Recommendations for High-resolution Peripheral Quantitative Computed Tomography Assessment of Bone Density, Microarchitecture, and Strength in Pediatric Populations.

PURPOSE OF REVIEW: The purpose of this review is to summarize current approaches and provide recommendations for imaging bone in pediatric populations using high-resolution peripheral quantitative computed tomography (HR-pQCT). RECENT FINDINGS: Imaging the growing skeleton is challenging and HR-pQCT protocols are not standardized across centers. Adopting a single-imaging protocol for all studies is unrealistic; thus, we present three established protocols for HR-pQCT imaging in children and adolescents and share advantages and disadvantages of each. Limiting protocol variation will enhance the uniformity of results and increase our ability to compare study results between different research groups. We outline special cases along with tips and tricks for acquiring and processing scans to minimize motion artifacts and account for growing bone. The recommendations in this review are intended to help researchers perform HR-pQCT imaging in pediatric populations and extend our collective knowledge of bone structure, architecture, and strength during the growing years.

Guidelines for the assessment of bone density and microarchitecture in vivo using high-resolution peripheral quantitative computed tomography.

INTRODUCTION: The application of high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess bone microarchitecture has grown rapidly since its introduction in 2005. As the use of HR-pQCT for clinical research continues to grow, there is an urgent need to form a consensus on imaging and analysis methodologies so that studies can be appropriately compared. In addition, with the recent introduction of the second-generation HrpQCT, which differs from the first-generation HR-pQCT in scan region, resolution, and morphological measurement techniques, there is a need for guidelines on appropriate reporting of results and considerations as the field adopts newer systems. METHODS: A joint working group between the International Osteoporosis Foundation, American Society of Bone and Mineral Research, and European Calcified Tissue Society convened in person and by teleconference over several years to produce the guidelines and recommendations presented in this document. RESULTS: An overview and discussion is provided for (1) standardized protocol for imaging distal radius and tibia sites using HR-pQCT, with the importance of quality control and operator training discussed; (2) standardized terminology and recommendations on reporting results; (3) factors influencing accuracy and precision error, with considerations for longitudinal and multi-center study designs; and finally (4) comparison between scanner generations and other high-resolution CT systems. CONCLUSION: This article addresses the need for standardization of HR-pQCT imaging techniques and terminology, provides guidance on interpretation and reporting of results, and discusses unresolved issues in the field.

Impact of anticoagulation and vasoactive medication on regained radial artery patency after catheterization: a case-control study.

BACKGROUND: Radial artery access is the primary approach for coronary interventions due to higher safety profile in comparison to femoral access. Radial artery occlusion (RAO) is the main complication of transradial catheterization that can lead to severe symptoms and a permanent artery occlusion. The incidence of RAO after transradial access ranges from 5 to 38% and data regarding treatment is scarce. Whether anticoagulation and vasoactive medication provides an additional benefit in recovery of radial artery patency (RAP) after catheterization has not been investigated in detail. AIM: The objective was to investigate the impact of anticoagulation and vasoactive medication on regained patency after documented RAO following transradial catheterization. PATIENTS AND METHODS: Overall 2635 patients were screened. 2215 (84%) catheterizations were performed by femoral and 420 (16%) by radial access. In 30 patients RAO was observed. In case of RAO patients were classified in three groups: Anticoagulation, anticoagulation added with alprostadil and controls. Follow-up was conducted after 3 months with ultrasound and clinical examination. RESULTS: Eight patients received anticoagulation and 11 patients anticoagulation together with alprostadil. Eleven patients served as controls. Recovery of RAP after catheterization was higher following either treatment (79.5%) compared to controls (0%, p = 0.006). Subgroup analysis yielded a higher RAP recovery in patients treated with anticoagulation (62.5%) as compared to controls (0%, p = 0.002). No effect on regained RAP was found with additional alprostadil therapy (33.3%) compared to anticoagulation therapy (62.5%, p = 0.229). CONCLUSION: RAO should be treated with anticoagulation to regain patency. Addition of vasoactive medication does not lead to further beneficial effects. Further research is needed regarding preventive and therapeutic strategies following RAO.

Weight loss in men in late life and bone strength and microarchitecture: a prospective study.

Weight loss in men in late life was associated with lower bone strength. In contrast, weight gain was not associated with a commensurate increase in bone strength. Future studies should measure concurrent changes in weight and parameters of bone strength and microarchitecture and evaluate potential causal pathways underlying these associations. INTRODUCTION: Our aim was to determine associations of weight loss with bone strength and microarchitecture. METHODS: We used data from 1723 community-dwelling men (mean age 84.5 years) who attended the MrOS study Year (Y) 14 exam and had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans at ≥ 1 skeletal sites (distal tibia, distal radius, or diaphyseal tibia). Weight change from Y7 to Y14 exams (mean 7.3 years between exams) was classified as moderate weight loss (loss ≥ 10%), mild weight loss (loss 5 to < 10%), stable weight (< 5% change), or weight gain (gain ≥ 5%). Mean HR-pQCT parameters (95%CI) were calculated by weight change category using linear regression models adjusted for age, race, site, health status, body mass index, limb length, and physical activity. The primary outcome measure was estimated failure load. RESULTS: There was a nonlinear association of weight change with failure load at each skeletal site with different associations for weight loss vs. weight gain (p < 0.03). Failure load and total bone mineral density (BMD) at distal sites were lower with greater weight loss with 7.0-7.6% lower failure loads and 4.3-5.8% lower BMDs among men with moderate weight loss compared to those with stable weight (p < 0.01, both comparisons). Cortical, but not trabecular, BMDs at distal sites were lower with greater weight loss. Greater weight loss was associated with lower cortical thickness at all three skeletal sites. CONCLUSION: Weight loss in men in late life is associated with lower peripheral bone strength and total BMD with global measures reflecting cortical but not trabecular parameters.

High dairy protein intake is associated with greater bone strength parameters at the distal radius and tibia in older men: a cross-sectional study.

Dairy protein but not plant protein was associated with bone strength of the radius and tibia in older men. These results are consistent with previous results in women and support similar findings related to fracture outcomes. Bone strength differences were largely due to thickness and area of the bone cortex. INTRODUCTION: Our objective was to determine the association of protein intake by source (dairy, non-dairy animal, plant) with bone strength and bone microarchitecture among older men. METHODS: We used data from 1016 men (mean 84.3 years) who attended the Year 14 exam of the Osteoporotic Fractures in Men (MrOS) study, completed a food frequency questionnaire (500-5000 kcal/day), were not taking androgen or androgen agonists, and had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal or diaphyseal tibia. Protein was expressed as percentage of total energy intake (TEI); mean ± SD for TEI = 1548 ± 607 kcal/day and for total protein = 16.2 ± 2.9%TEI. We used linear regression with standardized HR-pQCT parameters as dependent variables and adjusted for age, limb length, center, education, race/ethnicity, marital status, smoking, alcohol intake, physical activity level, corticosteroids use, supplement use (calcium and vitamin D), and osteoporosis medications. RESULTS: Higher dairy protein intake was associated with higher estimated failure load at the distal radius and distal tibia [radius effect size = 0.17 (95% CI 0.07, 0.27), tibia effect size = 0.13 (95% CI 0.03, 0.23)], while higher non-dairy animal protein was associated with higher failure load at only the distal radius. Plant protein intake was not associated with failure load at any site. CONCLUSION: The association between protein intake and bone strength varied by source of protein. These results support a link between dairy protein intake and skeletal health, but an intervention study is needed to evaluate causality.

The comparability of HR-pQCT bone measurements is improved by scanning anatomically standardized regions.

We investigated the sensitivity of distal bone density, structure, and strength measurements by high-resolution peripheral quantitative computed tomography (HR-pQCT) to variability in limb length. Our results demonstrate that HR-pQCT should be performed at a standard %-of-total-limb-length to avoid substantial measurement bias in population study comparisons and the evaluation of individual skeletal status in a clinical context. INTRODUCTION: High-resolution peripheral quantitative computed tomography (HR-pQCT) measures of bone do not account for anatomic variability in bone length: a 1-cm volume is acquired at a fixed offset from an anatomic landmark. Our goal was to evaluate HR-pQCT measurement variability introduced by imaging fixed vs. proportional volumes and to propose a standard protocol for relative anatomic positioning. METHODS: Double-length (2-cm) scans were acquired in 30 adults. We compared measurements from 1-cm sub-volumes located at the default fixed offset, and the average %-of-length offset. The average position corresponded to 4.0% ± 1.1 mm for radius, and 7.2% ± 2.2 mm for tibia. We calculated the RMS difference in bone parameters and T-scores to determine the measurement variability related to differences in limb length. We used anthropometric ratios to estimate the mean limb length for published HR-pQCT reference data, and then calculated mean %-of-length offsets. RESULTS: Variability between fixed vs. relative scan positions was highest in the radius, and for cortical bone in general (RMS difference Ct.Th = 19.5%), while individuals had T-score differentials as high as +3.0 SD (radius Ct.BMD). We estimated that average scan position for published HR-pQCT reference data corresponded to 4.0% at the radius, and 7.3% at tibia. CONCLUSION: Variability in limb length introduces significant bias to HR-pQCT measures, confounding cross-sectional analyses and limiting the clinical application for individual assessment of skeletal status. We propose to standardize scan positioning using 4.0 and 7.3% of total bone length for the distal radius and tibia, respectively.

Operator variability in scan positioning is a major component of HR-pQCT precision error and is reduced by standardized training.

In this study, we determined that operator positioning precision contributes significant measurement error in high-resolution peripheral quantitative computed tomography (HR-pQCT). Moreover, we developed software to quantify intra- and inter-operator variability and demonstrated that standard positioning training (now available as a web-based application) can significantly reduce inter-operator variability. INTRODUCTION: HR-pQCT is increasingly used to assess bone quality, fracture risk, and anti-fracture interventions. The contribution of the operator has not been adequately accounted in measurement precision. Operators acquire a 2D projection ("scout view image") and define the region to be scanned by positioning a "reference line" on a standard anatomical landmark. In this study, we (i) evaluated the contribution of positioning variability to in vivo measurement precision, (ii) measured intra- and inter-operator positioning variability, and (iii) tested if custom training software led to superior reproducibility in new operators compared to experienced operators. METHODS: To evaluate the operator in vivo measurement precision, we compared precision errors calculated in 64 co-registered and non-co-registered scan-rescan images. To quantify operator variability, we developed software that simulates the positioning process of the scanner's software. Eight experienced operators positioned reference lines on scout view images designed to test intra- and inter-operator reproducibility. Finally, we developed modules for training and evaluation of reference line positioning. We enrolled six new operators to participate in a common training, followed by the same reproducibility experiments performed by the experienced group. RESULTS: In vivo precision errors were up to threefold greater (Tt.BMD and Ct.Th) when variability in scan positioning was included. The inter-operator precision errors were significantly greater than the short-term intra-operator precision (p < 0.001). New trained operators achieved comparable intra-operator reproducibility to experienced operators and lower inter-operator reproducibility (p < 0.001). Precision errors were significantly greater for the radius than for the tibia. CONCLUSION: Operator reference line positioning contributes significantly to in vivo measurement precision and is significantly greater for multi-operator datasets. Inter-operator variability can be significantly reduced using a systematic training platform, now available online ( http://webapps.radiology.ucsf.edu/refline/ ).

Cortical bone laminar analysis reveals increased midcortical and periosteal porosity in type 2 diabetic postmenopausal women with history of fragility fractures compared to fracture-free diabetics.

UNLABELLED: We investigated the characteristics and spatial distribution of cortical bone pores in postmenopausal women with type 2 diabetes (T2D). High porosity in the midcortical and periosteal layers in T2D subjects with fragility fractures suggests that these cortical zones might be particularly susceptible to T2D-induced toxicity and may reflect cortical microangiopathy. INTRODUCTION: Elevated cortical porosity is regarded as one of the main contributors to the high skeletal fragility in T2D. However, to date, it remains unclear if diabetic cortical porosity results from vascular cortical changes or from an expansion in bone marrow space. Here, we used a novel cortical laminar analysis technique to investigate the characteristics and spatial radial distribution of cortical pores in a T2D group with prior history of fragility fractures (DMFx, assigned high-risk group) and a fracture-free T2D group (DM, assigned low-risk group) and to compare their results to non-diabetic controls with (Fx) and without fragility fractures (Co). METHODS: Eighty postmenopausal women (n = 20/group) underwent high-resolution peripheral quantitative computed tomography (HR-pQCT) of the distal tibia and radius. Cortical bone was divided into three layers of equal width including an endosteal, midcortical, and periosteal layer. Within each layer, total pore area (TPA), total pore number (TPN), and average pore area (APA) were calculated. Statistical analysis employed Mann-Whitney tests and ANOVA with post hoc tests. RESULTS: Compared to the DM group, DMFx subjects exhibited +90 to +365 % elevated global porosity (p = 0.001). Cortical laminar analysis revealed that this increased porosity was for both skeletal sites confined to the midcortical layer, followed by the periosteal layer (midcortical +1327 % TPA, p ≤ 0.001, periosteal +634 % TPA, p = 0.002), and was associated in both layers and skeletal sites with high TPN (+430 % TPN, p < 0.001) and high APA (+71.5 % APA, p < 0.001). CONCLUSION: High porosity in the midcortical and periosteal layers in the high-risk T2D group suggests that these cortical zones might be particularly susceptible to T2D-induced toxicity and may reflect cortical microangiopathy.

[Psychosocial working conditions and mental health status of the German babyboomer generation]. / Psychosoziale Arbeitsbedingungen und mentale Gesundheit der Babyboomergeneration.

BACKGROUND: The baby boomers are the first to be available to the German labour market up to the age of 67. A crucial premise for a long working life is good health. However, there is evidence that psychosocial working conditions are related to health. More and more employees report psychosocial stress at work. In addition, mental illness has become one of the main reasons for the entry into disability pension. Against this background this study considers the relationship between psychosocial work conditions and mental health exemplarily for two birth cohorts of the German baby boomers. METHODS: For the analysis of the assumed relationships data of the lidA study "lidA - leben in der Arbeit - German Cohort Study on Work, Age and Health" is used (N=6 057). Mental health is assessed by the mental health scale of the SF-12. In addition, the items and the scales quantitative job requirements, work pace and support from colleagues from the Copenhagen Psychosocial Questionnaire (COPSOQ) are used. As further control variables cohort affiliation, level of education, occupational status and partnership are considered. RESULTS: Multivariate analyses of the relations between quantitative job requirements, work pace and the experienced support from colleagues show significant relationship to mental health. The increasing frequency of the requirement to work quickly and increasing quantitative job demands are negatively associated to mental health. However, support of colleagues shows a positive relationship to mental health. These results are similarly observed for women and men. CONCLUSION: For the regarded group of the German babyboomers, employees at the threshold to higher working age, it is clearly shown that psychosocial working conditions are related to mental health. Since this group still has to work up to 18 years given a statutory retirement age of 67, psychosocial working conditions should rather be in the focus of occupational safety.

Volumetric femoral BMD, bone geometry, and serum sclerostin levels differ between type 2 diabetic postmenopausal women with and without fragility fractures.

UNLABELLED: While type 2 diabetes (T2D) is associated with higher skeletal fragility, specific risk stratification remains incompletely understood. We found volumetric bone mineral density, geometry, and serum sclerostin differences between low-fracture risk and high-fracture risk T2D women. These features might help identify T2D individuals at high fracture risk in the future. INTRODUCTION: Diabetic bone disease, an increasingly recognized complication of type 2 diabetes mellitus (T2D), is associated with high skeletal fragility. Exactly which T2D individuals are at higher risk for fracture, however, remains incompletely understood. Here, we analyzed volumetric bone mineral density (vBMD), geometry, and serum sclerostin levels in two specific T2D subsets with different fracture risk profiles. We examined a T2D group with prior history of fragility fractures (DMFx, assigned high-risk group) and a fracture-free T2D group (DM, assigned low-risk group) and compared their results to nondiabetic controls with (Fx) and without fragility fractures (Co). METHODS: Eighty postmenopausal women (n = 20 per group) underwent quantitative computed tomography (QCT) to compute vBMD and bone geometry of the proximal femur. Additionally, serum sclerostin, vitamin D, parathyroid hormone (PTH), HbA1c, and glomerular filtration rate (GFR) levels were measured. Statistical analyses employed linear regression models. RESULTS: DMFx subjects exhibited up to 33 % lower femoral neck vBMD than DM subjects across all femoral sites (-19 % ≤ ΔvBMD ≤ -33 %, 0.008 ≤ p ≤0.021). Additionally, DMFx subjects showed significantly thinner cortices (-6 %, p = 0.046) and a trend toward larger bone volume (+10 %, p = 0.055) relative to DM women and higher serum sclerostin levels when compared to DM (+31.4 %, p = 0.013), Fx (+25.2 %, p = 0.033), and control (+22.4 %, p = 0.028) subjects. CONCLUSION: Our data suggest that volumetric bone parameters by QCT and serum sclerostin levels can identify T2D individuals at high risk of fracture and might therefore show promise as clinical tools for fracture risk assessment in T2D. However, future research is needed to establish diabetes-specific QCT- and sclerostin-reference databases.

Novel anthropomorphic hip phantom corrects systemic interscanner differences in proximal femoral vBMD.

Quantitative computed tomography (QCT) is increasingly used in osteoporosis studies to assess volumetric bone mineral density (vBMD), bone quality and strength. However, QCT is confronted by technical issues in the clinical research setting, such as potentially confounding effects of body size on vBMD measurements and lack of standard approaches to scanner cross-calibration, which affects measurements of vBMD in multicenter settings. In this study, we addressed systematic inter-scanner differences and subject-dependent body size errors using a novel anthropomorphic hip phantom, containing a calibration hip to estimate correction equations, and a contralateral test hip to assess the quality of the correction. We scanned this phantom on four different scanners and we applied phantom-derived corrections to in vivo images of 16 postmenopausal women scanned on two scanners. From the phantom study, we found that vBMD decreased with increasing phantom size in three of four scanners and that inter-scanner variations increased with increasing phantom size. In the in vivo study, we observed that inter-scanner corrections reduced systematic inter-scanner mean vBMD differences but that the inter-scanner precision error was still larger than expected from known intra-scanner precision measurements. In conclusion, inter-scanner corrections and body size influence should be considered when measuring vBMD from QCT images.

Postmenopausal women treated with combination parathyroid hormone (1-84) and ibandronate demonstrate different microstructural changes at the radius vs. tibia: the PTH and Ibandronate Combination Study (PICS).

SUMMARY: In postmenopausal women receiving combination parathyroid hormone (PTH) (1-84) therapy and ibandronate, we evaluated bone microarchitecture and biomechanics using high-resolution peripheral quantitative computed tomography (HR-pQCT). Cortical and trabecular changes were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. INTRODUCTION: PTH therapy and bisphosphonates decrease fracture risk in postmenopausal osteoporosis, but their effects on bone microstructure and strength have not been fully characterized, particularly during combination therapy. PTH increases trabecular bone mineral density (BMD) substantially but may decrease cortical BMD, possibly by stimulating intracortical remodeling. We evaluated bone microarchitecture and biomechanics with HR-pQCT at the radius (a nonweight-bearing site) and tibia (weight bearing) in women receiving combination PTH(1-84) and ibandronate. METHODS: Postmenopausal women with low bone mass (n = 43) were treated with 6 months of PTH(1-84) (100 µg/day), either as one 6- or two 3-month courses, in combination with ibandronate (150 mg/month) over 2 years. HR-pQCT was performed before and after therapy. RESULTS: Because changes in HR-pQCT parameters did not differ between treatment arms, groups were pooled into one cohort for analysis. Trabecular BMD increased at both radius and tibia (p < 0.01 for each). Cortical thickness and BMD decreased at the radius (p < 0.01), consistent with changes in dual-energy X-ray absorptiometry, while these parameters did not change at the tibia (p ≤ 0.02 for difference between radius and tibia). In contrast, cortical porosity increased at the tibia (p < 0.01) but not radius. Stiffness and failure load decreased at the radius (p < 0.0001) but did not change at the tibia. CONCLUSIONS: Cortical and trabecular changes in response to the PTH/ibandronate treatment combinations utilized in this study were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. Our findings support the possibility that weight bearing may optimize the effects of osteoporosis therapy.

Visual grading of motion induced image degradation in high resolution peripheral computed tomography: impact of image quality on measures of bone density and micro-architecture.

Motion artifacts are a common finding during high-resolution peripheral quantitative computed tomography (HR-pQCT) image acquisitions. To date it is not clear (i) when to repeat an acquisition, (ii) when to exclude a motion-degraded dataset post hoc, and (iii) how motion induced artifacts impact measures of trabecular and cortical parameters. In this study we present inter- and intra-observer reproducibility of a qualitative image quality grading score and report the prevalence of repeat acquisitions in our population. Finally the errors in bone density and micro-architectural parameters estimated from repeat acquisitions with and without motion degradation are presented. The relationship between these errors and the image quality grade is evaluated for each parameter. Repeat acquisitions performed due to operator-observed motion in the reconstructed image occurred for 22.7% of the exams (29.7% radius, 15.7% tibia). Of this subset, 88 exams with repeat acquisitions had at least one acquisition graded 1 (best quality). In this subset, the percent differences in bone density and micro-architecture measures tended to increase as the relative image quality decreased. Micro-architectural parameters were more sensitive to motion compared to geometric and densitometric parameters. These results provide estimates of the error in bone quality measures due to motion artifacts and provide an initial framework for developing standardized quality control criteria for cross-sectional and longitudinal HR-pQCT studies.

Teriparatide in bisphosphonate-resistant osteoporosis: microarchitectural changes and clinical results after 6 and 18 months.

A number of osteoporotic patients under bisphosphonate treatment present persistent fragility fractures and bone loss despite good compliance. The objective of this 18-month prospective study was to investigate the effect of teriparatide [rhPTH(1-34)] in 25 female osteoporotics who were inadequate responders to oral bisphosphonates and to correlate microarchitectural changes in three consecutive iliac crest biopsies measured by micro-computed tomography (µCT) with bone mineral density (BMD) and bone serum markers. Scanned biopsies at baseline (M0), 6 months (M6), and 18 months (M18) demonstrated early significant (P < 0.01) increases in bone volume per tissue volume (+34%) and trabecular number (+14%) at M6 with only moderate changes in most µCT structural parameters between M6 and M18. µCT-measured bone tissue density was significantly decreased at M18, expressing an overall lower degree of tissue mineralization characteristic for new bone formation despite unchanged trabecular thickness due to increased intratrabecular tunneling at M18. µCT results were consistent with serum bone turnover markers, reaching maximal levels of bone alkaline phosphatase and serum ß-crosslaps at M6, with subsequent decline until M18. BMD assessed by DXA demonstrated persistent increases at the lumbar spine until M12, whereas no significant change was observed at the hip. Type (alendronate/risedronate) and duration (3.5 ± 4 years) of prior bisphosphonate treatment did not influence outcome on µCT, BMD, or bone marker results. The overall results indicate a positive ceiling effect of teriparatide on bone microarchitecture and bone markers after 6 and 12 months for lumbar spine BMD, with no additional gain until M18 in bisphosphonate nonresponders.

Automated simulation of areal bone mineral density assessment in the distal radius from high-resolution peripheral quantitative computed tomography.

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 (aBMD(sim)) and by standard DXA analysis (aBMD(dxa)). RESULTS: The reproducibility of the simulation technique was 1.1% (root mean-squared coefficient of variation). HR-pQCT-based aBMD(sim) correlated strongly to aBMD(dxa) (Hologic: R (2) = 0.82, Lunar: R (2) = 0.87), though aBMD(sim) underestimated aBMD(dxa) for both DXA devices (p < 0.0001). Finally, aBMD(sim) predicted aBMD at the proximal femur and lumbar spine with equal power compared to aBMD(dxa). 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.

Assessment of bone tissue mineralization by conventional x-ray microcomputed tomography: comparison with synchrotron radiation microcomputed tomography and ash measurements.

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 nonuniformity in the muCT data, which were reduced (but not eliminated) using the 1200 mg HA/cm3 beam hardening correction, and did not exist in the SRmuCT data. This study represents the first quantitative comparison of muCT mineralization evaluation against SRnuCT and gravimetry. Our results indicate that muCT mineralization measures are underestimated but well-correlated with SRmuCT and gravimetric data, particularly when volume fraction groups are considered individually.

Assessment of trabecular bone structure comparing magnetic resonance imaging at 3 Tesla with high-resolution peripheral quantitative computed tomography ex vivo and in vivo.

UNLABELLED: In vivo high-resolution peripheral quantitative micro-CT (HR-pQCT) is a new modality for imaging peripheral sites like the distal tibia and the distal radius, providing structural bone parameters. Comparing HR-pQCT with MRI, we found that both modalities are capable of offering meaningful information on trabecular structure. BACKGROUND: Magnetic resonance imaging (MRI) has emerged as the leading in vivo method for measuring trabecular bone micro-architecture and providing structural information. Recently, an in vivo HR-pQCT modality was introduced for imaging peripheral sites like the distal tibia and the distal radius, providing structural bone parameters. The goal of this work was to compare and evaluate the performances and in vivo capabilities of HR-pQCT in comparison with MRI at 3 Tesla. METHODS: To this end images of 8 human specimens (5 tibiae and 3 radii) and 11 participants (6 tibia and 5 radii) were acquired with both modalities. Additionally, the radius specimens were scanned with micro-CT (muCT), which was used as a standard of reference. Structural parameters calculated from MRI were compared with results from HR-pQCT images and additionally muCT for the radii specimens. RESULTS: High correlations (r > 0.7) were found for trabecular number and trabecular spacing between the two modalities in vivo and ex vivo. 2D and 3D analysis revealed high correlations (r > 0.8) in structural bone parameters for all measurements. Using micro-CT as standard of reference both results from QCT and MRI correlated well. CONCLUSION: Both imaging modalities were found to perform equally well regarding trabecular bone measurements.

Conditional expression of a Gi-coupled receptor in osteoblasts results in trabecular osteopenia.

G protein-coupled receptors (GPCRs) coupled to activation of Gs, such as the PTH1 receptor (PTH1R), have long been known to regulate skeletal function and homeostasis. However, the role of GPCRs coupled to other G proteins such as Gi is not well established. We used the tet-off system to regulate the expression of an activated Gi-coupled GPCR (Ro1) in osteoblasts in vivo. Skeletal phenotypes were assessed in mice expressing Ro1 from conception, from late stages of embryogenesis, and after weaning. Long bones were assessed histologically and by microcomputed tomography. Expression of Ro1 from conception resulted in neonatal lethality that was associated with reduced bone mineralization. Expression of Ro1 starting at late embryogenesis resulted in a severe trabecular bone deficit at 12 wk of age (>51% reduction in trabecular bone volume fraction in the proximal tibia compared with sex-matched control littermates; n = 11; P < 0.01). Ro1 expression for 8 wk beginning at 4 wk of age resulted in a more than 20% reduction in trabecular bone volume fraction compared with sex-matched control littermates (n = 16; P < 0.01). Bone histomorphometry revealed that Ro1 expression is associated with reduced rates of bone formation and mineral apposition without a significant change in osteoblast or osteoclast surface. Our results indicate that signaling by a Gi-coupled GPCR in osteoblasts leads to osteopenia resulting from a reduction in trabecular bone formation. The severity of the phenotype is related to the timing and duration of Ro1 expression during growth and development. The skeletal phenotype in Ro1 mice bears some similarity to that produced by knockout of Gs-alpha expression in osteoblasts and thus may be due at least in part to Gi-mediated inhibition of adenylyl cyclase.

Fourier Transform Infrared Imaging of focal lesions in human osteoarthritic cartilage.

Fourier Transform Infrared Imaging (FTIRI) is a new method for quantitatively assessing the spatial-chemical composition of complex materials. This technique has been applied to examine the feasibility of measuring changes in the composition and distribution of collagen and proteoglycan macromolecules in human osteoarthritic cartilage. Human cartilage was acquired post-operatively from total joint replacement patients. Samples were taken at the site of a focal lesion, adjacent to the lesion, and from relatively healthy cartilage away from the lesion. Sections were prepared for FTIRI and histochemical grading. FTIRI spectral images were acquired for the superficial, intermediate, and deep layers for each sample. Euclidean distance mapping and quantitative partial least squares analysis (PLS) were performed using reference spectra for type-II collagen and chondroitin 6-sulphate (CS6). FTIRI results were correlated to the histology-based Mankin scoring system. PLS analysis found relatively low relative concentrations of collagen (38 +/- 10%) and proteoglycan (22 +/- 9%) in osteoarthritic cartilage. Focal lesions were generally found to contain less CS6 compared to cartilage tissue adjacent to the lesion. Loss of proteoglycan content was well correlated to histological Mankin scores (r=0.69, p<0.0008). The evaluation of biological tissues with FTIRI can provide unique quantitative information on how disease can affect biochemical distribution and composition. This study has demonstrated that FTIRI is useful in quantitatively assessing pathology-related changes in the composition and distribution of primary macromolecular components of human osteoarthritic cartilage.

Quantification of trabecular bone structure using magnetic resonance imaging at 3 Tesla--calibration studies using microcomputed tomography as a standard of reference.

The purpose of this study is to use high-resolution magnetic resonance (MR) imaging at 3 Tesla (3T) to quantify trabecular bone structure in vitro using femoral head specimens, and to correlate the calculated structure measures with those that were determined using microcomputed tomography (microCT), the standard of reference. Fifteen cylindrical cores were obtained from fresh femoral heads after total hip arthroplasty. MR images were obtained at 3T using a transmit-receive wrist coil. High-resolution coronal images were acquired using a modified three-dimensional (3D) fast-gradient echo sequence. From these data sets two-dimensional (2D) structural parameters analogous to bone histomorphometry were derived by using both mean intercept length (MIL) methods based on the plate model and the more recent model-assumption free 3D distance-transformation (DT) methods. The parameters measured by the 2D plate model-based MIL method and the DT method included apparent (App). BV/TV (bone volume/total volume), App. Tb.Th (trabecular thickness), App. Tb.Sp (trabecular separation), and App. Tb.N (trabecular number). Identical regions of interest were analyzed in the MR images and the microCT data sets, and similar structure measures were derived. The means and standard deviations of the parameters over all slices were calculated and MR-derived measures were correlated with those derived from the microCT data sets using linear regression analyses. Structure measures were overestimated with MRI, for example, the mean App. BV/TV was 0.45 for MRI and 0.20 for microT, and the slope of the graph was 1.45. App. Tb.Th was overestimated by a factor of 1.9, whereas App. Tb.Sp was underestimated; Tb.N showed the smallest effect. Correlations between the individual parameters were excellent (App. BV/TV, r2 = 0.82; App. Tb.Sp, r2 = 0.84; App. Tb.N, r2 = 0.81), except for App.Tb.Th (r2 = 0.67). The results of this study show that trabecular bone structure measures may be obtained using 3T MR imaging. These measures, although higher than the standard of reference, show a highly significant correlation with true structure measures obtained by microCT.