DXA-derived Bone Mineral Density Research Articles

Opportunistic Screening for Low Bone Mineral Density in Adults with Cystic Fibrosis Using Low-Dose Computed Tomography of the Chest with Artificial Intelligence.

Background: Cystic fibrosis bone disease (CFBD) is a common comorbidity in adult people with cystic fibrosis (pwCF), resulting in an increased risk of bone fractures. This study evaluated the capacity of artificial intelligence (AI)-assisted low-dose chest CT (LDCT) opportunistic screening for detecting low bone mineral density (BMD) in adult pwCF. Methods: In this retrospective single-center study, 65 adult pwCF (mean age 30.1 ± 7.5 years) underwent dual-energy X-ray absorptiometry (DXA) of the lumbar vertebrae L1 to L4 to determine BMD and corresponding z-scores and completed LDCTs of the chest within three months as part of routine clinical care. A fully automated CT-based AI algorithm measured the attenuation values (Hounsfield units [HU]) of the thoracic vertebrae Th9-Th12 and first lumbar vertebra L1. The ability of the algorithm to diagnose CFBD was assessed using receiver operating characteristic (ROC) curves. Results: HU values of Th9 to L1 and DXA-derived BMD and the corresponding z-scores of L1 to L4 showed a strong correlation (all p < 0.05). The area under the curve (AUC) for diagnosing low BMD was highest for L1 (0.796; p = 0.001) and Th11 (0.835; p < 0.001), resulting in a specificity of 84.9% at a sensitivity level of 75%. The HU threshold values for distinguishing normal from low BMD were <197 (L1) and <212 (Th11), respectively. Conclusions: Routine LDCT of the chest with the fully automated AI-guided determination of thoracic and lumbar vertebral attenuation values is a valuable tool for predicting low BMD in adult pwCF, with the best results for Th11 and L1. However, further studies are required to define clear threshold values.

Predictors of low and very low bone mineral density in long-term childhood acute lymphoblastic leukemia survivors: Toward personalized risk prediction.

Cohorts of childhood acute lymphoblastic leukemia (cALL) survivors reaching adulthood are increasing. Approximately 30% of survivors meet criteria for low bone mineral density (BMD) 10years after diagnosis. We investigated risk factors for low BMD in long-term cALL survivors. We recruited 245 cALL survivors from the PETALE (Prévenir les effets tardifs des traitements de la leucémie aiguë lymphoblastique chez l'enfant) cohort, who were treated with the Dana Farber Cancer Institute protocols, did not experience disease relapse or hematopoietic stem cell transplants, and presented with more than 5years of event-free survival. Median time since diagnosis was 15.1years. Prevalence of low DXA-derived BMD (Z-score ≤-1) ranged between 21.9% and 25.3%, depending on site (lumbar spine (LS-BMD), femoral neck (FN-BMD), and total body (TB-BMD), and between 3.7% and 5.8% for very low BMD (Z-score ≤-2). Males had a higher prevalence of low BMD than females for all three outcomes (26%-32% vs. 18%-21%), and male sex acted as a significant risk factor for low BMD in all models. Treatment-related factors such as cumulative glucocorticoid (GC) doses and cranial radiation therapy (CRT) were associated with lower BMDs in the full cohort and in females at the FN-BMD site. Low and very low BMD is more prevalent in male cALL survivors. Male sex, high cumulative GC doses, CRT, risk group, and low body mass index (BMI) were identified as risk factors for low BMD. A longer follow-up of BMD through time in these survivors is needed to establish if low BMD will translate into a higher risk for fragility fractures through adulthood.

Discordance between dual-energy X-ray absorptiometry bone mineral density and spinal computed tomography texture analysis: An investigation into low correlation rates

ObjectivesThis research delves into the application of texture analysis in spine computed tomography (CT) scans and its correlation with bone mineral density (BMD), as determined by dual-energy X-ray absorptiometry (DXA). It specifically addresses the discordance between the 2 measurements, suggesting that certain spinal-specific factors may contribute to this discrepancy. MethodsThe study involved 405 cases from a single institution collected between May 6, 2012 and June 30, 2021. Each case underwent a spinal CT scan and a DXA scan. BMD values at the lumbar region (T12 to S1) and total hip were recorded. Texture features from axial cuts of T12 to S1 vertebrae were extracted using gray-level co-occurrence matrices, and a regression model was constructed to predict the BMD values. ResultsThe correlation between CT texture analysis results and BMD from DXA was moderate, with a correlation coefficient ranging between 0.4 and 0.5. This discordance was examined in light of factors unique to the spine region, such as abdominal obesity, aortic calcification, and lumbar degenerative changes, which could potentially affect BMD measurements. ConclusionsEmerging from this study is a novel insight into the discordance between spinal CT texture analysis and DXA-derived BMD measurements, highlighting the unique influence of spinal attributes. This revelation calls into question the exclusive reliance on DXA scans for BMD assessment, particularly in scenarios where DXA scanning may not be feasible or accurate.

Quantitative CT Evaluation of Bone Mineral Density in the Thoracic Spine on 18F-Fluorocholine PET/CT Imaging in Patients With Primary Hyperparathyroidism

Introduction: Measurement of bone mineral density (BMD) with quantitative CT (QCT) carries several advantages over other densitometric techniques, including superior assessment of the spine. As most QCT studies evaluated the lumbar spine, measurements of the thoracic spine are limited. We performed QCT analysis of the thoracic spine in a cohort of patients with primary hyperparathyroidism. Materials and methods: This study was a retrospective QCT analysis of the thoracic spine on 18F-fluorocholine PET/CT scans in patients with primary hyperparathyroidism patients between March 2018 and December 2022. Correlations between QCT-derived BMD or Hounsfield units (HU) and demographic data, laboratory parameters, results from histopathological examination after parathyroidectomy and results of DXA imaging were analyzed, when available. Results: In 189 patients, mean QCT-derived BMD at the thoracic spine was 85.6 mg/cm3. Results from recent DXA were available in 122 patients. Mean thoracic QCT-derived BMD and HU were significantly correlated with DXA-derived BMD in lumbar spine, total hip and femoral neck and with the lowest T-score at DXA imaging. Only weak correlations were found with BMI or 18F-fluorocholine uptake, while no significant correlations were found with adenoma weight, PTH or calcium levels. Conclusion: Our study confirms correlation between QCT-derived BMD in the thoracic spine with age and DXA-derived BMD measurements within a population of patients with primary hyperparathyroidism. Establishment of reference BMD values for individual thoracic vertebrae, may allow direct osteoporosis classification on thoracic CT imaging.

Predicting Fractures Using Vertebral 18F-NaF Uptake in Prostate Cancer Patients

Background: Patients with prostate cancer tend to be at heightened risk for fracture due to bone metastases and treatment with androgen-deprivation therapy. Bone mineral density (BMD) derived from dual energy X-ray absorptiometry (DXA) is the standard for determining fracture risk in this population. However, BMD often fails to predict many osteoporotic fractures. Patients with prostate cancer also undergo 18F-sodium fluoride (&lt;sup&gt;18&lt;/sup&gt;F-NaF)-positron emission tomography/computed tomography (PET/CT) to monitor metastases. The purpose of this study was to assess whether bone deposition, assessed by &lt;sup&gt;18&lt;/sup&gt;F-NaF uptake in &lt;sup&gt;18&lt;/sup&gt;F-NaF PET/CT, could predict incident fractures better than DXA- or CT-derived BMD in patients with prostate cancer.Methods: This study included 105 males with prostate cancer who had undergone full body &lt;sup&gt;18&lt;/sup&gt;F-NaF PET/CT. Standardized uptake value (SUVmean and SUVmax) and CT-derived Hounsfield units (HU), a correlate of BMD, were recorded for each vertebral body. The average SUVmean, SUVmax, and HU were calculated for cervical, thoracic, lumbar, and sacral areas. The t-test was used to assess significant differences between fracture and no-fracture groups.Results: The SUVmean and SUVmax values for the thoracic area were lower in the fracture group than in the no-fracture group. There was no significant difference in cervical, thoracic, lumbar or sacral HU between the 2 groups.Conclusions: Our study reports that lower PET-derived non-metastatic bone deposition in the thoracic spine is correlated with incidence of fractures in patients with prostate cancer. CT-derived HU, a correlate of DXA-derived BMD, was not predictive of fracture risk. &lt;sup&gt;18&lt;/sup&gt;F-NaF PET/CT may provide important insight into bone quality and fracture risk.

Exploring the Paradox of Bone Mineral Density in Type 2 Diabetes: A Comparative Study Using Opportunistic Chest CT Texture Analysis and DXA.

This study aimed to validate the application of CT texture analysis in estimating Bone Mineral Density (BMD) in patients with Type 2 Diabetes (T2D) and comparing it with the results of dual-energy X-ray absorptiometry (DXA) in a normative cohort. We analyzed a total of 510 cases (145 T2D patients and 365 normal patients) from a single institution. DXA-derived BMD and CT texture analysis-estimated BMD were compared for each participant. Additionally, we investigated the correlation among 45 different texture features within each group. The correlation between CT texture analysis-estimated BMD and DXA-derived BMD in T2D patients was consistently high (0.94 or above), whether measured at L1 BMD, L1 BMC, total hip BMD, or total hip BMC. In contrast, the normative cohort showed a modest correlation, ranging from 0.66 to 0.75. Among the 45 texture features, significant differences were found in the Contrast V 64 and Contrast V 128 features in the normal group. In essence, our study emphasizes that the clinical assessment of bone health, particularly in T2D patients, should not merely rely on traditional measures, such as DXA BMD. Rather, it may be beneficial to incorporate other diagnostic tools, such as CT texture analysis, to better comprehend the complex interplay between various factors impacting bone health.

Feasibility of aluminum phantom radiography for osteoporosis detection in postmenopausal women with a fragility fracture of the distal radius compared toDXA and HR-pQCT.

Recently, promising results have been reported for detection of osteoporosis with use of an aluminum phantom. Therefore, the aim of this study was to evaluate the feasibility of radiography-based bone mineral density (BMD) measurement using a graded aluminum phantom. This study included 27 postmenopausal women with a distal radius fracture. Aluminum phantom radiography of the healthy radius was conducted as well as high-resolution peripheral quantitative computed tomography (HR-pQCT) measurement of the ultradistal radius and dual energy X-ray absorptiometry(DXA) of the radius, spine, and hip. A strong correlation was observed between aluminum phantom radiography-based mean gray value(mGV) and DXA-derived BMD, especially for the ultradistal radius (ρ = 0.75; p < 0.001). A moderate correlation for the femoral neck (ρ = 0.61 and p < 0.001) between modalities was found. Radius mGV and HR-pQCT-derived BMD only showed a moderate correlation (ρ = 0.48; p < 0.09). Aluminum phantom radiography might serve as a cost efficient, highly available, low-radiation dose screening, and diagnostic method for osteoporosis additively to DXAmeasurements. Especially, an application in areas with constrained DXA availability and such as preoperative trauma settings would be beneficial. However, further investigation and assessment of specificity and sensitivity is needed.

Associations of visceral adipose tissue with bone mineral density and fracture: observational and Mendelian randomization studies

BackgroundThe associations between visceral adipose tissue (VAT) and bone mineral density (BMD) or fracture have been controversial and the causality of the associations remains to be assessed. This study aimed to explore the associations of VAT^ (predicted value of VAT mass) with BMD and fracture risk in men and women, and to examine their potential causation by two-sample Mendelian randomization (MR) analyses.MethodsUK Biobank is a large, population-based prospective cohort study that recruited more than 500,000 participants aged 40–69 in the United Kingdom from 2006 to 2010. In this study, we used a validated and reliable prediction model to estimate the VAT amount of the participants. On this basis, linear and nonlinear multivariable statistical models were used to explore the association of VAT^ with BMD and fracture risk in different groups of sex and BMI. In observational analyses, the multivariable linear regression model and Cox proportional-hazards model were used to assess VAT^ association with BMD and fracture risk, respectively. Inverse variance weighting was used as the main result of MR analysis.ResultsIn 190,836 men, an inverted U-shaped association was observed between VAT^ and heel BMD (P for nonlinearity < 0.001), with a turning point of VAT^ = 1.25 kg. Per kg increase in VAT^ was associated with a 0.13 standard deviation (SD) increase in heel BMD (P = 1.5 × 10−16) among men with lower amounts of VAT^, and associated with a 0.05 SD decrease in heel BMD (P = 1.3 × 10−15) among men with higher amounts of VAT^. In 193,592 women, per kg increase in VAT^ was monotonically associated with a 0.16 SD increase in heel BMD (P = 1.2 × 10−136, P for VAT^-sex interaction = 8.4 × 10−51). During a median follow-up of 8.2 years, VAT^ was associated with lower risks of hip fractures in the overall men and women (P for VAT^-sex interaction = 1.9 × 10−4 for total fractures; 1.5 × 10−4 for other fractures). There were significant interactions of VAT^ and BMI on heel BMD and fracture risks in men only (P for VAT^-BMI interaction = 5.9 × 10−31 for heel BMD; 2.7 × 10−4 for total fractures; 5.7 × 10−3 for hip fractures; 6.8 × 10−3 for other fractures). In two-sample MR analyses, evidence of causality was not observed between VAT^ and DXA-derived BMD or fractures.ConclusionsThese novel findings demonstrated gender-dependent associations of VAT^ with BMD and fracture risk, with the association in men being modified by adiposity. Evidence of causality was not observed, suggesting that the observational association of VAT^ with BMD and fracture risk could be the result of confounding.

Deficits in the Functional Muscle–Bone Unit in Youths with Fontan Physiology

To determine whether dual energy X-ray absorptiometry (DXA), a clinically available tool, mirrors the magnitude of deficits in trabecular and cortical bone mineral density (BMD) demonstrated on peripheral quantitative computed tomography in youth with Fontan physiology. We aimed to describe DXA-derived BMD at multiple sites and to investigate the relationship between BMD and leg lean mass, a surrogate for skeletal muscle loading. Subjects with Fontan (n=46; aged 5-20years) underwent DXA in a cross-sectional study of growth and bone and muscle health as described previously. Data from the Bone Mineral Density in Childhood Study were used to calculate age-, sex-, and race-specific BMD z-scores of the whole body, lumbar spine, hip, femoral neck, distal one-third radius, ultradistal radius, and leg lean mass z-score (LLMZ). Fontan BMD z-scores were significantly lower than reference at all sites-whole body, -0.34±0.85 (P=.01); spine, -0.41±0.96 (P=.008); hip, -0.75±1.1 (P<.001); femoral neck, -0.73±1.0 (P<.001); distal one-third radius, -0.87±1.1 (P<.001); and ultradistal radius. -0.92±1.03 (P<.001)-as was LLMZ (-0.93±1.1; P<.001). Lower LLMZ was associated with lower BMD of the whole body (R2=0.40; P<.001), lumbar spine (R2=0.16; P=.005), total hip (R2=0.32; P<.001), femoral neck (R2=0.47; P<.001), and ultradistal radius (R2=0.35; P<.001). Patients with Fontan have marked deficits in both cortical (hip, distal one-third radius) and trabecular (lumbar spine, femoral neck, ultradistal radius) BMD. Lower LLMZ is associated with lower BMD and may reflect inadequate skeletal muscle loading. Interventions to increase muscle mass may improve bone accrual.

Deep learning of lumbar spine X-ray for osteopenia and osteoporosis screening: A multicenter retrospective cohort study.

Osteoporosis is a prevalent but underdiagnosed condition. As compared to dual-energy X-ray absorptiometry (DXA) measures, we aimed to develop a deep convolutional neural network (DCNN) model to classify osteopenia and osteoporosis with the use of lumbar spine X-ray images. Herein, we developed the DCNN models based on the training dataset, which comprising 1616 lumbar spine X-ray images from 808 postmenopausal women (aged 50 to 92years). DXA-derived bone mineral density (BMD) measures were used as the reference standard. We categorized patients into three groups according to DXA BMD T-score: normal (T≥-1.0), osteopenia (-2.5<T<-1.0), and osteoporosis (T≤-2.5). T-scores were calculated by using the BMD dataset of young Chinese female aged 20-40years as a reference. A 3-class DCNN model was trained to classify normal BMD, osteoporosis, and osteopenia. Model performance was tested in a validation dataset (204 images from 102 patients) and two test datasets (396 images from 198 patients and 348 images from 147 patients respectively). Model performance was assessed by the receiver operating characteristic (ROC) curve analysis. The results showed that in the test dataset 1, the model diagnosing osteoporosis achieved an AUC of 0.767 (95% confidence interval [CI]: 0.701-0.824) with sensitivity of 73.7% (95% CI: 62.3-83.1), the model diagnosing osteopenia achieved an AUC of 0.787 (95% CI: 0.723-0.842) with sensitivity of 81.8% (95% CI: 67.3-91.8); In the test dataset 2, the model diagnosing osteoporosis yielded an AUC of 0.726 (95% CI: 0.646-0.796) with sensitivity of 68.4% (95% CI: 54.8-80.1), the model diagnosing osteopenia yielded an AUC of 0.810 (95% CI, 0.737-0.870) with sensitivity of 85.3% (95% CI, 68.9-95.0). Accordingly, a deep learning diagnostic network may have the potential in screening osteoporosis and osteopenia based on lumbar spine radiographs. However, further studies are necessary to verify and improve the diagnostic performance of DCNN models.

Increased Burden of Common Risk Alleles in Children With a Significant Fracture History.

Extreme presentations of common disease in children are often presumed to be of Mendelian etiology, but their polygenic basis has not been fully explored. We tested whether children with significant fracture history and no osteogenesis imperfecta (OI) are at increased polygenic risk for fracture. A childhood significant fracture history was defined as the presence of low-trauma vertebral fractures or multiple long bone fractures. We generated a polygenic score of heel ultrasound-derived speed of sound, termed "gSOS," which predicts risk of osteoporotic fracture. We tested if individuals from three cohorts with significant childhood fracture history had lower gSOS. A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of which 68 had negative OI gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among which 18 had no OI. After excluding individuals with OI and ancestral outliers, we generated gSOS estimates and compared their mean to that of a UK Biobank subset, representing the general population. The average gSOS across all three cohorts (n = 131) was -0.47 SD lower than that in UK Biobank (n = 80,027, p = 1.1 × 10-5 ). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 × 10-10 ). Among the 131 individuals with a significant fracture history, we observed 8 individuals with gSOS below minus 2 SD from the mean; their mean lumbar spine DXA-derived bone mineral density Z-score was -1.7 (SD 0.8). In summary, children with significant fracture history but no OI have an increased burden of common risk alleles. This suggests that a polygenic contribution to disease should be considered in children with extreme presentations of fracture. © 2020 American Society for Bone and Mineral Research.

The genetic architecture of osteoporosis and fracture risk.

Osteoporosis and fracture risk are common complex diseases, caused by an interaction of numerous disease susceptibility genes and environmental factors. With the advances in genomic technologies, large-scale genome-wide association studies (GWAS) have been performed which have broadened our understanding of the genetic architecture and biological mechanisms of complex disease. Currently, more than ~90 loci have been found associated with DXA derived bone mineral density (BMD), over ~500 loci with heel estimated BMD and several others with other less widely available bone parameters such as bone geometry, shape, and microarchitecture. Notably, several of the pathways identified by the GWAS efforts correspond to pathways that are currently targeted for the treatment of osteoporosis. Overall, tremendous progress in the field of the genetics of osteoporosis has been achieved with the discovery of WNT16, EN1, DAAM2, and GPC6 among others. Assessment of the function and biological mechanisms of the remaining genes may further untangle the complex genetic landscape of osteoporosis and fracture risk. With this review we aimed to provide a general overview of the existing GWAS studies on osteoporosis traits and fracture risk.

Aortic vascular calcification is inversely associated with the trabecular bone score in patients receiving dialysis.

Progressive chronic kidney disease (CKD) confers a marked increase in risk for vascular calcification, cardiovascular disease, fracture and mortality, with likely contributing factors including dysregulated bone metabolism and mineral homeostasis. In general population studies, increased vascular calcification is directly related to mortality and inversely related to bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA). In patients with CKD, abnormalities in turnover, mineralization and bone volume reduce the ability of DXA to predict fracture. The trabecular bone score (TBS) obtained from lumbar spine DXA images, provides a surrogate measure of microarchitectural integrity not captured by BMD. This study aimed to examine the association of the TBS to prevalent abdominal aortic calcification (AAC) in patients with CKD receiving dialysis. We performed a cross-sectional study of dialysis patients awaiting transplantation. All patients underwent laboratory testing, lateral spinal radiographs including the abdominal aorta, DXA imaging and TBS assessment. AAC scores were determined using the Kauppila method. Correlations and linear regression models were used to determine predictors of AAC scores. 146 patients (60% male, mean age 48 ± 13 years) were included, of whom 49% had prevalent calcification with an AAC score ≥ 1. Of those with calcification, the mean AAC score was 7 ± 5.5 and 42 patients had scores ≥ 6, considered to indicate severe AAC. TBS values corresponding to intermediate or high risk for fracture (<1.31) were present in 35% of patients. TBS values correlated inversely to AAC scores (β = -0.206, p = 0.013) and remained significant in multivariable linear regression, adjusting for age, BMI and time on dialysis (-0.160, p = 0.031). There was no significant correlation of AAC scores to any BMD parameter. There is a high prevalence of AAC in relatively young dialysis patients awaiting transplantation and their AAC scores are inversely related to the TBS but not to DXA-derived BMD parameters. In patients with CKD on dialysis, TBS assessment reflects microarchitectural abnormalities of bone not captured by DXA. The inverse relationship of TBS to vascular calcification may provide insights into bone-vascular interactions in CKD.

The Osteogenic Response was higher in Postmenopausal than in Premenopausal Women Following The Same Exercise Intervention

Bone loading exercise is an important osteogenic stimulus, and multimodal exercise regimens associated with high bone strains are suggested to improve bone mass. However, it is discussed whether it is possible to induce improvements in bone mass after peak bone mass, especially after menopause. PURPOSE: To investigate the osteogenic impact of high-intensity, multimodal training in postmenopausal women (I-POM) compared to premenopausal women (I-PREM) and two matched control groups (C-POM and C-PREM). METHODS: The supervised intervention lasted 19 weeks, 3 x 30 min weekly. The varied training was of high musculoskeletal intensity aimed to elicit large and powerful forces on the skeleton. 49 healthy, sedentary women participated: I-POM (N=21; 57.1±4.8 yrs; 64.5±8.1 kg), C-POM (N=12; 57.9±3.9 yrs; 63.9±10.6 kg), I-PREM (N=9; 43.6±4.7 yrs; 76.5±15.5 kg), and C-PREM (N=7; 42.9±5.9 yrs; 66.0±12.3 kg). DXA-derived bone mineral density (BMD, g/cm2) in right (R) and left (L) proximal femur (PF) and lumbar spine (LS), plasma Osteocalcin (OC, μg/l), procollagen type 1 amino-terminal propeptide (P1NP, μg/l) and C-terminal telopeptide of type 1 collagen (CTX-1, μg/l) were measured at baseline and post-intervention. OC, P1NP and CTX-1 were also measured after 3 and 12 weeks. RESULTS: Post-intervention BMD was increased more (0.001<P<0.05) in I-POM than in C-POM in PF (total R 0.8±1.6% vs. -1.0±1.1%; total L 0.7±1.6% vs. -0.5±1.1%; shaft R 0.8±2.1% vs. -0.8±1.6%; shaft L 1.1±1.9% vs. -0.3±1.0%; trochanter R 1.2±2.4% vs -1.1±2.0%; trochanter L 0.8±3.4% vs. -0.3±1.9%) and in LS (L1-L4 0.9±2.3% vs. -1.1±2.8%; L2 1.3±3.1% vs. -1.3±3.2%). Plasma OC was increased more (0.0005<P<0.005) in I-POM than in C-POM after 3 weeks (11.7±20.5% vs. -9.3±19.4%), 12 weeks (23.7±17.6% vs. -11.5±29.0%) and post-intervention (18.0±25.9% vs. -14.8±28.6%), but plasma P1NP and CTX-1 did not differ between the groups. The change scores in BMD, plasma OC, P1NP and CTX-1 did not differ between I-PREM and C-PREM. CONCLUSION: The osteogenic effect of 19 weeks training was higher in postmenopausal than in premenopausal women following the same multimodal high-intensity exercise intervention. It was possible to improve bone mass after menopause and counteract the age-related reduction in BMD.

Characterization of trabecular bone plate-rod microarchitecture using multirow detector CT and the tensor scale: Algorithms, validation, and applications to pilot human studies.

Osteoporosis is a common bone disease associated with increased risk of low-trauma fractures leading to substantial morbidity, mortality, and financial costs. Clinically, osteoporosis is defined by low bone mineral density (BMD); however, increasing evidence suggests that trabecular bone (TB) microarchitectural quality is an important determinant of bone strength and fracture risk. A tensor scale based algorithm for in vivo characterization of TB plate-rod microarchitecture at the distal tibia using multirow detector CT (MD-CT) imaging is presented and its performance and applications are examined. The tensor scale characterizes individual TB on the continuum between a perfect plate and a perfect rod and computes their orientation using optimal ellipsoidal representation of local structures. The accuracy of the method was evaluated using computer-generated phantom images at a resolution and signal-to-noise ratio achievable in vivo. The robustness of the method was examined in terms of stability across a wide range of voxel sizes, repeat scan reproducibility, and correlation between TB measures derived by imaging human ankle specimens under ex vivo and in vivo conditions. Finally, the application of the method was evaluated in pilot human studies involving healthy young-adult volunteers (age: 19 to 21 yr; 51 females and 46 males) and patients treated with selective serotonin reuptake inhibitors (SSRIs) (age: 19 to 21 yr; six males and six females). An error of (3.2% ± 2.0%) (mean ± SD), computed as deviation from known measures of TB plate-width, was observed for computer-generated phantoms. An intraclass correlation coefficient of 0.95 was observed for tensor scale TB measures in repeat MD-CT scans where the measures were averaged over a small volume of interest of 1.05 mm diameter with limited smoothing effects. The method was found to be highly stable at different voxel sizes with an error of (2.29% ± 1.56%) at an in vivo voxel size as compared to the original ex vivo voxel size. Tensor scale measures derived from imaging under in vivo and ex vivo conditions with significantly different modulation transfer function, i.e., difference in "true resolution," showed strong linear correlation (r = 0.92). The study of healthy volunteers shows that, after adjustment for height and weight, males have a 14% higher mean TB plate-width as compared to females (p < 0.05). SSRI-treated patients have 12.5% lower mean TB plate-width (p = 0.052) as compared to age-similar and sex-, height-, and weight-matched healthy controls. In contrast, the observed group difference in dual-energy x-ray absorptiometry (DXA)-derived hip BMD was 10.5% between males and females and only 5.04% between healthy controls and patients on SSRIs. Tensor scale analysis of MD-CT images yields accurate and reproducible characterization of TB plate-rod microarchitecture that may be more sensitive than DXA-derived BMD to sex differences and to the skeletal changes associated with medical conditions or their treatments.

SP0201 Usefulness and Limitations of DXA for Diagnosing Osteoporosis

The inverse relationship between areal bone mineral density (BMD), measured by dual energy X-ray absorptiometry (DXA), and fracture risk in postmenopausal women and older men is well documented and is...

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

High-Resolution Bone Imaging for Osteoporosis Diagnostics and Therapy Monitoring Using Clinical MDCT and MRI

Osteoporosis is classified as a public health problem due to its increased risk for fragility fractures. Osteoporotic fractures, in particular spine and hip fractures, are associated with a high morbidity and mortality, and generate immense financial cost. The World Health Organisation (WHO) based the diagnosis of osteoporosis on the measurement of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA). However, BMD values of subjects with versus without osteoporotic fractures overlap. Furthermore, it was reported that the anti-fracture effects of drugs could be only partially explained by their effects on BMD. Bone strength reflects the integration of BMD and bone quality. The later can be partly determined by measurements of bone microstructure. Therefore, substantial research efforts have been undertaken to assess bone microstructure by using high-resolution imaging techniques, including high-resolution peripheral quantitative computed tomography (hr-pQCT), high-resolution multi-detector computed tomography (MDCT), and high-resolution magnetic resonance imaging (MRI). Clinical MDCT and MRI systems are broadly available and allow an adequate depiction of the bone microstructure at the clinically most important fracture sites, i.e. radius, spine and hip. Bone microstructure parameters and finite element models can be computed in high-resolution MDCT and MR images. These measurements improved the prediction of bone strength beyond the DXA-derived BMD and revealed pharmacotherapy effects, which are partly not captured by BMD. Therefore, high-resolution bone imaging using clinical MDCT and MRI may be beneficial for osteoporosis diagnostics and allow a highly sensitive monitoring of drug treatment, which plays an important role in the prevention of fragility fractures.

Replication of Caucasian loci associated with bone mineral density in Koreans

Most bone mineral density (BMD) loci were reported in Caucasian genome-wide association studies (GWAS). This study investigated the association between 59 known BMD loci (+200 suggestive SNPs) and DXA-derived BMD in East Asian population with respect to sex and site specificity. We also identified four novel BMD candidate loci from the suggestive SNPs. Most GWAS have reported BMD-related variations in Caucasian populations. This study investigates whether the BMD loci discovered in Caucasian GWAS are also associated with BMD in East Asian ethnic samples. A total of 2,729 unrelated Korean individuals from a population-based cohort were analyzed. We selected 747 single-nucleotide polymorphisms (SNPs). These markers included 547 SNPs from 59 loci with genome-wide significance (GWS, p value less than 5 × 10(-8)) levels and 200 suggestive SNPs that showed weaker BMD association with p value less than 5 × 10(-5). After quality control, 535 GWS SNPs and 182 suggestive SNPs were included in the replication analysis. Of the 535 GWS SNPs, 276 from 25 loci were replicated (p < 0.05) in the Korean population with 51.6 % replication rate. Of the 182 suggestive variants, 16 were replicated (p < 0.05, 8.8 % of replication rate), and five reached a significant combined p value (less than 7.0 × 10(-5), 0.05/717 SNPs, corrected for multiple testing). Two markers (rs11711157, rs3732477) are for the same signal near the gene CPN2 (carboxypeptidase N, polypeptide 2). The other variants, rs6436440 and rs2291296, were located in the genes AP1S3 (adaptor-related protein complex 1, sigma 3 subunit) and RARB (retinoic acid receptor, beta). Our results illustrate ethnic differences in BMD susceptibility genes and underscore the need for further genetic studies in each ethnic group. We were also able to replicate some SNPs with suggestive associations. These SNPs may be BMD-related genetic markers and should be further investigated.

Association of DXA-derived Bone Mineral Density and Fat Mass With African Ancestry

Both genes and environment have been implicated in determining the complex body composition phenotypes in individuals of European ancestry; however, few studies have been conducted in other race/ethnic groups. We conducted a genome-wide admixture mapping study in an attempt to localize novel genomic regions associated with genetic ancestry. We selected a sample of 842 African-American women from the Women's Health Initiative single nucleotide polymorphism (SNP) Health Association Resource for whom several dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) and fat mass phenotypes were available. We derived both global and local ancestry estimates for each individual from Affymetrix 6.0 data and analyzed the correlation of DXA phenotypes with global African ancestry. For each phenotype, we examined the association of local genetic ancestry (number of African ancestral alleles at each marker) and each DXA phenotype at 570 282 markers across the genome in additive models with adjustment for important covariates. We identified statistically significant correlations of whole-body fat mass, trunk fat mass, and all 6 measures of BMD with a proportion of African ancestry. Genome-wide (admixture) significance for femoral neck BMD was achieved across 2 regions ∼3.7 MB and 0.3 MB on chromosome 19q13; similarly, total hip and intertrochanter BMD were associated with local ancestry in these regions. Trunk fat was the most significant fat mass phenotype showing strong, but not genomewide significant associations on chromosome Xp22. Our results suggest that genomic regions in postmenopausal African-American women contribute to variance in BMD and fat mass existence and warrant further study.