The ESR1 (6q25) locus is associated with calcaneal ultrasound parameters and radial volumetric bone mineral density in European men

<p><b>Purpose:</b> 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 (BMD(a)) 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.</p> <p><b>Methods:</b> 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.</p> <p><b>Results:</b> 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 BMD(a), a 0.12 SD (95%CI 0.02, 0.23; p = 0.026) lower lumbar spine BMD(a) 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.</p> <p><b>Conclusions:</b> Our data replicate previous associations found between SNPs in the 6q25 locus and BMD(a) at the hip and extend these data to include associations with calcaneal ultrasound parameters and radial volumetric BMD.</p&gt

Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European male aging study (EMAS)

<p>Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.</p> <p>Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.</p> <p>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)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D 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.</p> <p>Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.</p> <p>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)2D 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)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D 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)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.</p> <p>Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.</p&gt

Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European male aging study (EMAS)

<p>Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.</p> <p>Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.</p> <p>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)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D 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.</p> <p>Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.</p> <p>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)2D 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)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D 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)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.</p> <p>Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.</p&gt

Inflammatory markers are associated with quality of life, physical activity, and gait speed but not sarcopenia in aged men (40-79 years)

Background: Age-related chronic low-grade inflammation (inflammaging) is one of the proposed mechanisms behind sarcopenia. However, findings regarding inflammatory markers in sarcopenic older adults are conflicting. This study aimed to determine the association between inflammatory markers, prevalent as well as incident sarcopenia, sarcopenia-defining parameters, quality of life (QoL), and physical activity in middle-aged and older men. Methods: Men aged 40–79 years (mean 59.66 ± 11.00y) were recruited from population registers in eight European centres for participation in the European Male Aging study (EMAS). Subjects were assessed at baseline (2003–2005) and again after a median follow-up of 4.29 years. In 2577 participants, associations between baseline inflammatory markers [high-sensitive C-reactive protein (hs-CRP), white blood cell count (WBC), albumin] and baseline physical activity (PASE) and QoL (SF-36) were analysed. In the Leuven and Manchester cohort (n = 447), data were available on muscle mass (whole-body dual X-ray absorptiometry) and strength. In this subgroup, cross-sectional associations between baseline inflammatory markers and sarcopenia-defining parameters (handgrip strength, chair stand test, appendicular lean mass, and gait speed) and prevalent sarcopenia were examined. In a further subgroup (n = 277), associations with knee extensor strength were explored. Longitudinally, predictive value of baseline inflammation on functional decline, physical activity, QoL, and incident sarcopenia was examined. Subgroup analyses were performed in subgroups with chronic inflammation and stratified by age. Linear and logistic regressions were used, adjusted for age, body mass index, centre, and smoking. Results: At baseline, hs-CRP and WBC were negatively associated with PASE score (hs-CRP: β = −7.920, P < 0.001; and WBC: β = −4.552, P < 0.001) and the physical component score of SF-36 (hs-CRP: β = −1.025, P < 0.001; and WBC: β = −0.364, P < 0.001). Baseline WBC levels were negatively associated with gait speed (β = −0.013; P = 0.025), quadriceps isometric 90° (β = −5.983; P = 0.035) and isokinetic 60°/s peak torque/body weight (β = −5.532; P = 0.027). The prevalence of sarcopenia at baseline was 18.1% (n = 81). Of those without sarcopenia at baseline, 64 (18.6%) satisfied criteria for sarcopenia at follow-up. There were no significant associations between baseline inflammatory markers and either prevalent or incident sarcopenia, or change in level of sarcopenia-defining parameters between baseline and follow-up. Conclusions: In middle-aged and older men, hs-CRP and WBC were negatively associated with QoL and PASE scores, while WBC was negatively associated with gait speed and knee strength. Associations with hs-CRP remained significant in all ages, whereas WBC levels were only associated with PASE, gait speed and knee strength in older adults (60–79 years). Baseline inflammatory markers (hs-CRP, WBC and albumin) did not predict functional decline, decline in physical activity, decreased QoL or incident sarcopenia

Symptomatic androgen deficiency develops only when both total and free testosterone decline in obese men who may have incident biochemical secondary hypogonadism: prospective results from the EMAS

Objective: Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex hormone binding globulin (SHBG) is altered. Low total testosterone (TT) is commonly encountered in obesity where SHBG is typically decreased. We aimed to assess the contribution of FT in improving the diagnosis of symptomatic secondary hypogonadism (SH), identified initially by low total testosterone (TT), and then further differentiated by normal FT (LNSH) or low FT (LLSH). Design: Prospective observational study with a median follow‐up of 4.3 years. Patients: 3369 community‐dwelling men aged 40‐79 years from eight European centres. Measurements: Subjects were categorised according to baseline and follow‐up biochemical status into persistent eugonadal (referent group; n=1880), incident LNSH (eugonadism to LNSH; n=101) and incident LLSH (eugonadism to LLSH; n=38). Predictors and clinical features associated with the transition from eugonadism to LNSH or LLSH were assessed. Results: The cumulative incidence of LNSH and LLSH over 4.3 years was 4.9% and 1.9% respectively. Baseline obesity predicted both LNSH and LLSH but the former occurred more frequently in younger men. LLSH, but not LNSH, was associated with new/worsened sexual symptoms, including low desire [OR= 2.67 (1.27‐5.60)], erectile dysfunction [OR= 4.53 (2.05‐10.01)] and infrequent morning erections [OR= 3.40 (1.48‐7.84)]. Conclusions: These longitudinal data demonstrate the importance of FT in the diagnosis of hypogonadism in obese men with low TT and SHBG. The concurrent fall in TT and FT identifies the minority (27.3%) of men with hypogonadal symptoms, which were not present in the majority developing low TT with normal FT

The androgen receptor gene CAG repeat in relation to 4-year changes in androgen-sensitive endpoints in community-dwelling older European men

Context: The Androgen Receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive.Objective: To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints which are influenced by testosterone (T) levels in middle-aged and elderly European men.Design: Multinational European observational prospective cohort studyParticipants: 1887 men (mean±sd age: 63±11 years; median follow-up: 4.3 years) from centres of 8 European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic-pituitary-testicular (HPT) axis.Main outcome measures: Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated both as a continuous and categorical (6-20; 21-23; 24-39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels.Results: The AR CAG repeat, when used as a continuous or categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels.Conclusion: Within a 4-year timeframe, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, that, which might be associated with the age-related decline in T levels

Osteoid osteoma of the femur in a 7-month-old infant treated with radiofrequency ablation

Osteoid osteoma occurs most commonly in children, adolescents, and young adults between the ages of 5 and 30 years. In the preschool age group, it is quite uncommon, accounting for only 3–8% of all osteoid osteoma cases. We report a case of osteoid osteoma in a 7-month-old infant, who presented with decreased use of the right lower extremity due to pain. Magnetic resonance imaging (MRI) showed an atypical appearance. A biopsy of the lesion, with histopathological examination, confirmed the diagnosis of osteoid osteoma. Radiofrequency ablation (RFA) of the nidus under computed tomography (CT) guidance was performed. The patient developed a recurrence after 3 months, which was treated with a second RFA. On subsequent follow-up, the infant did not show signs of pain after 1 month. In summary, this case report shows that osteoid osteoma can present in early infancy and can be successfully treated with RFA at this age, however, recurrence after the procedure can occur and close follow-up is recommended

Free 25-Hydroxyvitamin D: Impact of Vitamin D Binding Protein Assays on Racial-Genotypic Associations

Context: Total 25-hydroxyvitamin D (25OHD) is a marker of vitamin D status and is lower in African Americans than in whites. Whether this difference holds for free 25OHOD (f25OHD) is unclear, considering reported genetic-racial differences in vitamin D binding protein (DBP) used to calculate f25OHD.  Objectives: Our objective was to assess racial-geographic differences in f25OHD and to understand inconsistencies in racial associations with DBP and calculated f25OHD.  Design: This study used a cross-sectional design.  Setting: The general community in the United States, United Kingdom, and The Gambia were included in this study.  Participants: Men in Osteoporotic Fractures in Men and Medical Research Council studies (N = 1057) were included.  Exposures: Total 25OHD concentration, race, and DBP (GC) genotype exposures were included.  Outcome Measures: Directly measured f25OHD, DBP assessed by proteomics, monoclonal and polyclonal immunoassays, and calculated f25OHD were the outcome measures.  Results: Total 25OHD correlated strongly with directly measured f25OHD (Spearman r = 0.84). Measured by monoclonal assay, mean DBP in African-ancestry subjects was approximately 50% lower than in whites, whereas DBP measured by polyclonal DBP antibodies or proteomic methods was not lower in African-ancestry. Calculated f25OHD (using polyclonal DBP assays) correlated strongly with directly measured f25OHD (r = 0.80–0.83). Free 25OHD, measured or calculated from polyclonal DBP assays, reflected total 25OHD concentration irrespective of race and was lower in African Americans than in US whites.  Conclusions: Previously reported racial differences in DBP concentration are likely from monoclonal assay bias, as there was no racial difference in DBP concentration by other methods. This confirms the poor vitamin D status of many African-Americans and the utility of total 25OHD in assessing vitamin D in the general population