of osteoporotic fractures; bone mineral density and propensity to fall. In the present thesis, we display that the heritability of fractures is dependent on fracture site and age. With increasing age, lifestyle becomes the dominant explanatory factor. These results indicate that focus should be on lifestyle interventions for the prevention of fractures in the elderly. Although the genetic liability to impaired balance is modest, twins with self-reported impaired balance have a substantially increased risk of osteoporotic fractures compared to their co-twin without impaired balance. Asking a patient about his or her balance might be a simple tool for future risk assessment. The genetic influence on bone phenotypes is under strong genetic influence in Swedish adult twins. These findings are in agreement with the results from previous studies in other countries, with a lower incidence of osteoporotic fractures compared to Sweden. The high heritability of bone phenotypes together with the low heritability of fractures at old age, indicates that bone mineral density has a modest influence on fracture risk at old age. In summary, based on the results in this thesis, more emphasis should be targeted to the prevention of falls, by strength and balance training in order to prevent the occurrence of  low energy fractures in the elderly.

Research Objectives: Osteoporosis has become a significant public health problem in recent years, especially with the growth of the elderly population. Osteoporotic fractures exact a terrible toll on the population with respect to morbidity, cost, and to a lesser extent mortality. These effects can lead to psychological problems, social consequences, functional limitations, and poor quality of life. Thus, knowledge regarding osteoporotic fractures is needed to evaluate the impact of osteoporotic fractures on society, to identify high-risk populations, and to help policymakers to allocate resources accordingly. This study aims to investigate the influence factors of hospital readmissions among osteoporotic fractures patients in Taiwan, and the study results are expected to increase our understanding of the magnitude of the elderly population suffering from osteoporotic fractures and to urge policymakers to develop effective national prevention strategies. Study Design: Using Taiwan¡¦s National Health Insurance database, we identified elderly patients with a hospitalization for osteoporotic fractures between 2001 and 2007. We divided readmissions into different groups (14-day, 30-day, 180-day and over 180-day) and evaluated each group¡¦s demographic, hospital characteristics, and Charlson Comorbidity Index. The claims data are also used to calculate the health services utilization of osteoporotic fractures among those elderly patients with or without readmission of osteoporotic fractures. The data analyses were carried out by Chi-square test, t test, multiple linear regression and multivariate logistic regression. Population Studied: Patients aged 50 or older with osteoporotic fractures were identified based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Principle Findings: Among 5483 osteoporotic fractures patients, 6.9% of them were readmitted within 14 days, 34.7% were readmitted within 30 days and 13.9% were readmitted within 180 days. The medical resource utilizations were significantly higher in patients with readmissions than those without readmission. Age and Charlson Comorbidity Index were significantly affected the probabilities of readmissions. Conclusion: From the perspective of health policy, the issue of osteoporotic fractures will become increasingly important in the future. This national study will help raise awareness of osteoporotic fractures and hopefully motivate public health policy makers to develop effective national prevention strategies against osteoporosis to prevent osteoporotic fractures.

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Bone is refractory to most conventional biochemical Procedures. However because it is now possible to cut sections (e. g. lopm) of fresh, undemineralized adult bone, this tissue can be analyzed by suitably modified methods of quantitative cytochemistry. A new substrate for assaying hydroxyacyl dehydrogenase activity demonstrated that bone cells may use fatty acids as a major source of energy: detailed analysis of the activities of key enzymes indicated that the paradox of ‘aerobic glycolysis’ of bone could be explained by fatty acid oxidation satisfying the requirements of the Krebs' cycle and directing the conversion of pyruvate to lactate The influence of glucose 6-phosphate dehydrogenase (G6PD) activity in aerobic glycolysis has been considered. The inverse relationships between this activity and that of Na-K-ATPase led to the development of a new method for the latter, based on a new concept in cytochemistry ('hidden-capture' procedure). A major feature of fracture-healing is increased periosteal G6PD activity. The association with the vitamin K cycle has been investigated by feeding rats with dicoumarol which not only inhibited bone-formation but also G6PD activity. The stimulation of this activity in fracture-healing has been linked with ornithine decarboxylase (ODC) activity, for which a new method has been developed. Rats deficient in pyridoxal phosphate (cofactor for ODC) had decreased G6PD responses and also appeared to become osteoporotic. Studies on osteoporotic fractures in the human showed the presence of relatively large apatite crystals close to the fracture-site, and disorganized glycosaminoglycans (demonstrated by the new method of ‘induced birefringence’).

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.

The relationship between milk intake and risk of osteoporotic fractures is uncertain. Associations between milk intake and milk avoidance in relation to osteoporotic hip fracture were examined in the Utah Study of Nutrition and Bone Health (USNBH), a statewide case-control study. Cases were ascertained at Utah hospitals treating 98 percent of hip fractures during 1997-2001 and included 1188 men and women aged 50-89 years. Age- and gender-matched controls were randomly selected from Utah driver's license and Medicare databases (N= 1324). In-person interviews were conducted and participants reported frequency of milk intake per week at age 18 and during pregnancy among women who reported being pregnant. Milk avoidance for a period of more than one year and duration of milk avoidance were also reported. Diet and supplement intake in the one-year period before fracture (cases) or the interview (controls) was assessed using a picture-sort food frequency questionnaire. Milk consumption frequency was categorized into four levels of intake at each life stage. Total calcium intake was categorized into quintiles of distribution of intake. Logistic regression models were used to examine associations between milk intake and milk avoidance and risk of hip fracture while controlling for the potential confounding effects of gender, age, body mass index, alcohol use, smoking, physical activity, estrogen use, and total calorie, protein, calcium, and vitamin D intake. Recent milk intake, milk intake during pregnancy, and milk avoidance duration were not associated with risk of hip fracture. A borderline association was found at age 18 showing a decreased risk of hip fracture among those in the highest quartile (2: 15 cups of milk per week) of milk intake (odds ratio (OR): 0.86, 95 percent confidence interval (Cl): 0.75, 1.00; P = 0.046). Milk avoidance for a year or more was associated with an increased risk of hip fracture compared to those who did not avoid milk (OR: 1.38, 95 percent CI: 1.07, 1.78). A significant interaction was found between milk avoidance and quintile of total calcium intake (P = 0.02). Milk avoidance was associated with a significantly higher risk of hip fracture at the lowest two quintiles of calcium intake (OR: 1.72, 95 percent CI: 1.26, 2.17; P = 0.02 and OR: 1.58, 95 percent CI: 1.01, 2.15; P = 0.01, respectively) but was not associated with elevated risk among those with higher calcium intakes. In conclusion, milk intake during pregnancy for women, and in the year before hip fracture (for cases) or before interview (for controls), was not associated with hip fracture risk. The highest level of milk intake at age 18 was associated with decreased risk of hip fracture. Avoidance of milk for one year or more was associated with hip fracture risk, but only among those with low calcium intake (Q1 and Q2).

Prior studies have unequivocally established a consistent association between osteoporotic hip fracture risk and type 2 diabetes mellitus. One reason this association still remains unclear is primarily due to the limited amount of research conducted in this area. The Utah Study of Nutrition and Bone Health (USNBH) is a case-control study conducted in Utah during the period of 1997-2001 to determine risk factors for osteoporotic hip fracture. All study participants (n = 2590) were determined from Utah residents 50-90 years of age. Cases were determined from 18 Utah hospitals during 1997-2001. Age and gender-matched controls were randomly selected from the Utah Drivers License pool if less than 65 years of age and the Medicare databases if greater than 65 years of age. Logistic regression models were used to determine the association between type 2 diabetes and hip fracture risk. Logistic regression modeling controlled for gender, body mass index, smoking status, alcohol use, physical activity, education level, and estrogen use in women. The risk of hip fracture was associated with type 2 diabetes. The significant correlation was primarily found in females in which the risk of hip fracture increased accompanying diagnosis of type 2 diabetes. Estrogen usage in females decreased (p < 0.0001) hip fracture risk in both former or current users. Physical activity significantly decreased the risk of hip fracture for females (p < 0.0001) and for males (p = 0.001). Smoking and alcohol use may increase the risk of hip fracture, especially in women. This study substantiates the hypothesis that type 2 diabetes mellitus increases the risk of hip fracture.

Change in body weight is an important determinant of risk of osteoporotic hip fracture in aging adults. Weight loss has been associated with an increased risk of hip fracture and weight gain has been associated with a decreased risk of hip fracture . . Weight gain cannot be recommended as appropriate prevention against hip fracture, however, because it is associated with such adverse health outcomes as cardiovascular disease and diabetes, and weight loss is commonly recommended in the treatment of these types of diseases. Clarification of how weight loss is related to risk of hip fracture is needed to resolve this issue. An extensive review of published literature was completed to assess the relationships between hip fracture and body weight, weight change, and involuntary and voluntary weight loss. Change in body weight and weight lll loss that was either intentional or unintentional were then assessed for their effects on risk of hip fracture in a population-based case-control study of risk factors for osteoporotic hip fracture in aging Utah residents. Analyses of risk of hip fracture by quintile of weight change since age 18 and according to weight loss intention were performed through logistic regression modeling. Weight loss after age 18 was associated with an increased risk of hip fracture in men and women, and above average weight gain after age 18 was protective against hip fracture in women. Involuntary weight loss of more than 20 pounds was associated with an increased risk of hip fracture in men and women aged 50 to 69 years, but was not related to risk of hip fracture in participants aged 70 to 89. Voluntary weight loss of more than 20 pounds did not significantly increase risk of hip fracture in either age group. It was concluded that involuntary weight loss may be an important predictor of risk of hip fracture in aging adults and that voluntary weight loss may be safely recommended to aging adults without increasing their risk of hip fracture

京都大学 / 新制・課程博士 / 博士(社会健康医学) / 甲第24094号 / 社医博第125号 / 新制||社医||12(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 佐藤 俊哉, 教授 中山 健夫, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

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