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Background The association between low levels of vitamin D and the occurrence of chronic widespread pain (CWP) remains unclear. The aim of our analysis was to determine the relationship between low vitamin D levels and the risk of developing CWP in a population sample of middle age and elderly men. Methods Three thousand three hundred sixty nine men aged 40–79 were recruited from 8 European centres for a longitudinal study of male ageing, the European Male Ageing Study. At baseline participants underwent assessment of lifestyle, health factors, physical characteristics and gave a fasting blood sample. The occurrence of pain was assessed at baseline and follow up (a mean of 4.3 years later) by shading painful sites on a body manikin. The presence of CWP was determined using the ACR criteria for fibromyalgia. Serum 25-hydroxyvitamin D (25-(OH) D) was assessed by radioimmunoassay. Logistic regression was used to determine the relationship between baseline vitamin D levels and the new occurrence of CWP. Results Two thousand three hundred thirteen men, mean age 58.8 years (SD = 10.6), had complete pain and vitamin data available and contributed to this analysis. 151 (6.5 %) developed new CWP at follow up and 577 (24.9 %) were pain free at both time points, the comparator group. After adjustment for age and centre, physical performance and number of comorbidities, compared to those in upper quintile of 25-(OH) D ( ≥36.3 ng/mL), those in the lowest quintile (<15.6 ng/mL) were more likely to develop CWP (Odds Ratio [OR] = 1.93; 95 % CI = 1.0-3.6). Further adjustment for BMI (OR = 1.67; 95 % CI = 0.93-3.02) or depression (OR = 1.77; 95 % CI = 0.98-3.21), however rendered the association non-significant. Conclusions Low vitamin D is linked with the new occurrence of CWP, although this may be explained by underlying adverse health factors, particularly obesity and depression.

Context:There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)(2)D] on bone health including turnover.Objective:The objective of the study was to determine the influence of 1,25(OH)(2)D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.Design, Setting, and Participants:Men aged 40-79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)(2)D, 25(OH)D, and PTH were measured. 1,25(OH)(2)D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.Main Outcome Measure(s):QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.Results:A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)(2)D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)(2)D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)(2)D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)(2)D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.Conclusions:Serum 1,25(OH)(2)D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of

Context: Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men. Objective: Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes. Design and Setting: Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included. Main Outcome Measures: Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and anklebrachial index. Results: Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient r(S) 0.53-0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, r(S) = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP. Conclusions: Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.

Context: Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men. Objective: Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes. Design and Setting: Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included. Main Outcome Measures: Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and anklebrachial index. Results: Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient r(S) 0.53-0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, r(S) = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP. Conclusions: Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.

Context: Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men. Objective: Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes. Design and Setting: Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included. Main Outcome Measures: Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and anklebrachial index. Results: Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient r(S) 0.53-0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, r(S) = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP. Conclusions: Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.

Context: Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men. Objective: Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes. Design and Setting: Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included. Main Outcome Measures: Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and anklebrachial index. Results: Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient r(S) 0.53-0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, r(S) = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP. Conclusions: Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.

Context: Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men. Objective: Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes. Design and Setting: Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included. Main Outcome Measures: Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and anklebrachial index. Results: Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient r(S) 0.53-0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, r(S) = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP. Conclusions: Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.

Context:Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men.Objective:Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes.Design and Setting:Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included.Main Outcome Measures:Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and ankle-brachial index.Results:Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient rS 0.53-0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, rS = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP.Conclusions:Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.

Introduction: In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within two genes involved in the NF-kappa B cascade (GPR177 and MAP3K14) and bone mineral density (BMD) assessed at different skeletal sites, radial geometric parameters and bone turnover. Methods: Ten GPR177 SNPs previously associated with BMD with genome-wide significance and twelve tag SNPs (r(2) >= 0.8) within MAP3K14 (+/-10 kb) were genotyped in 2359 men aged 40-79 years recruited from 8 centres for participation in the European Male Aging Study (EMAS). Measurement of bone turnover markers (PINP and CTX-I) in the serum and quantitative ultrasound (QUS) at the calcaneus were performed in all centres. Dual energy X-ray absorptiometry (DXA), at the lumbar spine and hip, and peripheral quantitative computed tomography (pQCT), at the distal and midshaft radius, were performed in a subsample (2 centres). Linear regression was used to test for association between the SNPs and bone measures under an additive genetic model adjusting for study centre. Results: We validated the associations between SNPs in GPR177 and BMDa previously reported and also observed evidence of pleiotrophic effects on density and geometry. Rs2772300 in GPR177 was associated with increased total hip and LS BMDa, increased total and cortical vBMD at the radius and increased cortical area, thickness and stress strain index. We also found evidence of association with BMDa, vBMD, geometric parameters and CTX-I for SNPs in MAP3K14. None of the GPR177 and MAP3K14 SNPs were associated with calcaneal estimated BMD measured by QUS. Conclusion: Our findings suggest that SNPs in GPR177 and MAP3K14 involved in the NF-kappa B signalling pathway influence bone mineral density, geometry and turnover in a population-based cohort of middle aged and elderly men. This adds to the understanding of the role of genetic variation in this pathway in determining bone health.

Purpose: Genome-wide association studies (GWAS) have identified 6q25, which incorporates the oestrogen receptor alpha gene (ESR1), as a quantitative trait locus for areal bone mineral density (BMDa) of the hip and lumbar spine. The aim of this study was to determine the influence of this locus on other bone health outcomes; calcaneal ultrasound (QUS) parameters, radial peripheral quantitative computed tomography (pQCT) parameters and markers of bone turnover in a population sample of European men. Methods: Eight single nucleotide polymorphisms (SNP) in the 6q25 locus were genotyped in men aged 40-79 years from 7 European countries, participating in the European Male Ageing Study (EMAS). The associations between SNPs and measured bone parameters were tested under an additive genetic model adjusting for centre using linear regression. Results: 2468 men, mean (SD) aged 59.9 (11.1) years had QUS measurements performed and bone turnover marker levels measured. A subset of 628 men had DXA and pQCT measurements. Multiple independent SNPs showed significant associations with BMD using all three measurement techniques. Most notably, rs1999805 was associated with a 0.10 SD (95%CI 0.05, 0.16; p = 0.0001) lower estimated BMD at the calcaneus, a 0.14 SD (95%CI 0.05, 0.24; p = 0.004) lower total hip BMDa, a 0.12 SD (95%CI 0.02, 0.23; p = 0.026) lower lumbar spine BMDa and a 0.18 SD (95%CI 0.06, 0.29; p = 0.003) lower trabecular BMD at the distal radius for each copy of the minor allele. There was no association with serum levels of bone turnover markers and a single SNP which was associated with cortical density was also associated with cortical BMC and thickness. Conclusions: Our data replicate previous associations found between SNPs in the 6q25 locus and BMDa at the hip and extend these data to include associations with calcaneal ultrasound parameters and radial volumetric BMD.

Background: A number of single nucleotide polymorphisms (SNPs) have been associated with broadband ultrasound attenuation (BUA) and speed of sound (SOS) as measured by quantitative ultrasound (QUS) at the calcaneus in the Framingham 100K genome-wide association study (GWAS) but have not been validated in independent studies. The aim of this analysis was to determine if these SNPs are associated with QUS measurements assessed in a large independent population of European middle-aged and elderly men. The association between these SNPs and bone mineral density (BMD) measured using dual-energy X-ray absorptiometry (DXA) was also tested. Methods: Men aged 40-79 years (N = 2960) were recruited from population registers in seven European centres for participation in an observational study of male ageing, the European Male Ageing Study (EMAS). QUS at the calcaneus was measured in all subjects and blood was taken for genetic analysis. Lumbar spine (LS), femoral neck (FN) and total hip (TH) BMD were measured by DXA in a subsample of 620 men in two centres. SNPs associated with BUA or SOS in the Framingham study with p < 10(-4) were selected and genotyped using SEQUENOM technology. Linear regression was used to test for the association between SNPs and standardised (SD) bone outcomes under an additive genetic model adjusting for centre. The same direction of effect and p < 0.05 indicated replication. Results: Thirty-four of 38 selected SNPs were successfully genotyped in 2377 men. Suggestive evidence of replication was observed for a single SNP, rs3754032, which was associated with a higher SOS (beta(SD) = 0.07, p = 0.032) but not BUA (beta(SD) = 0.02, p = 0.505) and is located in the 3'UTR of WDR77 (WD repeat domain 77) also known as androgen receptor cofactor p44. A single SNP, rs238358, was associated with BMD at the LS (beta(SD) = -0.22, p = 0.014), FN (beta(SD) = -0.31, p = 0.001) and TH (beta(SD) = -0.36, p = 0.002) in a locus previously associated with LS BMD in large-s

Introduction Assessment of male sexual dysfunction has been the focus of substantial scientific effort. Less research has focused on the development of instruments for the measurement of sexual functioning in aging men. Aims The aims of this study were: (i) to characterize the psychometric properties of a new brief, reliable, and valid measure of male sexual functioning for use in a large population survey of middle-aged and elderly European men; and (ii) specifically, to determine whether the new instrument, the European Male Ageing Study–sexual function questionnaire (EMAS–SFQ), discriminates between men with high and low levels of circulating testosterone (T) (total T, free T, and bioavailable T). Method One thousand six hundred men aged 40–79 years completed the self-administered EMAS–SFQ, the Beck depression inventory, and provided a blood sample for assessment of sex hormones. Eighty-five men aged 35–74 years completed the EMAS–SFQ twice, 2 weeks apart to examine the test–retest reliability of the instrument. Main Outcome Measures Scores on the EMAS–SFQ in relation to age and T levels. Results Principal component analysis showed that the EMAS–SFQ had four distinct domains (overall sexual functioning [OSF], masturbation, sexual functioning-related distress, and change in sexual functioning). The instrument demonstrated excellent internal and test–retest reliability, as well as convergent, divergent, and discriminant validity. Men with the lowest levels of total, free, and bioavailable T reported lower OSF scores compared to men with the highest T levels. Conclusions The EMAS–SFQ is a valid and reproducible instrument, sensitive to age and T levels. It should be suitable for the assessment of sexual health in population samples of men in epidemiological studies of aging. O'Connor DB, Corona G, Forti G, Tajar A, Lee DM, Finn JD, Bartfai G, Boonen S, Casanueva FF, Giwercman A, Huhtaniemi IT, Kula K, O'Neill TW, Pendleton N, Punab M, Silman AJ, Vanderschueren D, Wu

Introduction Assessment of male sexual dysfunction has been the focus of substantial scientific effort. Less research has focused on the development of instruments for the measurement of sexual functioning in aging men. Aims The aims of this study were: (i) to characterize the psychometric properties of a new brief, reliable, and valid measure of male sexual functioning for use in a large population survey of middle-aged and elderly European men; and (ii) specifically, to determine whether the new instrument, the European Male Ageing Study–sexual function questionnaire (EMAS–SFQ), discriminates between men with high and low levels of circulating testosterone (T) (total T, free T, and bioavailable T). Method One thousand six hundred men aged 40–79 years completed the self-administered EMAS–SFQ, the Beck depression inventory, and provided a blood sample for assessment of sex hormones. Eighty-five men aged 35–74 years completed the EMAS–SFQ twice, 2 weeks apart to examine the test–retest reliability of the instrument. Main Outcome Measures Scores on the EMAS–SFQ in relation to age and T levels. Results Principal component analysis showed that the EMAS–SFQ had four distinct domains (overall sexual functioning [OSF], masturbation, sexual functioning-related distress, and change in sexual functioning). The instrument demonstrated excellent internal and test–retest reliability, as well as convergent, divergent, and discriminant validity. Men with the lowest levels of total, free, and bioavailable T reported lower OSF scores compared to men with the highest T levels. Conclusions The EMAS–SFQ is a valid and reproducible instrument, sensitive to age and T levels. It should be suitable for the assessment of sexual health in population samples of men in epidemiological studies of aging. O'Connor DB, Corona G, Forti G, Tajar A, Lee DM, Finn JD, Bartfai G, Boonen S, Casanueva FF, Giwercman A, Huhtaniemi IT, Kula K, O'Neill TW, Pendleton N, Punab M, Silman AJ, Vanderschueren D, Wu