Summary: The FRAX algorithm assesses the patient’s probability of sustaining an osteoporotic fracture and can be calculated with or without densitometric data. This study seeks to determine whether in men, FRAX scores calculated without BMD, correctly identify patients with BMD-defined osteoporosis. Introduction: The diagnosis of osteoporosis is based on densitometric data, the presence of a fragility fracture or increased fracture risk. The FRAX algorithm estimates the patient’s 10-year probability of sustaining an osteoporotic fracture and can be calculated with or without BMD data. The purpose of this study is to determine whether in men, FRAX calculated without BMD, can correctly identify patients with BMD-defined osteoporosis. Methods: Retrospectively retrieved data from 726 consecutive Caucasian males, 50 to 70 years old referred to our Osteoporosis Center. Results: In the population studied, 11.8 and 25.3% had BMD-defined osteoporosis when female and male reference populations were used respectively. When the National Osteoporosis Foundation thresholds to initiate treatment are used, only 27% of patients with BMD-defined osteoporosis, but 4% with normal BMD reached/exceeded these thresholds. Lowering the threshold increased sensitivity, but decreased specificity. Conclusions: Our results suggest that FRAX without BMD is not sensitive/specific enough to be used to identify Caucasian men 50 to 70 years old with BMD-defined osteoporosis.

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.

Background: The global burden of osteoporosis includes considerable numbers of fractures, morbidity, mortality and expenses, due mainly to vertebral, hip and forearm fractures. Underdiagnosis and undertreatment are common. Several studies have shown decreased health-related quality of life (HRQOL) after osteoporotic fracture, but there is a lack of data from long-term follow-up studies, particularly regarding vertebral fractures, which are often overlooked despite patients reporting symptoms. Aim: The overall aim of this thesis was to evaluate the usefulness of a recent low-energy fracture as index event in a case-finding strategy for osteoporosis and to describe and analyse long-term HRQOL in postmenopausal women with osteoporotic fracture. The specific aims were to describe bone mineral density and risk factors in women 55-75 years of age with a recent low-energy fracture (I), estimate the impact of osteoporotic fractures on HRQOL in women three months and two years after a forearm, proximal humerus, vertebral or hip fracture (II), investigate the changes and long-term impact of vertebral or hip fracture on HRQOL in women prospectively between two and seven years after the inclusion fracture (III), and describe how HRQOL and daily life had been affected in women with vertebral fracture several years after diagnosis (IV). Design and methods: Data were collected from southern Sweden between 1998 and 2008. A total of 303 women were included in Study I, and this group served as the basis for Studies II (n=303), III (n=67), and IV (n=10). A cross-sectional observational, case-control design (I), and a prospective longitudinal observational design (II-III) were used. In Study IV a qualitative inductive approach with interviews was used and data were analysed using a qualitative conventional content analysis. Results: The type of recent fracture and number of previous fractures are important information for finding the most osteoporotic women in terms of severity (I). Hip and vertebral fractures in particular have a significantly larger impact on HRQOL evaluated using the SF-36 than do humerus and forearm fractures, both during the three months after fracture and two years later, compared between the different fracture groups and the reference population (II). Women who had a vertebral fracture as inclusion fracture had remaining pronounced reduction of HRQOL at seven years. At the mean age of 75.5 years (±4.6 SD), the prevalence of vertebral fracture suggests more negative long-term impact on HRQOL, more severe osteoporosis and a poorer prognosis than a hip fracture does, and this effect may have been underestimated in the past (III). Study IV demonstrates that the women’s HRQOL and daily life have been strongly affected by the long-term impact of the vertebral fracture several years after diagnosis. The women strive to maintain their independence by trying to manage different types of symptoms and consequences in different ways. Conclusions and implications: Type and number of fractures should be taken into account in the case-finding strategy for osteoporosis in postmenopausal women between 55 and 75 years of age. The long-term reduction of HRQOL in postmenopausal women (age span 55-75 yr) with vertebral fracture emerged clearly, compared to women with other types of osteoporotic fractures and references in this thesis. The results ought to be taken into consideration when developing guidelines for more effective fracture prevention and treatment, including non-pharmacological intervention for women with osteoporotic fractures, with highest priority placed on vertebral fractures and multiple fractures, to increase or maintain HRQOL.

Rosiglitazone (RSG) is an insulin-sensitizing drug used to treat Type 2 Diabetes Mellitus (T2DM). Clinical trials show that women taking RSG experience more limb fractures than patients taking other T2DM drugs. The purpose of this study is to understand how RSG (3mg/kg/day and 10mg/kg/day) and the bisphosphonate alendronate (0.7mg/kg/week) alter bone quality in the male, female and female ovariectomized (OVX) Zucker fatty rat model over a 12 week period. Bone quality was evaluated by mechanical testing of cortical and trabecular bone. Microarchitecture, bone mineral density (BMD), cortical bone porosity, bone formation/resorption and mineralization were also measured. Female OVX RSG10mg/kg rats had significantly lower vertebral BMD and compromised trabecular architecture versus OVX controls. Increased cortical porosity and decreased mechanical properties occurred in these rats. ALN treatment prevented these negative effects in the OVX RSG model. Evidence of reduced bone formation and excess bone resorption was detected in female RSG-treated rats.

Rosiglitazone (RSG) is an insulin-sensitizing drug used to treat Type 2 Diabetes Mellitus (T2DM). Clinical trials show that women taking RSG experience more limb fractures than patients taking other T2DM drugs. The purpose of this study is to understand how RSG (3mg/kg/day and 10mg/kg/day) and the bisphosphonate alendronate (0.7mg/kg/week) alter bone quality in the male, female and female ovariectomized (OVX) Zucker fatty rat model over a 12 week period. Bone quality was evaluated by mechanical testing of cortical and trabecular bone. Microarchitecture, bone mineral density (BMD), cortical bone porosity, bone formation/resorption and mineralization were also measured. Female OVX RSG10mg/kg rats had significantly lower vertebral BMD and compromised trabecular architecture versus OVX controls. Increased cortical porosity and decreased mechanical properties occurred in these rats. ALN treatment prevented these negative effects in the OVX RSG model. Evidence of reduced bone formation and excess bone resorption was detected in female RSG-treated rats.

Testosterone is a steroid and anabolic hormone found in all mammals. Previous research indicates that testosterone levels correlates with physical capacities related to physical performance. However, these studies refers only to men and boys. The aim of present study was therefore to investigate the potential relationship between body composition, strength, power and endurance capabilities in relation to blood levels of testosterone and DHEAS in young female football players. Seventeen female elite football (age: 15,4 ± 0,6, body mass: 57,2 ± 7,4kg, height 1,65 ±0,04m) players volunteered for the study. Morning levels of testosterone were plotted against results of Dual-energy X-ray absorptiometry, Biodex isokinetic dynamometer, maximal counter movement jump, drop jump, 10 and 20 meters sprints and aerobic fitness (Yo-Yo intermittent endurance test). Testosterone levels were significant correlated with DHEAS as well as bone density (BMD) in L1-L4 (p <0,01) and whole body (WB) BMD (p <0,05). DHEAS also correlated with BMD in L1-L4 and WB (p <0,05). No correlations were found between testosterone, DHEAS and performance capacities. These results suggest that DHEAS predict the level of testosterone and BMD in young women. However, more research is needed to clarify the relationship between testosterone, DHEAS and physical capacities in a larger group of women.

Weißbüschelaffen sind häufig verwendete Tiermodelle in der Forschung. Jedoch gibt es zu wenige Untersuchungen zu ihrem Knochenaufbau und Knochenstoffwechsel, um sie auch als Modell auf dem Gebiet der Knochenkrankheiten einsetzen zu können. Somit war es das Ziel dieser Studie, Richtwerte der Knochendichte von Weißbüschelaffen aufzustellen, diese mit denen des Menschen und anderer nichtmenschlicher Primaten zu vergleichen, sowie bestimmte Einflussfaktoren, wie Gewicht, Alter oder hormonelle Umstellungen auf die Knochendichte abzuklären. Desweiteren sollte mittels einer histologischen Darstellung der Knochen, sowie mittels immunhistologischen Nachweisen verschiedener knochenspezifischer Antigene, Gemeinsamkeiten oder Unterschiede zum Menschen im Hinblick auf Veränderungen im Knochen aufgedeckt werden. Abschließend stellte sich dann noch die Frage, ob ein therapeutisches Eingreifen bei niedriger messbarer Knochendichte möglich ist, um die Lebenssituation wieder zu verbessern. Hierzu wurde von 58 C.j. mit Hilfe des Aloka®-CT knochenspezifische Parameter im Bereich des vierten Lendenwirbels (L4) gemessen. Zusätzlich wurde Ca, Pi, AP und Östrogen im Blut bestimmt. Knochenschnitte von L4, Femurkopf/Femurhals und Femurschaft von fünf euthanasierten C.j. (4 männliche, 1 weibliches) wurden histologisch, sowie immunhistologisch (Bestimmung von OPN, OC, RUNX 2, Kollagen Typ 1, Kollagen Typ 5) untersucht. Abschließend wurde bei 2 Tieren eine Therapie mittels Zufütterung von Ca und Vitamin D durchgeführt. Trotz Unterschieden in der Höhe des BMD zum Menschen, konnten Gemeinsamkeiten bei der Reaktion auf Gewichtsveränderungen und Alter festgestellt werden. Eine Zunahme des Gewichts führte zu einer signifikanten Zunahme des BMD. Männliche Weißbüschelaffen zeigten einen Anstieg des BMD bis zu einem Alter von 96 Monaten, was bei Menschen Knochenmassepeak genannt wird, und danach einen signifikanten Abfall. Das bedeutet, dass die Knochen im Alter, genau wie beim Menschen, eine größere Frakturneigung zeigen, als bei jungen Tieren. Desweiteren zeigten Tiere mit einem hohen BMD eine signifikant niedrigere AP, als Tiere mit einem niedrigen BMD. Somit konnte dargestellt werden, dass die AP auch beim C.j. einen Marker für die Osteopenie darstellt. Dies ist ebenfalls eine Gemeinsamkeit mit dem Menschen. Immunhistologisch konnten die Knochenformationsmarker OPN, OC und RUNX 2 nur in den stabilen, bruchfesten Knochen nachgewiesen werden. Kollagen Typ I und V wurden in allen Knochen detektiert. Eine Therapie mittels Ca und Vitamin D bei Tieren mit einem pathologisch niedrigem BMD und klinischen Symptomen, zeigte einen deutlichen Anstieg der Knochendichte nach einem halben Jahr, sowie ein Verschwinden der klinischen Symptome. Schlussfolgernd lässt sich sagen, dass der Weißbüschelaffe trotz unterschiedlicher Knochendichtewerte, ein sehr gutes Tiermodell darstellt zur Untersuchung von Erkrankungen, die sich im Knochen manifestieren (z.B. Osteoporose, Ostemalazie).

The purpose of this longitudinal repeated measures experimental study was to determine the effects of bone health testing using dual energy X-ray absorptiometry (DXA) on outcomes of intentions toward and actual engagement in bone health behaviors (calcium intake, vitamin D intake, physical activity) among perimenopausal women. The Perimenopausal Bone Health Behaviors Model was developed based on the Theory of Planned Behavior and guided this study to determine how perimenopausal women respond to DXA and bone health information compared to bone health information only.One hundred fifty community-based perimenopausal women (ages 35-55) were randomly assigned to an intervention group (n=75 DXA and bone health information) or to a comparison group (n=75 bone health information). Baseline demographic data were collected. The Prevention Intentions Questionnaire and Behaviors Questionnaire were administered at baseline, at two weeks, and at two months after both groups received assigned interventions.Results showed 32% (n = 24) of intervention group women had low bone density. The intervention of DXA and bone health information showed near-significance (p = .068) over the intervention of bone health information alone in affecting women's intentions, and showed near-significance in affecting calcium intake (p = .052). Lower bone density test scores were related to higher intentions (r(74) = -.23, p = .046) at two weeks after DXA and bone health information, and were related to improved vitamin D intake (r(73) = -.25, p = .03) at two months after DXA and bone health information. At study end, Attitudes contributed 27.0% of the variance in Intentions among women who received DXA and bone health information; Attitudes, Subjective Norms, and Perceived Behavioral Control contributed 62.0% of the variance in Intentions among women who received bone health information only.Nursing interventions focusing on perimenopausal women should include providing bone health information to all perimenopausal women. Interventions targeting attitudes toward bone health behaviors may motivate some perimenopausal women to participate in behaviors that contribute to decreased risk of osteoporosis. Early detection and intervention in perimenopausal bone loss may reduce osteoporosis morbidity and may impact women's quality of life, reduce financial consequences to individuals, families, communities, and the nation.

The purpose of this study was to determine the role of body composition and fat distribution on C-reactive protein (CRP) and interleukin-6 (IL-6); determine the differences in CRP and IL-6 among HT users and non-users; determine the effect of 12-months of resistance training and resulting body composition changes on IL-6 and CRP; determine the relationship between BMD and IL-6, CRP and creatine kinase (CK). Sedentary women (N=208, age 44-66, 3-10 years postmenopausal) taking HT (N=106) or not taking HT (N=102) were randomly assigned to resistance training: HTexercise (N=55), HT-no exercise (N=45), no HT-exercise (N=53), and no HT-no exercise (N=49). The program included three weekly 60-75 minute sessions of 8 exercises performed in 2 sets of 6-8 repetitions at 70-80% of 1RM. Total fat mass (TFM), lean soft tissue mass (LSTM) and BMD were assessed by dual-energy X-ray absorptiometry (DXA). Abdominal fat mass (AFM) was assessed using DXA region of interest. For each subject, baseline and 1- year IL-6, CRP and CK were measured. High TFM, high IL-6 and HT use were independently associated with high CRP levels. A stronger relationship between IL-6 and AFM compared to TFM was found in HT users. High TFM and LSTM were significantly related to higher IL-6 levels. A stronger relationship between CRP and AFM compared to TFM was found in HT non-users. CRP was higher in HT users (5.47±5.40 mg/L) compared to non-users (2.70±3.05 mg/L) and was higher in oral (5.76±5.29 mg/L opposed; 6.14±5.97 mg/L unopposed) compared to transdermal HT users (2.65±4.44 mg/L). CRP increased slightly (p=0.077) in exercisers (0.54 ± 0.34 mg/L) not taking HT compared to controls (-0.39 ± 0.35 mg/L). Reductions in TFM were associated with reductions in IL-6 and CRP in HT users. CK was positively associated to all BMD sites at baseline. IL-6 change was positively associated with change in femur neck BMD. CRP change was inversely correlated with change in lumbar spine BMD. CK change was directly related to change in total body and femur trochanter BMD. In conclusion, reductions in TFM were accompanied by reductions in IL-6 and CRP; AFM was more strongly correlated with inflammation than TFM; 12-months of resistance training did not decrease IL-6 or CRP; IL-6 and CK were positively related to BMD, and CRP was inversely associated with BMD.

Cardiovascular disease (CVD) is the leading cause of death in the Western World, although the incidence of myocardial infarction (MI) has declined over the last decades. However, obesity, which is one of the most important risk factors for CVD, is increasingly common. Osteoporosis is also on the rise because of an aging population. Based on considerable overlap in the prevalence of CVD and osteoporosis, a shared etiology has been proposed. Furthermore, the possibility of interplay between the skeleton and adipose tissue has received increasing attention the last few years with the discovery that leptin can influence bone metabolism and that osteocalcin can influence adipose tissue. A main aim of this thesis was to investigate the effects of fat mass distribution and bone mineral density on the risk of MI. Using dual-energy x-ray absorptiometry (DEXA) we measured 592 men and women for regional fat mass in study I. In study II this was expanded to include 3258 men and women. In study III 6872 men and women had their bone mineral density measured in the total hip and femoral neck using DEXA. We found that a fat mass distribution with a higher proportion of abdominal fat mass was associated with both an adverse risk factor profile and an increased risk of MI. In contrast, a higher gynoid fat mass distribution was associated with a more favorable risk factor profile and a decreased risk of MI, highlighting the different properties of abdominal and gynoid fat depots (study I-II). In study III, we investigated the association of bone mineral density and risk factors shared between CVD and osteoporosis, and risk of MI. We found that lower bone mineral density was associated with hypertension, and also tended to be associated to other CVD risk factors. Low bone mineral density was associated with an increased risk of MI in both men and women, apparently independently of the risk factors studied (study III). In study IV, we investigated 50 healthy, young men to determine if a high-impact loading intervention in the form of a series of jumps would lead to changes in glucose and lipid metabolism. We found that the intervention group had significantly lowered serum glucose levels compared to the control group. Changes in all metabolic parameters favored the intervention group with an increase in lipolysis from baseline and a decrease in cholesterol. In summary, the proportion of abdominal and gynoid fat mass displayed contrasting associations to both CVD risk factors and MI risk. Abdominal fat mass was associated with a higher risk while a high proportion of gynoid fat mass was associated with a lower risk. Bone mineral density displayed an inverse association with MI risk, seemingly independently of CVD risk factors, suggesting other explanations to a shared pathogenesis. Finally, high impact loading on the skeleton in young, healthy men decreased serum glucose levels and tended to improve other metabolic parameters, suggesting that the skeleton can affect energy metabolism.