Impact of lean mass and fat mass on bone mineral density: The Hordaland Health Study

OBJECTIVES: To examine the relationship between soft tissue composition and bone mineral density (BMD) of the hip and whether these relationships differ by gender and age. METHODS: Femoral neck BMD and total body soft tissue composition were measured by dual X-ray absorptiometry in a population-based sample of 5205 men and women 47-50 and 71-75 years old. Analysis of covariance was used to explore possible modifying effects of sex and gender on the impact of fat and lean mass on BMD. RESULTS: The difference in BMD per kilo lean mass (LM) was larger than the difference per kilo fat mass (FM). The effect of FM on BMD was significantly greater among women than among men. In multivariate adjusted analyses, 10kg increase in LM was associated with a 0.083 (95% confidence interval [CI]: 0.075, 0.092)g/cm(2) increase in BMD. A 10kg increase in FM was associated with 0.013 (0.007, 0.019)g/cm(2) increase in BMD among men and 0.021 (0.017, 0.026)g/cm(2) among women. There was indication of a steeper dose-response relationship at lower levels of FM among women. CONCLUSIONS: Compared to FM, LM was generally more strongly related to BMD of the femoral neck in middle-aged and elderly men and women. FM was a significantly stronger predictor of BMD among women than among men, particularly at lower levels of FM.     

Lean body mass and bone mineral density in physically exercising postmenopausal women

OBJECTIVES: To investigate whether the relative contribution of body composition (lean and fat mass component) to postmenopausal bone mineral density (BMD) differs between women participating in physical exercise and sedentary women. METHODS: Subjects were 45 postmenopausal women participating in regular physical exercise and 89 sedentary controls aged 50-60 years. Baseline characteristics included age, height, weight, body mass index (BMI, Wt/Ht(2)), age at menopause, and years since menopause (YSM). Body fat mass, percentage of body fat, lean body mass, and lumbar spine BMD (L2-4) were measured by dual-energy X-ray absorptiometry. RESULTS: Although age, height, weight, BMI, and YSM did not differ between the two groups, lean body mass and lumbar spine BMD were significantly higher (P<0.05 and <0.001, respectively), while body fat mass and percentage of body fat mass were significantly lower in exercising women than in sedentary controls (P<0.05 and <0.05, respectively). In exercising women, BMD was positively correlated with lean body mass (r=0.415, P<0.01) but not with body fat mass (r=0.155, NS). Conversely, in sedentary controls, BMD was correlated with body fat mass (r=0.251, P<0.05) and lean body mass (r=0.228, P<0.05). CONCLUSIONS: Lean body mass is a more significant determinant of postmenopausal BMD in physically exercising women than in sedentary women.     

Identification of novel variants in transforming growth factor-beta 1 (TGFB1) gene and association analysis with bone mineral density

Human transforming growth factor-beta1 (TGFB1) is a family of polypeptides that regulate cell growth, cell differentiation, and cell function as a multifunctional regulator of cellular activity. TGFB1 is produced by osteoblasts and stored in substantial amounts in the bone matrix, which is an important regulator of both skeletal development and homeostasis of bone metabolism. In the present study, we identified four new polymorphisms in TGFB1 and examined whether these polymorphisms are risk factors for osteoporosis. We have sequenced all exons including in the promoter region up to -1,800bp to identify additional genetic polymorphisms in TGFB1. Four novel polymorphisms were newly identified: one in 5' region (g.14129555_14129557dupAGG), one in promoter region (g.14128838C>T), and two in intron (g.14106505G>A and g.14106215G>A). Two known SNPs (g.14128554C>T and g.14127139T>C) were also confirmed. The frequencies of each SNP were 0.479 (g.14129555_14129557dupAGG), 0.007 (g.14128838C>T), 0.478 (g.14128554C>T), 0.476 (g.14127139T>C), 0.016 (g.14106505G>A), and 0.004 (g.14106215G>A) in the Korean population (n=1,885), respectively. Haplotypes and their frequencies were estimated by EM algorithm, and linkage disequilibrium coefficients (mid R:/D'/: and r2) between polymorphism pairs were calculated. We analyzed genetic associations of TGFB1 polymorphisms and haplotypes with spinal bone mineral density (BMD) value of 433 postmenopausal Korean women. By statistical analysis, we could not find any associations with spinal BMD. The information from this study of the critical TGFB1 would be useful for genetic studies of other diseases.     

A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features

Array-CGH analysis using 244k Agilent oligoarray revealed a de novo 17q21.31 microduplication in a 10-year-old girl with severe psychomotor developmental delay, facial dysmorphism, microcephaly, abnormal digits and hirsutism. The duplication encompassed the MAPT and CRHR1 genes and was reciprocal to the recently described 17q21.31 microdeletion, associated with a recognizable clinical phenotype. Genotyping showed that the duplication was derived from non-allelic homologous recombination of paternal H1 and H2 haplotypes. To our knowledge this is the first report of a patient with a 17q21.31 microduplication.     

Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.     

Univariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density

Osteoporosis is a common condition characterized by reduced skeletal strength and increased susceptibility to fracture. The single major risk factor for osteoporosis is low bone mineral density (BMD) and strong evidence exists that genetic factors are in part responsible for an individual's BMD. A cohort of 40 multiplex Caucasian families selected through a proband with osteoporosis was genotyped for microsatellite markers spaced at an average of 10 cM, and linkage to femoral neck (FN), lumbar spine (LS) and trochanter (TR) BMD was analyzed using univariate and bivariate variance component linkage analysis. Maximum univariate multipoint lod-scores were 2.87 on chromosome 1p36 for FN BMD, 1.89 on 6q27 for TR BMD, and 2.15 on 7p15 for LS BMD. Results of bivariate linkage analysis were highly correlated with those of the univariate analysis, although generally less significant, suggesting the possibility that some of these susceptibility loci may exert pleiotropic effects on multiple skeletal sites.     

Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: a prospective observation study

Background

Non-celiac gluten sensitivity (NCGS) or ‘wheat sensitivity’ (NCWS) is included in the spectrum of gluten-related disorders. No data are available on the prevalence of low bone mass density (BMD) in NCWS. Our study aims to evaluate the prevalence of low BMD in NCWS patients and search for correlations with other clinical characteristics.

Methods

This prospective observation study included 75 NCWS patients (63 women; median age 36 years) with irritable bowel syndrome (IBS)-like symptoms, 65 IBS and 50 celiac controls. Patients were recruited at two Internal Medicine Departments. Elimination diet and double-blind placebo controlled (DBPC) wheat challenge proved the NCWS diagnosis. All subjects underwent BMD assessment by Dual Energy X-Ray Absorptiometry (DXA), duodenal histology, HLA DQ typing, body mass index (BMI) evaluation and assessment for daily calcium intake.

Results

DBPC cow's milk proteins challenge showed that 30 of the 75 NCWS patients suffered from multiple food sensitivity. Osteopenia and osteoporosis frequency increased from IBS to NCWS and to celiac disease (CD) (P <0.0001). Thirty-five NCWS patients (46.6%) showed osteopenia or osteoporosis. Low BMD was related to low BMI and multiple food sensitivity. Values of daily dietary calcium intake in NCWS patients were significantly lower than in IBS controls.

Conclusions

An elevated frequency of bone mass loss in NCWS patients was found; this was related to low BMI and was more frequent in patients with NCWS associated with other food sensitivity. A low daily intake of dietary calcium was observed in patients with NCWS.

     

Bone mineral density,bone turnover markers,lean mass,and fat mass in Egyptian children with congenital adrenal hyperplasia

Introduction

Aim of this paper is to assess bone mineral density (BMD) and body composition, by dual energy X-ray absorptiometry (DXA), and various markers of bone growth, in a group of children with congenital adrenal hyperplasia (CAH) on long-term glucocorticoid therapy.

Material and methods

A case-control study included thirty patients with CAH with different states of metabolic control. Their mean age was 7.5 ±4.2 years. All patients are subjected to BMD using DXA at the neck of the femur and lumbar spine. A blood sample was taken for assessment of osteocalcin, osteoprotegerin, and procollagen type 1, as markers of bone formation, as well as RANKL and urinary deoxypyridinoline (DPD), as markers of bone resorption.

Results

We found no difference in BMD in patients and control subjects; however, patients showed significantly lower serum osteocalcin (p = 0.008) and osteoprotegerin (p = 0.0001) and significantly higher serum RANKL levels (p = 0.0001). Our results show that patients had significantly lower lean body mass (p = 0.005) and fat/lean ratio (p = 0.008) compared to matched controls. The duration of treatment showed a significant negative correlation with procollagen type 1 (r = –0.49, p = 0.02) and lean mass % (r = –0.43, p = 0.04); however, it showed a significant positive correlation with total fat mass % (r = 0.6, p = 0.0006), and fat/lean ratio (r = 0.43, p = 0.04). Dose of steroid had a significant positive correlation with BMI SDS (r = 0.4, p = 0.02).

Conclusions

Bone mineral density is normal but bone turnover is low in patients with CAH. There is an increase in fat/lean mass in patients with CAH.     

The effects of physical exercise on body fat distribution and bone mineral density in postmenopausal women

OBJECTIVE: The present cross-sectional study investigated the effects of physical exercise on body fat distribution and bone mineral density (BMD). METHODS: Subjects were 57 postmenopausal women (mean age, 60.5+/-6.4 years) who had exercised regularly for at least 2 years. Controls were 130 age-matched sedentary women. Age, years since menopause (YSM), height, weight, and body mass index (BMI, wt./ht.(2)) were recorded. Total fat mass, percentage of body fat, trunk fat mass, leg fat mass, the ratio of trunk fat mass to leg fat mass (trunk-leg fat ratio), total body lean mass, percentage of body lean, and lumbar spine BMD (L2-L4) were measured by dual-energy X-ray absorptiometry. RESULTS: Baseline characteristics and leg fat mass did not differ between the two groups. Total fat mass, percentage of body fat, trunk fat mass, and trunk-leg fat ratio were lower (P<0.05, P<0.01, P<0.01 and P<0.001, respectively), while total body lean mass, percentage of body lean mass, and lumbar spine BMD were higher in exercising women (P<0.05, P<0.05 and P<0.01, respectively). Performing physical exercise was inversely correlated with trunk-leg fat ratio (standardized regression coefficient=-0.178, P<0.01), but positively correlated with BMD (0. 203, P<0.01) irrespective of age, height, YSM, and total fat mass. CONCLUSION: Physical exercise has beneficial effects on body fat distribution and BMD in postmenopausal women. Reduction of upper body fat distribution with physical exercise may be more attributable to the decrease in trunk fat mass.     

Farnesyl diphosphate synthase: a novel genotype association with bone mineral density in elderly women

OBJECTIVE: We evaluated the association between a single nucleotide polymorphism in the farnesyl diphosphate synthase gene (FDPS), BMD and bone turnover markers. METHODS: Two hundred and eighty-three community-dwelling Caucasian women aged 65 or older were screened from the greater Boston area. A validated FDPS SNP (rs2297480, A/C) was genotyped and evaluated for effect on bone mineral density (spine, hip, forearm) and bone turnover markers (urine N-telopeptide cross-linked collagen type 1, osteocalcin and bone-specific alkaline phosphatase). RESULTS: BMD was lower at all sites measured in women with the C/C or C/A genotypes. Statistically significant differences (p<0.05) were found at the PA spine, trochanter, distal radius, and proximal ulna after adjustment for age and BMI. No significant differences were found in bone turnover markers. CONCLUSION: These findings suggest that a single nucleotide polymorphism in the FDPS gene (rs2297480) may be a genetic marker for lower BMD in postmenopausal Caucasian women.     

Relative importance of lean and fat mass on bone mineral density in a group of adolescent girls and boys

The aim of this study was to determine the relative importance of lean mass (LM) and fat mass (FM) on bone mineral density (BMD) in a group of adolescent girls and boys. A total of 65 adolescent boys and 35 adolescent girls participated in this study. Whole body (WB) and lumbar spine (L1–L4) BMD were measured by dual-energy X-ray absorptiometry (DXA). Body composition was assessed using the same technique. In boys, LM was strongly related to WBBMD (r = 0.68; p < 0.001) and to L1–L4 BMD (r = 0.61; p < 0.001), whereas FM was not positively related to BMD and was negatively associated with WB bone mineral apparent density (WBBMAD). In girls, both LM and FM were positively related to WBBMD (r = 0.41; p < 0.05 and r = 0.49; p < 0.01, respectively), whereas only FM was correlated to L1–L4 BMD (r = 0.33; p < 0.05). Finally, in a multiple regression analysis, FM was found to be a better positive determinant of WBBMD than LM in girls, whereas in boys, FM was found to be a negative determinant of WBBMD and L1–L4 BMD. This study suggests that LM is a strong determinant of WBBMD and L1–L4 BMD in boys, and that FM is a stronger determinant of WBBMD than LM in girls.     

Non-weight-bearing effect of trunk and peripheral fat mass on bone mineral density in pre- and post-menopausal women

ObjectiveTo investigate the non-weight-bearing effect of trunk fat mass (composed of visceral and subcutaneous fat mass) and peripheral fat mass (subcutaneous fat mass alone) on bone mineral density (BMD) in pre- and post-menopausal women.MethodsThe subjects were 412 pre-menopausal women, 20–50 years of age and 228 post-menopausal women, 50–75 years of age. Age, years since menopause (YSM), height, body weight, and body mass index were recorded. Trunk, peripheral (extremities), left arm (non-weight-bearing site), lean mass, and BMD were measured by dual-energy X-ray absorptiometry.ResultsIn pre-menopausal women, the amount of trunk fat mass was 6.8 ± 4.1 kg, which was significantly lower than the amount of peripheral fat mass (11.6 ± 3.8 kg, p < 0.001). Although trunk fat mass was positively correlated with arm BMD on Pearson's correlation test, arm lean mass was the only significant predictor of BMD on multiple regression analysis. In post-menopausal women, the amount of trunk fat mass (8.7 ± 3.6 kg) was also significantly lower than the peripheral fat mass (10.3 ± 3.4 kg, p < 0.001). On multiple regression analysis, however, trunk fat mass, but not arm lean mass, was the significant predictor of BMD. In both groups, peripheral fat mass was not correlated with left arm BMD.ConclusionThe effect of adipocyte-derived biochemical factors on BMD may differ with menopausal status and the sites of adipocyte deposition.     

体脂对DXA骨密度测量结果及骨质疏松诊断的影响

随着社会老龄化和生活水平提高,制约老年人健康长寿的骨质疏松症受到越来越多的重视。双能Ｘ线吸收测量法(dual energy X-ray absorptiometer,DXA)测量骨密度是诊断骨质疏松的金标准,但它的精确性受身体脂肪含量的影响。体脂可以干扰DXA测量骨密度的结果,这可能会导致体脂分布改变显著者（如绝经后体脂分布变化较大的女性）骨质疏松诊断的偏倚,造成此类人群骨质疏松时误诊或漏诊的发生。本文就脂肪对骨密度测量结果及骨质疏松诊断的影响作一综述。     

A genome-wide linkage scan for bone mineral density in an extended sample: evidence for linkage on 11q23 and Xq27

Background: Osteoporosis is a major public health problem, mainly quantified by low bone mineral density (BMD). The majority of BMD variation is determined by genetic effects. A pilot whole genome linkage scan (WGS) was previously reported in 53 white pedigrees with 630 subjects. Several genomic regions were suggested to be linked to BMD variation.

Objective: To substantiate these previous findings and detect new genomic regions.

Methods: A WGS was conducted on an extended sample where the size was almost tripled (1816 subjects from 79 pedigrees). All the subjects were genotyped with 451 microsatellite markers spaced ~8.1 cM apart across the human genome. Two point and multipoint linkage analyses were carried out using the variance component method.

Results: The strongest linkage signal was obtained on Xq27 with two point LOD scores of 4.30 for wrist BMD, and 2.57 for hip BMD, respectively. Another important region was 11q23, which achieved a maximum LOD score of 3.13 for spine BMD in multipoint analyses, confirming the results on this region in two earlier independent studies. Suggestive linkage evidence was also found on 7p14 and 20p12.

Conclusions: Together with the findings from other studies, the current study has further delineated the genetic basis of bone mass and highlights the importance of increasing sample size to confirm linkage findings and to identify new regions of linkage.

     

Proopiomelanocortin gene variants are associated with serum leptin and body fat in a normal female population

A major quantitative trait locus (QTL) determining leptin levels has been linked to the proopiomelanocortin (POMC) region on chromosome 2. Most studies, based on under 350 lean or obese subjects, have shown no association between POMC SNP 8246 C/T and serum leptin, but significant associations have been reported with RsaI 8246 C/T SNP haplotypes. We have investigated association of four POMC SNPs with body composition and serum leptin in 2758 normal Caucasian female subjects (mean age 47.4+/-12.5 years), from the St Thomas' UK Adult Twin Registry (Twins UK): RsaI and 51 G/C in the 5'UTR and 8246 C/T and 7965 C/T in the 3'UTR. Under the recessive model, the 8246 T allele (freq. 0.18) was significantly associated with higher mean BMI (P=0.032) and total fat (P=0.046, both after age adjustment). Significant associations were maintained in sib-TDT with waist (P=0.049), total fat (P=0.037) and emerged with serum leptin (P=0.016). Initial significant associations between RsaI (-) allele (freq. 0.30) and higher waist (P=0.04) or % central fat (P=0.02) were not maintained in sib-TDT. No significant associations were found between body composition or serum leptin and RsaI/8246 C/T haplotype and none with 51 G/C (freq. 0.01) or 7965 C/T (freq. 0.004). There was minimal pairwise LD between the four loci, apart from RsaI and 8246 C/T (D'=-0.78 (P<0.0001)). Associations of BMI, weight and total fat with SNPs in regions flanking the POMC gene in this powerful study suggest that regulation of POMC expression may be influential in determining body weight.     

Body fat distribution is associated with lumbar spine bone density independently of body weight in postmenopausal women

Objective

To assess the association between the body fat distribution and axial bone mineral density (BMD) in postmenopausal women with or without hormone replacement therapy (HRT).

Design

Cross-sectional population-based study.

Setting

University of Eastern Finland, Bone and Cartilage Research Unit, Kuopio, Finland.

Population

198 postmenopausal women, mean age 67.5 (1.9 SD), mean BMI 27.1 (3.9 SD).

Methods

Regional body composition and BMD assessed by dual X-ray absorptiometry (DXA, Prodigy).

Main outcome measures

Spinal and Femoral BMD.

Results

Out of the body composition parameters, FM was the main determinant of postmenopausal bone mass. Only the lumbar spine (L2–L4) BMD, not the femoral neck BMD, was positively associated with the trunk FM. Positive trends for association were revealed between the spinal BMD and the trunk FM regardless of the use of HRT. Adjustments did not change the results.

Conclusions

Higher trunk fat mass was associated with the spinal BMD, but not with the hip BMD in postmenopausal women, irrespective of the HRT use. In addition to biological factors, uncertainties related to DXA measurements in patients with varying body mass may contribute to this phenomenon.