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Summary: In elderly men included in MrOS-Sweden, subclinical hyperthyroidism (SHyper) was markedly associated with increased risk of vertebral fractures. Introduction: Overt hyperthyroidism is associated with increased risk of fractures. However, only a few studies have investigated whether SHyper is associated with fracture risk in elderly men. We therefore investigated if SHyper was a risk factor for fractures in Swedish men. Methods: We followed (median 9.8 years) elderly men (n = 1856; mean age 75, range 69–81 years) participating in the Gothenburg and Malmö subcohorts of the prospective, population-based MrOS-Sweden study. The statistical analyses included Cox proportional hazards regression. SHyper was defined as serum thyroid-stimulating hormone (TSH) < 0.45 mIU/L (n = 38). Results: SHyper was associated with increased risk of all fractures [n = 456; hazard ratio (HR) adjusted for age, study center, and levothyroxine treatment = 1.99, 95% confidence interval (CI): 1.20–3.32], major osteoporotic fractures (MOF, n = 338; HR 2.44, 95% CI: 1.42–4.21), and vertebral fractures (n = 176; HR 3.79, 95% CI: 2.02–7.11). These associations remained after full adjustment for covariates including total hip bone mineral density and in subanalyses including only men with serum free thyroxine ≤ the upper normal limit. However, after exclusion of men receiving levothyroxine treatment, the associations with all fractures and MOF lost significance. Conclusions: In elderly Swedish men, there was a strong association between SHyper and increased risk of vertebral fractures, whereas the associations with all incident fractures and MOF need to be confirmed in further studies. [ABSTRACT FROM AUTHOR]

Summary: In elderly ambulatory men, high platelet and high neutrophil counts are related to low bone mineral density (BMD), after adjustment for relevant covariates. Low hemoglobin (hgb) is even associated with low BMD, but this relationship seems to be dependent on estradiol and osteocalcin. Purpose: Blood and bone cells exist in close proximity to each other in the bone marrow. Accumulating evidence, from both preclinical and clinical studies, indicates that these cell types are interconnected. Our hypothesis was that BMD measurements are associated with blood count variables and bone remodeling markers. Methods: We analyzed blood count variables, bone remodeling markers, and BMD, in subjects from the MrOS cohort from Gothenburg, Sweden. Men with at least one blood count variable (hgb, white blood cell count, or platelet count) analyzed were included in the current analysis (n = 1005), median age 75.3 years (range 69–81 years). Results: Our results show that high platelet counts were related to low BMD at all sites (total hip BMD; r = − 0.11, P = 0.003). No statistically significant association was seen between platelet counts and bone remodeling markers. Neutrophil counts were negatively associated with total body BMD (r = − 0.09, P = 0.006) and total hip BMD (r = − 0.08, P = 0.010), and positively related to serum ALP (r = 0.15, P < 0.001). Hgb was positively related to total hip BMD (r = 0.16, P < 0.001), and negatively to serum osteocalcin (r = − 0.13, P < 0.001). The association between platelet and neutrophil counts and total hip BMD was statistically significant after adjustments for other covariates, but the association between hgb and total hip BMD was dependent on estradiol and osteocalcin. Conclusions: Our observations support the hypothesis of an interplay between blood and bone components. [ABSTRACT FROM AUTHOR]

Summary: Death of a spouse is associated with poorer physical and mental health. We followed all married individuals, born from 1902 to 1942, during the period from 1987 to 2002, and found that widows and widowers had higher risk for hip fracture, compared with still married women and men. Introduction: Spousal bereavement can lead to poorer physical and mental health. We aimed to determine whether married women and men had an elevated risk of hip fracture after death of a spouse. Methods: In a retrospective cohort study, we followed all Swedish married individuals aged 60 to 100 years (n = 1,783,035), from 1987 to 2002. Data are presented as mean with 95% confidence interval (CI). Results: During the follow-up period, 21,305 hip fractures among widows and 6538 hip fractures among widowers were noted. The hazard ratio (HR) for hip fracture in widows compared with married women was 1.34 (95% CI 1.31 to 1.37) and for widowers compared with married men 1.32 (95% CI 1.29 to 1.35). The HR for hip fracture in the first 6 months after death of a spouse was in widows compared with married women 1.62 (95% CI 1.53 to 1.71) and in widowers compared with married men 1.84 (95% CI 1.68 to 2.03). The elevated risk was especially prominent in young widowers in the age range 60–69 years. During the first 6 months they showed a HR of 2.76 (95% CI 1.66 to 4.58) for a hip fractvure compared with age matched married men. Widows aged 60–69 years showed a HR of 1.59 (95% CI 1.26 to 1.99) compared with age matched married women. Conclusion: Our observation of a higher hip fracture risk in both genders in connection with the death of a spouse indicates a possible effect of bereavement on frailty. [ABSTRACT FROM AUTHOR]

Mice with impaired acute inflammatory responses within adipose tissue display reduced diet-induced fat mass gain associated with glucose intolerance and systemic inflammation. Therefore, acute adipose tissue inflammation is needed for a healthy expansion of adipose tissue. Because inflammatory disorders are associated with bone loss, we hypothesized that impaired acute adipose tissue inflammation leading to increased systemic inflammation results in a lower bone mass. To test this hypothesis, we used mice overexpressing an adenoviral protein complex, the receptor internalization and degradation (RID) complex that inhibits proinflammatory signaling, under the control of the aP2 promotor (RID tg mice), resulting in suppressed inflammatory signaling in adipocytes. As expected, RID tg mice had lower high-fat diet-induced weight and fat mass gain and higher systemic inflammation than littermate wild-type control mice. Contrary to our hypothesis, RID tg mice had increased bone mass in long bones and vertebrae, affecting trabecular and cortical parameters, as well as improved humeral biomechanical properties. We did not find any differences in bone formation or resorption parameters as determined by histology or enzyme immunoassay. However, bone marrow adiposity, often negatively associated with bone mass, was decreased in male RID tg mice as determined by histological analysis of tibia. In conclusion, mice with reduced fat mass due to impaired adipose tissue inflammation have increased bone mass. [ABSTRACT FROM AUTHOR]

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membraneinitiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (μCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis. [ABSTRACT FROM AUTHOR]

Estrogen treatment has positive effects on the skeleton, and we have shown that estrogen receptor alpha (ERα) expression in cells of hematopoietic origin contributes to a normal estrogen treatment response in bone tissue. T lymphocytes are implicated in the estrogenic regulation of bone mass, but it is not known whether T lymphocytes are direct estrogen target cells. Therefore, the aim of this study was to determine the importance of ERα expression in T lymphocytes for the estrogenic regulation of the skeleton using female mice lacking ERα expression specifically in T lymphocytes (Lck-ERα-/-) and ERαflox/flox littermate (control) mice. Deletion of ERα expression in T lymphocytes did not affect bone mineral density (BMD) in sham-operated Lck-ERα-/- compared to control mice, and ovariectomy (ovx) resulted in a similar decrease in BMD in control and Lck-ERα-/- mice compared to sham-operated mice. Furthermore, estrogen treatment of ovx Lck-ERα-/- led to an increased BMD that was indistinguishable from the increase seen after estrogen treatment of ovx control mice. Detailed analysis of both the appendicular (femur) and axial (vertebrae) skeleton showed that both trabecular and cortical bone parameters responded to a similar extent regardless of the presence of ERα in T lymphocytes. In conclusion, ERα expression in T lymphocytes is dispensable for normal estrogenic regulation of bone mass in female mice. [ABSTRACT FROM AUTHOR]

Aim: Hospitalization for heart failure amongst younger men has increased. The reason for this is unknown but it coincides with the obesity epidemic. The aim of this study was to evaluate the association between childhood BMI (Body Mass Index) and BMI change during puberty for risk of adult heart failure in men.Methods: Using the BMI Epidemiology Study (BEST), a population-based study in Gothenburg, Sweden, we collected information on childhood BMI at age 8 years and BMI change during puberty (BMI at age 20 - BMI at 8) for men born 1945-1961, followed until December 2013 (n = 37 670). BMI was collected from paediatric growth charts and mandatory military conscription tests. Information on heart failure was retrieved from high-quality national registers (342 first hospitalizations for heart failure).Results: BMI change during puberty was independently of childhood BMI associated with risk of heart failure in a nonlinear J-shaped manner. Subjects in the upper quartile of BMI change during puberty (Q4) had more than twofold increased risk of heart failure compared with subjects in Q1 [HR (Hazard Ratio) = 2.29, 95% CI (Confidence Interval) 1.68-3.12]. Childhood BMI was not independently associated with risk of heart failure. Boys developing overweight during puberty (HR 3.14; 95% CI 2.25-4.38) but not boys with childhood overweight that normalized during puberty (HR 1.12, 95% CI 0.63-2.00) had increased risk of heart failure compared with boys without childhood or young adult overweight.Conclusion: BMI change during puberty is a novel risk factor for adult heart failure in men. [ABSTRACT FROM AUTHOR]

Summary: We aimed to study the risk of hip fracture and risk of hip arthroplasty among farmers in Sweden. Our results indicate that farming, representing an occupation with high physical activity, in men is associated with a lower risk of hip fracture but an increased risk of hip arthroplasty.Introduction: The risks of hip fracture and hip arthroplasty are influenced by factors including socioeconomic status, education, urbanization, latitude of residence, and physical activity. Farming is an occupation encompassing rural living and high level of physical activity. Therefore, we aimed to study the risk of hip fracture and risk of hip arthroplasty among farmers in Sweden.Methods: We studied the risk of hip fracture, and hip arthroplasty due to primary osteoarthritis, in all men and women aged 35 years or more in Sweden between 1987 and 2002. Documented occupations were available in 3.5 million individuals, of whom 97,136 were farmers. The effects of age, sex, income, education, location of residence, and occupation on risk of hip fracture or hip arthroplasty were examined using a modification of Poisson regression.Results: A total of 4027 farmers and 93,109 individuals with other occupations sustained a hip fracture, while 5349 farmers and 63,473 others underwent a hip arthroplasty. Risk of hip fracture was higher with greater age, lower income, lower education, higher latitude, and urban area for all men and women. Compared to all other occupations, male farmers had a 20% lower age-adjusted risk of hip fracture (hazard ratio (HR) 0.80, 95%CI 0.77-0.84), an effect that was not seen in female farmers (HR 0.96, 95% CI 0.91-1.01). Both male and female farmers had a higher age-adjusted risk for hip arthroplasty.Conclusions: Our results indicate that farming, representing an occupation with high physical activity, in men is associated with a lower risk of hip fracture but an increased risk of hip arthroplasty. [ABSTRACT FROM AUTHOR]

Summary: Spouses tend to share habits and therefore have an increased risk of same diseases. We followed all married couples in Sweden, born 1902 to 1942, in hospital records from 1987 to 2002, and found that individuals whose spouse had a hip fracture had an increased risk of hip fracture. Introduction: The purpose of this study was to determine whether spouses of hip fracture patients have an elevated risk of hip fracture. Methods: We performed a retrospective cohort study of all couples married for at least 5 years in Sweden and born between 1902 and 1942 ( n = 904,451) and all patients registered with a hip fracture ( n = 218,285) in the National Inpatients Register in Sweden from 1987 to 2002. Results: During the period 1987 to 2002 hip fractures occurred among spouses in 4212 married couples. The hazard ratio (HR) for hip fracture in a married woman following hip fracture in the husband was 1.11 (95 % confidence interval 1.07 to 1.16) compared to a woman whose husband did not have hip fracture. The corresponding HR for a married man was 1.20 (1.15 to 1.26) compared to a man whose wife did not have hip fracture. The risk was significantly elevated over the age range 60 to 90 years. The increased risk for hip fracture among spouses remained after adjustments for income, education, geographical latitude and urbanisation. In a common model with spouses and their siblings, the HR for spousal effect were 1.63 (1.01 to 2.64) and for sibling effect 2.18 (1.55 to 3.06) compared to married with spouse and sibling respectively without hip fracture. Conclusion: The novel finding of an increased risk for hip fracture among spouses provides evidence indicating that there is a homogamy effect due to common social and lifestyle factors but could also be due to assortative mating. [ABSTRACT FROM AUTHOR]

Objective: To identify and describe characteristics of the bias of reported energy intake of participants in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study.Design: A validated diet history with a detailed questionnaire and an interview was used. Body fat was analysed by dual-energy X-ray absorptiometry. The ratio of energy intake (EI) to BMR was used to define under-reporters (EI:BMR<1.30), acceptable reporters (EI:BMR >or= 1.30 to <2.64) and over-reporters (EI:BMR >or= 2.64).Setting: Sahlgrenska University Hospital, Gothenburg, Sweden.Subjects: A total of 695 males (18-20 years).Results: Sixty-eight per cent were classed as acceptable reporters, 22% as over-reporters and 10% as under-reporters. The under-reporters had higher BMI and body fat percentage than acceptable reporters (P<0.001), while over-reporters had lower BMI and body fat percentage (P<0.001). Over-reporters had more frequent use of protein supplements than acceptable reporters and higher physical activity. Over-reporters had a more regular and under-reporters a less regular meal pattern compared with acceptable reporters.Conclusions: Important knowledge of dietary reporting bias in a previously sparsely studied population has been provided. Over-reporting of energy intake was more common than under-reporting in the present population of young men and characteristics of under- and over-reporters were identified. The GOOD study was initiated with the central aim to determine environmental and genetic factors involved in the regulation of bone and fat mass, and the nutrient data of the acceptable reporters can be used for further investigation of the health effects of energy and nutrient intake. [ABSTRACT FROM AUTHOR]

Background: Bone loss at peripheral sites in the elderly is mainly cortical and involves increased cortical porosity. However, an association between bone loss at these sites and 25-hydroxyvitamin D has not been reported.Objective: To investigate the association between serum levels of 25-hydroxyvitamin D, bone microstructure and areal bone mineral density (BMD) in elderly men.Methods: A population-based cohort of 444 elderly men (mean ± SD age 80.2 ± 3.5 years) was investigated. Bone microstructure was measured by high-resolution peripheral quantitative computed tomography, areal BMD by dual-energy X-ray absorptiometry and serum 25-hydroxyvitamin D and parathyroid hormone levels by immunoassay.Results: Mean cortical porosity at the distal tibia was 14.7% higher (12.5 ± 4.3% vs. 10.9 ± 4.1%, P < 0.05) whilst cortical volumetric BMD, area, trabecular bone volume fraction and femoral neck areal BMD were lower in men in the lowest quartile of vitamin D levels compared to the highest. In men with vitamin D deficiency (<25 nmol L-1 ) or insufficiency [25-49 nmol L-1 , in combination with an elevated serum level of parathyroid hormone (>6.8 pmol L-1 )], cortical porosity was 17.2% higher than in vitamin D-sufficient men (P < 0.01). A linear regression model including age, weight, height, daily calcium intake, physical activity, smoking vitamin D supplementation and parathyroid hormone showed that 25-hydroxyvitamin D independently predicted cortical porosity (standardized β = -0.110, R2 = 1.1%, P = 0.024), area (β = 0.123, R2 = 1.4%, P = 0.007) and cortical volumetric BMD (β = 0.125, R2 = 1.4%, P = 0.007) of the tibia as well as areal BMD of the femoral neck (β = 0.102, R2 = 0.9%, P = 0.04).Conclusion: Serum vitamin D is associated with cortical porosity, area and density, indicating that bone fragility as a result of low vitamin D could be due to changes in cortical bone microstructure and geometry. [ABSTRACT FROM AUTHOR]

Background: It has been suggested that osteoblasts are involved in the regulation of haematopoietic stem cells. Whether osteocalcin, which is derived from osteoblasts and is metabolically active, influences blood haemoglobin (Hb) levels is not known.Objective: To determine whether plasma osteocalcin is a determinant of Hb in elderly men.Methods: A total of 993 men (mean age 75.3 ± 3.2 years) participated in the population-based MrOS (osteoporotic fractures in men) study. Plasma osteocalcin concentration was evaluated in relation to Hb and adjustments were made for potential confounders (i.e. age, body mass index, erythropoietin, total oestradiol, fasting insulin, adiponectin, ferritin and cystatin C).Results: Hb correlated (age adjusted) negatively with osteocalcin in the total study group (r = -0.12, P < 0.001) as well as in the subgroup of nondiabetic men (r = -0.16, P < 0.001). In nondiabetic men with higher osteocalcin levels, it was more likely that Hb would be in the lowest quartile (odds ratio per SD decrease in osteocalcin 1.32, 95% confidence interval 1.13-1.53). Quartiles of Hb were negatively associated (age adjusted) with osteocalcin (P < 0.001). Anaemic men (47/812) (Hb <130 g L(-1) ) had significantly higher mean osteocalcin levels than nonanaemic men (33.9 vs. 27.1 μg L(-1) , P < 0.001). In multiple stepwise linear regression analyses (adjusted for age, body mass index, total oestradiol, adiponectin, erythropoietin, fasting insulin, cystatin C, leptin, ferritin and holotranscobalamin), osteocalcin was an independent predictor of Hb concentration in nondiabetic men (P < 0.05).Conclusions: These data add further support to the evidence indicating that the bone-specific protein osteocalcin has several endocrine functions targeting the pancreas, testes, adipocytes, brain. An additional novel finding is that osteocalcin may also have a paracrine function as a regulator of haematopoiesis. [ABSTRACT FROM AUTHOR]

Summary: Falls and fractures share several common risk factors. Although past falls is not included as an input variable in the FRAX calculator, we demonstrate that FRAX probability predicts risk of incident falls in the MrOs Sweden cohort. Introduction: Although not included in the FRAX® algorithm, it is possible that increased falls risk is partly dependent on other risk factors that are incorporated into FRAX. The aim of the present study was to determine whether fracture probability generated by FRAX might also predict risk of incident falls and the extent that a falls history would add value to FRAX. Methods: We studied the relationship between FRAX probabilities and risk of falls in 1836 elderly men recruited to the MrOS study, a population-based prospective cohort of men from Sweden. Baseline data included falls history, clinical risk factors, bone mineral density (BMD) at femoral neck, and calculated FRAX probabilities. Incident falls were captured during an average of 1.8 years of follow-up. An extension of Poisson regression was used to investigate the relationship between FRAX, other risk variables, and the time-to-event hazard function of falls. All associations were adjusted for age and time since baseline. Results: At enrolment, 15.5 % of the men had fallen during the preceding 12 months (past falls) and 39 % experienced one or more falls during follow-up (incident falls). The risk of incident falls increased with increasing FRAX probabilities at baseline (hazard ratio (HR) per standard deviation (SD), 1.16; 95 % confidence interval (95%CI), 1.06 to 1.26). The association between incident falls and FRAX probability remained after adjustment for past falls (HR per SD, 1.12; 95%CI, 1.03 to 1.22). High compared with low baseline FRAX score (>15 vs <15 % probability of major osteoporotic fracture) was strongly predictive of increased falls risk (HR, 1.64; 95%CI, 1.36 to 1.97) and remained stable with time. Whereas past falls were a significant predictor of incident falls (HR, 2.75; 95%CI, 2.32 to 3.25), even after adjustment for FRAX, the hazard ratio decreased markedly with increasing follow-up time. Conclusions: Although falls are not included as an input variable, FRAX captures a component of risk for future falls and outperforms falls history with an extended follow-up time. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Blood haemoglobin (Hb) concentration declines in elderly men, whilst the level of the adipocyte-derived protein adiponectin increases with age. The association between erythropoiesis and adiponectin in elderly men is unclear. The aim of this study was to determine whether adipokines such as adiponectin and leptin are associated with anaemia and Hb concentration in elderly community-dwelling men. DESIGN AND SETTING: The Gothenburg part of the population-based Swedish Osteoporotic Fractures in Men (MrOS) cohort (n = 1010; median age 75.3 years, range 69-81). MAIN OUTCOME MEASURES: We investigated the associations between levels of adiponectin and Hb before and after adjusting for potential confounders [i.e. age, body composition, erythropoietin (EPO), total oestradiol, leptin, cystatin C and iron and B vitamin status]. RESULTS: In these elderly men, age was negatively associated with Hb (r = -0.12, P < 0.001) and positively associated with adiponectin level (r = 0.13, P < 0.001). In age-adjusted partial correlations, Hb and adiponectin levels were negatively correlated (r = -0.20, P < 0.001); this association remained significant after multivariable adjustment for age, body composition, EPO, fasting insulin, sex hormones, leptin and ferritin. Age-adjusted mean adiponectin concentrations were significantly higher in anaemic men (66/1005; Hb <130 g L(-1) ) compared to nonanaemic men (14.0 vs. 11.7 [mu]g mL(-1) , P < 0.05). In multivariate analysis, adiponectin together with EPO, total oestradiol, insulin, albumin, transferrin saturation, HDL cholesterol, cystatin C, total body fat mass and free thyroxine, but not leptin, explained 35% of the variation in Hb level. These results remained essentially unchanged after exclusion of men with diabetes. CONCLUSIONS: Serum adiponectin, but not leptin, was negatively and independently associated with Hb. This finding suggests a possible role of adiponectin in the age-related decline in Hb level observed in apparently healthy elderly men. [ABSTRACT FROM AUTHOR]

Objectives Blood haemoglobin (Hb) concentration declines in elderly men, whilst the level of the adipocyte-derived protein adiponectin increases with age. The association between erythropoiesis and adiponectin in elderly men is unclear. The aim of this study was to determine whether adipokines such as adiponectin and leptin are associated with anaemia and Hb concentration in elderly community-dwelling men. Design and setting The Gothenburg part of the population-based Swedish Osteoporotic Fractures in Men (Mr OS) cohort ( n = 1010; median age 75.3 years, range 69-81). Main outcome measures We investigated the associations between levels of adiponectin and Hb before and after adjusting for potential confounders [i.e. age, body composition, erythropoietin ( EPO), total oestradiol, leptin, cystatin C and iron and B vitamin status]. Results In these elderly men, age was negatively associated with Hb ( r = −0.12, P < 0.001) and positively associated with adiponectin level ( r = 0.13, P < 0.001). In age-adjusted partial correlations, Hb and adiponectin levels were negatively correlated ( r = −0.20, P < 0.001); this association remained significant after multivariable adjustment for age, body composition, EPO, fasting insulin, sex hormones, leptin and ferritin. Age-adjusted mean adiponectin concentrations were significantly higher in anaemic men (66/1005; Hb <130 g L−1) compared to nonanaemic men (14.0 vs. 11.7 μg mL−1, P < 0.05). In multivariate analysis, adiponectin together with EPO, total oestradiol, insulin, albumin, transferrin saturation, HDL cholesterol, cystatin C, total body fat mass and free thyroxine, but not leptin, explained 35% of the variation in Hb level. These results remained essentially unchanged after exclusion of men with diabetes. Conclusions Serum adiponectin, but not leptin, was negatively and independently associated with Hb. This finding suggests a possible role of adiponectin in the age-related decline in Hb level observed in apparently healthy elderly men. [ABSTRACT FROM AUTHOR]

WNTs are extracellular proteins that activate different cell surface receptors linked to canonical and noncanonical WNT signalling pathways. The Wnt genes were originally discovered as important for embryonic development of fruit flies and malignant transformation of mouse mammary cancers. More recently, WNTs have been implicated in a wide spectrum of biological phenomena and diseases. During the last decade, several lines of clinical and preclinical evidence have indicated that WNT signalling is critical for trabecular and cortical bone mass, and this pathway is currently an attractive target for drug development. Based on detailed knowledge of the different WNT signalling pathways, it appears that it might be possible to develop drugs that specifically target cortical and trabecular bone. Neutralization of a bone-specific WNT inhibitor is now being evaluated as a promising anabolic treatment for patients with osteoporosis. Here, we provide the historical background to the discoveries of WNTs, describe the different WNT signalling pathways and summarize the current understanding of how these proteins regulate bone mass by affecting bone formation and resorption. [ABSTRACT FROM AUTHOR]

Summary: Serum adiponectin is a risk factor for fracture. The predictive value attenuates with time in elderly men so that its use for the risk assessment in the long term is questionable. The study underlines the importance of testing the long-term stability of potential risk factors. Introduction: High serum adiponectin is associated with an increased risk of fracture in elderly men. The aim of the present study was to determine the impact of adiponectin on the probability of fracture as a function of time. Methods: The probability of osteoporotic fracture was computed in 989 elderly men from the MrOS study in Sweden. Baseline data included clinical risk factors for fracture, femoral neck BMD and serum adiponectin. Men were followed for up to 7.4 years with a mean follow up of 5.3 years (range 0.0-7.4 years). Poisson regression was used to model the hazard function for osteoporotic fracture and death to determine the 10 year probability of fracture. Results: During follow up, 124 men sustained one or more osteoporotic fracture. There was a significant interaction between adiponectin and time since baseline ( p = 0.026) such that the longer time since baseline, the lower the gradient of fracture risk. When using this interaction in the calculation of 10-year probability of fracture, the probabilities of osteoporotic fracture varied little over the range of adiponectin values. Conclusion: Serum adiponectin is a risk factor for fracture. Nevertheless, the predictive value attenuates with time so that its use for the risk assessment in the long term is questionable. This study underlines the importance of testing the long-term stability of potential risk factors that might be used in fracture risk assessment. [ABSTRACT FROM AUTHOR]

Summary: In a population-based study on cobalamin status and incident fractures in elderly men ( n = 790) with an average follow-up of 5.9 years, we found that low levels of metabolically active and total cobalamins predict incident fractures, independently of body mass index (BMI), bone mineral density (BMD), plasma total homocysteine (tHcy), and cystatin C. Introduction: Cobalamin deficiency in elderlies may affect bone metabolism. This study aims to determine whether serum cobalamins or holotranscobalamin (holoTC; the metabolic active cobalamin) predict incident fractures in old men. Methods: Men participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) Sweden cohort and without ongoing vitamin B medication were included in the present study ( n = 790; age range, 70-81 years). Results: During an average follow-up of 5.9 years, 110 men sustained X-ray-verified fractures including 45 men with clinical vertebral fractures. The risk of fracture (adjusted for age, smoking, BMI, BMD, falls, prevalent fracture, tHcy, cystatin C, 25-OH-vitamin D, intake of calcium, and physical activity (fully adjusted)), increased per each standard deviation decrease in cobalamins (hazard ratio (HR), 1.38; 95 % confidence intervals (CI), 1.11-1.72) and holoTC (HR, 1.26; 95 % CI, 1.03-1.54), respectively. Men in the lowest quartile of cobalamins and holoTC (fully adjusted) had an increased risk of all fracture (cobalamins, HR = 1.67 (95 % CI, 1.06-2.62); holoTC, HR = 1.74 (95 % CI, 1.12-2.69)) compared with quartiles 2-4. No associations between folate or tHcy and incident fractures were seen. Conclusions: We present novel data showing that low levels of holoTC and cobalamins predicting incident fracture in elderly men. This association remained after adjustment for BMI, BMD, tHcy, and cystatin C. However, any causal relationship between low cobalamin status and fractures should be explored in a prospective treatment study. [ABSTRACT FROM AUTHOR]

Estrogens are important endocrine regulators of skeletal growth and maintenance in both females and males. Studies have demonstrated that the estrogen receptor (ER)-α is the main mediator of these estrogenic effects in bone. Therefore, estrogen signaling via ERα is a target both for affecting longitudinal bone growth and bone remodeling. However, treatment with estradiol (E2) leads to an increased risk of side effects such as venous thromboembolism and breast cancer. Thus, an improved understanding of the signaling pathways of ERα will be essential in order to find better bone specific treatments with minimal adverse effects for different estrogen-related bone disorders. This review summarizes the recent data regarding the intracellular signaling mechanisms, in vivo, mediated by the ERα activation functions (AFs), AF-1 and AF-2, and the effect on bone, growth plate and other estrogen responsive tissues. In addition, we review the recent cell-specific ERα-deleted mouse models lacking ERα specifically in neuronal cells or growth plate cartilage. The newly characterized signaling pathways of estrogen, described in this review, provide a better understanding of the ERα signaling pathways, which may facilitate the design of new, bone-specific treatment strategies with minimal adverse effects. [ABSTRACT FROM AUTHOR]

Summary: In this population-based study of 24-year-old men, we have investigated the association between sport-specific exercise loading and different bone parameters. We reveal that the association between exercise loading and bone parameters is sport-specific, indicating that nonspecific resistance exercise does not impact bone density, geometry, or microstructure in young men. Introduction: In this cross-sectional study, the association between nonspecific resistive exercise and areal and volumetric bone density, bone geometry, or bone microstructure was investigated in young adult men. Methods: A total of 184 male athletes, 24.0 ± 0.6 years of age (mean ± SD), representing nonspecific resistive exercise and soccer (proportion of recreational athletes, 93.4 and 7.7 %, respectively), and 177 nonathletic age-matched controls were measured with dual-energy X-ray absorptiometry. Radius and tibia were measured by peripheral quantitative computed tomography (pQCT) at the diaphysis and by three-dimensional pQCT at the metaphysis. Results: Men in the nonspecific resistive exercise group had higher grip strength(9.1 % or 0.4 SD) and higher lean mass(5.6 % or 0.5 SD) than those in the nonathletic group( p < 0.01 and p < 0.001, respectively). However, men who participated in nonspecific resistive exercise did not have higher bone density or a more favorable bone microstructure or geometry than their nonathletic referents. In contrast, men playing soccer had higher areal bone mineral density (aBMD) at the femoral neck (19.5 % or 1.2 SD) and lumbar spine (12.6 % or 1.0 SD), as well as larger cortical cross-sectional area (16.4 % or 1.1 SD) and higher trabecular bone volume fraction (14.5 % or 0.9 SD), as a result of increased trabecular number (8.7 % or 0.6 SD) and thickness (5.7 % or 0.4 SD) at the tibia than men in the nonathletic group( p < 0.001). Conclusions: Weight-bearing exercise with impacts from varying directions (playing soccer) is associated with aBMD and volumetric BMD, cortical bone geometry, as well as trabecular microstructure of weight-bearing bone. Nonspecific recreational resistance exercise does not appear to be a strong determinant of bone density, geometry, or microstructure in young adult men. [ABSTRACT FROM AUTHOR]

High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα-/-) or ERαAF-1 (ERαAF-1º) were evaluated. Old (16- to 19-mo-old) female ERα-/- mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-1º mice (tibia: -4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-1º mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα-/- mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure. [ABSTRACT FROM AUTHOR]

Summary: This study examines the association between sex steroids, bone mineral density (BMD), and incident fractures in 1,489 community-living Chinese men aged 65 and over. Chinese men with low serum estradiol levels display elevated bone loss and increased risk of fractures similar to findings in Caucasians. Introduction: This study examines the association between serum total testosterone (TT), free testosterone (free T), estradiol (E), bioavailable estradiol (bioE), sex hormone binding globulin (SHBG), BMD, and incident fractures. Methods: This is a cohort study with 4-year follow-up in the community in Hong Kong SAR, China. One thousand four hundred eighty-nine community-living Chinese men aged 65 and over participated. Sex steroid levels and BMD were measured at baseline; BMD was repeated after 4 years of follow-up, and fracture incidence from ascertainment from hospital databases was determined over 4 years of follow-up. Results: The strongest age-adjusted positive association with total hip and femoral neck BMD was with bioE, followed by E. Greater bone loss occurred in the lowest quartile of E and bioE. The lowest quartile of free T and bioE and the two highest quartile of SHBG were associated with the highest percentage of participants with incident fractures. Those in the lowest quartile of E and bioE had approximately a 50% increased risk of incident fractures compared with the other three quartiles. This relationship remains significant for nonvertebral incident fractures (hip, radius, pelvis, and humerus) for E only, but not bioE. Compared with the group with the three highest quartiles of TT and E, the group with the lowest quartile of both had approximately twice the risk of nonvertebral osteoporosis-related incident fractures. Conclusion: Chinese men with low serum estradiol levels display elevated bone loss and increased risk of fractures similar to findings in Caucasians. [ABSTRACT FROM AUTHOR]

Summary: In elderly man, low serum 25-hydroxyvitamin D (25(OH)D) was associated with a substantial excess risk of death compared to 25(OH)D values greater than 50-70 nmol/l, but the association attenuated with time. Introduction: The aim of the present study was to determine whether poor vitamin D status was associated with an increase in the risk of death in elderly men. Methods: We studied the relationship between serum 25(OH)D and the risk of death in 2,878 elderly men drawn from the population and recruited to the MrOS study in Sweden. Baseline data included general health and lifestyle measures and serum 25(OH)D measured by competitive RIA. Men were followed for up to 8.2 years (average 6.0 years). Results: Mortality adjusted for comorbidities decreased by 5% for each SD increase in 25(OH)D overall (gradient of risk 1.05; 95% confidence interval 0.96-1.14). The predictive value of 25(OH)D for death was greatest below a threshold value of 50-70 nmol/l, was greatest at approximately 3 years after baseline and thereafter decreased with time. Conclusions: Low serum 25(OH)D is associated with a substantial excess risk of death compared to 25(OH)D values greater than 50-70 nmol/l, but the association attenuates with time. These findings, if causally related, have important implications for intervention in elderly men. [ABSTRACT FROM AUTHOR]

Summary: Advancing maternal age has been related to increased risk of fetal death and morbidity, as well as higher fracture risk during childhood, in the offspring. In the present study, we demonstrate that advancing maternal age is independently associated with reduced bone mass in the young adult male offspring. Introduction: In Sweden the maternal age in both primi- and multipara mothers has steadily increased during the last three decades. It has been previously reported that advancing maternal age increases the risk of fetal death, but also of morbidity in the offspring, such as chromosome abnormalities, leukemia, diabetes mellitus type 1, and schizophrenia. Whether or not maternal age influences peak bone mass has not been reported. The aim of the present study was to investigate whether a high maternal age was associated with lower peak bone mass, as measured using DXA in a large cohort of male offspring [the Gothenburg Osteoporosis and Obesity Determinants study (GOOD)]. Methods: Through the Swedish multi-generation register, we identified the mothers of 1,009 GOOD study subjects. From the Swedish medical birth register detailed information about the medical circumstances at the time of child birth were obtained, including maternal and offspring anthropometrics (birth height and weight), maternal age, and smoking habits, parity and length of pregnancy. Results: Maternal age was inversely correlated to areal BMD (aBMD) at the total body ( r =−0.07, p = 0.03) and the lumbar spine ( r =−0.09, p < 0.01). Using a linear regression model (with covariates including current physical activity, smoking, calcium intake, weight, present height and birth height, total body lean and fat mass in the offspring, and length of pregnancy), we found that maternal age negatively independently predicted lumbar spine aBMD ( β =−0.08, p < 0.01) in the male offspring. Conclusions: In conclusion, our results suggest that advancing maternal age could negatively affect bone mass in young adult men. [ABSTRACT FROM AUTHOR]

Vitamin D status, parathyroid hormone (PTH) level and their associations with blood pressure in Chinese population are unknown. This study examined these associations in older Chinese men. Blood pressure, serum 25-hydroxyvitamin D (25OHD) and PTH was measured in 939 community-dwelling Chinese men aged 65 years and older. Linear regression analyses were performed with adjustments for age, body mass index, education, season of measurement, medication use, self-reported history of stroke and Parkinson's disease, and other lifestyle factors. In either crude or adjusted models, serum 25OHD was not associated with blood pressure, whereas increasing PTH levels was associated with higher blood pressure. Men in the highest quartile of serum PTH level had a mean difference of 3.4 mm Hg and 2.8 mm Hg higher in as systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively, than men in the lowest quartile of serum PTH level (Ptrend=0.019 for SBP and <0.001 for DBP). In conclusion, the findings support an association between serum PTH and blood pressure, but not for serum 25OHD in older Chinese men whose vitamin D status is optimal. The lack of association between serum 25OHD and blood pressure may possibly because of the relatively high serum 25OHD levels of the study sample. [ABSTRACT FROM AUTHOR]

Oestradiol and the selective oestrogen receptor modulator (SERM) raloxifene have been shown to ameliorate collagen-induced arthritis (CIA) in rats and in mice. One aim was to investigate if raloxifene exerts its anti-arthritic and anti-osteoporotic effects during the induction or effector phase of arthritis. A second aim was to analyse if raloxifene activates the oestrogen response element (ERE) to produce its immune-modulator effects. CIA or collagen-antibody-induced arthritis (CAIA) was induced in ovariectomized DBA/1-mice. CIA was used for evaluation of treatment during the induction, and CAIA for the effector phase of arthritis and osteoporosis development. Raloxifene, oestradiol or vehicle was administered 5 days/week. The clinical disease was evaluated continuously. Bone marrow density (BMD) was analysed with peripheral quantitative computer tomography, paws were collected for histological examination, and sera were analysed for markers of bone and cartilage turnover and proinflammatory cytokines. Transgenic luciferase (Luc)-ERE mice were immunized with collagen (CII), and after 10 days injected once with raloxifene, oestradiol or vehicle before termination. Spleens were analysed for luciferase activity to measure ERE activation. Treatment with oestradiol or raloxifene during the induction phase of CIA failed to affect arthritis. Raloxifene did not hamper disease activity in CAIA, whereas oestradiol delayed the onset and ameliorated the severity. Both raloxifene and oestradiol preserved BMD in CAIA. CII-immunization increased the oestradiol-induced ERE activation in spleen, and raloxifene activated the ERE at about 25% the intensity of oestradiol. Further experiments are needed to elucidate the exact mechanisms behind this finding. [ABSTRACT FROM AUTHOR]

Summary: We studied the nature of the relationship between bone mineral density (BMD) and the risk of death among elderly men. BMD was associated with mortality risk and was independent of adjustments for other co-morbidities. A piecewise linear function described the relationship more accurately than assuming the same gradient of risk over the whole range of BMD ( p = 0.020). Low BMD was associated with a substantial excess risk of death, whilst a higher than average BMD had little impact on mortality. Introduction: Previous studies have demonstrated an association between low BMD and an increased risk of death among men and women. The aim of the present study was to examine the pattern of the risk in men and its relation to co-morbidities. Methods: We studied the nature of the relationship between BMD and death among 3,014 elderly men drawn from the population and recruited to the MrOS study in Sweden. Baseline data included general health questionnaires, life style questionnaires and BMD measured using DXA. Men were followed for up to 6.5 years (average 4.5 years). Poisson regression was used to investigate the relationship between BMD, co-morbidities and the hazard function of death. Results: During follow-up, 382 men died (all-cause mortality). Low BMD at all measured skeletal sites was associated with increased mortality. In multivariate analyses, the relationship between BMD and mortality was non-linear, and a piecewise linear function described the relationship more accurately than assuming the same gradient of risk over the whole range of BMD ( p = 0.020). Conclusions: Low BMD is associated with a substantial excess risk of death compared to an average BMD, whereas a higher than average BMD has a more modest effect on mortality. These findings, if confirmed elsewhere, have implications for the constructing of probability-based fracture risk assessment tools. [ABSTRACT FROM AUTHOR]

The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-α (ERα), which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand binding domain. To evaluate the role of ERα AF-1 and ERα AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ERα protein (ERα-/-, ERα AF-1 (ERαAF-1°), or ERα AF-2 (ERαAF-2°). Estradiol (E2) treatment increased the amount of both trabecular and cortical bone in ovariectomized (OVX) WI mice. Neither the trabecular nor the cortical bone responded to E2 treatment in OVX ERα-/- or OVX ERαAF2° mice. OVX ERαAF-1° mice displayed a normal E2 response in cortical bone but no E2 response in trabecular bone. Although E2 treatment increased the uterine and liver weights and reduced the thymus weight in OVX WT mice, no effect was seen on these parameters in OVX ERα-/- or OVX ERαAF-2° mice. The effect of E2 in OVX ERαAF-1° mice was tissue-dependent, with no or weak E2 response on thymus and uterine weights but a normal response on liver weight. In conclusion, ERα AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ERα AF-1 is tissue-specific, with a crucial role in trabecular bone and uterus but not cortical bone. Selective ER modulators stimulating ERα with minimal activation of ERα AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs. [ABSTRACT FROM AUTHOR]

Background: Hip fracture is a common diagnosis in the older population, with often serious consequences. Drug treatment may be of significance for both falls and fractures. Objective: To investigate drug treatment in older hip fracture patients, focusing on use of fall-risk-increasing and fracture-preventing drugs before and after the fracture. Methods: This was an observational study conducted in Sahlgrenska University Hospital, Gothenburg, Sweden. The participants were 100 consecutive hip fracture patients aged ≥65 years with a median age of 86 (range 66-97) years. Seventy-three patients were female, and 87 patients had at least one strong risk factor for a fracture. Four patients died during the hospital stay, and a further 18 died within 6 months after discharge. Treatment with fall-risk-increasing and fracture-preventing drugs at admission to hospital, at discharge and 6 months after the hip fracture was measured. Results: The numbers of patients treated with fall-risk-increasing drugs were 93 (93%), 96 (100%) and 73(94%) at admission, discharge and 6-month follow-up, respectively. The median (range) number of such drugs was 3 (0-9), 4(1-10) and 3(0-10), respectively. A total of 17(17%), 32(33%) and 29(37%) patients were treated with fracture-preventing drugs, predominantly calcium plus vitamin D, at admission, discharge and 6-month follow-up, respectively. Five patients (5%) used bisphosphonates or selective estrogen receptor modulators at admission. No additional patients had these drugs prescribed during the hospital stay. At 6-month follow-up, four more patients were treated with bisphosphonates. Conclusions: Treatment with fall-risk-increasing drugs was extensive among older hip fracture patients both before and after the fracture. The proportion of patients with fracture-preventing drugs was low at admission and increased slightly during the follow-up period. Hence, drug treatment in older hip fracture patients can be improved regarding both fall-risk-increasing drugs and fracture-preventing drugs. [ABSTRACT FROM AUTHOR]

Context:Regulation of fat mass appears to be associated with immune functions. Studies of knockout mice show that endogenous interleukin (IL)-6 can suppress mature-onset obesity.Objective:To systematically investigate associations of single nucleotide polymorphisms (SNPs) near the IL-6 (IL6) and IL-6 receptor (IL6R) genes with body fat mass, in support for our hypothesis that variants of these genes can be associated with obesity.Design and Study Subjects:The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based cross-sectional study of 18- to 20-year-old men (n=1049), from the Gothenburg area (Sweden). Major findings were confirmed in two additional cohorts consisting of elderly men from the Osteoporotic Fractures in Men (MrOS) Sweden (n=2851) and MrOS US (n=5611) multicenter population-based studies.Main Outcome:The genotype distributions and their association with fat mass in different compartments, measured with dual-energy X-ray absorptiometry.Results:Out of 18 evaluated tag SNPs near the IL6 and IL6R genes, a recently identified SNP rs10242595 G/A (minor allele frequency=29%) 3′ of the IL6 gene was negatively associated with the primary outcome total body fat mass (effect size −0.11 standard deviation (s.d.) units per A allele, P=0.02). This negative association with fat mass was also confirmed in the combined MrOS Sweden and MrOS US cohorts (effect size −0.05 s.d. units per A allele, P=0.002). When all three cohorts were combined (n=8927, Caucasian subjects), rs10242595*A showed a negative association with total body fat mass (effect size −0.05 s.d. units per A allele, P<0.0002). Furthermore, the rs10242595*A was associated with low body mass index (effect size −0.03, P<0.001) and smaller regional fat masses. None of the other SNPs investigated in the GOOD study were reproducibly associated with body fat.Conclusions:The IL6 gene polymorphism rs10242595*A is associated with decreased fat mass in three combined cohorts of 8927 Caucasian men. [ABSTRACT FROM AUTHOR]

Objective: To measure dietary salt intake in a Swedish population. Design: A cross-sectional study with measured 24 h urinary excretion of Na and K. Completeness of urine collection was assessed using p-aminobenzoic acid. The subjects were interviewed on their habitual food intake. Setting: Sahlgrenska University Hospital, Gothenburg, Sweden. Subjects: Eighty-six young men (age 18-20 years), randomly selected from the population of Gothenburg. Seven men were excluded due to incomplete urine collection. Results: The mean excretion of Na and K over 24 h was 198 and 84 mmol, respectively (corresponding to 11∙5 g NaCl and 3∙3 g K). The mean 24 h excretion in the highest quartile of Na excretion was 297 mmol Na and 105 mmol K, and in the lowest quartile, 100 mmol Na and 68 mmol K. The mean Na:K ratio was 2∙3, and respectively 3∙2 and 1∙8 in the highest and lowest Na excretion quartiles. Calculated energy intake did not differ between the highest and lowest quartiles of Na excretion, but body weight, BMI and the intake of certain foods known to be Na-rich did. Conclusions: Salt intake in young men was alarming high and even subjects in the lowest quartile of Na excretion did not meet present recommendations to limit salt intake to 5-6 g/d. At this point we can only speculate what the consequences of the high salt intake may be for CVD and stroke later in life. Regulation of the salt content in processed and fast food and in snacks is advocated, to curtail the salt burden on society imposed by the food industry. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The effects of estrogen may be exerted via the nuclear estrogen receptors (ERs) ERalpha or ERbeta or via the recently proposed transmembrane estrogen receptor G protein-coupled receptor 30 (GPR-30). The purpose of this study was to elucidate the ER specificity for the ameliorating effects of estrogen on arthritis and bone loss in a model of postmenopausal rheumatoid arthritis (RA). METHODS: Female DBA/1 mice underwent ovariectomy or sham operation, and type II collagen-induced arthritis was induced. Mice were treated subcutaneously 5 days/week with the specific agonists propylpyrazoletriol (PPT; for ERalpha), diarylpropionitrile (DPN; for ERbeta), G1 (for GPR-30), or with a physiologic dose of estradiol. Clinical arthritis scores were determined continuously. At termination of the study, bone mineral density (BMD) was analyzed, paws were collected for histologic assessment, serum was analyzed for cytokines and markers of bone and cartilage turnover, and bone marrow was subjected to fluorescence-activated cell sorting. RESULTS: Treatment with PPT as well as estradiol dramatically decreased the frequency and severity of arthritis. Furthermore, estradiol and PPT treatment resulted in preservation of bone and cartilage, as demonstrated by increased BMD and decreased serum levels of bone resorption markers and cartilage degradation markers, whereas no effect was seen after DPN or G1 treatment. CONCLUSION: In a well-established model of postmenopausal RA, ERalpha, but not ERbeta or GPR-30 signaling, was shown to ameliorate the disease and the associated development of osteoporosis. Since long-term treatment with estrogen has been associated with significant side effects, increased knowledge about the mechanisms behind the beneficial effects of estrogen is useful in the search for novel treatments of postmenopausal RA. [ABSTRACT FROM AUTHOR]

We evaluated the relation between serum FGF23 and bone mineral density (BMD) in a community-based cohort of elderly men. There was a weak correlation between FGF23 and BMD, which was primarily dependent on body weight. FGF23 is a hormonal factor produced in bone and regulates serum levels of phosphate (Pi) and vitamin D. FGF23 over-expression is associated with skeletal abnormalities, including rickets/osteomalacia. The relation between FGF23 and Bone Mineral Density (BMD) in the community remains unexplored. We employed a large, population-based cohort of 3014 Swedish men aged 69–80 years, without known renal disease. BMD was measured with dual X-ray absorptiometry (DXA) in the hip and lumbar spine. Serum intact FGF23 was analyzed with a two-site monoclonal ELISA. There was a weak but significant correlation between FGF23 and BMD in femoral neck ( r = 0.04, p < 0.05), femoral trochanter ( r = 0.05, p = 0.004), total hip ( r = 0.06, p = 0.0015) and lumbar spine ( r = 0.07, p = 0.0004). The correlations remained significant when adjusting for biochemical covariates (Pi, calcium, PTH, 25(OH)D and renal function). However, the association became insignificant in all regions when adjusting for established confounding variables including age, height, weight and smoking. Further analysis confirmed a significant correlation between FGF23 and body weight ( r = 0.13, p < 0.0001). The weak correlation between FGF23 and BMD in elderly male subjects is mainly due to an association between FGF23 and body weight. Therefore, FGF23 may not play a significant role in the hormonal regulation of BMD. [ABSTRACT FROM AUTHOR]

The aetiology of benign prostatic hyperplasia (BPH) remains unclear. The objective of the present study was to test the insulin, oestradiol and metabolic syndrome hypotheses as promoters of BPH. The design was a risk factor analysis of BPH in which the total prostate gland volume was related to endocrine and anthropometric factors. The participants studied were 184 representative men, aged 72–76 years, residing in Göteborg, Sweden. Using a multivariate analysis, BPH as measured by the total prostate gland volume correlated statistically significantly with fasting serum insulin (β=0.200, P=0.028), free oestradiol (β=0.233, P=0.008) and lean body mass (β=0.257, P=0.034). Insulin and free oestradiol appear to be independent risk factors for BPH, confirming both the insulin and the oestradiol hypotheses. Our findings also seem to confirm the metabolic syndrome hypothesis. The metabolic syndrome and its major endocrine aberration, hyperinsulinaemia, are possible primary events in BPH.Prostate Cancer and Prostatic Diseases (2009) 12, 160–165; doi:10.1038/pcan.2008.50; published online 30 September 2008 [ABSTRACT FROM AUTHOR]

Context:Immune functions seem to have connections to variations in body fat mass. Studies of knockout mice indicate that endogenous interleukin (IL)-1 can suppress mature-onset obesity.Objective:To systematically investigate our hypotheses that single-nucleotide polymorphisms (SNPs) and/or haplotypes variants in the IL-1 gene system are associated with fat mass.Subjects:The Gothenburg osteoporosis and obesity determinants (GOOD) study is a population-based cross-sectional study of 18–20 year-old men (n=1068), from Gothenburg, Sweden. Major findings were confirmed in elderly men (n=3014) from the Swedish part of the osteoporotic fractures in men (MrOS) multicenter population-based study.Main Outcome Measure:The genotype distributions and their association with body fat mass in different compartments, measured with dual-energy X-ray absorptiometry (DXA).Results:Out of 15 investigated SNPs in the IL-1 receptor antagonist (IL1RN) gene, a recently identified 3′ untranslated region C>T (rs4252041, minor allele frequency=4%) SNP was associated with the primary outcome total fat mass (P=0.003) and regional fat masses, but not with lean body mass or serum IL-1 receptor 1 (IL1RN) levels. This SNP was also associated with body fat when correcting the earlier reported IL1RN+2018 T>C (rs419598) SNP (in linkage disequilibrium with a well-studied variable number tandem repeat of 86 bp). The association between rs4252041 SNP and body fat was confirmed in the older MrOS population (P=0.03). The rs4252041 SNP was part of three haplotypes consisting of five adjacent SNPs that were identified by a sliding window approach. These haplotypes had a highly significant global association with total body fat (P<0.001). None of the other investigated members of the IL-1 gene family displayed any SNPs that have not been described previously to be significantly associated with body fat.Conclusions:The IL1RN gene, shown to enhance obesity by suppressing IL-1 effects in experimental animals, have no previously described gene polymorphisms and haplotypes that are associated with fat, but not lean mass in two populations of men.International Journal of Obesity (2009) 33, 525–533; doi:10.1038/ijo.2009.47; published online 17 March 2009 [ABSTRACT FROM AUTHOR]

Objective: The amount of visceral adipose tissue is a risk factor for the metabolic syndrome. It is unclear how BMI changes during childhood and adolescence predict adult fat distribution. We hypothesized that there are critical periods during development for the prediction of adult subcutaneous and visceral fat mass by BMI changes during childhood and adolescence.Research Design and Methods: Detailed growth charts were retrieved for the men participating in the population-based Gothenburg Osteoporosis and Obesity Determinants (GOOD) Study (n = 612). Body composition was analyzed using dual-energy X-ray absorptiometry and adipose tissue areas using abdominal computed tomography at 18 to 20 years of age.Results: The main finding in the present study was that subjects with increases in BMI Z score of more than 1 SD during adolescence had, independent of prepubertal BMI, both larger subcutaneous (+138%; P < 0.001) and visceral adipose tissue areas (+91%; P < 0.001) than subjects with unchanged BMI Z-score. In contrast, subjects with increases in BMI Z score of more than 1 SD during late childhood had a larger amount of adult subcutaneous adipose tissue (+83%; P < 0.001) than subjects with unchanged BMI Z score but an unaffected amount of visceral adipose tissue. BMI changes during adolescence predict both visceral and subcutaneous adipose tissue of the abdomen, whereas BMI changes during late childhood predict only the subcutaneous adipose tissue.Conclusions: The amount of visceral adipose tissue in young adult men was associated with BMI changes specifically during adolescence, whereas the amount of subcutaneous adipose tissue was associated with BMI changes during both late childhood and adolescence. [ABSTRACT FROM AUTHOR]

In this population-based study of 75-year-old men ( n = 498), we investigated the association between physical activity (PA) early in life and present bone mineral density (BMD). We demonstrate that a high frequency of competitive sports early in life is associated with BMD at several bone sites, indicating that increases in BMD following PA are preserved longer than previously believed. Physical activity (PA) increases bone mineral density (BMD) during growth. It is unclear if the positive effects remain at old age. In this study, we aimed to determine if PA early in life was associated with BMD in elderly men. In this population-based study, 498 men, 75.2 ± 3.3 (mean±SD) years old, were included. BMD was assessed using DXA. Data concerning lifetime PA, including both competitive (CS) and recreational sports (RS), and occupational physical load (OPL), were collected at interview. Subjects in the highest frequency group of CS in the early period (10–35 years), had higher BMD at the total body (4.2%, p < 0.01), total hip (7.0%, p < 0.01), trochanter (8.7%, p < 0.01), and lumbar spine (7.9%, p < 0.01), than subjects not involved in CS. A stepwise linear regression model showed that frequency of CS in the early period independently positively predicted present BMD at the total body (β = 0.12, p < 0.01), total hip (β = 0.11, p < 0.01), trochanter (β = 0.12, p < 0.01), and lumbar spine (β = 0.11, p = 0.01). We demonstrate that PA in CS early in life is associated with BMD in 75-year-old Swedish men, indicating that increases in BMD following PA are preserved longer than previously believed. [ABSTRACT FROM AUTHOR]

Herein we investigated the association between polymorphisms in the LRP5 gene and bone phenotypes and fractures in three large male cohorts based on the rationale that mutations in LRP5 cause severe bone phenotypes. Results showed an association of the Val667Met SNP with spine BMD in 3,800 young and elderly men. The low-density lipoprotein receptor-related protein 5 (LRP5 )-Wnt signalling system is of importance for regulating osteoblastic activity, which became clear after findings that inactivating mutations in LRP5 cause osteoporosis. The overall aim of this study was to investigate the association between polymorphisms in the LRP5 gene and bone mineral density (BMD) in three large cohorts of young and elderly men. The cohorts used were MrOS Sweden ( n = 3014, aged 69–81 years) and MrOs Hong Kong ( n = 2000, aged > 65 years) and the Swedish GOOD study ( n = 1068, aged 18–20 years). The polymorphisms Val667Met and Ala1330Val were genotyped using a TaqMan assay. When combining the data from the Swedish cohorts in a meta-analysis ( n = 3,800), men carrying the 667Met-allele had 3% lower BMD at lumbar spine compared with non-carriers ( p < 0.05). The Val667Met SNP was not polymorphic in the Hong Kong population and thus were not included. There were no associations between the Ala1330Val SNP and bone phenotypes in the study populations. No associations between the LRP5 polymorphisms and self-reported fractures were seen in MrOs Sweden. Results from these three large cohorts indicate that the Val667Met polymorphism but not the Ala1330Val contributes to the observed variability in BMD in the Swedish populations. [ABSTRACT FROM AUTHOR]

Both oestrogen deficiency and the inflammatory disease contribute to the generalized bone loss seen in postmenopausal rheumatoid arthritis (RA). Oestradiol and the selective oestrogen receptor modulator raloxifene have been shown to ameliorate the disease in collagen-induced arthritis (CIA), a well-established animal model for human RA. The aim of this study was to investigate whether raloxifene-treatment would be beneficial in long-term treatment of established CIA, both regarding anti-arthritic and anti-osteoporotic properties. Female dilute brown agouti mice were ovariectomized and CIA was induced. Raloxifene or vehicle treatment was administered 5 days per week, and the clinical arthritis score was evaluated continuously. At termination, bone mineral density was analysed, paws were collected for histological examination and sera were analysed for markers of bone and cartilage turnover, as well as antibodies to type II collagen and levels of interleukin (IL)-6. Treatment with raloxifene is beneficial in long-term treatment of established CIA. It hampers the disease severity and frequency, protects the joints from destruction and protects against the development of osteoporosis. The proinflammatory cytokine IL-6 was down-regulated in raloxifene-treated mice compared with controls. The serum levels of antibodies to collagen were not affected by raloxifene-treatment. Long-term treatment with raloxifene has both anti-arthritic and anti-osteoporotic effects in established experimental postmenopausal polyarthritis. [ABSTRACT FROM AUTHOR]

The objective of the present study was to examine if near infrared reflectance spectroscopy (NIRS) could be used to predict degradation parameters and effective degradation from scans of original forage samples. Degradability of dry matter (DM), crude protein (CP) and neutral detergent fibre (NDF) of 61 samples of perennial ryegrass ( Lolium perenne L.) and orchardgrass ( Dactylis glomerata L.) was tested by using the in situ technique. The grass samples were harvested at three different stages, early vegetative growth, early reproductive growth and late reproductive growth. Degradability was described in terms of immediately rumen soluble fraction ( a fraction, for DM and CP only as NDF does not contain a soluble fraction), the degradable but not soluble faction ( b fraction) and the rate of degradation of the b fraction ( c value). Overall effective degradability of DM, CP and NDF was also calculated. Near infrared reflectance spectroscopy was examined for its ability to predict degradation parameters and to make a direct prediction of effective degradation from scans of the original samples of perennial ryegrass and orchardgrass. Prediction of effective degradation of the different feed fractions showed different accuracy. The coefficients of determination ( R2) from regressions of predicted vs. measured effective degradation, using a cross-validation method, were 0.92 for DM, 0.78 for CP and 0.61 for NDF. The attempt to predict the degradation parameters ( a, b and c) by NIRS was less successful as the coefficients of determination for the degradation parameters were low. Concentrations of CP and NDF in the original samples were predicted by using NIRS and the validated R2 value was 0.98 for CP and 0.92 for NDF. It is concluded that using NIRS predictions from scans of original samples is a promising method to obtain values for the effective degradation of DM, CP and NDF in ruminant feeds, but that larger calibration sets are necessary for obtaining improved accuracy. [ABSTRACT FROM AUTHOR]

Genetic variation in the androgen metabolizing enzymes is important to identify and feature as they may influence the risk of prostate cancer and help clarify the etiology of the disease. Human 17β-hydroxysteroid dehydrogenase type 5 (AKR1C3) is highly expressed in the prostate gland and plays a major role in the formation and metabolism of androgens. We identified five novel polymorphisms in the AKR1C3 gene. One of those an A>G substitution in exon 2 that confers a Glu77Gly change occurred in 4.8% in Caucasians but was completely absent in Orientals. Interestingly, the testosterone level in serum was significantly lower in subjects with the Gly77 allele. A promoter A>G polymorphism was associated with significantly altered promoter activity in reporter constructs, but was not associated with any change in testosterone levels. In conclusion, the Glu77Gly polymorphism is associated with lower testosterone levels in serum.The Pharmacogenomics Journal (2007) 7, 282–289; doi:10.1038/sj.tpj.6500419; published online 19 September 2006 [ABSTRACT FROM AUTHOR]

Objectives. To determine the frequency of osteoporosis and possible risk factors of low bone mineral density (BMD) in women with systemic lupus erythematous (SLE) in western Sweden. In addition, to evaluate if adequate anti-osteoporotic treatment was provided. [ABSTRACT FROM PUBLISHER]

The role of puberty and normal variations in pubertal timing for the development of obesity in men is unclear. The aim of the current study was to investigate the impact of pubertal timing and prepubertal BMI (kg/m(2)) for young adult BMI and fat mass distribution. Detailed growth charts from birth to age 18-20 years were retrieved for the men participating in the population-based Gothenburg Osteoporosis and Obesity Determinants study. Age at peak height velocity (PHV) and BMI at age 10 years were estimated for 579 subjects, and PHV was used as an assessment of pubertal timing. The fat mass characterization and distribution were analyzed using dual X-ray absorptiometry and peripheral as well as abdominal computed tomography at age 18.9 +/- 0.5 years. We demonstrate that age at PHV is an independent negative predictor of young adult BMI and whole-body fat mass. Interestingly, age at PHV is an independent negative predictor of central, but not peripheral, fat mass. In contrast, BMI at 10 years of age predicts both central and peripheral subcutaneous fat mass. In conclusion, we demonstrate that early pubertal onset specifically predicts a central fat mass distribution, while a predominantly subcutaneous obese phenotype is strongly predicted by a high prepubertal BMI. [ABSTRACT FROM AUTHOR]

The Arg16Gly and the Gln27Glu polymorphisms in the gene for the β2-adrenergic receptor (β2AR) have been linked to an increased risk for cardiovascular disease. The aim of the present study was to evaluate the significance of these haplotypes for development of myocardial infarction (MI) as well as other cardiovascular phenotypes. In a prospective study cohort (CAPPP), 522 hypertensive patients (174 MI and 348 matched controls) were analysed for the Arg16Gly and the Gln27Glu polymorphisms by dynamic allele-specific hybridisation. The haplotype could successfully be determined in 516 patients. Haplotype was not significantly associated with MI. Systolic blood pressure (SBP) was higher in patients with Arg16Gly+Gln27Gln and lower in patients with Arg16Gly+Gln27Glu as compared with the other haplotypes. Haplotype was not associated with body mass index, diastolic blood pressure, cholesterol, LDL, HDL triglycerides or a diagnosis of diabetes mellitus. The present study found no evidence that haplotype for the two most common polymorphisms in the β2AR are associated with development of MI in a Swedish hypertensive population, but haplotype may be associated with SBP.Journal of Human Hypertension (2005) 19, 705–708. doi:10.1038/sj.jhh.1001897; published online 2 June 2005 [ABSTRACT FROM AUTHOR]

Background and aims: The gastric hormone ghrelin has been reported to stimulate food intake, increase weight gain, and cause obesity but its precise physiological role remains unclear. We investigated the long term effects of gastrectomy evoked ghrelin deficiency and of daily ghrelin injections on daily food intake, body weight, fat mass, lean body mass, and bone mass in mice. Methods: Ghrelin was given by subcutaneous injections (12 nmol/mouse once daily) for eight weeks to young female mice subjected to gastrectomy or sham operation one week previously. Results: Gastrectomy reduced plasma concentrations of total ghrelin (octanoylated and des-octanoylated) and active (octanoylated) ghrelin by ∼80%. Immediately after injection of ghrelin, the plasma concentration was supraphysiological and was still elevated 16 hours later. Daily food intake was not affected by either gastrectomy or ghrelin treatment. The effect of ghrelin on meal initiation was not studied. At the end point of the study, mean body weight was 15% lower in gastrectomised mice than in sham operated mice (p<0.001); daily ghrelin injections for eight weeks partially prevented this weight loss. In sham operated mice, ghrelin had no effect on body weight. The weight of fat was reduced in gastrectomised mice (-30%; p<0.01). This effect was reversed by ghrelin, enhancing the weight of fat in sham operated mice also (+20%; p<0.05). Gastrectomy reduced lean body mass (-10%; p

Erlandsson MC, Islander U, Moverare S, Ohlsson C, Carlsten H. Estrogenic agonism and antagonism of the soy isoflavone genistein in uterus, bone and lymphopoiesis in mice. APMIS 2005;113:317–23.The isoflavone genistein (Gen) is a naturally occurring phytoestrogen found in high concentrations in soy. The biological effects of Gen have been extensively studied. The immunomodulating properties of Gen are, however, less well investigated and the results are contradictory. Our aim was to study possible estrogen agonistic and antagonistic properties of Gen in uterus, bone, lymphopoiesis and B-cell function by comparing effects in castrated and intact female mice, respectively. Oophorectomized (OVX) and sham-operated mice were treated with s.c. doses of 17β-estradiol (E2) (0.16 mg/kg), Gen (50 mg/kg), or vehicle (olive oil) as control. Effects on bone mineral density (BMD) were studied using peripheral quantitative computerized tomography, uterine and thymus weights were examined, lymphopoiesis in thymus and bone marrow was analyzed using flow cytometry, and the frequency of immunoglobulin-producing B cells in bone marrow and spleen was studied using an ELISPOT assay. Gen was clearly antagonizing endogenous estrogen in sham-operated female mice as shown by inhibiting the uterine weight and by increasing the frequency of B lymphopoietic cells in bone marrow. The only agonistic effect of Gen was shown by increased BMD in OVX mice. Our results are discussed in the context of estrogen receptor biology. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the effect of adding testosterone undecanoate 40 mg daily to estrogen therapy on bone markers, bone mineral density and body composition in oophorectomized women. Methods. Fifty women, 45-60 years old, who had undergone a hysterectomy and bilateral salpingo-oophorectomy for benign disorders, were randomly assigned to oral treatment with testosterone undecanoate 40 mg plus estradiol valerate 2 mg daily or placebo plus estradiol valerate 2 mg daily. Twenty-four weeks later, cross-over was performed to the other treatment regimen. Forty-four women completed the study. Their serum concentrations of insulin-like growth factor (IGF)- I, IGF binding protein (IGFBP)-3, osteocalcin, carboxyterminal telopeptide aminoterminal (ICTP), of type I collagen propeptide of type I procollagen (PICP) and interleukin (IL)-1 receptor antagonist were measured at baseline and after 24 weeks of both treatments, as were also their body mass index (BMI) and blood pressure. Bone mineral density of the total body, spine and hip and total body fat, total lean body mass, trunk fat and trunk lean mass were determined by dual-energy X-ray absorptiometry measurements at baseline and after 24 weeks of both regimens. Results. During treatment, the addition of testosterone counteracted the decrease in IGF-I and PICP seen with estrogen therapy alone. Osteocalcin and ICTP were significantly reduced to the same extent by both therapies. No change ocurred in the IL-1 receptor antagonist. A significant increase was seen in total lean body mass with the estrogen/testosterone regimen, but the total fat mass, trunk lean or fat mass remained unchanged after 24 weeks of both treatments. No effect was detected on total, hip or spinal bone mineral density after treatment with estrogen alone or estrogen/testosterone. Likewise, BMI and blood pressure were unaffected. Conclusions. The addition of testosterone to oral estrogen might have positive effects on bone as suggested by the fact that it counteracted the decline in IGF-I and PICP levels. An anabolic effect on muscle was reflected by an increase in the total lean body mass. No adverse effects were noted on BMI, fat distribution or blood pressure during the 6-month treatment with oral testosterone undecanoate. [ABSTRACT FROM AUTHOR]