| 1. |
- Grundberg, Elin, et al.
(författare)
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The Impact of Estradiol on Bone Mineral Density is modulated by The Specific Estrogen Receptor-{alpha} Cofactor RIZ1 Insertion/Deletion Polymorphism.
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 92:Mar 13, s. 2300-2306
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Tidskriftsartikel (refereegranskat)abstract
- Context: Estrogens regulate bone mass by binding to the estrogen receptor (ER)-alpha as well as ER-beta. The specific ER -cofactor retinoblastoma-interacting zinc finger protein (RIZ)-1 enhances ER alpha function in the presence of estrogen. Objective: The objective of the study was to determine whether a RIZ P704 insertion (+)/ deletion (-) (indel) polymorphism modulates the impact of estradiol on bone mineral density (BMD) and study the association between the polymorphism and BMD in elderly subjects. Design: This was a population-based, prospective, and cross-sectional study, the Swedish MrOS Study, and the Malmo OPRA Study, respectively. Setting: The study was conducted at three academic medical centers: Sahlgrenska Academy in Gothenburg, Malmo University Hospital, and Uppsala University Hospital. Participants: In total, 4058 men and women, aged 69 -81 yr, were randomly selected from population registries. Main Outcome Measures: BMD(grams per square centimeter) was measured at femoral neck, trochanter, lumbar spine, and total body. Results: The RIZ P704(+/+) genotype was associated with low BMD in both women (femoral neck, P < 0.001; trochanter, P < 0.01; lumbar spine, P < 0.05; total body, P < 0.01) and men (lumbar spine, P < 0.05). However, the association between the polymorphism and BMD was dependent on estradiol status. The positive correlation between serum estradiol and BMD was significantly modulated by the genotype with a stronger correlation in the P704(+/+) group than the P704(+/+) group (r = 0.19 vs. r = 0.08, P < 0.05). Conclusions: These large-scale studies of elderly men and women indicate that the ER alpha cofactor RIZ gene has a prominent effect on BMD, and the P704 genotype modulates the impact of estradiol on BMD. Further studies are required to determine whether this polymorphism modulates the estrogenic response to estradiol treatment.
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| 2. |
- Grundberg, Elin, et al.
(författare)
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Vitamin D receptor 3' haplotypes are unequally expressed in primary human bone cells and associated with increased fracture risk: the MrOS Study in Sweden and Hong Kong.
- 2007
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 0884-0431. ; 22:6, s. 832-40
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Tidskriftsartikel (refereegranskat)abstract
- The VDR is a prime candidate gene for osteoporosis. Here, we studied three common VDR haplotypes in relation to bone phenotypes in 5014 participants of the global MrOS Study. We also studied the relative expression of the haplotypes in human bone cells. One haplotype was associated with increased fracture risk and differently expressed in primary human bone cells. INTRODUCTION: Vitamin D plays an essential role in skeletal metabolism by binding to its nuclear steroid receptor, the vitamin D receptor (VDR). The heritability of BMD is well established, and the VDR gene is considered a prime candidate suggested to partially account for genetically controlled BMD variance in the population. MATERIALS AND METHODS: Here, we reconstructed common haplotypes in the VDR 3' untranslated region (UTR) and studied the association to BMD and risk of vertebral fractures in elderly men from Sweden (n = 3014) and Hong Kong (n = 2000), all participants of the global MrOS Study. To assess any functional implications of the VDR polymorphisms, we studied allele-specific expressions of the different VDR 3' UTR haplotypes in the normal chromosomal context of 70 unrelated human trabecular bone samples. This was performed by quantitative genotyping of coding polymorphisms in RNA samples and in corresponding DNA samples isolated from the bone samples. RESULTS: Three major haplotypes were reconstructed and in agreement with the previously well-defined baT, BAt, and bAT haplotypes, herein denoted Hap1, Hap2, and Hap3. The Hap1 haplotype was independently associated with increased risk of vertebral fractures in Swedish men (OR, 1.655; 95% CI, 1.146-2.391; p < 0.01) and with lower lumbar spine BMD in elderly men from Sweden (p < 0.01) and Hong Kong (p < 0.05). The VDR gene was also shown to exhibit a 3' UTR haplotype dependent allelic imbalance, indicating that the VDR Hap1 allele was overexpressed in human trabecular bone samples. CONCLUSIONS: The results indicate that the relatively overexpressed VDR Hap1 haplotype could be considered a risk allele for osteoporosis regardless of ethnicity.
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| 3. |
- Mellström, Dan, 1945, et al.
(författare)
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Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden.
- 2006
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 0884-0431. ; 21:4, s. 529-35
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Tidskriftsartikel (refereegranskat)abstract
- The role of androgens for bone health in elderly men is unclear. We show that free testosterone within the normal range is a predictor of BMD at predominantly cortical bone sites and of previous osteoporosis-related fractures in elderly Swedish men. INTRODUCTION: Osteoporosis-related fractures constitute a major health concern not only in women but also in men. Previous studies have clearly shown that serum levels of estradiol are associated with BMD, whereas more conflicting data have been presented regarding the predictive value of testosterone (T) for bone health in elderly men. The aim of this study was to investigate if serum levels of T are associated with BMD and/or prevalent fractures in a large cohort of elderly men. MATERIALS AND METHODS: In the Swedish part of the MrOS study (n = 2908; average age, 75.4 years), bone parameters were measured using DXA, and prevalent fractures were recorded using standardized questionnaires and by vertebral X-ray analyses. Serum levels of total T, total estradiol (E2), and sex hormone-binding globulin (SHBG) were measured by radioimmunoassay, and free T (FT) and free E2 (FE2) were derived from the mass action equations. Height, weight, age, physical activity, smoking habits, and calcium intake were included together with FT and FE2 in regression models for BMD. RESULTS: FT was an independent positive predictor of BMD in total body, total hip, femur trochanter, and arm but not in the lumbar spine. The highest independent predictive value of FT was found in the arm and the hip (with a relatively high content of cortical bone). FE2 was an independent predictor of BMD at all bone sites studied, and the highest predictive value was seen for lumbar spine (with relatively high content of trabecular bone) BMD. FT but not FE2 was a positive predictor of total body bone area and BMC. FT levels below the median were independent predictors of prevalent osteoporosis-related fractures (OR, 1.56; 95% CI, 1.14-2.14; p < 0.01) and X-ray-verified vertebral fractures (OR, 2.00; 95% CI, 1.34-2.86; p < 0.001). The predictive value of FT for prevalent fractures was not affected by adjustment for BMD. CONCLUSIONS: These findings show that variation of FT within the normal range is an independent but modest predictor of BMD at predominantly cortical bone sites and of previous osteoporosis-related fractures in elderly men. Our data indicate that not only estrogens but also androgens are of importance for bone health in elderly men. Longitudinal studies investigating the predictive value of T for fracture risk in elderly men are required.
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| 4. |
- Mellström, Dan, 1945, et al.
(författare)
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Older men with low serum estradiol and high serum SHBG have an increased risk of fractures.
- 2008
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Ingår i: Journal of bone and mineral research. - 1523-4681. ; 23:10, s. 1552-60
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis-related fractures constitute a major health concern not only in women but also in men. To study the predictive role of serum sex steroids for fracture risk in men, serum sex steroids were analyzed by the specific gas chromatography-mass spectrometry technique at baseline in older men (n = 2639; mean, 75 yr of age) of the prospective population-based MrOS Sweden cohort. Fractures occurring after baseline were validated (average follow-up of 3.3 yr). The incidence for having at least one validated fracture after baseline was 20.9/1000 person-years. Estradiol (E2; hazard ratio [HR] per SD decrease, 1.34; 95% CI, 1.22-1.49), free estradiol (fE2; HR per SD decrease, 1.41; 95% CI, 1.28-1.55), testosterone (T; HR per SD decrease, 1.27; 95% CI, 1.16-1.39), and free testosterone (fT; HR per SD decrease, 1.32; 95% CI, 1.21-1.44) were all inversely, whereas sex hormone-binding globulin (SHBG; HR per SD increase, 1.41; 95% CI, 1.22-1.63) was directly related to fracture risk. Multivariable proportional hazards regression models, adjusted for age, suggested that fE2 and SHBG (p < 0.001), but not fT, were independently associated with fracture risk. Further subanalyses of fracture type showed that fE2 was inversely associated with clinical vertebral fractures (HR per SD decrease, 1.57; 95% CI, 1.36-1.80), nonvertebral osteoporosis fractures (HR per SD decrease, 1.42; 95% CI, 1.23-1.65), and hip fractures (HR per SD decrease, 1.44; 95% CI, 1.18-1.76). The inverse relation between serum E2 and fracture risk was nonlinear with a strong relation <16 pg/ml for E2 and 0.3 pg/ml for fE2. In conclusion, older Swedish men with low serum E2 and high SHBG levels have an increased risk of fractures.
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