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Objective

To identify determinants of musculoskeletal deficits (muscle cross-sectional area [mCSA], trabecular volumetric bone mineral density [vBMD], and cortical bone strength [section modulus]) in patients with juvenile idiopathic arthritis (JIA) and to determine if cortical bone strength is appropriately adapted to muscle forces.

Methods

Peripheral quantitative computed tomography (pQCT) of the tibia was performed in 101 patients with JIA (79% female; 24 with oligoarticular JIA, 40 with polyarticular JIA, 18 with systemic JIA, and 19 with spondylarthritis [SpA]) and 830 healthy control subjects; all were ages 5–22 years. Outcomes of pQCT were expressed as sex- and race-specific Z scores. Multivariable linear regression models assessed mCSA and bone status in JIA patients compared with controls and identified factors associated with musculoskeletal deficits in JIA.

Results

The median duration of JIA was 40 months; 29% of the JIA patients had active arthritis, and 28% had received glucocorticoid therapy during the previous year. Compared with the controls, the mCSA and section modulus Z scores were significantly lower in patients with polyarticular JIA and those with SpA. Trabecular vBMD Z scores were significantly lower in patients with polyarticular JIA, those with systemic JIA, and those with SpA. Significant predictors of musculoskeletal deficits included active arthritis in the previous 6 months (mCSA), temporomandibular joint disease (mCSA and section modulus), functional disability (mCSA and vBMD), short stature (vBMD), infliximab exposure (vBMD), and JIA duration (section modulus). The section modulus was significantly reduced relative to mCSA in patients with JIA after adjustment for age and limb length.

Conclusion

Marked deficits in vBMD and bone strength occur in JIA in association with severe and longstanding disease. Contrary to the findings of previous studies, bone deficits were greater than expected relative to the mCSA, which illustrates the importance of adjusting for age and bone length.

Determination of osteoporotic status is based primarily on areal bone mineral density (aBMD) obtained through dual x-ray absorptiometry (DXA). However, many fractures occur in patients with T-scores above the WHO threshold of osteoporosis, in part because DXA measures are insensitive to biomechanically important alterations in bone quality. The goal of this study was to determine – within groups of subjects with identical radius aBMD values – the extant variation in densitometric, geometric, microstructural, and biomechanical parameters. High resolution peripheral quantitative computed tomography (HR-pQCT) and DXA radius data from males and females spanning large ranges in age, osteoporotic status, and anthropometrics were compiled. 262 distal radius data sets were processed for this study. HR-pQCT scans were analyzed according to the manufacturer's standard clinical protocol to quantify densitometric, geometric, and microstructural indices. Micro finite element analysis was performed to calculate biomechanical indices. Factor of risk of wrist fracture was calculated. Simulated aBMD calculated from HR-pQCT data was used to group scans for evaluation of variation in quantified indices. Indices reflecting the greatest variation within aBMD level were BMD in the central portion of the trabecular compartment (max CV 142), trabecular heterogeneity (max CV 90), and intra-cortical porosity (max CV 151). Of the biomechanical indices, cortical load fraction had the greatest variation (max CV 38). Substantial variations in indices reflecting density, structure, and biomechanical competence exist among subjects with identical aBMD levels. Overlap of these indices among osteoporotic status groups reflects the reported incidence of osteoporotic fracture in subjects classified as osteopenic or normal.

Measurement of areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) has been shown to predict fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) yields additional information about volumetric BMD (vBMD), microarchitecture, and strength that may increase understanding of fracture susceptibility. Women with (n = 68) and without (n = 101) a history of postmenopausal fragility fracture had aBMD measured by DXA and trabecular and cortical vBMD and trabecular microarchitecture of the radius and tibia measured by HR-pQCT. Finite-element analysis (FEA) of HR-pQCT scans was performed to estimate bone stiffness. DXA T-scores were similar in women with and without fracture at the spine, hip, and one-third radius but lower in patients with fracture at the ultradistal radius (p <.01). At the radius fracture, patients had lower total density, cortical thickness, trabecular density, number, thickness, higher trabecular separation and network heterogeneity (p <.0001 to .04). At the tibia, total, cortical, and trabecular density and cortical and trabecular thickness were lower in fracture patients (p <.0001 to .03). The differences between groups were greater at the radius than at the tibia for inner trabecular density, number, trabecular separation, and network heterogeneity (p <.01 to .05). Stiffness was reduced in fracture patients, more markedly at the radius (41% to 44%) than at the tibia (15% to 20%). Women with fractures had reduced vBMD, microarchitectural deterioration, and decreased strength. These differences were more prominent at the radius than at the tibia. HR-pQCT and FEA measurements of peripheral sites are associated with fracture prevalence and may increase understanding of the role of microarchitectural deterioration in fracture susceptibility.

Measurement of areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) has been shown to predict fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) yields additional information about volumetric BMD (vBMD), microarchitecture, and strength that may increase understanding of fracture susceptibility. Women with (n = 68) and without (n = 101) a history of postmenopausal fragility fracture had aBMD measured by DXA and trabecular and cortical vBMD and trabecular microarchitecture of the radius and tibia measured by HR-pQCT. Finite-element analysis (FEA) of HR-pQCT scans was performed to estimate bone stiffness. DXA T-scores were similar in women with and without fracture at the spine, hip, and one-third radius but lower in patients with fracture at the ultradistal radius (p < .01). At the radius fracture, patients had lower total density, cortical thickness, trabecular density, number, thickness, higher trabecular separation and network heterogeneity (p < .0001 to .04). At the tibia, total, cortical, and trabecular density and cortical and trabecular thickness were lower in fracture patients (p < .0001 to .03). The differences between groups were greater at the radius than at the tibia for inner trabecular density, number, trabecular separation, and network heterogeneity (p < .01 to .05). Stiffness was reduced in fracture patients, more markedly at the radius (41% to 44%) than at the tibia (15% to 20%). Women with fractures had reduced vBMD, microarchitectural deterioration, and decreased strength. These differences were more prominent at the radius than at the tibia. HR-pQCT and FEA measurements of peripheral sites are associated with fracture prevalence and may increase understanding of the role of microarchitectural deterioration in fracture susceptibility. © 2010 American Society for Bone and Mineral Research.

Idiopathic osteoporosis (IOP) in premenopausal women is a poorly understood entity in which otherwise healthy women have low-trauma fracture or very low bone mineral density (BMD). In this study, we applied individual trabeculae segmentation (ITS)–based morphological analysis to high-resolution peripheral quantitative computed tomography (HR-pQCT) images of the distal radius and distal tibia to gain greater insight into skeletal microarchitecture in premenopausal women with IOP. HR-pQCT scans were performed for 26 normal control individuals and 31 women with IOP. A cubic subvolume was extracted from the trabecular bone compartment and subjected to ITS-based analysis. Three Young’s moduli and three shear moduli were calculated by micro–finite element (μFE) analysis. ITS-based morphological analysis of HR-pQCT images detected significantly decreased trabecular plate and rod bone volume fraction and number, decreased axial bone volume fraction in the longitudinal axis, increased rod length, and decreased rod-to-rod, plate-to-rod, and plate-to-plate junction densities at the distal radius and distal tibia in women with IOP. However, trabecular plate and rod thickness did not differ. A more rod-like trabecular microstructure was found in the distal radius, but not in the distal tibia. Most ITS measurements contributed significantly to the elastic moduli of trabecular bone independent of bone volume fraction (BV/TV). At a fixed BV/TV, plate-like trabeculae contributed positively to the mechanical properties of trabecular bone. The results suggest that ITS-based morphological analysis of HR-pQCT images is a sensitive and promising clinical tool for the investigation of trabecular bone microstructure in human studies of osteoporosis.

Idiopathic osteoporosis (IOP) in premenopausal women is a poorly understood entity in which otherwise healthy women have low-trauma fracture or very low bone mineral density (BMD). In this study, we applied individual trabeculae segmentation (ITS)–based morphological analysis to high-resolution peripheral quantitative computed tomography (HR-pQCT) images of the distal radius and distal tibia to gain greater insight into skeletal microarchitecture in premenopausal women with IOP. HR-pQCT scans were performed for 26 normal control individuals and 31 women with IOP. A cubic subvolume was extracted from the trabecular bone compartment and subjected to ITS-based analysis. Three Young's moduli and three shear moduli were calculated by micro–finite element (µFE) analysis. ITS-based morphological analysis of HR-pQCT images detected significantly decreased trabecular plate and rod bone volume fraction and number, decreased axial bone volume fraction in the longitudinal axis, increased rod length, and decreased rod-to-rod, plate-to-rod, and plate-to-plate junction densities at the distal radius and distal tibia in women with IOP. However, trabecular plate and rod thickness did not differ. A more rod-like trabecular microstructure was found in the distal radius, but not in the distal tibia. Most ITS measurements contributed significantly to the elastic moduli of trabecular bone independent of bone volume fraction (BV/TV). At a fixed BV/TV, plate-like trabeculae contributed positively to the mechanical properties of trabecular bone. The results suggest that ITS-based morphological analysis of HR-pQCT images is a sensitive and promising clinical tool for the investigation of trabecular bone microstructure in human studies of osteoporosis. © 2010 American Society for Bone and Mineral Research.

Image quality degradation due to subject motion is a common artifact affecting in vivo high-resolution peripheral quantitative computed tomography (HR-pQCT) of bone. These artifacts confound the accuracy and reproducibility of bone density, geometry, and cortical and trabecular structure measurements. Observer-based systems for grading image quality and criteria for deciding when to repeat an acquisition and post hoc data quality control remain highly subjective and non-standardized. This study proposed an objective, quantitative technique for measuring subject motion in HR-pQCT acquisitions from the raw projection data, using image similarity measures applied to the parallelized projections at 0° and 180°.

A total of 88 HR-pQCT exams with repeated acquisitions of the distal radius (N=54) or distal tibia (N=34) of 49 women (age = 59 ± 14 yr) and 3 men (46 ± 2 yr) were retrospectively evaluated. All images were graded from 1 (no visible motion artifacts) to 5 (severe motion artifacts) according to the manufacturer-suggested image quality grading system. In addition, to serve as the reference case without motion artifacts, two cadaveric wrists and two ankles specimens were imaged twice with repositioning. The motion-induced error was calculated as the percent difference in each bone parameter for the paired scans with and without visually apparent motion artifacts. Quantitative motion estimates (QMEs) for each motion-degraded scan were calculated using two different image similarity measures: sum of squared differences (SSD) and normalized cross-correlation (NCC).

The mean values of QMESSD and QMENCC increased with the image quality grade for both radius and tibia. The quality grades were differentiated between grade 2 and 3 using QMESSD, but not with QMENCC, in addition to between grade 4 and 5. Both QMEs correlated significantly to the motion-induced errors in the measurements and their empirical relationship was derived. Subject motion had greater impact on the precision of trabecular structure indices than on the densitometric indices.

The results of this study may provide a basis for establishing a threshold for motion artifacts in accordance to the study design as well as a standardized quality control protocol across operators and imaging centers.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a new in vivo imaging technique for assessing three-dimensional microstructure of cortical and trabecular bone at the distal radius and tibia. No studies have investigated the extent to which measurements of the peripheral skeleton by HR-pQCT reflect those of the spine and hip, where the most serious fractures occur. To address this research question, we performed dual energy absorptiometry (DXA), central QCT (cQCT), HR-pQCT, and image-based finite element analyses in 69 premenopausal women to evaluate relationships among cortical and trabecular bone density, geometry, microstructure, and stiffness of the lumbar spine, proximal femur, distal radius and distal tibia. Significant correlations were found between stiffness of the two peripheral sites (r=0.86), two central sites (r=0.49), and between peripheral and central skeletal sites (r=0.56-0.70). These associations were partially explained by significant correlations in areal BMD (aBMD), volumetric BMD (vBMD), and cross-sectional area (CSA) between the multiple skeletal sites. For prediction of proximal femoral stiffness, vBMD (r=0.75) and stiffness (r=0.69) of the distal tibia by HR-pQCT were comparable to direct measurements of the proximal femur: aBMD of hip by DXA (r=0.70) and vBMD of hip by cQCT (r=0.64). For prediction of vertebral stiffness, trabecular vBMD (r=0.58) and stiffness (r=0.70) of distal radius by HR-pQCT were comparable to direct measurements of lumbar spine: aBMD by DXA (r=0.78) and vBMD by cQCT (r=0.67). Our results suggest that bone density, microstructural and mechanical properties measured by HR-pQCT of the distal radius and tibia reflect mechanical competence of the central skeleton.

Objectives

To determine (1) the error attributable to external tibia-length measurements by using peripheral quantitative computed tomography (pQCT) and (2) the effect these errors have on scan location and tibia trabecular bone mineral density (BMD) after spinal cord injury (SCI).

Design

Blinded comparison and criterion standard in matched cohorts.

Setting

Primary care university hospital.

Participants

Eight able-bodied subjects underwent tibia length measurement. A separate cohort of 7 men with SCI and 7 able-bodied age-matched male controls underwent pQCT analysis.

Interventions

Not applicable.

Main Outcome Measures

The projected worst-case tibia-length–measurement error translated into a pQCT slice placement error of ±3mm. We collected pQCT slices at the distal 4% tibia site, 3mm proximal and 3mm distal to that site, and then quantified BMD error attributable to slice placement.

Results

Absolute BMD error was greater for able-bodied than for SCI subjects (5.87mg/cm3 vs 4.5mg/cm3). However, the percentage error in BMD was larger for SCI than able-bodied subjects (4.56% vs 2.23%).

Conclusions

During cross-sectional studies of various populations, BMD differences up to 5% may be attributable to variation in limb-length–measurement error.

Osteoporosis is typically diagnosed by dual energy x-ray absorptiometry (DXA) measurements of areal bone mineral density (aBMD). Emerging technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), may increase the diagnostic accuracy of DXA and enhance our mechanistic understanding of decreased bone strength in osteoporosis. Women with (n=68) and without (n=101) a history of postmenopausal fragility fracture had aBMD measured by DXA, trabecular plate and rod microarchitecture measured by HR-pQCT image-based individual trabeculae segmentation (ITS) analysis, and whole bone and trabecular bone stiffness by micro finite element analysis (μFEA) of HR-pQCT images at the radius and tibia. DXA T-scores were similar in women with and without fractures at the spine, hip and 1/3 radius, but lower in fracture subjects at the ultradistal radius. Trabecular microarchitecture of fracture subjects was characterized by preferential reductions in trabecular plate bone volume, number, and connectivity over rod trabecular parameters, loss of axially aligned trabeculae, and a more rod-like trabecular network. In addition, decreased thickness and size of trabecular plates were observed at the tibia. The differences between groups were greater at the radius than the tibia for plate number, rod bone volume fraction and number and plate-rod and rod-rod junction densities. Most differences between groups remained after adjustment for T-score by DXA. At a fixed bone volume fraction, trabecular plate volume, number and connectivity were directly associated with bone stiffness. In contrast, rod volume, number and connectivity were inversely associated with bone stiffness. In summary, HR-pQCT-based ITS and μFEA measurements discriminate fracture status in postmenopausal women independent of DXA measurements. Moreover, these results suggest that preferential loss of plate-like trabeculae contribute to lower trabecular bone and whole bone stiffness in women with fractures. We conclude that HR-pQCT-based ITS and μFEA measurements increase our understanding of the microstructural pathogenesis of fragility fracture in postmenopausal women.

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.

We sought to determine the influence of single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG on volumetric bone mineral density (vBMD) and bone geometry at the radius in men. Pairwise tag SNPs (r2 ≥ 0.8) for RANKL (n = 8), RANK (n = 44), and OPG (n = 22) and five SNPs near RANKL and OPG strongly associated with areal BMD in genomewide association studies were previously genotyped in men aged 40–79 years in the European Male Ageing Study (EMAS). Here, these SNPs were analyzed in a subsample of men (n = 589) who had peripheral quantitative computed tomography (pQCT) performed at the distal (4%) and mid-shaft (50%) radius. Estimated parameters were total and trabecular vBMD (mg/mm3) and cross-sectional area (mm2) at the 4% site and cortical vBMD (mg/mm3); total, cortical, and medullary area (mm2); cortical thickness (mm); and stress strain index (SSI) (mm3) at the 50% site. We identified 12 OPG SNPs associated with vBMD and/or geometric parameters, including rs10505348 associated with total vBMD (β [95% CI] = 9.35 [2.12–16.58], P = 0.011), cortical vBMD (β [95% CI] = 5.62 [2.10–9.14], P = 0.002), cortical thickness (β [95% CI] = 0.08 [0.03–0.13], P = 0.002), and medullary area (β [95% CI] = −2.90 [−4.94 to −0.86], P = 0.005) and rs2073618 associated with cortical vBMD (β [95% CI] = −4.30 [−7.78 to −0.82], P = 0.015) and cortical thickness (β [95% CI] = −0.08 [−0.13 to −0.03], P = 0.001). Three RANK SNPs were associated with vBMD, including rs12956925 associated with trabecular vBMD (β [95% CI] = −7.58 [−14.01 to −1.15], P = 0.021). There were five RANK SNPs associated with geometric parameters, including rs8083511 associated with distal radius cross-sectional area (β [95% CI] = 8.90 [0.92–16.88], P = 0.029). No significant association was observed between RANKL SNPs and pQCT parameters. Our findings suggest that genetic variation in OPG and RANK influences radius vBMD and geometry in men.

Electronic supplementary material

The online version of this article (doi:10.1007/s00223-011-9532-y) contains supplementary material, which is available to authorized users.

Background

Proximal phalanges in horses are among bones that are most prone to injuries. So far, the detailed analysis of densitometric and geometric parameters of both front legs proximal phalanges in horses has not been investigated. The aim of this study was to compare the densitometric and geometric parameters between proximal phalanges in equine both front legs with the use of peripheral quantitative computed tomography (pQCT).

Methods

The study material comprised isolated both front legs proximal phalanges derived from 22 horses. The structure analysis of the proximal phalanges was conducted with the pQCT. The following bone parameters were determined: bone mineral content, volumetric bone mineral density, total bone area, trabecular area, cortical area, cortical thickness, periosteal circumference, endocortical circumference, Strength Strain Index. Tomographic analysis of proximal phalanges was conducted at three levels: at 15%, 50% and 85% of the bone length.

Results

The statistical analysis showed that both the densitometric and geometric parameters of the bone at 50% and 85% of its length, did not present any statistically significant differences for the left or right proximal phalanges of the forelimb. At the same time, all examined parameters measured at 15% of the bone length, in the vicinity of the proximal metaphysis revealed significant statistical differences between both front legs proximal phalanges.

Conclusions

The proximal phalanx parameters in the forelimbs are significantly different for the left and right proximal phalanx at 15% of the length and they indicate higher Strength Strain Index of the left bone in this location. The densitometric and geometric parameters of the bone at 50% and 85% of its length, did not present any statistically significant differences for the left or right proximal phalanges of the left and right forelimbs. The most serious changes caused by asymmetrical load of the thoracic limbs in horses occur near the proximal metaphysis, where the spongious substance is most abundant. This may happen because the metabolism of the spongious bone tissue is eight times faster compared to the compact bone tissue. Thus, any changes, including those caused by asymmetrical strain exerted on the right and left thoracic limbs, are the earliest to be observed.

Associations between childhood obesity and adult bone traits were assessed among 62 obese premenopausal women, of which 12 had been obese since childhood (ObC), and 50 had gained excess weight in adulthood (ObA). Body composition and bone mineral content (BMC) of the total body, spine, and proximal femur were assessed with DXA. Total cross-sectional area and cortical (diaphyseal CoD) and trabecular (epiphyseal TrD) bone density of the radius and tibia were measured with pQCT. Compared to ObA-group, ObC-group was 5.2 cm taller having 2.5 and 3.5 kg more lean and fat mass, respectively. Depending on the statistical adjustment, ObC-group had 5–10% greater TrD both in tibia and in radius. The remaining bone traits did not significantly differ between the groups. Current preliminary observations bring up an interesting question whether childhood obesity can result in denser trabecular bone in adulthood. However, prudence must be exercised in the statistical adjustment.

Regional variation in trabecular structure across axial sections is often obscured by the conventional global analysis, which takes an average value for the entire trabecular compartment. The objective of this study is to characterize spatial variability in trabecular structure within a cross-section at the distal radius and tibia, and gender and age effects using in vivo HR-pQCT.

HR-pQCT images of the distal radius and tibia were acquired from 146 healthy individuals aged 20–78 years. Trabecular bone volume fraction (BV/TV), number (Tb.N), thickness (Tb.Th), separation (Tb.Sp), and heterogeneity (Tb.1/N.SD) were obtained in a total of 11 regions – the entire trabecular compartment (the global means), inner, outer, and 8 defined subregions. Regional variations were examined with respect to the global means, and compared between women and men, and between young (20–29 yo) and elderly (65–79 yo) adults.

Substantial regional variations in trabecular bone structure at the distal radius and tibia were revealed (e.g. BV/TV varied −40% to +57% and −59% to +100% of the global means, respectively, for elderly women). The inner-lateral (IL) subregion had low BV/TV, Tb.N, and Tb.Th, and low Tb.Sp and Tb.1/N.SD at both sites; the opposite was true in the outer-anterior (OA) subregion at the distal radius and the outer-medial (OM) and -posterior (OP) subregions at the distal tibia. Gender differences were most pronounced in the inner-anterior (IA) subregion compared to the other regions or the global mean differences at both sites. Trabecular structure correlated with age and differed between young and elderly adults predominantly in the inner-posterior (IP) subregion at the distal radius and in the IL and IA subregions at the distal tibia; on the other hand, it remained unchanged in the OA subregion at the distal radius and in the OM subregion at the distal tibia for both women and men.

This study demonstrated that not only the conventional global analysis can obscure regional differences, but also assuming bone status from that of smaller subregion may introduce a confounding sampling error. Therefore, a combined approach of investigating the entire region, each subregion, and the cortical compartment may offer more complete information.

Understanding the influence of total body fat mass (TBFM) on bone during the peri-pubertal years is critical for the development of future interventions aimed at improving bone strength and reducing fracture risk. Thus, we evaluated the relationship of TBFM to volumetric bone mineral density (vBMD), geometry, and strength at metaphyseal and diaphyseal sites of the femur and tibia of young girls. Data from 396 girls aged 8–13 years from the “Jump-In: Building Better Bones” study were analyzed. Bone parameters were assessed using peripheral quantitative computed tomography (pQCT) at the 4% and 20% distal femur and 4% and 66% distal tibia of the non-dominant leg. Bone parameters at the 4% sites included trabecular vBMD, periosteal circumference, and bone strength index (BSI), while at the 20% femur and 66% tibia, parameters included cortical vBMD, periosteal circumference, and strength-strain index (SSI). Multiple linear regression analyses were used to assess associations between bone parameters and TBFM, controlling for muscle cross-sectional area (MCSA). Regression analyses were then repeated with maturity, bone length, physical activity, and ethnicity as additional covariates. Analysis of covariance (ANCOVA) was used to compare bone parameters among tertiles of TBFM. In regression models with TBFM and MCSA, associations between TBFM and bone parameters at all sites were not significant. TBFM explained very little variance in all bone parameters (0.2–2.3%). In contrast, MCSA was strongly related (p < 0.001) to all bone parameters, except cortical vBMD. The addition of maturity, bone length, physical activity, and ethnicity did not alter the relationship between TBFM and bone parameters. With bone parameters expressed relative to total body mass, ANCOVA showed that all outcomes were significantly (p < 0.001) greater in the lowest compared to the middle and highest tertiles of TBFM. Although TBFM is correlated with femur and tibia vBMD, periosteal circumference, and strength in young girls, this relationship is significantly attenuated after adjustment for MCSA. Nevertheless, girls with higher TBFM relative to body mass have markedly diminished vBMD, geometry, and bone strength at metaphyseal and diaphyseal sites of the femur and tibia.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a newly developed in vivo clinical imaging modality. It can assess the 3D microstructure of cortical and trabecular bone at the distal radius and tibia and is suitable as an input for microstructural finite element (µFE) analysis to evaluate bone’s mechanical competence. In order for microstructural and image-based µFE analyses to become standard clinical tools, validation with a current gold standard, namely, high-resolution micro-computed tomography (µCT), is required. Microstructural measurements of 19 human cadaveric distal tibiae were performed for the registered HR-pQCT and µCT images, respectively. Next, whole bone stiffness, trabecular bone stiffness, and elastic moduli of cubic subvolumes of trabecular bone in both HR-pQCT and µCT images were determined by µFE analysis. The standard HR-pQCT patient protocol measurements, derived bone volume fraction (BV/TVd), trabecular number (Tb.N*), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), and cortical thickness (Ct.Th), as well as the voxel-based direct measurements, BV/TV, Tb.N*, Tb.Th*, Tb.Sp*, Ct.Th, bone surface-to-volume ratio (BS/BV), structure model index (SMI), and connectivity density (Conn.D), correlated well with their respective gold standards, and both contributed to µFE-predicted mechanical properties in either single or multiple linear regressions. The mechanical measurements, although overestimated by HR-pQCT, correlated highly with their gold standards. Moreover, elastic moduli of cubic subvolumes of trabecular bone predicted whole bone or trabecular bone stiffness in distal tibia. We conclude that microstructural measurements and mechanical parameters of distal tibia can be efficiently derived from HR-pQCT images and provide additional information regarding bone fragility.

Summary

An automated image processing method is presented for simulating areal bone mineral density measures using high-resolution peripheral quantitative computed tomography (HR-pQCT) in the ultra-distal radius. The accuracy of the method is validated against clinical dual X-ray absorptiometry (DXA). This technique represents a useful reference to gauge the utility of novel 3D quantification methods applied to HR-pQCT in multi-center clinical studies and potentially negates the need for separate forearm DXA measurements.

Introduction

Osteoporotic status is primarily assessed by measuring areal bone mineral density (aBMD) using 2D dual X-ray absorptiometry (DXA). However, this technique does not sufficiently explain bone strength and fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) has been introduced as a method to quantify 3D bone microstructure and biomechanics. In this study, an automated method is proposed to simulate aBMD measures from HR-pQCT distal radius images.

Methods

A total of 117 subject scans were retrospectively analyzed from two clinical bone quality studies. The distal radius was imaged by HR-pQCT and DXA on one of two devices (Hologic or Lunar). Areal BMD was calculated by simulation from HR-pQCT images (aBMDsim) and by standard DXA analysis (aBMDdxa).

Results

The reproducibility of the simulation technique was 1.1% (root mean-squared coefficient of variation). HR-pQCT-based aBMDsim correlated strongly to aBMDdxa (Hologic: R2 = 0.82, Lunar: R2 = 0.87), though aBMDsim underestimated aBMDdxa for both DXA devices (p < 0.0001). Finally, aBMDsim predicted aBMD at the proximal femur and lumbar spine with equal power compared to aBMDdxa.

Conclusion

The results demonstrate that aBMD can be simulated from HR-pQCT images of the distal radius. This approach has the potential to serve as a surrogate forearm aBMD measure for clinical HR-pQCT studies when axial bone mineral density values are not required.

High bone mass (HBM), detected in 0.2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations. We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans.

pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls.

HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm3), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p < 0.001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use). Similar results were obtained at the distal radius. Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p < 0.001). Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p < 0.05 versus family controls), suggesting greater periosteal apposition. Cortical thickness was increased at the mid tibia and radius (adjusted p < 0.001), implying reduced endosteal expansion. Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p < 0.001). We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted β − 0.01 [− 0.02, 0.01], p = 0.41), but declined in family controls (− 0.05 [− 0.03, − 0.07], p < 0.001) interaction p = 0.002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent. In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD.

HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength. In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype.

Highlights

► High Bone Mass (HBM) is characterised by increased bone size, cortical BMD, cortical thickness and increased strength strain index. ► In HBM, trabecular density is also increased at both the distal radius and tibia. ► Tibial cortical and trabecular BMD decline with age in controls, but not in HBM implying attenuation of age-related loss. ► Similar differences in age-related bone loss are not seen at the radius, suggesting a possible interaction with weight-bearing.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a newly developed in vivo clinical imaging modality. It can assess the 3D microstructure of cortical and trabecular bone at the distal radius and tibia and is suitable as an input for microstructural finite element (µFE) analysis to evaluate bone's mechanical competence. In order for microstructural and image-based µFE analyses to become standard clinical tools, validation with a current gold standard, namely, high-resolution micro-computed tomography (µCT), is required. Microstructural measurements of 19 human cadaveric distal tibiae were performed for the registered HR-pQCT and µCT images, respectively. Next, whole bone stiffness, trabecular bone stiffness, and elastic moduli of cubic subvolumes of trabecular bone in both HR-pQCT and µCT images were determined by µFE analysis. The standard HR-pQCT patient protocol measurements, derived bone volume fraction (BV/TVd), trabecular number (Tb.N*), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), and cortical thickness (Ct.Th), as well as the voxel-based direct measurements, BV/TV, Tb.N*, Tb.Th*, Tb.Sp*, Ct.Th, bone surface-to-volume ratio (BS/BV), structure model index (SMI), and connectivity density (Conn.D), correlated well with their respective gold standards, and both contributed to µFE-predicted mechanical properties in either single or multiple linear regressions. The mechanical measurements, although overestimated by HR-pQCT, correlated highly with their gold standards. Moreover, elastic moduli of cubic subvolumes of trabecular bone predicted whole bone or trabecular bone stiffness in distal tibia. We conclude that microstructural measurements and mechanical parameters of distal tibia can be efficiently derived from HR-pQCT images and provide additional information regarding bone fragility. © 2010 American Society for Bone and Mineral Research.

Background & Aims

The impact of childhood Crohn’s disease (CD) on volumetric bone mineral density (vBMD), bone structure, and muscle mass have not been established. The objective of this longitudinal study was to assess musculoskeletal outcomes in an incident cohort of children with CD using peripheral quantitative computed tomography (pQCT).

Methods

Tibia pQCT was performed in 78 CD subjects (ages, 5–18 years) at diagnosis and in 67 over the subsequent year. pQCT outcomes were converted to sex- and race-specific z scores based on reference data in over 650 controls. Multivariable linear regression models identified factors associated with changes in bone outcomes.

Results

At diagnosis, CD subjects had significant deficits in trabecular vBMD (z score, −1.32 ± 1.32; P < .001), cortical section modulus (a measure of bone geometry and strength) (z score, −0.44 ± 1.11; P < .01), and muscle (z score, −0.96 ± 1.02; P < .001) compared with controls. Over the first 6 months, trabecular vBMD and muscle z scores improved significantly (both, P < .001); however, section modulus worsened (P = .0001), and all 3 parameters remained low after 1 year. Increases in muscle z scores were associated with less severe declines in cortical section modulus z scores. Improvements in trabecular vBMD z scores were greater in prepubertal subjects. Glucocorticoids were associated with increases in cortical vBMD.

Conclusions

Substantial deficits in trabecular vBMD, cortical bone geometry, and muscle were observed at CD diagnosis. Trabecular vBMD improved incompletely; however, cortical deficits progressed despite improvements in muscle. Glucocorticoids were not associated with bone loss. Therapies to improve bone accrual in childhood CD are needed.

Quantitative computed tomography (QCT) can estimate volumetric bone mineral density (vBMD) and distinguish trabecular from cortical bone. Few comprehensive studies have examined correlates of vBMD in older men. This study evaluated the impact of demographic, anthropometric, lifestyle, and medical factors on vBMD in 1172 men aged 69 to 97 years and enrolled in the Osteoporotic Fractures in Men Study (MrOS). Peripheral quantitative computed tomography (pQCT) was used to measure vBMD of the radius and tibia. The multivariable linear regression models explained up to 10% of the variance in trabecular vBMD and up to 9% of the variance in cortical vBMD. Age was not correlated with radial trabecular vBMD. Correlates associated with both cortical and trabecular vBMD were age (−), caffeine intake (−), total calcium intake (+), nontrauma fracture (−), and hypertension (+). Higher body weight was related to greater trabecular vBMD and lower cortical vBMD. Height (−), education (+), diabetes with thiazolidinedione (TZD) use (+), rheumatoid arthritis (+), using arms to stand from a chair (−), and antiandrogen use (−) were associated only with trabecular vBMD. Factors associated only with cortical vBMD included clinic site (−), androgen use (+), grip strength (+), past smoker (−), and time to complete five chair stands (−). Certain correlates of trabecular and cortical vBMD differed among older men. An ascertainment of potential risk factors associated with trabecular and cortical vBMD may lead to better understanding and preventive efforts for osteoporosis in men. © 2010 American Society for Bone and Mineral Research.

Bone mineral density (BMD) contributes to bone strength, and methods for clinical assessment of bone quality characteristics beyond what can be gathered by BMD are awaited. Peripheral quantitative computed tomography (pQCT) allows for separate assessments of cortical and trabecular bone, providing information on bone geometry. Previous studies examining the relationship between estrogen receptor α (ERα) gene polymorphisms and BMD have been performed in large populations. However, only limited information is available on the possible segregation of ERα gene polymorphisms with bone structural properties. The aim of our study was to evaluate the association of XbaI and PvuII ERα gene polymorphisms with QCT parameters. We studied 900 subjects (541 women, 449 men) participating to the InCHIANTI study. By tibial pQCT we evaluated trabecular volumetric BMD, cortical volumetric BMD, cortical bone area, and cortical thickness (CtTh). Subjects were genotyped for ERα gene PvuII and XbaI polymorphisms. Analysis of variance was used for statistical analysis. Male subjects with PP and XX genotypes had higher geometric parameters, and female subjects with XX and PP genotypes showed higher densitometric parameters than other genotypes; however, the differences did not reach statistical significance. After adjustment for potential confounders, we found a significant (P = 0.002) CtTh difference across PvuII polymorphism in male subjects, with higher CtTh values in PP genotypes with respect to Pp and pp genotypes. These results show a relationship between the presence of the P allele and higher values of CtTh in male subjects, indicating for ERα a role in the control of tibial bone geometry.

Recently 3T magnetic resonance imaging (MRI) has been introduced for bone imaging. Through higher signal-to-noise ratios, as compared to 1.5 T MRI, it promises to be a more powerful tool for the assessment of cortical and trabecular bone measures. The goal of our study was to compare MRI derived cortical and trabecular bone measures to quantitative computed tomography (QCT) derived bone mineral density (BMD).

Using 3T MRI in 51 postmenopausal women apparent (app.) measures of bone volume/total volume, trabecular number (Tb.N), trabecular thickness (Tb.Th) and trabecular separation were derived at the distal radius, distal tibia and calcaneus. Cortical thickness (Ct.Th) was calculated at the distal radius and distal tibia. These measures were compared to QCT derived BMD of the spine, hip and radius.

Significant correlations (*p<0.05; **p<0.001; ***p<0.0001) were found between spine BMD and MRI derived Ct.Th (rradius=0.55*; rtibia=0.67***) and app. Tb.N (rradius=0.33*; rtibia=0.35*) at the radius and tibia. Furthermore within the first 10mm at the radius an inverse correlation for cort. thick and app. BV/TV (r6mm=−0.56, p<0.001; r10mm=−0.36, p<0.05) and app. Tb.Th (r6mm=− 0.54, p<0.001; r10mm=− 0.41, p<0.05) was found..

Many fractures occur in individuals without osteoporosis defined by areal bone mineral density (aBMD). Inclusion of other aspects of skeletal strength may be useful in identifying at-risk subjects. We used surrogate measures of bone strength at the radius and tibia measured by peripheral quantitative computed tomography (pQCT) to evaluate their relationships with nonvertebral fracture risk. Femoral neck (FN) aBMD, measured by dual-energy X-ray absorptiometry (DXA), also was included. The study population consisted of 1143 white men aged 69+ years with pQCT measures at the radius and tibia from the Minneapolis and Pittsburgh centers of the Osteoporotic Fractures in Men (MrOS) study. Principal-components analysis and Cox proportional-hazards modeling were used to identify 21 of 58 pQCT variables with a major contribution to nonvertebral incident fractures. After a mean 2.9 years of follow-up, 39 fractures occurred. Men without incident fractures had significantly greater bone mineral content, cross-sectional area, and indices of bone strength than those with fractures by pQCT. Every SD decrease in the 18 of 21 pQCT parameters was significantly associated with increased fracture risk (hazard ration ranged from 1.4 to 2.2) independent of age, study site, body mass index (BMI), and FN aBMD. Using area under the receiver operation characteristics curve (AUC), the combination of FN aBMD and three radius strength parameters individually increased fracture prediction over FN aBMD alone (AUC increased from 0.73 to 0.80). Peripheral bone strength measures are associated with fracture risk and may improve our ability to identify older men at high risk of fracture. © 2011 American Society for Bone and Mineral Research.