Association study of the oestrogen signalling pathway genes in relation to age at natural menopause

Genetic factors play a significant role in influencing the variation of age at natural menopause (AANM). Estrogen receptor β (ESR2), is an important factor in the mechanism of action of estrogen, while the aromatase gene (CYP19) and the 17-alphahydroxylase gene (CYP17) are involved in the biosynthesis of estrogen. We tested whether polymorphisms of ESR2, CYP19 and CYP17 genes are associated with AANM in Caucasian females. A total of 52 SNPs (17 for ESR2, 28 for CYP19, and 7 for CYP17) were successfully genotyped for 229 Caucasian women having experienced natural menopause. Comprehensive statistical analyses focusing on the association of these genes with AANM were conducted. The effects of age, height and age at menarche on AANM were adjusted when conducting association analyses. We found that six SNPs (2, 6–7, 9, 13 and 16) within ESR2 were not significantly associated with AANM after Bonferroni correction. However, two blocks of ESR2 were associated with AANM. For CYP19, two SNPs (24 and 27) were nominally associated with AANM. No significant association was observed between CYP17 and AANM. Our results suggest that genetic variation in the ESR2 and CYP19 genes may influence the variation in AANM in Caucasian women.     

Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study

A cross-sectional study on intestinal microbiota composition was performed on 230 healthy subjects at four European locations in France, Germany, Italy, and Sweden. The study participants were assigned to two age groups: 20 to 50 years (mean age, 35 years; n = 85) and >60 years (mean age, 75 years; n = 145). A set of 14 group- and species-specific 16S rRNA-targeted oligonucleotide probes was applied to the analysis of fecal samples by fluorescence in situ hybridization coupled with flow cytometry. Marked country-age interactions were observed for the German and Italian study groups. These interactions were inverse for the predominant bacterial groups Eubacterium rectale-Clostridium coccoides and Bacteroides-Prevotella. Differences between European populations were observed for the Bifidobacterium group only. Proportions of bifidobacteria were two- to threefold higher in the Italian study population than in any other study group, and this effect was independent of age. Higher proportions of enterobacteria were found in all elderly volunteers independent of the location. Gender effects were observed for the Bacteroides-Prevotella group, with higher levels in males than in females. In summary, age-related differences in the microbiota makeup were detected but differed between the study populations from the four countries, each showing a characteristic colonization pattern.     

The effects of weight loss on relative bone mineral density in premenopausal women

Objective:

This study compared BMD relative to body weight following a ～6‐month weight loss program and a 1‐year weight maintenance phase in premenopausal women and determined whether African American (AA) and European‐American (EA) women's BMD respond similarly during weight loss.

Design and Methods:

Premenopausal women (n = 115, 34 ± 5 years) were evaluated in an overweight state (BMI between 27 and 30 kg/m²), following an 800 kcal/day diet/exercise program designed to reduce BMI<25 kg/m², and 1‐year following weight loss.

Results:

BMD relative to body weight (Z‐scores) increased after weight loss, but decreased during the 1‐year weight maintenance phase. All 1‐year follow‐up BMD Z‐scores were increased (except L1) compared to baseline measurements (P < 0.05). These sites included the hip neck (+0.088, P = 0.014), total hip (+0.099, P = 0.001), L2 (+0.127, P = 0.013), L3 (+0.135, P = 0.014), and L4 (+0.199, P = 0.002). AAs had significantly higher absolute BMD at all sites (P < 0.05) compared to EAs, but no time by race interactions were evident during weight loss (except in L3).

Conclusion:

These results may indicate that weight loss is safe with regard to bone health for overweight premenopausal women.     

Measuring and interpreting age‐related loss of vertebral bone mineral density in a medieval population

This study investigates the age‐ and sex‐related patterns in vertebral bone mineral density (BMD) and the relationship between BMD and vertebral osteophytosis (VO), using a specialized peripheral densitometer in a skeletal sample excavated from the British medieval village Wharram Percy. A total of 58 individuals were divided by sex into three broad age categories (18–29, 30–49, 50+ years.). Each fourth intact vertebral centra was scored for VO and 5‐mm thick coronal sections scanned in a specialized peripheral densitometer (GE Lunar Piximus DXA). Changes in BMD associated with age, sex, and VO severity were examined in the whole vertebral section, a strictly trabecular region, and a primarily cortical region of bone separately. Significant change in vertebral BMD was found to occur by middle age with little or no statistical change in BMD between middle and old age. Females appear to suffer greater bone loss at an earlier age with no change in BMD between middle and old age, whereas males show a more steady loss of BMD across the age groups. The bone mineral content and BMD of the cortical region is higher in individuals with pronounced/severe osteophytosis. The unusual age‐ and sex‐related patterns of change in vertebral BMD at Wharram Percy are compared with the patterns of age‐related change from recent longitudinal population‐based studies. The results emphasize the different pattern of bone loss in young adulthood seen in trabecular regions of the skeleton and highlight the importance of consideration of degenerative joint disease in BMD studies. The influence of lifestyle factors on vertebral BMD in this medieval population is also discussed. Am J Phys Anthropol 2009. © 2009 Wiley‐Liss, Inc.     

Influence of the menopause and aging on spinal density in French women

Dual photon absorptiometry (DPA) was used to measure the bone mineral density (BMD) of the lumbar spine in 510 normal women from the south of France. Long-term precision was 2.2%. BMD was stable in young adults and again in women over 70 years of age. Perimenopausal women at an average age of 51 years already evidenced a slight bone diminution (5%) compared to young adults and women within 2 years of the menopause already had a 10% diminution. The average rate of apparent bone loss in this cross-sectional study was 1% per year from age 45 to 65 years, but about 75% of this decrease occurred in the first decade after the menopause. Spinal BMD in our normal French population appears to be 5–10% lower than US values.     

Confirmation of linkage to chromosome 1q for peak vertebral bone mineral density in premenopausal white women

Peak bone mineral density (BMD) is a highly heritable trait and is a good predictor of the risk of osteoporosis and fracture in later life. Recent studies have sought to identify the genes underlying peak BMD. Linkage analysis in a sample of 464 premenopausal white sister pairs detected linkage of spine BMD to chromosome 1q (LOD 3.6). An independent sample of 254 white sister pairs has now been genotyped, and it also provides evidence of linkage to chromosome 1q (LOD 2.5) for spine BMD. Microsatellite markers were subsequently genotyped for a 4-cM map in the chromosome 1q region in all available white sister pairs (n=938), and a LOD score of 4.3 was obtained near the marker D1S445. Studies in the mouse have also detected evidence of linkage to BMD phenotypes in the region syntenic to our linkage finding on chromosome 1q. Thus, we have replicated a locus on 1q contributing to BMD at the spine and have found further support for the region in analyses employing an enlarged sample. Studies are now ongoing to identify the gene(s) contributing to peak spine BMD in women.     

Coronary heart disease in relation to age,sex, and the menopause.

Examination of the Registrar General''s mortality data suggested that women do not lose protection from coronary heart disease (CHD) after the menopause. Apparently, at around the age of 50 men begin to lose a factor that had previously put them at increased risk of developing CHD compared with women. Male sex hormones may be risk factors for CHD, and further studies are needed to clarify their role in the aetiology of CHD in men.     

Automated determination of bone age and bone mineral density in patients with juvenile idiopathic arthritis: a feasibility study

Introduction

Chronic inflammation combined with glucocorticoid treatment and immobilization puts juvenile idiopathic arthritis (JIA) patients at risk of impaired growth and reduced bone mineral density (BMD). Conventional methods for evaluating bone age and BMD are time-consuming or come with additional costs and radiation exposure. In addition, an automated measurement of bone age and BMD is likely to be more consistent than visual evaluation. In this study, we aimed to evaluate the feasibility of an automated method for determination of bone age and (cortical) bone mineral density (cBMD) in severely affected JIA patients. A secondary objective was to describe bone age and cBMD in this specific JIA population eligible for biologic treatment.

Methods

In total, 69 patients with standard hand radiographs at the start of etanercept treatment and of calendar age within the reliability ranges (2.5 to 17 years for boys and 2 to 15 years for girls) were extracted from the Dutch Arthritis and Biologicals in Children register. Radiographs were analyzed using the BoneXpert method, thus automatically determining bone age and cBMD expressed as bone health index (BHI). Agreement between measurements of the left- and right-hand radiographs and a repeated measurement of the left hand were assessed with the intraclass correlation coefficient (ICC). Regression analysis was used to identify variables associated with Z-scores of bone age and BHI.

Results

The BoneXpert method was reliable in the evaluation of radiographs of 67 patients (radiographs of 2 patients were rejected because of poor image quality). Agreement between left- and right-hand radiographs (ICC = 0.838 to 0.996) and repeated measurements (ICC = 0.999 to 1.000) was good. Mean Z-scores of bone age (−0.36, P = 0.051) and BHI (−0.85, P < 0.001) were lower compared to the healthy population. Glucocorticoid use was associated with delayed bone age (0.79 standard deviation (SD), P = 0.028), and male gender was associated with a lower Z-score of BHI (0.65 SD, P = 0.021).

Conclusions

BoneXpert is an easy-to-use method for assessing bone age and cBMD in patients with JIA, provided that radiographs are of reasonable quality and patients’ bone age lies within the age ranges of the program. The population investigated had delayed bone maturation and lower cBMD than healthy children.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0424-1) contains supplementary material, which is available to authorized users.     

Reversal of postmenopausal vertebral bone loss by oestrogen and progestogen: a double blind placebo controlled study

Because of uncertainty about the place of hormones in the treatment of postmenopausal bone loss vertebral and forearm bone loss was measured by absorptiometry in early post-menopausal women before and after continuous or sequential treatment with combined oestrogen and progestogen in a double blind placebo controlled trial. Treatment with hormones significantly reversed the vertebral bone loss. The net gain in vertebral bone density amounted to 6·4% a year with continuous supplementation and 5·4% a year with sequential supplementation; the net gain in forearm bone density was lower (3·6% with continuous and 3·7% with sequential supplementation).Before a policy of supplementation with hormones can be recommended to all postmenopausal women with the aim of reducing the incidence of vertebral crush fractures further studies with different doses and combinations of hormones, administered over several years, are needed.     

Reduced trabecular bone mineral density and cortical thickness accompanied by increased outer bone circumference in metacarpal bone of rheumatoid arthritis patients: a cross-sectional study

Introduction

The objective of this study was to assess three-dimensional bone geometry and density at the epiphysis and shaft of the third meta-carpal bone of rheumatoid arthritis (RA) patients in comparison to healthy controls with the novel method of peripheral quantitative computed tomography (pQCT).

Methods

PQCT scans were performed in 50 female RA patients and 100 healthy female controls at the distal epiphyses and shafts of the third metacarpal bone, the radius and the tibia. Reproducibility was determined by coefficient of varia-tion. Bone densitometric and geometric parameters were compared between the two groups and correlated to disease characteristics.

Results

Reproducibility of different pQCT parameters was between 0.7% and 2.5%. RA patients had 12% to 19% lower trabecular bone mineral density (BMD) (P ≤ 0.001) at the distal epiphyses of radius, tibia and metacarpal bone. At the shafts of these bones RA patients had 7% to 16% thinner cortices (P ≤ 0.03). Total cross-sectional area (CSA) at the metacarpal bone shaft of pa-tients was larger (between 5% and 7%, P < 0.02), and relative cortical area was reduced by 13%. Erosiveness by Ratingen score correlated negatively with tra-becular and total BMD at the epiphyses and shaft cortical thickness of all measured bones (P < 0.04).

Conclusions

Reduced trabecular BMD and thinner cortices at peripheral bones, and a greater bone shaft diameter at the metacarpal bone suggest RA spe-cific bone alterations. The proposed pQCT protocol is reliable and allows measuring juxta-articular trabecular BMD and shaft geometry at the metacarpal bone.     

Low bone turnover in premenopausal women with type 2 diabetes mellitus as an early process of diabetes-associated bone alterations: a cross-sectional study

Background

Individuals with Diabetes Mellitus (DM) are at increased risk for fracture due to the decrease in bone strength and quality. Serum procollagen type I intact N-terminal (P1NP) and serum C-terminal cross-linking telopeptide of type I collagen (CTX) as markers of bone formation and resorption, respectively, have been reported to be decreased in T2DM. It remains unclear whether diabetes-associated alterations in the bone turnover of T2DM individuals are related to the longer duration of the disease or may occur earlier. Furthermore, previous studies on BTMs in T2DM individuals have mostly been done in postmenopausal women with T2DM, which might have masked the DM-induced alterations of bone turnover with concurrent estrogen deficiency. This study aims to assess the levels of serum P1NP and CTX as markers of bone turnover in premenopausal women with and without T2DM.

Methods

This cross-sectional study involves 41 premenopausal women with T2DM, and 40 premenopausal women without DM. Sampling was done consecutively. P1NP and CTX measurement was done using the electrochemi-luminescence immunoassay (ECLIA) method. Other data collected include levels of HbA1C, ALT, creatinine, eGFR and lipid profile.

Results

Median (interquartile range) P1NP in T2DM is 29.9 ng/ml (24.7–41.8 ng/ml), while in non-DM is 37.3 ng/ml, (30.8–47.3 ng/ml; p?=?0.007). Median (interquartile range) CTX in T2DM is 0.161 ng/ml (0.106–0.227 ng/ml), while in non-DM is 0.202 ng/ml (0.166–0.271 ng/ml; p?=?0.0035). Levels of P1NP and CTX in the T2DM group did not correlate with the duration of disease, age, BMI or the levels of HbA1C.

Conclusions

Premenopausal women with T2DM indeed have lower bone turnover when compared with non-DM controls. This significantly lower bone turnover process starts relatively early in the premenopausal age, independent of the duration of DM. Gaining understanding of the early pathophysiology of altered bone turnover may be key in developing preventive strategies for diabetoporosis.

     

Influence of vitamin D receptor genotype on bone mineral density in postmenopausal women: a twin study in Britain.

OBJECTIVES--To investigate the possible association between vitamin D receptor genotype and bone mineral density in a large group of postmenopausal twins. DESIGN--Cross sectional twin study. SETTING--Twin population based in Britain. SUBJECTS--95 dizygotic (non-identical) pairs of twins and 87 monozygotic (identical) pairs of twins aged 50-69 years, postmenopausal, and free of diseases affecting bone, recruited from a national register of twins and with a media campaign. MAIN OUTCOME MEASURES--Bone mineral density measured at the hip, lumbar spine, forearm, and for the whole body by dual energy x ray absorptiometry in relation to differences in the vitamin D receptor genotype. RESULTS--At all sites the values of bone density among dizygotic twins were more similar in those of the same vitamin D receptor genotype than in those of differing genotype, and the values in the former were closer to the correlations seen in monozygotic twins. Women with the genotype that made them at risk of osteoporotic fracture had an adjusted bone mineral density that was significantly lower by SD 0.5 to 0.6 at the hip, lumbar spine, and for the whole body. The results could not be explained by differences in age, weight, years since menopause, or use of hormone replacement therapy. CONCLUSIONS--The findings that in postmenopausal women in Britain bone density-particularly at the hip and spine-is genetically linked and specifically associated with the vitamin D receptor genotypes should lead to novel approaches to the prevention and treatment of osteoporosis.     

Influence of cardiovascular disease risk factors on the relationship between low bone mineral density and type 2 diabetes mellitus in a multiethnic us population of women and men: A cross-sectional study

Introduction: Higher bone mineral density (BMD) has been reported among white women and men with type 2 diabetes mellitus (DM) compared with nondiabetic white individuals, but there is scant evidence for nonwhite persons. It is also not known whether cardiovascular disease (CVD) risk factors may confound any association between BMD and type 2 DM.Objective: The present study examined the relationship between low BMD and type 2 DM in a multiethnic population of women and men while controlling for the influence of osteoporosis and CVD risk factors including body mass index (BMI), cigarette smoking, physical inactivity, total cholesterol and its components, blood pressure, and C-reactive protein.Methods: Data collected from 4929 African American, Mexican American, and white women and men aged 50 to 79 years who participated in the household interview and clinical examinations during the Third National Health and Nutrition Examination Survey were analyzed. CVD risk factors associated with type 2 DM in this study population were included as covariates in gender-specific multiple logistic regression models assessing the relationship between type 2 DM and low BMD while controlling for osteoporosis risk factors. Gender- and race/ethnicity-specific mean BMD values at the total hip for young adults aged 20 to 29 years were used to establish race/ethnicity and gender-specific low BMD T-scores.Results: The final study population included 2505 women and 2424 men. More women and men with type 2 DM than women and men without type 2 DM were nonwhite and had high BMI. Osteoporosis risk factors but not CVD risk factors were associated with low BMD in both women and men. Type 2 DM was not associated with low BMD among women (odds ratio [OR] = 0.77; 95% CI, 0.56-1.08). Based on a statistically significant interaction between type 2 DM status and race/ethnicity, white men with type 2 DM were less likely to have low BMD than were white men without type 2 DM (OR = 0.56; 95% CI, 0.37-0.86; P = 0.01). There was no significant BMD difference between diabetic and nondiabetic nonwhite men.Conclusion: CVD risk factors did not appear to influence the relationship between low BMD and type 2 DM in this study     

Salivary cortisol differs with age and sex and shows inverse associations with WHR in Swedish women: a cross-sectional study

Background

The rising prevalence of type 2 diabetes underlines the importance of secondary strategies for the prevention of target organ damage. While access to diabetes education centers and diabetes intensification management has been shown to improve blood glucose control, these services are not available to all that require them, particularly in rural and northern areas. The provision of these services through the Home Care team is an advance that can overcome these barriers. Transfer of blood glucose data electronically from the home to the health care provider may improve diabetes management.

Methods and design

The study population will consist of patients with type 2 diabetes with uncontrolled A1c levels living on reserve in the Battlefords region of Saskatchewan, Canada. This pilot study will take place over three phases. In the first phase over three months the impact of the introduction of the Bluetooth enabled glucose monitor will be assessed. In the second phase over three months, the development of guidelines based treatment algorithms for diabetes intensification will be completed. In the third phase lasting 18 months, study subjects will have diabetes intensification according to the algorithms developed.

Discussion

The first phase will determine if the use of the Bluetooth enabled blood glucose devices which can transmit results electronically will lead to changes in A1c levels. It will also determine the feasibility of recruiting subjects to use this technology. The rest of the Diabetes Risk Evaluation and Management Tele-monitoring (DreamTel) study will determine if the delivery of a diabetes intensification management program by the Home Care team supported by the Bluetooth enabled glucose meters leads to improvements in diabetes management.

Trial Registration

Protocol NCT00325624