Bone mineral (31)P and matrix-bound water densities measured by solid-state (31)P and (1)H MRI.
ABSTRACT: Bone is a composite material consisting of mineral and hydrated collagen fractions. MRI of bone is challenging because of extremely short transverse relaxation times, but solid-state imaging sequences exist that can acquire the short-lived signal from bone tissue. Previous work to quantify bone density via MRI used powerful experimental scanners. This work seeks to establish the feasibility of MRI-based measurement on clinical scanners of bone mineral and collagen-bound water densities, the latter as a surrogate of matrix density, and to examine the associations of these parameters with porosity and donors' age. Mineral and matrix-bound water images of reference phantoms and cortical bone from 16 human donors, aged 27-97 years, were acquired by zero-echo-time 31-phosphorus ((31)P) and 1-hydrogen ((1)H) MRI on whole body 7T and 3T scanners, respectively. Images were corrected for relaxation and RF inhomogeneity to obtain density maps. Cortical porosity was measured by micro-computed tomography (μCT), and apparent mineral density by peripheral quantitative CT (pQCT). MRI-derived densities were compared to X-ray-based measurements by least-squares regression. Mean bone mineral (31)P density was 6.74 ± 1.22 mol/l (corresponding to 1129 ± 204 mg/cc mineral), and mean bound water (1)H density was 31.3 ± 4.2 mol/l (corresponding to 28.3 ± 3.7 %v/v). Both (31)P and bound water (BW) densities were correlated negatively with porosity ((31)P: R(2) = 0.32, p < 0.005; BW: R(2) = 0.63, p < 0.0005) and age ((31)P: R(2) = 0.39, p < 0.05; BW: R(2) = 0.70, p < 0.0001), and positively with pQCT density ((31)P: R(2) = 0.46, p < 0.05; BW: R(2) = 0.50, p < 0.005). In contrast, the bone mineralization ratio (expressed here as the ratio of (31)P density to bound water density), which is proportional to true bone mineralization, was found to be uncorrelated with porosity, age or pQCT density. This work establishes the feasibility of image-based quantification of bone mineral and bound water densities using clinical hardware.
Project description:PURPOSE:To develop and evaluate an integrated imaging protocol for bone water and phosphorus quantification in vivo by solid-state 1H and 31P MRI. MATERIALS AND METHODS:All studies were HIPAA-compliant and were performed with institutional review board approval and written informed consent. Proton (1H) ultra-short echo-time (UTE) and phosphorus (31P) zero echo-time (ZTE) sequences were designed and implemented on a 3 T clinical MR scanner to quantify bone water and mineral in vivo. The left tibia of ten healthy subjects (including both genders, 49±15 y/o) was examined with a custom-built 1H/31P dual-frequency extremity RF coil. Total bone water (TW), water bound to the collagen matrix (BW) and bone 31P were quantified from MR images with respect to reference samples of known 1H or 31P concentration, and pore water (PW) was subsequently determined from TW and BW. Porosity index (PI) was calculated as the ratio between UTE images acquired at two echo times. MRI parameters were compared with bone density measures obtained by high-resolution peripheral quantitative CT (HR-pQCT). RESULTS:The total scan time for the bone water and 31P quantification protocol was about 50 minutes. Average TW, BW, PW and 31P concentrations were 13.99±1.26, 10.39±0.80, 3.34±1.41 mol/L and 7.06±1.53 mol/L for the studied cohort, respectively, in good agreement with previous results conducted ex vivo. Average intra-subject coefficients of variation were 3.47%, 2.60% and 7.50% for TW, BW and PW and 5.60% for 31P. Negative correlations were observed between PW and vBMD (p<0.05) as well as between PI and 31P (p<0.05), while bone mineral content (BMC) estimated from 31P MRI and HR-pQCT were strongly positively correlated (p<0.0001). CONCLUSION:This work demonstrates the feasibility of quantifying bone water and mineral phosphorus in human subjects in a single MRI session with a clinically practical imaging protocol.
Project description:<h4>Objective</h4>To determine the effect of an antibody to vascular endothelial growth factor (VEGF) on bone blood flow, bone strength, and bone mass in the young adult mouse.<h4>Methods</h4>Ten-week-old male BALB/cJ mice were body weight-randomized into either a rodent anti-VEGF monoclonal antibody (anti-VEGF, B20-4.1.1; 5?mg/kg 2×/wk.; n?=?12) group or a vehicle (VEH; n?=?12) group. After 42?days, mice were evaluated for bone blood flow at the distal femur by <sup>18</sup>F-NaF-PET/CT and then necropsied. Samples from trabecular and cortical bone regions were evaluated for bone strength by mechanical testing, bone mass by peripheral quantitative computed tomography (pQCT), and micoarchitecture (MicroCT). Hydration of the whole femur was studied by proton nuclear magnetic resonance relaxometry (<sup>1</sup>H NMR).<h4>Results</h4>Distal femur blood flow was 43% lower in anti-VEGF mice than in VEH mice (p?=?0.009). Ultimate load in the lumbar vertebral body was 25% lower in anti-VEGF than in VEH mice (p?=?0.013). Bone mineral density (BMD) in the trabecular region of the proximal humeral metaphysis by pQCT, and bone volume fraction and volumetric BMD by MicroCT were the same in the two groups. Volume fraction of bound water (BW) of the whole femur was 14% lower in anti-VEGF than in VEH mice (p?=?0.003). Finally, BW, but not cortical tissue mineral density, helped section modulus explain the variance in the ultimate moment experienced by the femur in three-point bending.<h4>Conclusion</h4>Anti-VEGF caused low bone blood flow and bone strength in trabecular bone regions without influencing BMD and microarchitecture. Low bone strength was also associated with low bone hydration. These data suggest that bone blood flow is a novel bone property that affects bone quality.
Project description:High-resolution peripheral quantitative computed tomography (HR-pQCT) assesses both volumetric bone mineral density (vBMD) and trabecular and cortical microarchitecture. However, studies of the association of HR-pQCT parameters with fracture history have been small, predominantly limited to postmenopausal women, often performed limited adjustment for potential confounders including for BMD, and infrequently assessed strength or failure measures. We used data from the Osteoporotic Fractures in Men (MrOS) study, a prospective cohort study of community-dwelling men aged ?65?years, to evaluate the association of distal radius, proximal (diaphyseal) tibia and distal tibia HR-pQCT parameters measured at the Year 14 (Y14) study visit with prior clinical fracture. The primary HR-pQCT exposure variables were finite element analysis estimated failure loads (EFL) for each skeletal site; secondary exposure variables were total vBMD, total bone area, trabecular vBMD, trabecular bone area, trabecular thickness, trabecular number, cortical vBMD, cortical bone area, cortical thickness, and cortical porosity. Clinical fractures were ascertained from questionnaires administered every 4?months between MrOS study baseline and the Y14 visit and centrally adjudicated by masked review of radiographic reports. We used multivariate-adjusted logistic regression to estimate the odds of prior clinical fracture per 1 SD decrement for each Y14 HR-pQCT parameter. Three hundred forty-four (19.2%) of the 1794 men with available HR-pQCT measures had a confirmed clinical fracture between baseline and Y14. After multivariable adjustment, including for total hip areal BMD, decreased HR-pQCT finite element analysis EFL for each site was associated with significantly greater odds of prior confirmed clinical fracture and major osteoporotic fracture. Among other HR-pQCT parameters, decreased cortical area appeared to have the strongest independent association with prior clinical fracture. Future studies should explore associations of HR-pQCT parameters with specific fracture types and risk of incident fractures and the impact of age and sex on these relationships.
Project description:Combined teriparatide and denosumab increases spine and hip bone mineral density more than either drug alone. The effect of this combination on skeletal microstructure and microarchitecture, however, is unknown. Because skeletal microstructure and microarchitecture are important components of skeletal integrity, we performed high-resolution peripheral quantitative computed tomography (HR-pQCT) assessments at the distal tibia and radius in postmenopausal osteoporotic women randomized to receive teriparatide 20?µg daily (n?=?31), denosumab 60?mg every 6 months (n?=?33), or both (n?=?30) for 12 months. In the teriparatide group, total volumetric bone mineral density (vBMD) did not change at either anatomic site but increased in both other groups at both sites. The increase in vBMD at the tibia was greater in the combination group (3.1?±?2.2%) than both the denosumab (2.2?±?1.9%) and teriparatide groups (-0.3?±?1.9%) (p?<?0.02 for both comparisons). Cortical vBMD decreased by 1.6?±?1.9% at the tibia and by 0.9?±?2.8% at the radius in the teriparatide group, whereas it increased in both other groups at both sites. Tibia cortical vBMD increased more in the combination group (1.5?±?1.5%) than both monotherapy groups (p?<?0.04 for both comparisons). Cortical thickness did not change in the teriparatide group but increased in both other groups. The increase in cortical thickness at the tibia was greater in the combination group (5.4?±?3.9%) than both monotherapy groups (p?<?0.01 for both comparisons). In the teriparatide group, radial cortical porosity increased by 20.9?±?37.6% and by 5.6?±?9.9% at the tibia but did not change in the other two groups. Bone stiffness and failure load, as estimated by finite element analysis, did not change in the teriparatide group but increased in the other two groups at both sites. Together, these findings suggest that the use of denosumab and teriparatide in combination improves HR-pQCT measures of bone quality more than either drug alone and may be of significant clinical benefit in the treatment of postmenopausal osteoporosis.
Project description:Accurate quantification of bone microstructure plays a significant role in understanding bone mechanics and response to disease or treatment. High-resolution peripheral quantitative computed tomography (HR-pQCT) allows for the quantification of trabecular and cortical structure in vivo, with the capability of generating images at multiple voxel sizes (41, 82, and 123 μm). The aim of this study was to characterize the effect of voxel size on structural measures of trabecular and cortical bone and to determine accuracy in reference to micro-CT ([micro sign]CT), the gold standard for bone microstructure quantification.Seventeen radii from human cadaver specimens were imaged at each HR-pQCT voxel size and subsequently imaged using [micro sign]CT. Bone density and microstructural assessment was performed in both the trabecular and cortical compartments, including cortical porosity quantification. Two distinct analysis techniques were applied to the 41 μm HR-pQCT data: the standard clinical indirect analysis and a direct analysis requiring no density or structural model assumptions. Analysis parameters were adjusted to enable segmentation and structure extraction at each voxel size.For trabecular microstructural measures, the 41 μm HR-pQCT data displayed the strongest correlations and smallest errors compared to [micro sign]CT data. The direct analysis technique applied to the 41 μm data yielded an additional improvement in accuracy, especially for measures of trabecular thickness. The 123 μm data performed poorly, with all microstructural measures either having moderate or nonsignificant correlations with [micro sign]CT data. Trabecular densitometric measures showed strong correlations to [micro sign]CT data across all voxel sizes. Cortical thickness was strongly correlated with [micro sign]CT values across all HR-pQCT voxel sizes. The accuracy of cortical porosity parameters was highly dependent on voxel size; again, the 41 μm data was most strongly correlated. Measures of cortical density and pore diameter at all HR-pQCT voxel sizes had either weak or nonsignificant correlations.This study demonstrates the effect of voxel size on the accuracy of HR-pQCT measurements of trabecular and cortical microstructure and presents parameters for HR-pQCT analysis at nonstandard resolutions. For all parameters measured, correlations were strongest at 41 μm. Weak correlations for porosity measures indicate that a better understanding of pore structure and resolution dependence is needed.
Project description:Cortical bone assessment using magnetic resonance imaging (MRI) has recently received great attention in an effort to avoid the potential harm associated with ionizing radiation-based techniques. Ultrashort echo time MRI (UTE-MRI) techniques can acquire signal from major hydrogen proton pools in cortical bone, including bound and pore water, as well as from the collagen matrix. This study aimed to develop and evaluate the feasibility of a technique for mapping bound water, pore water, and collagen proton densities in human cortical bone ex vivo and in vivo using three-dimensional UTE Cones (3D-UTE-Cones) MRI. Eight human tibial cortical bone specimens (63?±?19?years old) were scanned using 3D-UTE-Cones sequences on a clinical 3?T MRI scanner and a micro-computed tomography (?CT) scanner. Total, bound, and pore water proton densities (TWPD, BWPD, and PWPD, respectively) were measured using UTE and inversion recovery UTE (IR-UTE) imaging techniques. Macromolecular proton density (MMPD), a collagen representation, was measured using TWPD and macromolecular fraction (MMF) obtained from two-pool UTE magnetization transfer (UTE-MT) modeling. The correlations between proton densities and ?CT-based measures were investigated. The 3D-UTE-Cones techniques were further applied on ten young healthy (34?±?3?years old) and five old (78?±?6?years old) female volunteers to evaluate the techniques' feasibility for translational clinical applications. In the ex vivo study, PWPD showed the highest correlations with bone porosity and bone mineral density (BMD) (R?=?0.79 and -?0.70, p?<?0.01). MMPD demonstrated moderate to strong correlations with bone porosity and BMD (R?=?-0.67 and 0.65, p?<?0.01). MMPD showed strong correlation with age in specimens from female donors (R?=?-0.91, p?=?0.03, n?=?5). The presented comprehensive 3D-UTE-Cones imaging protocol allows quantitative mapping of protons in major pools of cortical bone ex vivo and in vivo. PWPD and MMPD can serve as potential novel biomarkers to assess bone matrix and microstructure, as well as bone age- or injury-related variations.
Project description:BACKGROUND:Erdheim-Chester Disease (ECD) is a rare type of non-Langerhans histiocytosis. Skeletal structures are affected in over 95% ECD patients. Due to the lack of proper imaging assessment tools, the alteration of bone microarchitecture in ECD has not been well studied. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a newly developed assessment of bone mineral density and bone microarchitecture. METHODS:We performed a cross-sectional study with 13 patients diagnosed with ECD in Peking Union Medical College Hospital between October 2018 and June 2019. The diagnosis of ECD was based on typical pathological findings in the context of appropriate clinical and radiological manifestations. Bone geometry, volumetric bone mineral density and bone microarchitecture of those ECD patients were assessed using HR-pQCT at the non-dominant distal radius and distal tibia. Those HR-pQCT parameters were then compared to an ongoing population-based database of HR-pQCT for Mainland Chinese. RESULTS:As a result, remarkable heterogeneity of osteosclerosis in the HR-pQCT images was found in ECD patients, ranging from apparent normal structure, scattered thickening of trabecula, to homogenous consolidation. In terms of quantitative measurements, total volumetric BMD (383.50?mg/cm3, 1.352 times of normal mean, p?=?0.023) of the tibia differed significantly in ECD patients, due to the increased trabecular volumetric BMD (291?mg/cm3, 2.058 times of normal mean, p?=?0.003). The increased trabecular volumetric BMD of tibia was associated with remarkably increased number of trabecula (1.7/mm, 1.455 times of normal mean, p?=?0.002) and increased thickness of trabecula (0.37?mm, 1.466 times of normal mean, p?=?0.003). These differences could be due to the existence of dense bone interposed in the trabecula. CONCLUSION:This study is the first to assess the volumetric bone mineral density and bone microstructure with HR-pQCT in a cohort of ECD patients and indicated that the application of HR-pQCT may help to reveal the nature of bone lesions in the disease.