Estimated Heel Bone Mineral Density Research Articles

Bone health, cardiovascular disease, and imaging outcomes in UK Biobank: a causal analysis.

This study examined the association of estimated heel bone mineral density (eBMD, derived from quantitative ultrasound) with: (1) prevalent and incident cardiovascular diseases (CVDs: ischemic heart disease (IHD), myocardial infarction (MI), heart failure (HF), non-ischemic cardiomyopathy (NICM), arrhythmia), (2) mortality (all-cause, CVD, IHD), and (3) cardiovascular magnetic resonance (CMR) measures of left ventricular and atrial structure and function and aortic distensibility, in the UK Biobank. Clinical outcomes were ascertained using health record linkage over 12.3yr of prospective follow-up. Two-sample Mendelian randomization (MR) was conducted to assess causal associations between BMD and CMR metrics using genetic instrumental variables identified from published genome-wide association studies. The analysis included 485 257 participants (55% women, mean age 56.5±8.1yr). Higher heel eBMD was associated with lower odds of all prevalent CVDs considered. The greatest magnitude of effect was seen in association with HF and NICM, where 1-SD increase in eBMD was associated with 15% lower odds of HF and 16% lower odds of NICM. Association between eBMD and incident IHD and MI was non-significant; the strongest relationship was with incident HF (SHR: 0.90 [95% CI, 0.89-0.92]). Higher eBMD was associated with a decreased risk in all-cause, CVD, and IHD mortality, in the fully adjusted model. Higher eBMD was associated with greater aortic distensibility; associations with other CMR metrics were null. Higher heel eBMD is linked to reduced risk of a range of prevalent and incident CVD and mortality outcomes. Although observational analyses suggest associations between higher eBMD and greater aortic compliance, MR analysis did not support a causal relationship between genetically predicted BMD and CMR phenotypes. These findings support the notion that bone-cardiovascular associations reflect shared risk factors/mechanisms rather than direct causal pathways.

Metformin treatment reduces the incidence of osteoporosis: a two-sample Mendelian randomized study

SummaryIt remains unclear whether the association between metformin and osteoporosis (OP) risk is causal. This two-sample Mendelian randomization (MR) study suggests a causal relationship between metformin treatment and a decrease in OP and fracture incidence, as well as an increase in bone mineral density (BMD) in the lumbar spine, femoral neck, and heel. Nonetheless, no significant causal effect is observed on forearm BMD.PurposeWe utilize a MR approach to investigate the association between metformin treatment and the risk of OP.MethodsMetformin treatment was selected as exposures. Outcomes included OP; BMD at the forearm (FA), femoral neck (FN), and lumbar spine (LS); estimated heel bone mineral density (eBMD); and fracture. Summary statistics for exposures and outcomes were obtained from corresponding genome-wide association studies. Inverse variance-weighted (IVW) analysis was mainly applied; the weighted median (WM), penalized weighted median (PWM), maximum likelihood (ML), and MR-Egger regression (MR-Egger) method were also used to obtain robust estimates. A series of sensitivity analyses including Cochran’s Q test, MR-Egger regression, leave-one-out analysis, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were used to detect pleiotropy or heterogeneity.ResultsIn the main analysis, IVW estimates demonstrated that metformin treatment had a definite causal effect on the risk of OP (odds ratio (OR): 0.859, 95% CI: 0.774–0.953, P = 0.004), LS-BMD (OR: 1.063, 95% CI: 1.023–1.105, P = 0.002), FN-BMD (OR: 1.034, 95% CI: 1.000–1.069, P = 0.049), eBMD (OR: 1.035, 95% CI: 1.023–1.047, P ≤ 0.001), and fracture(OR: 0.958, 95% CI: 0.928–0.989, P = 0.008). However, it did not have an effect on FA-BMD(OR: 1.050, 95% CI: 0.969–1.138, P = 0.237).ConclusionsThis study indicated that metformin treatment is significantly associated with a reduction in the risk of OP, fracture and higher LS-BMD, FN-BMD, and eBMD. However, there was no significant association with FA-BMD.

Genetic insight into the putative causal proteins and druggable targets of osteoporosis: a large-scale proteome-wide mendelian randomization study.

Background: Osteoporosis is a major causative factor of the global burden of disease and disability, characterized by low bone mineral density (BMD) and high risks of fracture. We aimed to identify putative causal proteins and druggable targets of osteoporosis. Methods: This study utilized the largest GWAS summary statistics on plasma proteins and estimated heel BMD (eBMD) to identify causal proteins of osteoporosis by mendelian randomization (MR) analysis. Different GWAS datasets were used to validate the results. Multiple sensitivity analyses were conducted to evaluate the robustness of primary MR findings. We have also performed an enrichment analysis for the identified causal proteins and evaluated their druggability. Results: After Bonferroni correction, 67 proteins were identified to be causally associated with estimated BMD (eBMD) (p < 4 × 10-5). We further replicated 38 of the 67 proteins to be associated with total body BMD, lumbar spine BMD, femoral neck BMD as well as fractures, such as RSPO3, IDUA, SMOC2, and LRP4. The findings were supported by sensitivity analyses. Enrichment analysis identified multiple Gene Ontology items, including collagen-containing extracellular matrix (GO:0062023, p = 1.6 × 10-10), collagen binding (GO:0005518, p = 8.6 × 10-5), and extracellular matrix structural constituent (GO:0005201, p = 2.7 × 10-5). Conclusion: The study identified novel putative causal proteins for osteoporosis which may serve as potential early screening biomarkers and druggable targets. Furthermore, the role of plasma proteins involved in collagen binding and extracellular matrix in the development of osteoporosis was highlighted. Further studies are warranted to validate our findings and investigate the underlying mechanism.

A Mendelian randomization study on the association of bone mineral density with periodontitis.

Observational studies indicated that individuals with osteoporosis could be at an increased risk of periodontitis. This study aimed to investigate whether there is a causal association of bone mineral density (BMD) with periodontitis using Mendelian randomization (MR). Summary statistics were sourced from genome-wide association study on BMD measured at different skeletal sites, including estimated heel BMD (eBMD, N = 426,824), forearm BMD (FA-BMD, N = 8143), femoral neck BMD (FN-BMD, N = 32,735), and lumbar spine BMD (LS-BMD, N = 28,498). Genetic variants of periodontitis (N = 45,563) and loose teeth (N = 461,031) were used as outcome surrogates. Inverse variance weighted meta-analysis (IVW) was adopted as main analyses. Other sensitivity MR approaches were used to boost power and account for pleiotropy. IVW results suggested no evidence for a causal association of any phenotypes of BMD with periodontitis (eBMD, odds ratio [OR] = 0.984, 95% confidence interval [CI] = 0.885-1.083; FA-BMD, OR = 1.028, 95%CI = 0.864-1.193; FN-BMD, OR = 1.033, 95%CI = 0.896-1.169; LS-BMD, OR = 0.991, 95%CI =0.878-1.103; all P > 0.65). Such null associations were consistent through other sensitivity MR approaches. Similarly, no significant causal effects of BMD on loose teeth were found. Within the limitation of the study, our MR estimates suggested that a decreased BMD is unlikely to substantially increase the risk of periodontitis.

Association of antihypertensive drugs with fracture and bone mineral density: A comprehensive drug-target Mendelian randomization study.

Observational studies have investigated the associations between antihypertensive drugs and fracture risk as well as bone mineral density (BMD), but yielding controversial results. In this study, a comprehensive drug-target Mendelian randomization (MR) analysis was conducted to systematically examine the associations between genetic proxies for eight common antihypertensive drugs and three bone health-related traits (fracture, total body BMD [TB-BMD], and estimated heel BMD [eBMD]). The main analysis used the inverse-variance weighted (IVW) method to estimate the causal effect. Multiple MR methods were also employed to test the robustness of the results. The genetic proxies for angiotensin receptor blockers (ARBs) were associated with a reduced risk of fracture (odds ratio [OR] = 0.67, 95% confidence interval [CI]: 0.54 to 0.84; P = 4.42 × 10-4; P-adjusted = 0.004), higher TB-BMD (β = 0.36, 95% CI: 0.11 to 0.61; P = 0.005; P-adjusted = 0.022), and higher eBMD (β = 0.30, 95% CI: 0.21 to 0.38; P = 3.59 × 10-12; P-adjusted = 6.55 × 10-11). Meanwhile, genetic proxies for calcium channel blockers (CCBs) were associated with an increased risk of fracture (OR = 1.07, 95% CI: 1.03 to 1.12; P = 0.002; P-adjusted = 0.013). Genetic proxies for potassium sparing diuretics (PSDs) showed negative associations with TB-BMD (β = -0.61, 95% CI: -0.88 to -0.33; P = 1.55 × 10-5; P-adjusted = 1.86 × 10-4). Genetic proxies for thiazide diuretics had positive associations with eBMD (β = 0.11, 95% CI: 0.03 to 0.18; P = 0.006; P-adjusted = 0.022). No significant heterogeneity or pleiotropy was identified. The results were consistent across different MR methods. These findings suggest that genetic proxies for ARBs and thiazide diuretics may have a protective effect on bone health, while genetic proxies for CCBs and PSDs may have a negative effect.

Causal effects of homocysteine levels on the changes of bone mineral density and risk for bone fracture: A two-sample mendelian randomization study

Observational studies have demonstrated the relations of homocysteine (HCY) with bone mineral density (BMD) and bone fracture risk, but yielding contradictory results. The present study was conducted to evaluate whether the genetically predicted plasma HCY levels were causally associated with the change of BMD and the risk of bone fracture. Genetic summary statistics were extracted from genome-wide association study (GWAS) meta-analysis of plasma HCY levels (n=44,147), GWAS meta-analyses of measured forearm (FA), femoral neck (FN) and lumbar spine (LS) BMD (n=up to 32,735), UK Biobank estimated heel BMD (eBMD) (n=426,824) and fracture (n=426,795) GWAS data. Two Sample Mendelian Randomization (TSMR) analysis was performed to assess the causal effects of genetically determined plasma HCY on the BMD and bone fractures. The MR analysis indicated that, genetically decreased plasma HCY was associated with the increased FA-BMD based on the inverse variance weighting (IVW) method (standard deviation [SD]=0.348, 95% CI: 0.146 to 0.550, P=7×10-4). However, there were no significant associations of genetically decreased plasma HCY with FN-BMD, LS-BMD, eBMD and the risk for bone fracture (SD=-0.041, 95% CI:-0.189 to 0.106, P=0.582; SD=-0.053, 95% CI:-0.238 to 0.131, P=0.572; SD=-0.030, 95% CI:-0.090 to 0.030, P=0.328, odds ratio [OR]: 1.03, 95% CI: 0.94 to 1.13, P=0.562, respectively). Moreover, the results also found that genetically determined HCY increase was not correlated with the changes of BMD and the risk for bone fracture. Our study revealed that genetically decreased plasma HCY was associated with increase of FA-BMD.

Relationship between Serum Nutritional Factors and Bone Mineral Density: A Mendelian Randomization Study.

Multiple risk factors have been implicated in the development of osteoporosis. This study examined potential associations between serum nutritional factors and bone mineral density (BMD). Six nutritional factors were selected as exposures. Outcomes included total body BMD (n = 66 945); BMD at the forearm (FA), femoral neck (FN) and lumbar spine (LS) (n = 8143, n = 32 735, and n = 28 498, respectively); estimated heel BMD (HL eBMD) (n = 394 929); and HL eBMD stratified by sex (n = 206 496). A 2-sample Mendelian randomization approach was adopted to estimate the association between serum nutritional factors and BMD. The threshold for adjusted P value was 1.39 × 10-3. Serum calcium levels were inversely associated with LS BMD (effect = -0.55; 95% CI, -0.86 to -0.24; P = 0.001), whereas serum selenium levels were positively correlated with HL eBMD (effect = 0.22; 95% CI, 0.10 to 0.33; P = 1.70 × 10-4). Regarding nominal significance, there was a positive association between serum selenium levels and FA BMD. Nominally significant results were also obtained for serum retinol as well as vitamin E levels and HL eBMD. Moreover, sex-specific effects of serum retinol and vitamin E levels on BMD were observed in men. Serum calcium and selenium levels influence BMD at specific skeletal sites. This implies that these nutritional factors play crucial roles in bone metabolism.

Assessing causal relationship from gut microbiota to heel bone mineral density.

Recent studies have demonstrated the important role played by gut microbiota in regulating bone development, but the evidence of such causal relationship is still sparse in human population. The aim of this study is to assess the causal relationship from gut microbiota to bone development and to identify specific causal bacteria taxa via a Mendelian randomization (MR) approach. A genome-wide association study (GWAS) summary statistic based two-sample MR analysis was performed. Summary statistics of microbiome GWAS (MGWAS) in 1126 twin pairs of the TwinsUK study was used as discovery sample, and the MGWAS in 984 Dutch participants from the LifeLines-DEEP cohort was used as replication sample. Estimated heel bone mineral density (eBMD) GWAS in 426,824 participants from the UK biobank (UKB) cohort was used as outcome. Bacteria were grouped into taxa features at both order and family levels. In the discovery sample, a total of 25 bacteria features including 9 orders and 16 families were analyzed. Fourteen features (5 orders+9 families) were nominally significant, including 5 orders (Bacteroidales, Clostridiales, Lactobacillales, Pasteurellales and Verrucomicrobiales) and 9 families (Bacteroidaceae, Clostridiaceae, Lachnospiraceae, Mogibacteriaceae, Pasteurellaceae, Porphyromonadaceae, Streptococcaceae, Verrucomicrobiaceae and Veillonellaceae). One order Clostridiales and its child taxon, family Lachnospiraceae, were successfully replicated in the replication sample (Clostridiales Pdiscovery=3.32×10-3Preplication=7.29×10-3; Lachnospiraceae Pdiscovery=0.03 Preplication=7.29×10-3). Our findings provided evidence of causal relationship from microbiota to bone development, as well as identified specific bacteria taxa that regulated bone mass variation, thus providing new insights into the microbiota mediated bone development mechanism.

Identification of pleiotropic loci underlying hip bone mineral density and trunk lean mass.

Bone mineral density (BMD) and lean body mass (LBM) not only have a considerable heritability each, but also are genetically correlated. However, common genetic determinants shared by both traits are largely unknown. In the present study, we performed a bivariate genome-wide association study (GWAS) meta-analysis of hip BMD and trunk lean mass (TLM) in 11,335 subjects from 6 samples, and performed replication in estimated heel BMD and TLM in 215,234 UK Biobank (UKB) participants. We identified 2 loci that nearly attained the genome-wide significance (GWS, p < 5.0 × 10-8) level in the discovery GWAS meta-analysis and that were successfully replicated in the UKB sample: 11p15.2 (lead SNP rs12800228, discovery p = 2.88 × 10-7, replication p = 1.95 × 10-4) and 18q21.32 (rs489693, discovery p = 1.67 × 10-7, replication p = 1.17 × 10-3). The above 2 pleiotropic loci may play a pleiotropic role for hip BMD and TLM development. So our findings provide useful insights that further enhance our understanding of genetic interplay between BMD and LBM.

Twelve New Genomic Loci Associated With Bone Mineral Density.

Aiming to identify more genomic loci associated with bone mineral density (BMD), we conducted a joint association analysis of 2 genome-wide association study (GWAS) by the integrative association method multi-trait analysis of GWAS (MTAG). The first one is the single GWAS of estimated heel BMD (eBMD) in the UK biobank (UKB) cohort (N = 426,824), and the second one is the GWAS meta-analysis of total body BMD (TB-BMD) in 66,628 participants from 30 studies. Approximate conditional association analysis was performed in the identified novel loci to identify secondary association signal. Statistical fine-mapping was conducted to prioritize plausible credible risk variants (CRVs). Candidate genes were prioritized based on the analyses of cis- expression quantitative trait locus (cis-eQTL) and cis-protein QTL (cis-pQTL) information as well as the functional category of the SNP. By integrating the information carried in over 490,000 participants, this largest joint analysis of BMD GWAS identified 12 novel genomic loci at the genome-wide significance level (GWS, p = 5.0 × 10−8), nine of which were for eBMD and four were for TB-BMD, explaining an additional 0.11 and 0.23% heritability for the two traits, respectively. These loci include 1p33 (lead SNP rs10493130, peBMD = 3.19 × 10−8), 5q13.2 (rs4703589, peBMD = 4.78 × 10−8), 5q31.3 (rs9324887, pTB−BMD = 1.36 × 10−9), 6p21.32 (rs6905837, peBMD = 3.32 × 10−8), 6q14.1 (rs10806234, peBMD = 2.63 × 10−8), 7q21.11 (rs10806234, pTB−BMD = 3.37 × 10−8), 8q24.12 (rs11995866, peBMD = 6.72 × 10−9), 12p13.31 (rs1639122, peBMD = 4.43 × 10−8), 12p12.1 (rs58489179, peBMD = 4.74 × 10−8), 12q24.23 (rs75499226, peBMD = 1.44 × 10−8), 19q13.31 (rs7255083, pTB−BMD = 2.18 × 10−8) and 22q11.23 (rs13056137, pTB−BMD = 2.54 × 10−8). All lead SNPs in these 12 loci are nominally significant in both original studies as well as consistent in effect direction between them, providing solid evidence of replication. Approximate conditional analysis identified one secondary signal in 5q13.2 (rs11738874, pconditional = 5.06 × 10−9). Statistical fine-mapping analysis prioritized 269 CRVs. A total of 65 candidate genes were prioritized, including those with known biological function to bone development (such as FGF1, COL11A2 and DEPTOR). Our findings provide novel insights into a better understanding of the genetic mechanism underlying bone development as well as candidate genes for future functional investigation.

Are calcaneal quantitative ultrasound variables better than radial bone mineral density in identifying women with osteoporosis?

In certain circumstances when axial bone mineral density (BMD) cannot be measured using dual-energy X-ray absorptiometry (DXA), DXA BMD of the one-third radius (33% radius) can be used for the diagnosis of osteoporosis. Calcaneal quantitative ultrasound (cQUS) variables may also be used for assessing osteoporosis. The aim of this study was to test the hypothesis that cQUS variables may be better than one-third radius (33% radius) BMD for the identification of axial osteoporosis in women. Two hundred and nine women aged between 21 and 85 years whose posteroanterior spine, hip, and 33%radius DXA BMD measurements as well as cQUS variables were measured were included in this study. WHO criteria were employed for defining osteoporosis in postmenopausal women and premenopausal women with Z-scores of ≤ −2.0 were considered as having osteoporosis in axial regions. We used receiver operating characteristic (ROC) analysis to evaluate lumbar spine or hip osteoporosis discriminative performance of radius DXA BMD and cQUS parameters. While 33% radius BMD and its T-score revealed greater areas under ROC curves (AUCs) (0.760 and 0.759) than those of the cQUS variables [0.707 for quantitative ultrasound index (QUI), 0.705 for QUI T-score, 0.682 for broadband ultrasound attenuation (BUA), 0.718 for speed of sound (SOS), and 0.706 for estimated heel BMD (eBMD)] for identifying lumbar spine osteoporosis, the AUC values for all cQUS variables (0.816 for QUI, 0.815 for QUI T-score, 0.829 for BUA, 0.791 for SOS, and 0. 813 for eBMD) in the discrimination of femoral neck osteoporosis were greater than those of 33% radius DXA BMD and its T-score (0.779 and 0.783). The results of this study confirmed our hypothesis for femoral neck osteoporosis, but not for lumbar spine osteoporosis. Our results have implications that cQUS can be used for the prediction of femoral neck osteoporosis in women whose hip DXA BMD cannot be measured.

Bone mineral density and risk of type 2 diabetes and coronary heart disease: A Mendelian randomization study

Background: Observational studies have demonstrated that increased bone mineral density is associated with a higher risk of type 2 diabetes (T2D), but the relationship with risk of coronary heart disease (CHD) is less clear. Moreover, substantial uncertainty remains about the causal relevance of increased bone mineral density for T2D and CHD, which can be assessed by Mendelian randomisation studies. Methods: We identified 235 independent single nucleotide polymorphisms (SNPs) associated at p<5×10 -8 with estimated heel bone mineral density (eBMD) in 116,501 individuals from the UK Biobank study, accounting for 13.9% of eBMD variance. For each eBMD-associated SNP, we extracted effect estimates from the largest available GWAS studies for T2D (DIAGRAM: n=26,676 T2D cases and 132,532 controls) and CHD (CARDIoGRAMplusC4D: n=60,801 CHD cases and 123,504 controls). A two-sample design using several Mendelian randomization approaches was used to investigate the causal relevance of eBMD for risk of T2D and CHD. In addition, we explored the relationship of eBMD, instrumented by the 235 SNPs, on 12 cardiovascular and metabolic risk factors. Finally, we conducted Mendelian randomization analysis in the reverse direction to investigate reverse causality. Results: Each one standard deviation increase in genetically instrumented eBMD (equivalent to 0.14 g/cm 2) was associated with an 8% higher risk of T2D (odds ratio [OR] 1.08; 95% confidence interval [CI]: 1.02 to 1.14; p=0.012) and 5% higher risk of CHD (OR 1.05; 95%CI: 1.00 to 1.10; p=0.034). Consistent results were obtained in sensitivity analyses using several different Mendelian randomization approaches. Equivalent increases in eBMD were also associated with lower plasma levels of HDL-cholesterol and increased insulin resistance. Mendelian randomization in the reverse direction using 94 T2D SNPs or 52 CHD SNPs showed no evidence of reverse causality with eBMD. Conclusions: These findings suggest a causal relationship between elevated bone mineral density with risks of both T2D and CHD.

Bone mineral density and risk of type 2 diabetes and coronary heart disease: A Mendelian randomization study.

Background: Observational studies have demonstrated that increased bone mineral density is associated with a higher risk of type 2 diabetes (T2D), but the relationship with risk of coronary heart disease (CHD) is less clear. Moreover, substantial uncertainty remains about the causal relevance of increased bone mineral density for T2D and CHD, which can be assessed by Mendelian randomisation studies. Methods: We identified 235 independent single nucleotide polymorphisms (SNPs) associated at p<5×10 -8 with estimated heel bone mineral density (eBMD) in 116,501 individuals from the UK Biobank study, accounting for 13.9% of eBMD variance. For each eBMD-associated SNP, we extracted effect estimates from the largest available GWAS studies for T2D (DIAGRAM: n=26,676 T2D cases and 132,532 controls) and CHD (CARDIoGRAMplusC4D: n=60,801 CHD cases and 123,504 controls). A two-sample design using several Mendelian randomization approaches was used to investigate the causal relevance of eBMD for risk of T2D and CHD. In addition, we explored the relationship of eBMD, instrumented by the 235 SNPs, on 12 cardiovascular and metabolic risk factors. Finally, we conducted Mendelian randomization analysis in the reverse direction to investigate reverse causality. Results: Each one standard deviation increase in genetically instrumented eBMD (equivalent to 0.14 g/cm 2) was associated with an 8% higher risk of T2D (odds ratio [OR] 1.08; 95% confidence interval [CI]: 1.02 to 1.14; p=0.012) and 5% higher risk of CHD (OR 1.05; 95%CI: 1.00 to 1.10; p=0.034). Consistent results were obtained in sensitivity analyses using several different Mendelian randomization approaches. Equivalent increases in eBMD were also associated with lower plasma levels of HDL-cholesterol and increased insulin resistance. Mendelian randomization in the reverse direction using 94 T2D SNPs or 52 CHD SNPs showed no evidence of reverse causality with eBMD. Conclusions: These findings suggest a causal relationship between elevated bone mineral density with risks of both T2D and CHD.

Association between Bone Mineral Density and Body Composition in South Indian Rheumatoid Arthritis Patients: A Cross Sectional Study

The aim of the present study was to compare and correlate body composition measurements and bone mineral density in patients with rheumatoid arthritis (RA) and age-matched controls to identify the possible prediction factors for low bone mass, and body composition changes. 92 RA patients and 92 age- and sex-matched healthy controls were included for the study. The following assessments as well as measurements were carried out in each individual in a standard way: i) health assessment questionnaire (HAQ) score, ii) disease activity score (DAS-28), iii) forearm ulna bone mineral density (BMD) using dual energy x-ray absorptiometry (DXA), iv) estimated heel BMD using quantitative ultrasound, v) body composition parameters using bioelectrical impedence analysis, and vi) blood analysis using biochemical methods. Body fat mass (BFM) differed significantly between RA patient group (26.37±10.05 (kg)) and normal controls (30.11±8.64 (kg), <0.05). The Fat free mass (FFM) was also significantly different between RA patients (37.63±9.82 kg) and controls (42.97±6.68 kg, p<0.01). Forearm BMD and estimated heel BMD was significantly higher in controls (0.377±0.04 g/cm²; 0.493±0.08 g/cm²), than in RA patients (0.320±0.13 g/cm², 0.452±0.10 g/cm²; p<0.01 and p<0.05, respectively). The Fat free mass (FFM), muscle mass (MM), segmental muscle mass (SMM) were significantly correlated with the estimated heel BMD as well as forearm BMD. These findings indicated that the body composition measurements might be useful for predicting bone mineral density (BMD) in RA patients. High RA activity was found to be associated with reduced function, and altered body composition and BMD.

Characteristics of Androgen Deficiency in Late-Onset Hypogonadism: Results from the European Male Aging Study (EMAS)

Late-onset hypogonadism (LOH) has been defined as a syndrome in middle-aged and elderly men reporting symptoms in the presence of low testosterone (T). The objective of the study was to seek objective biochemical and end-organ evidence of androgen deficiency in men classified as having LOH according to our previously published criteria. The design of the study included cross-sectional data from the European Male Aging Study on 2966 community-dwelling men aged 40-79 years in eight European countries. Waist circumference, body mass index, muscle mass, estimated heel bone mineral density (eBMD), hemoglobin, insulin sensitivity, physical activity, metabolic syndrome, insulin resistance index, and cardiovascular disease were measured. Sixty-three men (2.1%) were classified as having LOH: 36 moderate and 27 severe. They were older and more obese than eugonadal men and had, in proportion to the graded T deficiency, lower muscle mass, eBMD, and hemoglobin, with poorer general health. Both moderate and severe LOH was associated with lower hemoglobin, mid-upper arm circumference, eBMD, physical function (measured by the Short Form-36 questionnaire), slower gait speed and poorer general health. Only men with severe LOH showed significant associations with larger waist circumference (β=1.93 cm; 0.04-3.81), insulin resistance (β=2.81; 1.39-4.23), and the metabolic syndrome (odds ratio 9.94; 2.73-36.22) after adjustments for confounders. Men with low testosterone only (irrespective of symptoms) showed lesser magnitudes of association with the same end points. LOH is associated with multiple end-organ deficits compatible with androgen deficiency. These data support the existence of a syndrome of LOH in only a minority of aging men, especially those with T below 8 nmol/liter.

Modifications of T-Scores by Quantitative Ultrasonography for the Diagnosis of Osteoporosis in Koreans

To identify a proper T-score threshold for the diagnosis of osteoporosis in Koreans using quantitative ultrasonography (QUS), normative data from 240 females and 238 males (ages 20-29 yr) were newly generated. Then, the osteoporosis prevalence estimate for men and women over 50 yr of age was analyzed using previous World Health Organization (WHO) methods and heel QUS. T-scores were calculated from the normative data. There were definite negative correlations between age and all of the QUS parameters, such as speed of sound (SOS), broadband ultrasound attenuation (BUA), and estimated heel bone mineral density (BMD) (p<0.0001). After applying the recently determined prevalence of incident vertebral fracture in Koreans over 50 yr of age (11.6% and 9.1%, female vs male, respectively) to the diagnosis of osteoporosis by T-scores from heel BMD as measured by QUS, it was revealed that applicable T-scores for women and men were -2.25 and -1.85, respectively. These data suggest that simply using a T-score of -2.5, the classical WHO threshold for osteoporosis, underestimates the true prevalence when using peripheral QUS. Further prospective study of the power of QUS in predicting the absolute risk of fracture is needed.

Calcaneal Quantitative Ultrasound Measurements in Young Male and Female Professional Dancers

The aim of this study was to assess the bone status of dancers using calcaneal quantitative ultrasound (QUS). Twenty-four male and 26 female dancers (aged 19-36 years) and 100 age- and sex-matched nonathletic controls were included in this study. QUS parameters (broadband ultrasound attenuation [BUA], speed of sound [SOS], quantitative ultrasound index [QUI], and estimated heel bone mineral density [eBMD]) were obtained for both heels in all subjects using a gel-coupled QUS device. Two-way analysis of variance, including the factors of dancing status and gender, revealed significant differences in all QUS parameters between the dancers and the controls (p < 0.001 for all), without a significant interaction with gender status. For each heel (right versus left), the mean QUI, BUA, SOS, and eBMD values of the male and female dancers were 22.0% vs. 20.9% and 16.6% vs. 16.0%; 21.6% vs. 24.1% and 13.2% vs. 14.3%; 2.3% vs. 2.0% and 1.7% vs. 1.7%; and 25.0% vs. 23.9% and 19.0% vs. 18.6% higher than those of the male and female controls, respectively. Analysis of covariance still revealed significant differences between the dancers and the controls after controlling for the influence of body mass index (p < 0.001). Furthermore, the finding that significant bilateral differences in BUA did exist in the controls but not in the dancers demonstrated site-specific effects of exercise on bone, indicating that it is the dance that improved bone properties. Calcaneal QUS, with a strong discriminative ability between those involved in professional dance and normally active individuals, emerges as an attractive technology for exploring the benefits of exercise on bone, which might be a challenge for those in the conditioning field, who need to identify those who need intervention in terms of bone status and promote participation in high-impact physical activity, such as dance, to enhance bone quality.

Differences between the right and the left foot in calcaneal quantitative ultrasound measurements.

A total of 621 women, aged 30-80 years, who were grouped according to having single (group 1) or duplicate measurements of their both calcanei with quantitative ultrasound (QUS) on the same day (group 2) or on a different day than the first measurement (group 3) were evaluated for differences between the right and left foot. Despite similar mean values of QUS indices on both sides, individual percentage differences were found varying from 7.3 to 9.5% in the quantitative ultrasound index (QUI), from 11.1 to 12.5% in broadband ultrasound attenuation (BUA), from 0.62 to 0.86% in speed of sound (SOS) and from 8.9 to 10.9% in estimated heel bone mineral density as measured using the Sahara Clinical Bone Sonometer in three groups of subjects. The percentage of subjects with a proportional difference exceeding the coefficient of variation of duplicate measurements of the same heel was the highest for BUA, varying from 63 to 76.7%, and ranged between 43.1 and 76.7% in other QUS indices. We conclude that there is a real inter-individual difference between the right and left foot in QUS parameters, whether measured once or twice or on different occasions. We recommend measuring both sides when using QUS to avoid misleading implications regarding a subject's bone status.

Bone Mineral Density Referral for Dual-Energy X-Ray Absorptiometry Using Quantitative Ultrasound as a Prescreening Tool in Postmenopausal Women from the General Population: A Cost-Effectiveness Analysis

The aim of our study was to assess, from the perspective of the National Health Services in Spain, the cost-effectiveness of quantitative ultrasound (QUS) as a prescreen referral method for bone mineral density (BMD) assessment by dual-energy X-ray absorptiometry (DXA) in postmenopausal women of the general population. Using femoral neck DXA and heel QUS. We evaluated 267 consecutive postmenopausal women 65 years and older and attending primary care physician offices for any medical reason. Subjects were classified as osteoporotic or nonosteoporotic (normal or osteopenic) using the WHO definition for DXA. Effectiveness was assessed in terms of the sensitivity and specificity of the referral decisions based on the QUS measurement. Local costs were estimated from health services and actual resource used. Cost-effectiveness was evaluated in terms of the expected cost per true positive osteoporotic case detected. Baseline prevalence of osteoporosis evaluated by DXA was 55.8%. The sensitivity and specificity for the diagnosis of osteoporosis by QUS using the optimal cutoff thresholds for the estimated heel BMD T-score were 97% and 94%, respectively. The average cost per osteoporotic case detected based on DXA measurement alone was 23.85 euros. The average cost per osteoporotic case detected using QUS as a prescreen was 22.00 euros. The incremental cost-effectiveness of DXA versus QUS was 114.00 euros per true positive case detected. Our results suggest that screening for osteoporosis with QUS while applying strict cufoff values in postmenopausal women of the general population is not substantially more cost-effective than DXA alone for the diagnosis of osteoporosis. However, the screening strategy with QUS may be an option in those circumstances where the diagnosis of osteoporosis is deficient because of the difficulty in accessing DXA equipment.

Can the WHO criteria for diagnosing osteoporosis be applied to calcaneal quantitative ultrasound?

With the increasing number of quantitative ultrasound (QUS) devices in use worldwide it is important to develop strategies for the clinical use of QUS. The aims of this study were to examine the age-dependence of T-scores and the prevalence of osteoporosis using the World Health Organization Study Group criteria for diagnosing osteoporosis and to examine the T-score threshold that would be appropriate to identify women at risk of osteoporosis using QUS. Two groups of women were studied: (i) 420 healthy women aged 20-79 years with no known risk factors associated with osteoporosis; (ii) 97 postmenopausal women with vertebral fractures. All subjects had dual-energy X-ray absorptiometry (DXA) measurements of the spine and hip and QUS measurements on three calcaneal ultrasound devices (Hologic Sahara, Hologic UBA575+, Osteometer DTUone). A subgroup of 102 (76 on the DTUone) healthy women aged 20-40 years was used to estimate the young adult mean and SD for each QUS and DXA measurement parameter to calculate T-scores. The age-related decline in T-scores for QUS measurement parameters was half the rate observed for the bone mineral density (BMD) measurements. The average T-score for a woman aged 65 years was -1.2 for QUS measurements and -1.75 for the BMD measurements. When osteoporosis was defined by a T-score < or = -2.5 the prevalence of osteoporosis in healthy postmenopausal women was 17%, 16% and 12% for lumbar spine, femoral neck and total hip BMD respectively. When the same definition was used for QUS measurements the prevalence of osteoporosis ranged from 2% to 8% depending on which ultrasound device and measurement parameter was used. Four different approaches, based on DXA-equivalent prevalence rates of osteoporosis, were utilized to examine which T-score threshold would be appropriate for identifying postmenopausal women at risk of osteoporosis using QUS measurements. These ranged from -1.05 to -2.12 depending upon the approach used to estimate the threshold and on which QUS device the measurements were performed, but all were significantly lower than the threshold of -2.5 used for BMD measurements. In conclusion, the WHO threshold of T = -2.5 for diagnosing osteoporosis requires modification when using QUS to assess skeletal status. For the three QUS devices used in this study, a T-score threshold of -1.80 would result in the same percentage of postmenopausal women classified as osteoporotic as the WHO threshold for BMD measurements. Corresponding T-score thresholds for individual measurement parameters on the two commercially available devices were -1.61, -1.94 and -1.90 for Sahara BUA, SOS and estimated heel BMD respectively and -1.45 and -2.10 for DTU BUA and SOS respectively Additional studies are needed to determine suitable T-score thresholds for other commercial QUS devices.