Cortical bone contributes the majority of overall bone mass and bears the bulk of axial loads in the peripheral skeleton. Bone metabolic disorders often are manifested by cortical microstructural changes via osteonal remodeling and endocortical trabecularization. The goal of this study was to characterize intracortical porosity in a cross-sectional patient cohort using novel quantitative computational methods applied to high-resolution peripheral quantitative computed tomography (HR-pQCT) images of the distal radius and tibia. The distal radius and tibia of 151 subjects (57 male, 94 female; 47 ± 16 years of age, range 20 to 78 years) were imaged using HR-pQCT. Intracortical porosity (Ct.Po) was calculated as the pore volume normalized by the sum of the pore and cortical bone volume. Micro–finite element analysis (µFE) was used to simulate 1% uniaxial compression for two scenarios per data set: (1) the original structure and (2) the structure with intracortical porosity artificially occluded. Differential biomechanical indices for stiffness (ΔK), modulus (ΔE), failure load (ΔF), and cortical load fraction (ΔCt.LF) were calculated as the difference between original and occluded values. Regression analysis revealed that cortical porosity, as depicted by HR-pQCT, exhibited moderate but significant age-related dependence for both male and female cohorts (radius ρ = 0.7; tibia ρ = 0.5; p < .001). In contrast, standard cortical metrics (Ct.Th, Ct.Ar, and Ct.vBMD) were more weakly correlated or not significantly correlated with age in this population. Furthermore, differential µFE analysis revealed that the biomechanical deficit (ΔK) associated with cortical porosity was significantly higher for postmenopausal women than for premenopausal women (p < .001). Finally, porosity-related measures provided the only significant decade-wise discrimination in the radius for females in their fifties versus females in their sixties (p < .01). Several important conclusions can be drawn from these results. Age-related differences in cortical porosity, as detected by HR-pQCT, are more pronounced than differences in standard cortical metrics. The biomechanical significance of these structural differences increases with age for men and women and provides discriminatory information for menopause-related bone quality effects. © 2010 American Society for Bone and Mineral Research.

The goal of this study was to characterize longitudinal changes in bone microarchitecture and function in women treated with an established antifracture therapeutic. In this double-blind, placebo-controlled pilot study, 53 early postmenopausal women with low bone density (age = 56 ± 4 years; femoral neck T-score = −1.5 ± 0.6) were monitored by high-resolution peripheral quantitative computed tomography (HR-pQCT) for 24 months following randomization to alendronate (ALN) or placebo (PBO) treatment groups. Subjects underwent annual HR-pQCT imaging of the distal radius and tibia, dual-energy X-ray absorptiometry (DXA), and determination of biochemical markers of bone turnover (BSAP and uNTx). In addition to bone density and microarchitecture assessment, regional analysis, cortical porosity quantification, and micro-finite-element analysis were performed. After 24 months of treatment, at the distal tibia but not the radius, HR-pQCT measures showed significant improvements over baseline in the ALN group, particularly densitometric measures in the cortical and trabecular compartments and endocortical geometry (cortical thickness and area, medullary area) (p < .05). Cortical volumetric bone mineral density (vBMD) in the tibia alone showed a significant difference between treatment groups after 24 months (p < .05); however, regionally, significant differences in Tb.vBMD, Tb.N, and Ct.Th were found for the lateral quadrant of the radius (p < .05). Spearman correlation analysis revealed that the biomechanical response to ALN in the radius and tibia was specifically associated with changes in trabecular microarchitecture (|ρ| = 0.51 to 0.80, p < .05), whereas PBO progression of bone loss was associated with a broad range of changes in density, geometry, and microarchitecture (|ρ| = 0.56 to 0.89, p < .05). Baseline cortical geometry and porosity measures best predicted ALN-induced change in biomechanics at both sites (ρ > 0.48, p < .05). These findings suggest a more pronounced response to ALN in the tibia than in the radius, driven by trabecular and endocortical changes. © 2010 American Society for Bone and Mineral Research.

Bone structural measures obtained by two noninvasive imaging tools-3T MRI and HRpQCT-were compared. Significant but moderate correlations and 2-to 4-fold discrepancies in parameter values were detected, suggesting that differences in acquisition and analysis must be considered when interpreting data from these imaging modalities.Introduction: High-field MRI and high resolution (HR)-pQCT are currently being used in longitudinal bone structure studies. Substantial differences in acquisition and analysis between these modalities may influence the quantitative data produced and could potentially influence clinical decisions based on their results. Our goal was to compare trabecular and cortical bone structural measures obtained in vivo by 3T MRI and HR-pQCT. Materials and Methods: Postmenopausal osteopenic women (n ‫ס‬ 52) were recruited for this study. HR-pQCT imaging of the radius and tibia was performed using the XtremeCT scanner, with a voxel size of 82 × 82 × 82 m

The multiscale hierarchical structure of bone is naturally optimized to resist fractures. In osteogenesis imperfecta, or brittle bone disease, genetic mutations affect the quality and/or quantity of collagen, dramatically increasing bone fracture risk. Here we reveal how the collagen defect results in bone fragility in a mouse model of osteogenesis imperfecta (oim), which has homotrimeric α1(I) collagen. At the molecular level we attribute the loss in toughness to a decrease in the stabilizing enzymatic crosslinks and an increase in non-enzymatic crosslinks, which may break prematurely inhibiting plasticity. At the tissue level, high vascular canal density reduces the stable crack growth, and extensive woven bone limits the crack-deflection toughening during crack growth. This demonstrates how modifications at the bone molecular level have ramifications at larger length scales affecting the overall mechanical integrity of the bone; thus, treatment strategies have to address multiscale properties in order to regain bone toughness. In this regard, findings from the heterozygous oim bone, where defective as well as normal collagen are present, suggest that increasing the quantity of healthy collagen in these bones helps to recover toughness at the multiple length scales.

Assessment of bone tissue mineral density (TMD) may provide information critical to the understanding of mineralization processes and bone biomechanics. High-resolution three-dimensional assessment of TMD has recently been demonstrated using synchrotron radiation microcomputed tomography (SRmuCT); however, this imaging modality is relatively inaccessible due to the scarcity of SR facilities. Conventional desktop muCT systems are widely available and have been used extensively to assess bone microarchitecture. However, the polychromatic source and cone-shaped beam geometry complicate assessment of TMD by conventional muCT. The goal of this study was to evaluate muCT-based measurement of degree and distribution of tissue mineralization in a quantitative, spatially resolved manner. Specifically, muCT measures of bone mineral content (BMC) and TMD were compared to those obtained by SRmuCT and gravimetric methods. Cylinders of trabecular bone were machined from human femoral heads (n = 5), vertebrae (n = 5), and proximal tibiae (n = 4). Cylinders were imaged in saline on a polychromatic muCT system at an isotropic voxel size of 8 microm. Volumes were reconstructed using beam hardening correction algorithms based on hydroxyapatite (HA)-resin wedge phantoms of 200 and 1200 mg HA/cm3. SRmuCT imaging was performed at an isotropic voxel size of 7.50 microm at the National Synchrotron Light Source. Attenuation values were converted to HA concentration using a linear regression derived by imaging a calibration phantom. Architecture and mineralization parameters were calculated from the image data. Specimens were processed using gravimetric methods to determine ash mass and density, muCT-based BMC values were not affected by altering the beam hardening correction. Volume-averaged TMD values calculated by the two corrections were significantly different (p = 0.008) in high volume fraction specimens only, with the 1200 mg HA/cm3 correction resulting in a 4.7% higher TMD value. MuCT and SRmuCT provided significantly different measurements of both BMC and TMD (p < 0.05). In high volume fraction specimens, muCT with 1200 mg HA/cm3 correctionteg resulted in BMC and TMD values 16.7% and 15.0% lower, respectively, than SRmuCT values. In low volume fraction specimens, muCT with 1200 mg HA/cm3 correction resulted in BMC and TMD values 12.8% and 12.9% lower, respectively, than SRmuCT values. MuCT and SRmuCT values were well-correlated when volume fraction groups were considered individually (BMC R2 = 0.97-1.00; TMD R2 = 0.78-0.99). Ash mass and density were higher than the SRmuCT equivalents by 8.6% in high volume fraction specimens and 10.9% in low volume fraction specimens (p < 0.05). BMC values calculated by tomography were highly correlated with ash mass (ash versus muCT R2 = 0.96-1.00; ash versus SRmuCT R2 = 0.99-1.00). TMD values calculated by tomography were moderately correlated with ash density (ash versus muCT R2 = 0.64-0.72; ash versus SRmuCT R2 = 0.64). Spatially resolved comparisons highlighted substantial geometric nonunif...

Micro-computed tomography (µCT) has become an important tool for morphological characterization of cortical and trabecular bone. Quantitative assessment of bone tissue mineral density (TMD) from µCT images may be possible; however, the methods for calibration and accuracy have not been thoroughly evaluated. This study investigated hydroxyapatite (HA) phantom sampling limitations, short-term reproducibility of phantom measurements, and accuracy of TMD measurements by correlation to ash density. Additionally, the performance of a global and a local threshold for determining TMD was tested. The full length of a commercial density phantom was imaged by µCT, and mean calibration parameters were determined for a volume of interest (VOI) at 10 random positions along the longitudinal axis. Ten different VOI lengths were used (0.9-13 mm). The root mean square error (RMSE) was calculated for each scan length. Short-term reproducibility was assessed by five repeat phantom measurements for three source voltage settings. Accuracy was evaluated by imaging rat cortical bone (n = 16) and bovine trabecular bone (n = 15), followed by ash gravimetry. Phantom heterogeneity was associated with<0.5% RMSE. The coefficient of variation for five repeat measurements was generally<0.25% across all energies and phantom densities. Bone mineral content was strongly correlated to ash weight (R 2 = 1.00 for both specimen groups and both threshold methods). Ash density was well correlated for the trabecular bone specimens (R 2 > 0.80). In cortical bone specimens, the correlation was somewhat weaker when a global threshold was applied (R 2 = 0.67) compared to the local threshold method (R 2 = 0.78). © Springer Science+Business Media, LLC 2008Correspondence to: Andrew J. Burghardt, andrew.burghardt@radiology.ucsf.edu. NIH Public Access Author ManuscriptCalcif Tissue Int. Author manuscript; available in PMC 2010 January 4. Micro-computed tomography (µCT) has become an important tool for addressing a wide range of research questions related to the biology of bone and other calcified tissues. Quantitative measures derived from µCT have generally been limited to geometric and topological parameters describing the size and shape of trabecular and cortical bone [1][2][3][4]. These microstructural features have been shown to improve the prediction of bone strength independently of traditional measures of bone density [5,6] and, therefore, represent a target for therapeutic manipulation. In addition to geometry, bone material composition is a determinant of bone strength [7] and can be positively modified pharmacologically [8].Quantification of the mineral and organic properties of bone tissue has primarily been limited to two-dimensional (2D), destructive methods, including microradiography [9], infrared spectroscopic imaging [10], and backscatter electron imaging [11]. The ability to characterize tissue-level mineralization through 3D, nondestructive means would be an attractive complement to microstructural and biomechanical analyses already e...

Purpose: Accurate quantification of bone microstructure plays a significant role in understanding bone mechanics and response to disease or treatment. High‐resolution peripheral quantitative computed tomography (HR‐pQCT) allows for the quantification of trabecular and cortical structurein vivo, with the capability of generating images at multiple voxel sizes (41, 82, and 123 μm). The aim of this study was to characterize the effect of voxel size on structural measures of trabecular and cortical bone and to determine accuracy in reference to micro‐CT (µCT), the gold standard for bone microstructure quantification. Methods: Seventeen radii from human cadaver specimens were imaged at each HR‐pQCT voxel size and subsequently imaged using µCT. Bone density and microstructural assessment was performed in both the trabecular and cortical compartments, including cortical porosity quantification. Two distinct analysis techniques were applied to the 41 μm HR‐pQCT data: the standard clinical indirect analysis and a direct analysis requiring no density or structural model assumptions. Analysis parameters were adjusted to enable segmentation and structure extraction at each voxel size. Results: For trabecular microstructural measures, the 41 μm HR‐pQCT data displayed the strongest correlations and smallest errors compared to µCT data. The direct analysis technique applied to the 41 μm data yielded an additional improvement in accuracy, especially for measures of trabecular thickness. The 123 μm data performed poorly, with all microstructural measures either having moderate or nonsignificant correlations with µCT data. Trabecular densitometric measures showed strong correlations to µCT data across all voxel sizes. Cortical thickness was strongly correlated with µCT values across all HR‐pQCT voxel sizes. The accuracy of cortical porosity parameters was highly dependent on voxel size; again, the 41 μm data was most strongly correlated. Measures of cortical density and pore diameter at all HR‐pQCT voxel sizes had either weak or nonsignificant correlations. Conclusions: This study demonstrates the effect of voxel size on the accuracy of HR‐pQCT measurements of trabecular and cortical microstructure and presents parameters for HR‐pQCT analysis at nonstandard resolutions. For all parameters measured, correlations were strongest at 41 μm. Weak correlations for porosity measures indicate that a better understanding of pore structure and resolution dependence is needed.

High resolution peripheral quantitative computed tomography (HR-pQCT) is a promising method for detailed in vivo 3D characterization of the densitometric, geometric, and microstructural features of human bone. Currently, a hybrid densitometric, direct, and plate model-based calculation is used to quantify trabecular microstructure. In the present study, this legacy methodology is compared to direct methods derived from a new local thresholding scheme independent of densitometric and model assumptions. Human femoral trabecular bone samples were acquired from patients undergoing hip replacement surgery. HR-pQCT (82 microm isotropic voxels) and micro-tomography (16 microm isotropic voxels) images were acquired. HR-pQCT images were segmented and analyzed in three ways: (1) using the hybrid method provided by the manufacturer based on a fixed global threshold, (2) using direct 3D methods based on the fixed global threshold segmentation, and (3) using direct 3D methods based on a novel local threshold scheme. The results were compared against standard direct 3D indices from microCT analysis. Standard trabecular parameters determined by HR-pQCT correlated strongly to microCT. BV/TV and Tb.Th were significantly underestimated by the hybrid method and significantly overestimated by direct methods based on the global threshold segmentation while the local method yielded optimal intermediate results. The direct-local method also performed favorably for Tb.N (R(2) = 0.85 vs. R(2) = 0.70 for direct-global method) and Tb.Sp (R(2) = 0.93 vs. R(2) = 0.85 for the hybrid method and R(2) = 0.87 for the direct-global method). These results indicate that direct methods, with the aid of advanced segmentation techniques, may yield equivalent or improved accuracy for quantification of trabecular bone microstructure without relying on densitometric or model assumptions.