Sweden has one of the highest incidences of osteoporotic fractures in the world. A more sedentary lifestyle is one of several proposed reasons for the increase in osteoporosis seen in the developed countries. The aim of this thesis was primarily to study the influence of muscle strength, and body composition, on bone mineral density, BMD, in young adults. The second aim was to evaluate the possible influence of estrogen on muscle strength in women. A population-based study of 113 subjects (53 men and 60 women) aged 22-85 showed associations for premenopausal, but not postmenopausal women, between isometric quadriceps muscle strength and BMD in the total body, lumbar spine, and femoral neck. In men there was only an association between muscle strength and BMD in the total body. Another population-based study of 125 randomly selected young adults (64 women and 61 men) showed that total body BMD, TBMD, is influenced by isokinetic knee flexion and extension strength in women but not in men where body composition influenced TBMD. In 159 randomly selected young adult women (20-39 years) knee flexion and extension strength influenced not only TBMD but also total hip BMD, and heel BMD. However, lean body mass and body weight were better predictors for BMD at these skeletal sites. An extension of this study involving 335 women again demonstrated that lean body mass is the best predictor of BMD. This study also showed that Uppsala women aged 20-39 years have a BMD that is approximately 0.1-1.2 SD (2-12 %) above international/national references. In addition marked variations in BMD T-scores between various skeletal sites were noted. In Conclusion: The association between muscle strength and BMD is evident in women in their early twenties but with age lean body mass and body weight becomes better predictors for BMD. In men lean body mass and body composition but not muscle strength predicted BMD. Hormone replacement therapy does not influence muscle strength and there is no association between allelic variations in the estrogen receptor alpha and muscle strength in women.

Important candidate genes to human bone phenotypes are those involved in the regulation of hormonal action, such as the vitamin D receptor (VDR) and the estrogen receptor-α (ERα) genes and their cofactors. RIZ1 is a specific ERα cofactor proved to strongly enhance the function of the ERα. The main focus of this thesis has been to study genetic variants in the VDR and RIZ genes and their associations to human bone phenotypes using candidate gene and functional approaches. Specifically, polymorphisms in the VDR 3’ untranslated region (UTR) and a deletion/insertion polymorphism of a proline in the RIZ gene were investigated. The candidate gene approach was applied to large-scale population-based cohorts of pre-and post-menopausal women from Sweden and of elderly men from Sweden and Hong Kong. VDR 3’ UTR polymorphisms were associated with peak bone mass and body composition in young women. Further analysis of common VDR 3’ UTR haplotypes confirmed the association with BMD and risk of fractures in elderly men from Sweden and Hong Kong. The VDR polymorphisms were investigated for cis-acting effects, affecting allelic expression in the normal chromosomal context of human bone cells. The VDR allelic transcripts in the bone samples were unequally expressed, suggesting presence of regulatory variants in the 3’ UTR. The polymorphism in the RIZ gene was strongly associated to BMD in pre- and postmenopausal women and in elderly men. The functional analyses included reporter constructs containing the RIZ polymorphic variants transfected in a cell line and its abilities in coactivating the ERα were examined. The variants were functionally different in coactivating the ERα-receptor complex. To summarize, the results of this thesis show novel evidence for functional relevant polymorphisms in candidate genes to human bone phenotypes. These polymorphisms may contribute to the variation seen in BMD and risk of fractures in the population.

Reactive oxygen species (ROS) induce oxidative stress and although are primarily recognized for playing a deleterious biological role, they can be beneficial to cell systems. ROS are extremely short-lived and normally tightly regulated by antioxidant defence systems. Cells react to oxidative stress in different ways, which primarily depends on cell type, stress severity, or both. There is a general limitation in extrapolating to humans conclusions drawn from in vitro and animal studies because of important species-specific differences. Therefore, the general aim of this thesis was to study the influence of oxidative stress on human muscle and bone in vivo. In paper I we presented a one-step HPLC method optimized for the simultaneous determination of purine degradation products in small microdialysis samples. The clinical utility of the method was successfully tested in a patient with traumatic brain injury. In paper II we evaluated microdialysis as an in vivo method to characterize the relative kinetics of ROS-related metabolites in human skeletal muscle exposed to ischaemia-reperfusion. Results indicated that microdialysis was feasible and safe to use in monitoring metabolic events during tourniquet-assisted surgery. In paper III we investigated the association between an oxidative stress marker (urinary 8-iso-PGF2α) and bone mineral density (BMD) and whether α-tocopherol modified the association. The main finding was the negative association between 8-iso-PGF2α and BMD and that the association was further dependent on serum α-tocopherol level. In paper IV we performed a randomized controlled trial to evaluate the influence of Q10 supplementation on exercise performance and metabolites of muscular damage. We did not observe any effects on exercise capacity after 8 weeks of Q10 administration. Nor did we find a significant effect on serum markers related to oxidative stress. In conclusion we have studied the influence of oxidative stress on muscle and bone in vivo in humans. The oxidative stress was triggered by four different causes (trauma, ischemia-reperfusion, ageing, and exercise exhaustion).

In Sweden approximately 25000 distal radius fractures occur annually, which is 37 % of all fractures related to osteoporosis. In this thesis, risk factors for osteoporosis, bone mineral density (BMD) and health-related quality of life (the SF-36) were compared in patients who suffered a distal radius fracture after low energy trauma with a control group matched on the basis of age, gender, and municipality of residence. The aim was also to analyse, among these patients, whether a risk factor questionnaire, tests on dynamic and static balance and a one-leg rise test could identify those, who have osteopenia or osteoporosis, and run a risk of new falls. Moreover, in a three-year follow-up, mortality, the need for in- and outpatient care, and health-related quality of life after radius fracture were investigated and compared between the patients and matched controls. Finally, the effect of a preventive intervention program including patient education and self-training was evaluated. Falls were reported in a risk factor questionnaire and in a fall diary. The patients aged 45-64 years showed lower, although not statistically significant, BMD, compared with the controls of the same age, but there was no difference concerning their history of falls. In contrast, the patients aged 64 years or older had a history of falling more often than the corresponding controls, but no difference in BMD was found. For all other risk factors, except falls, no differences were found between the patients and the controls. The results of the one-leg rise test were associated with those of dynamic and static balance, but none of the functional tests were associated with the number of falls. Decreased height and cigarette smoking were the only risk factors, which predicted osteopenia and osteoporosis. Five patients, although none of the controls, died during the study time. The patients needed statistically significantly more episodes as inpatients than the controls. The patients also had lower SF-36, Role Physical scores, than the controls at three months. This difference disappeared by the time of the follow-up. Both the patients, who participated in a four-week intervention program, “the osteoporosis school” followed by a one-year home-based exercise program, and the controls showed statistically significantly improved dynamic and static balance, ability to walk backwards and to stand on one leg with eyes open and closed at the end of the study. However, no significant differences were found between the patients and the controls in any of the tests, in BMD or in the number of the falls. The thesis shows that, except for the falls in patients aged over 64 years, there were no significant differences between patients and controls with respect to BMD and other risk factors related to osteoporosis. Consequently, in patients aged 45-64 years and older, the underlying cause of a distal radius fracture is more related to falls than to osteoporosis. Furthermore, the thesis shows that the functional tests and the risk factor questionnaire seem to be of limited value for identifying 8 people with a radius fracture, who are at risk of falling or have osteopenia or osteoporosis. If, in spite of this, functional tests on musculoskeletal function are considered for testing of functional ability in patients with a recent radius fracture, the one leg-rise test may be sufficient. There seems to be an increased mortality and morbidity necessitating inpatient care among patients with a recent radius fracture. The osteoporosis school had no significant effect on BMD, balance, muscle strength or falls in this thesis. Therefore, the lack of proven efficacy of the osteoporosis school for the secondary prevention of distal radius fractures highlights the need for more and long-term randomised controlled follow-up studies in this specific population.

The main purpose of this study was to determine whether playing soccer at high intensity training for a long period causes degeneration of the lumbar spine or not. This degeneration may occur without any symptoms or low back pain. Results of the present study were discussed in the framework of lumbar disc degeneration, trunk strength, lumbar and hip bone mineral density, trunk flexibility, activity MET scores for active and veteran soccer groups. There have been four subject groups in this study (15 active soccer players, 15 sedentary participants, 14 veteran soccer players, 13 sedentary participants). The BMD was measured in anterior-posterior view with a second-generation dual energy X-ray absorptiometry (DEXA) device. Isokinetic trunk strength data were recorded with the Biodex System Dynamometer (Biobex Medical Inc, Shirly, NY) at the 60&ordm / /sec and 120&ordm / /sec. Plain lateral radiographs were taken. The presence of degenerative changes of each lumbar vertebra was determined by using the Kellgren and Lowrence Score. A modified Schober test was used to measure lumbar flexion. Findings of the study demonstrated that veteran soccer players displayed greater lumbar disc degeneration than other groups. Moreover, v active soccer group had more BMD than other groups, but the veteran group&amp / #8217 / s BMD results were not different while comparing the control participants. Isokinetic test findings of the current study, trunk extension strength at 60/sec was significantly higher in active 1st group players than 2nd group participants, but there were no significant differences between the 1st group and 2nd group in terms of trunk flexion strength and agonist/antagonist ratio at 60/sec. In conclusion, Findings of the study support the main hypothesis that playing soccer at high intensity training at a long period of time may cause lumbar spine degeneration. Degeneration may occur without low back symptoms. Moreover, results supported the idea that Soccer can be accepted an impact loading sport that are to keep or accelerate bone mineral density. At last, having abnormal trunk extension strength while playing actively may cause lumbar disc degeneration on the spine at later years. A similar study should be carried out with a larger number of subjects, and longitudinal studies should be designed to examine the factors that effect the degeneration on the lumbar spine.

No description available.

No description available.

No description available.

The objective of this study was to examine the link between radiographic measures of bone quality and total knee implant migration as measured by radiostereometric analysis (RSA). Two uncemented total knee arthroplasty studies (n=65) with RSA and bone mineral density (BMD) exams up to two years post surgery, and one study with cemented total knees with one year RSA data (n=18) were examined. Radiograph image texture analysis was used to characterize the bone microarchitecture, and a feasibility study was conducted to determine if a given x-ray machine could be used to obtain bone mineral density at the same time as the RSA exams. Random ForestTM ensemble classification tree statistical models classified patients into groups based on implant migration with a range of cut-points. Models based on bone texture parameters measured from the two year radiographs had a sensitivity of 87.5% and specificity of 80% when classifying patients who had more than 0.3mm maximum total point motion (MTPM) at two years using the one year exam as reference. Other cut-points were examined, with models generally having a lower specificity if the acceptable migration was smaller, and lower sensitivity if higher migrations were tolerable. In a predictive model, post-operative bone texture could be used to create a model with a sensitivity of 75% and a specificity of 80% when predicting those subjects with cemented implants who went on to more than 0.4mm total migration by one year. Bone mineral density of the proximal tibia, as determined by clinical scanners, was not found to increase the accuracy of implant migration group classification. An empirical fit to central regions of a purposed-built cross-wedge calibration phantom returned residuals of less than ±1.5% for the bone-equivalent thicknesses. The coefficient of variation of the region greyscale values in three images spread over three days is under 4%, showing the stability of the system to hold a calibration between phantom exams and patient scans. Scatter and dynamic range issues will need to be considered for an accurate calibration across the full range of areal bone mineral densities in the distal femur and proximal tibia.

Background: Phytoestrogens are diphenolic compounds found in plants with a structure and molecular weight similar to oestradiol which enables them to bind to the oestrogen receptor. Isoflavonoids occur mainly within the legume family with highest concentration in soybeans. Lignans are found in a range of plant foods and the richest known source is linseed. Few studies have been published on intake of isoflavonoids and none were located on intake of lignans in Australian women. The validity of methods designed to estimate intake can be assessed using urinary excretion of isoflavonoids and lignans as studies have found an association between intake and excretion of isoflavonoids and lignans. It has been proposed that, through their ability to act like oestrogen, phytoestrogens could decrease bone turnover and attenuate the loss of bone mineral density (BMD) at menopause. The aims of this research were to determine the pattern of intake of isoflavonoids and lignans in 500 women from food and supplements and to assess a questionnaire used to estimate intake using excretion in a sub-sample of 141 women. Associations between usual intake or excretion of isoflavonoids and lignans and biomarkers of bone health were also examined. Methods: A cross-sectional study was conducted involving 500 women aged 40-80 years participating in the Longitudinal Assessment of Ageing in Women (LAW), a 5 year study being conducted in the Betty Byrne Henderson Centre at the Royal Brisbane and Women's Hospital. Subjects were randomly selected from the electoral role and stratified into ten year age groups. Intake of isoflavonoids and lignans from food and supplements was assessed using a specially designed questionnaire containing 110 items. Values for individual items were obtained from published literature and summed to provide average daily intakes of isoflavonoids and lignans (mg/d). A sub-sample of 141 women was recruited to take part in the assessment of the association between phytoestrogen intake and excretion. Participants collected three 24-h urine samples spaced over one week. Samples were analysed using high performance liquid chromatography MS/MS for seven isoflavonoids and four lignans. Bone mineral densities (BMD) of the femur neck, total hip and lumbar spine were measured by dual energy x-ray absorptiometry. Bone formation was assessed using serum bone alkaline phosphatase (bone ALP) and osteocalcin (OC) and bone resorption was assessed using deoxypyridinoline (DPD) and urinary excretion of N-terminal cross-linking telopeptide of type-I collagen (NTX). Potential confounding factors were also evaluated. Statistical analyses were conducted using SPSS for windows (version 10). Participants were defined as consumers if they reported intake of one or more serves of soy or linseed in the prior month. Differences in socio-demographic and lifestyle characteristics between groups were assessed using ANOVA and Chi Square tests. Associations between intake and excretion of phytoestrogens were assessed using Spearman's rank-order correlations () for non-normal data. Phytoestrogen intake was categorised into four groups for the assessment of the association with markers of bone health. Associations between phytoestrogen excretion and markers of bone health were assessed using Pearson's product moment correlations for normal data (r) and Spearman's rank-order correlations for non-normal data. A value of P < 0.05 was taken as statistically significant. Results: Consumption of soy food was reported by 40% and consumption of linseed by 34% of women. Median (range) intakes among soy/linseed consumers for isoflavonoids, 3.87 (0-173) mg/d, and lignans, 2.40 (0.1-33) mg/d, were significantly higher than corresponding intakes among non consumers of 0.005 (0-2.6) and 1.57 (0.4-4.7) mg/d, respectively (P < 0.001). Soy/linseed consumers reported higher intakes of energy (P=0.043), dietary fibre (P=0.003) and polyunsaturated fat (P=0.004); and a higher level of physical activity (P=0.006), SEP (P < 0.001), education (P < 0.001) and supplement use (P < 0.001). Use of non-prescription supplements for menopause in the previous month was reported by 13% of women. A review of supplements available for treatment of menopause indicated that use of soy, red clover, black cohosh and sage could have a role in treatment of menopause symptoms. Evidence supporting the presence of oestrogenic components was available for soy and red clover isoflavonoids only. There was a significant association between intake and excretion of isoflavonoids within the total group (r=0.207, P < 0.05), with a stronger association in soy consumers (r=0.364, P < 0.01). Excretion of isoflavonoids was detected in women who did not report known intake of soy foods, suggesting isoflavonoids could be derived in small amounts from other plant foods or use of soy as an ingredient in processed foods. There was no significant association between intake and excretion of lignans, however both intake and excretion were associated with dietary fibre (r=0.303 and r=0.230, respectively, P < 0.01 for both). Bone ALP was higher among the very low isoflavonoid intake group (P=0.005) for the total sample (P=0.005) and women with BMI≤25 kg/m2 (P=0.002). Data also demonstrated an inverse association between excretion of isoflavonoids and NTX within women with BMI≤25 kg/m2 (r=-0.33, P < 0.05). There was a positive association between lignan excretion and bone ALP in the total sample (r=0.21, P < 0.05) which was strengthened in women with osteoporosis/osteopenia (r=0.41, P < 0.05) and a positive association between lignan excretion and DPD among women with BMI≤25 kg/m2 (ρ=0.28, P < 0.05) All associations remained significant after adjustment for confounding. Conclusions: Few women who chose phytoestrogen-rich foods consumed amounts similar to women with traditional soy-based diets although some achieved high intakes with supplements. Women who consumed soy or linseed foods differed in lifestyle and sociodemographic characteristics that could influence the association with disease in epidemiological studies. Results indicated that the phytoestrogen questionnaire was useful for assessment of isoflavonoids but was not acceptably precise for measurement of lignans. Findings suggest that there is an inverse association between isoflavonoid status and bone ALP and NTX although the precise mechanism of action has not been clarified. The association between lignan intake and bone is less well understood; however findings of a positive association with bone ALP indicate that further research on the lignan content of foods and the inclusion of lignans in studies is warranted.