<p>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.</p><p>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. </p><p><i>In Conclusion: </i>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.</p>

<p>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. </p><p>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.</p><p>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. </p><p>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. </p><p>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.</p>

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.

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