Multicenter precision of cortical and trabecular bone quality measures assessed by high‐resolution peripheral quantitative computed tomography

High‐resolution peripheral quantitative computed tomography (HR‐pQCT) has recently been introduced as a clinical research tool for in vivo assessment of bone quality. The utility of this technology to address important skeletal health questions requires translation to standardized multicenter data pools. Our goal was to evaluate the feasibility of pooling data in multicenter HR‐pQCT imaging trials. Reproducibility imaging experiments were performed using structure and composition‐realistic phantoms constructed from cadaveric radii. Single‐center precision was determined by repeat scanning over short‐term (<72 hours), intermediate‐term (3–5 months), and long‐term intervals (28 months). Multicenter precision was determined by imaging the phantoms at nine different HR‐pQCT centers. Least significant change (LSC) and root mean squared coefficient of variation (RMSCV) for each interval and across centers was calculated for bone density, geometry, microstructure, and biomechanical parameters. Single‐center short‐term RMSCVs were <1% for all parameters except cortical thickness (Ct.Th) (1.1%), spatial variability in cortical thickness (Ct.Th.SD) (2.6%), standard deviation of trabecular separation (Tb.Sp.SD) (1.8%), and porosity measures (6% to 8%). Intermediate‐term RMSCVs were generally not statistically different from short‐term values. Long‐term variability was significantly greater for all density measures (0.7% to 2.0%; p < 0.05 versus short‐term) and several structure measures: cortical thickness (Ct.Th) (3.4%; p < 0.01 versus short‐term), cortical porosity (Ct.Po) (15.4%; p < 0.01 versus short‐term), and trabecular thickness (Tb.Th) (2.2%; p < 0.01 versus short‐term). Multicenter RMSCVs were also significantly higher than short‐term values: 2% to 4% for density and micro–finite element analysis (µFE) measures (p < 0.0001), 2.6% to 5.3% for morphometric measures (p < 0.001), whereas Ct.Po was 16.2% (p < 0.001). In the absence of subject motion, multicenter precision errors for HR‐pQCT parameters were generally less than 5%. Phantom‐based multicenter precision was comparable to previously reported in in vivo single‐center precision errors, although this was approximately two to five times worse than ex vivo short‐term precision. The data generated from this study will contribute to the future design and validation of standardized procedures that are broadly translatable to multicenter study designs. © 2013 American Society for Bone and Mineral Research.     

Age- and gender-related differences in cortical geometry and microstructure: Improved sensitivity by regional analysis

ObjectiveWhile the importance of cortical structure quantification is increasingly underscored by recent literature, conventional analysis techniques obscure potentially important regional variations in cortical structure. The objective of this study was to characterize the spatial variability in cortical geometry and microstructure at the distal radius and tibia using high resolution peripheral quantitative computed tomography (HR-pQCT). We show that spatially-resolved analysis is able to identify cortical sub-regions with increased sensitivity to the effects of gender and aging.MethodsHR-pQCT scans of 146 volunteers (92 female/54 male) spanning a wide range of ages (20–78 years) were analyzed. For each subject, radius and tibia scans were obtained using a clinical HR-pQCT system. Measures describing geometry (cortical bone thickness (Ct.Th)), microstructure (porosity (Ct.Po), pore diameter (Ct.Po.Dm), and pore size heterogeneity (Ct.Po.Dm SD)), and cortical bone density were calculated from the image data. Biomechanical parameters describing load and stress distribution were calculated using linear finite element analysis. Cortical quadrants were defined based on anatomic axes to quantify regional parameter variation. Subjects were categorized by gender, and age, and menopausal status for analysis.ResultsSignificant regional variation was found in all geometric and microstructural parameters in both the radius and tibia. In general, the radius showed more pronounced and significant variations in all parameters as compared with the tibia. At both sites, Ct.Po displayed the greatest regional variations. Correlation coefficients for Ct.Po and Ct.Th with respect to load and stress distribution provided evidence of an association between regional cortical structure and biomechanics in the tibia. Comparing women to men, differences in Ct.Po were most pronounced in the anterior quadrant of the radius (36% lower in women (p < 0.01)) and the posterior quadrant of the tibia (27% lower in women (p < 0.01)). Comparing elderly to young women, differences in Ct.Po were most pronounced in the lateral quadrant of the radius (328% higher in elderly women (p < 0.001)) and the anterior quadrant of the tibia (433% higher in elderly women (p < 0.001)). Comparing elderly to young men, the most pronounced age differences were found in the anterior radius (205% higher in elderly men, (p < 0.001)) and the anterior tibia (190% higher in elderly men (p < 0.01)). All subregional Ct.Po differences provided greater sensitivity to gender and age effects than those based on the global means.ConclusionThese results show significant regional variation in all geometric and microarchitectural parameters studied in both the radius and tibia. Quantification of region-specific parameters provided increased sensitivity in the analysis of age- and gender-related differences, in many cases providing statistically significant differentiation of groups where conventional global analysis failed to detect differences. These results suggest that regional analysis may be important in studies of disease and therapeutic effects, particularly where microstructural parameters based on global analyses have thus far failed to identify a response in bone quality.     

How Tough Is Brittle Bone? Investigating Osteogenesis Imperfecta in Mouse Bone

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 cross‐links and an increase in nonenzymatic cross‐links, 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. © 2014 American Society for Bone and Mineral Research.     

Accuracy of volumetric bone mineral density measurement in high-resolution peripheral quantitative computed tomography

Accurate bone mineral density (BMD) quantification is critical in clinical assessment of fracture risk and in the research of age-, disease-, and treatment-related musculoskeletal changes. The development of high-resolution peripheral quantitative computed tomography (HR-pQCT) imaging has made possible in vivo assessment of compartmental volumetric BMD (vBMD) and bone micro-architecture in the distal radius and tibia. HR-pQCT imaging relies on a polychromatic X-ray source and therefore is subject to beam hardening as well as scatter artifacts. In light of these limitations, we hypothesize that the accuracy of HR-pQCT vBMD measurement in the trabecular compartment (vBMD_trab) is not independent of bone density and geometry, but rather influenced by variations in trabecular bone volume fraction and cortical thickness. The goal of this study, therefore, was to evaluate the accuracy of HR-pQCT vBMD_trab measurement in the radius and tibia, and to determine the dependence of this measurement on geometric and densitometric parameters. Our approach was to use a series of idealized hydroxyapatite (HA) phantoms with varying densities and geometries to quantify the accuracy of HR-pQCT analysis. Two sets of custom-made HA phantoms designed to mimic the distal tibia and distal radius were manufactured. Geometric and densitometric specifications were based on a dataset of healthy volunteers and osteopenic patients. Multiple beam hardening correction (BHC) algorithms were implemented and evaluated in their ability to reduce measurement error. Substantial errors in measured vBMD_trab were found. Overestimation of vBMD_trab increased proportional to cortical shell thickness and decreased proportional to insert density. The most pronounced vBMD_trab overestimation therefore occurred in the phantoms with the lowest insert densities and highest shell thickness, where error was as high as 20 mg HA/cm³ (33%) in the radius phantom and 25 mg HA/cm³ (41%) in the tibia phantom. Error in vBMD_trab propagates to the calculation of micro-architectural measures; 41% error in vBMD_trab will produce 41% error in volume fraction (BV/TV) and trabecular thickness (Tb.Th), and 5% error in trabecular separation (Tb.Sp). BHC algorithms supplied by the manufacturer failed to eliminate these errors. Our results confirm that geometric and densitometric variations influence the accuracy of HR-pQCT vBMD_trab measurements, and must be considered when interpreting data across populations or time-points.     

Quantitative Assessment of Bone Tissue Mineralization with Polychromatic Micro-Computed Tomography

Micro-computed tomography (muCT) has become an important tool for morphological characterization of cortical and trabecular bone. Quantitative assessment of bone tissue mineral density (TMD) from muCT 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 muCT, 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).     

Mineral Composition is Altered by Osteoblast Expression of an Engineered G<Subscript>s</Subscript>-Coupled Receptor

Activation of the G_s G protein–coupled receptor Rs1 in osteoblasts increases bone mineral density by 5- to 15-fold in mice and recapitulates histologic aspects of fibrous dysplasia of the bone. However, the effects of constitutive G_s signaling on bone tissue quality are not known. The goal of this study was to determine bone tissue quality in mice resulting from osteoblast-specific constitutive G_s activation, by the complementary techniques of FTIR spectroscopy and synchrotron radiation micro-computed tomography (SRμCT). Col1(2.3)-tTA/TetO-Rs1 double transgenic (DT) mice, which showed osteoblast-specific constitutive G_s signaling activity by the Rs1 receptor, were created. Femora and calvariae of DT and wild-type (WT) mice (6 and 15 weeks old) were analyzed by FTIR spectroscopy. WT and DT femora (3 and 9 weeks old) were imaged by SRμCT. Mineral-to-matrix ratio was 25% lower (P = 0.010), carbonate-to-phosphate ratio was 20% higher (P = 0.025), crystallinity was 4% lower (P = 0.004), and cross-link ratio was 11% lower (P = 0.025) in 6-week DT bone. Differences persisted in 15-week animals. Quantitative SRμCT analysis revealed substantial differences in mean values and heterogeneity of tissue mineral density (TMD). TMD values were 1,156 ± 100 and 711 ± 251 mg/cm³ (mean ± SD) in WT and DT femoral diaphyses, respectively, at 3 weeks. Similar differences were found in 9-week animals. These results demonstrate that continuous G_s activation in murine osteoblasts leads to deposition of immature bone tissue with reduced mineralization. Our findings suggest that bone tissue quality may be an important contributor to increased fracture risk in fibrous dysplasia patients.     

New imaging technologies in the diagnosis of osteoporosis

In the context of osteoporosis, bone quality—which encompasses trabecular and cortical micro-architecture, mass, and tissue mechanical & compositional properties—plays an important and as yet undiscovered role. Non-invasive assessment of bone quality has recently received considerable attention, as bone density alone has not been able to predict existing or future osteoporotic fractures, or to explain therapeutic effects of emerging treatments. The goal of this review, therefore, is to present imaging modalities and related analysis methods capable of assessing bone quality for improved diagnosis and care of osteoporotic individuals. The techniques described include quantitative ultrasound, quantitative computed tomography, peripheral quantitative tomography, micro computed tomography, magnetic resonance, radiographic texture analysis, as well as finite element analysis based on the above-mentioned imaging modalities. The performance of these techniques in predicting osteoporotic fracture and assessing strength indices are discussed.     

Statistical Parametric Mapping of HR-pQCT Images: A Tool for Population-Based Local Comparisons of Micro-Scale Bone Features

HR-pQCT enables in vivo multi-parametric assessments of bone microstructure in the distal radius and distal tibia. Conventional HR-pQCT image analysis approaches summarize bone parameters into global scalars, discarding relevant spatial information. In this work, we demonstrate the feasibility and reliability of statistical parametric mapping (SPM) techniques for HR-pQCT studies, which enable population-based local comparisons of bone properties. We present voxel-based morphometry (VBM) to assess trabecular and cortical bone voxel-based features, and a surface-based framework to assess cortical bone features both in cross-sectional and longitudinal studies. In addition, we present tensor-based morphometry (TBM) to assess trabecular and cortical bone structural changes. The SPM techniques were evaluated based on scan-rescan HR-pQCT acquisitions with repositioning of the distal radius and distal tibia of 30 subjects. For VBM and surface-based SPM purposes, all scans were spatially normalized to common radial and tibial templates, while for TBM purposes, rescans (follow-up) were spatially normalized to their corresponding scans (baseline). VBM was evaluated based on maps of local bone volume fraction (BV/TV), homogenized volumetric bone mineral density (vBMD), and homogenized strain energy density (SED) derived from micro-finite element analysis; while the cortical bone framework was evaluated based on surface maps of cortical bone thickness, vBMD, and SED. Voxel-wise and vertex-wise comparisons of bone features were done between the groups of baseline and follow-up scans. TBM was evaluated based on mean square errors of determinants of Jacobians at baseline bone voxels. In both anatomical sites, voxel- and vertex-wise uni- and multi-parametric comparisons yielded non-significant differences, and TBM showed no artefactual bone loss or apposition. The presented SPM techniques demonstrated robust specificity thus warranting their application in future clinical HR-pQCT studies.     

A longitudinal HR‐pQCT study of alendronate treatment in postmenopausal women with low bone density: Relations among density,cortical and trabecular microarchitecture,biomechanics, and bone turnover

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.