We investigated the association of postmenopausal vertebral deformities and fractures with bone parameters derived from distal extremities using MRI and pQCT. Distal extremity measures showed variable degrees of association with vertebral deformities and fractures, highlighting the systemic nature of postmenopausal bone loss.Prevalent vertebral deformities and fractures are known to predict incident further fractures. However, the association of distal extremity measures and vertebral deformities in postmenopausal women has not been fully established.This study involved 98 postmenopausal women (age range 60-88 years, mean 70 years) with DXA BMD T-scores at either the hip or spine in the range of -1.5 to -3.5. Wedge, biconcavity, and crush deformities were computed on the basis of spine MRI. Vertebral fractures were assessed using Eastell's criterion. Distal tibia and radius stiffness was computed using MRI-based finite element analysis. BMD at the distal extremities were obtained using pQCT.Several distal extremity MRI and pQCT measures showed negative association with vertebral deformity on the basis of single parameter correlation (r up to 0.67) and two-parameter regression (r up to 0.76) models involving MRI stiffness and pQCT BMD. Subjects who had at least one prevalent vertebral fracture showed decreased MRI stiffness (up to 17.9 %) and pQCT density (up to 34.2 %) at the distal extremities compared to the non-fracture group. DXA lumbar spine BMD T-score was not associated with vertebral deformities.The association between vertebral deformities and distal extremity measures supports the notion of postmenopausal osteoporosis as a systemic phenomenon.

ObjectiveTo evaluate the response of bone to 2 anabolic stimuli, teriparatide and mechanical loading, in subjects with spinal cord injury.DesignA pilot study, 1 group, pretest‐posttest.SettingA rehabilitation hospital.ParticipantsA convenience sample of 12 nonambulatory chronic spinal cord injury subjects.MethodsThe subjects were administered open‐label teriparatide 20 μg/d while undergoing robotic‐assisted stepping 3 times a week for 6 months, followed by 6 months of teriparatide alone.Main Outcome MeasurementsBone status was evaluated at 3, 6, and 12 months by using dual‐energy x‐ray absorptiometry to calculate bone mineral density (BMD) at the spine and hip, magnetic resonance imaging to assess bone microarchitecture of the distal tibia, and serum bone markers.ResultsMean (SD) baseline BMD measurements at the spine and the left and right total hip were 1.05 ± 0.162 g/cm2, 0.638 ± 0.090 g/cm2 and 0.626 ± 0.088 g/cm2, respectively. After 6 months of treatment, BMD changed 2.19% ± 3.61%, 0.02% ± 2.21%, and 0.74% ± 2.80% at the spine, and left and right total hip, respectively. These changes were not statistically significant (P > .05 for all). Magnetic resonance imaging supported an anabolic effect after 3 months of treatment with significant (P < .05) changes in trabecular thickness, 4.4% ± 4.06%; surface‐to‐curve ratio, 23.6% ± 22.3%; and erosion index, −17.04% ± 12.9%. Although the trend remained after 6 months, statistical significance was not retained. At 6 months, bone markers indicated an increase in mean levels of bone‐specific alkaline phosphatase, 53.8% ± 62.9%; C‐terminal telopeptides of type I collagen, 137.6% ± 194.6%; and intact amino‐terminal propeptide of type I procollagen, 61.4% ± 99.3%.ConclusionIn this limited pilot study, teriparatide and mechanical loading resulted in a numerical but not statistically significant increase in lumbar spine BMD and no significant BMD changes at the hip. Magnetic resonance imaging at the distal tibia suggested an anabolic effect, but the high sensitivity offered by this technique was challenged by the limited ability to obtain analyzable data from all the subjects. Further studies that involve longer treatment periods and greater mechanical loading are warranted.

Instrumented indentation is a common technique for measuring the elastic properties of bulk materials as well as thin films on substrates. However, in traditional indentation, it can be difficult to determine the true deformation of a specimen due to the effects of machine compliance and thermal drift. In the present work, a method is developed to track the in-plane and out-of-plane deformation of a specimen during indentation tests using fluorescent microparticles. Bead tracking and quantitative defocusing methods are used to track the in-plane and out-of-plane displacements of the beads, respectively. Here, we describe the calibration of the system and assess the effects of particle size and magnification on the accuracy and resolution of the system. In addition, results from preliminary indentation tests performed on bulk polydimethylsiloxane specimens are reported. An analysis algorithm was developed to extract the elastic properties by measuring the displacements on the surface as a function of applied indentation force. Results are compared to traditional indentation measurements in which load and displacement are only measured at the indenter.

Instrumented indentation is a technique that can be used to measure the elastic properties of soft thin films supported on stiffer substrates, including polymer films, cellulosic sheets, and thin layers of biological materials. When measuring thin film properties using indentation, the effect of the substrate must be considered. Most existing models for determining the properties of thin films from indentation measurements were developed for metal and dielectric films bonded to semiconductor substrates and have been applied to systems with film-substrate modulus ratios between 0.1 and 10. In the present work, flat punch indentation of a thin film either bonded to or in contact with a substrate is examined using finite element modeling. A broad range of film-substrate modulus ratios from 0.0001 to 1 are investigated. As the substrate is effectively rigid compared to the film when the film-substrate modulus ratio is less than 0.0001, the results are also useful for understanding systems with lower film-substrate modulus ratios. The effects of the contact radius, film thickness, elastic properties, and friction between the film and the substrate on the measured stiffness were quantified using finite element modeling in order to understand how the elastic properties of the film can be extracted from indentation measurements. A semi-analytical model was developed to describe the finite element modeling results and facilitate the use of the results to analyze experimental measurements. The model was validated through analysis of indentation measurements of thin polyethylene sheets that were supported on substrates of various stiffness.

Instrumented indentation is a commonly used technique to determine the mechanical properties of bulk materials and thin films by measuring the load and displacement during indentation into a specimen. However, in traditional indentation measurements, it can often be difficult to determine the true deformation of the specimen due to the machine compliance and drift in the system. The issue of drift is particularly problematic in tests that occur over extended time scales, such as creep tests on soft materials. In the present work, a new method, in which the full-field deformation of the sample material around the indenter is measured, is presented to overcome these challenges. Specifically, the deformation of specimens during cylindrical flat punch indentation tests is monitored by tracking discrete particles, such as microbeads, near the surface of the sample. This method allows for direct measurement of the specimen surface as it is deformed. In the current implementation, it is applicable to transparent materials, including many polymers, gels, and biological materials. An inverse method was developed to extract mechanical properties of the specimen from the measured displacement fields. A numerical parametric study was performed to quantify the effect of changes in Poisson’s ratio, magnification, particle density, and experimental noise on the elastic properties calculated using the inverse method.

The relationship between fabric (a measure of structural anisotropy) and elastic properties of trabecular bone was examined by invoking morphology and homogenization theory on the basis of micromagnetic resonance images from the distal tibia in specimens (N = 30) and human subjects (N = 16) acquired at a 160 × 160 × 160 μm(3) voxel size. The fabric tensor was mapped in 7.5 × 7.5 × 7.5 mm(3) cubic subvolumes by a three-dimensional mean-intercept-length method. Elastic constants (three Young's and three shear moduli) were derived from linear microfinite element simulations of three-dimensional grayscale bone volume fraction-mapped images. In the specimen data, moduli fit power laws of bone volume fraction (bone volume/total volume) for all three test directions and subvolumes (R(2) = 0.92-0.98) with exponents ranging from 1.3 to 1.8. Weaker linear relationships were found for the in vivo data because of a narrower range in bone volume/total volume. When pooling the data for all test directions and subvolumes, bone volume/total volume predicted elastic moduli less well in the specimens (mean R(2) = 0.74) and not at all in vivo. A model of bone volume/total volume and fabric was highly predictive of microfinite element-derived Young's moduli: mean R(2) s of 0.98 and 0.82 (in vivo). The results show that fabric, an important predictor of bone mechanical properties, can be assessed in the limited resolution and signal-to-noise ratio regime of micromagnetic resonance images.

Serial reproducibility and reliability critically determine sensitivity to detect changes in response to intervention and provide a basis for sample size estimates. Here, we evaluated the performance of the MRI-based virtual bone biopsy in terms of 26 structural and mechanical parameters in the distal radius of 20 women in the age range of 50 to 75 years (mean=62.0 years, S.D.=8.1 years), representative of typical study populations in drug intervention trials and fracture studies. Subjects were examined three times at average intervals of 20.2 days (S.D.=14.5 days) by MRI at 1.5 T field strength at a voxel size of 137×137×410 μm(3). Methods involved prospective and retrospective 3D image registration and auto-focus motion correction. Analyses were performed from a central 5×5×5 mm(3) cuboid subvolume and trabecular volume consisting of a 13 mm axial slab encompassing the entire medullary cavity. Whole-volume axial stiffness and sub-regional Young's and shear moduli were computed by finite-element analysis. Whole-volume-derived aggregate mean coefficient of variation of all structural parameters was 4.4% (range 1.8% to 7.7%) and 4.0% for axial stiffness; corresponding data in the subvolume were 6.5% (range 1.6% to 13.0%) for structural, and 5.5% (range 4.6% to 6.5%) for mechanical parameters. Aggregate ICC was 0.976 (range 0.947 to 0.986) and 0.992 for whole-volume-derived structural parameters and axial stiffness, and 0.946 (range 0.752 to 0.991) and 0.974 (range 0.965 to 0.978) for subvolume-derived structural and mechanical parameters, respectively. The strongest predictors of whole-volume axial stiffness were BV/TV, junction density, skeleton density and Tb.N (R(2) 0.79-0.87). The same parameters were also highly predictive of sub-regional axial modulus (R(2) 0.88-0.91). The data suggest that the method is suited for longitudinal assessment of the response to therapy. The underlying technology is portable and should be compatible with all general-purpose MRI scanners, which is appealing considering the very large installed base of this modality.

Purpose: To assess the performance of a 3D fast spin echo (FSE) pulse sequence utilizing out-of-slab cancellation through phase alternation and micro-magnetic resonance imaging (mu MRI)-based virtual bone biopsy processing methods to probe the serial reproducibility and sensitivity of structural and mechanical parameters of the distal tibia at 7.0T.Materials and Methods: The distal tibia of five healthy subjects was imaged at three timepoints with a 3D FSE sequence at 137 x 137 x 410 mu m(3) voxel size. Follow-up images were retrospectively 3D registered to baseline Images. Coefficients of variation (CV) and intraclass correlation coefficients (ICCs) for measures of scale and topology of the whole tibial trabecular bone (TB) cross-section as well as finite-element-derived Young's and shear moduli of central cuboidal TB subvolumes (8 x 8 x 5 mm(3)) were evaluated as measures of reproducibility and reliability. Four additional cubic TB subregions (anterior, medial, lateral, and posterior) of similar dimensions were extracted and analyzed to determine associations between whole cross-section and subregional structural parameters.Results: The mean signal-to-noise ratio (SNR) over the 15 image acquisitions was 27.5 +/- 2.1. Retrospective registration yielded an average common analysis volume of 67% across the three exams per subject. Reproducibility (mean CV = 3.6%; range, 1.5%-5%) and reliability (ICCs, 0.95-0.99) of all parameters permitted parameter-based discrimination of the five subjects in spite of the narrow age range (26-36 years) covered. Parameters characterizing topology were better able to distinguish two individuals who demonstrated similar values for scalar measurements (approximate to 34% difference, P < 0.001). Whole-section axial stiffness encompassing the cortex was superior at distinguishing two individuals relative to its central subregional TB counterpart (approximate to 18% difference; P < 0.05). Interregion comparisons showed that although all parameters were correlated (mean R-2 = 0.78; range 0.57-0.99), the strongest associations observed were those for the erosion index (mean R-2 = 0.95, P < 0.01).Conclusion: The reproducibility and structural and mechanical parameter-based discriminative ability achieved in five healthy subjects suggests that 7T-derived mu MRI of TB can be applied towards serial patient studies of osteoporosis and may enable earlier detection of disease or treatment-based effects.

The use of instrumented indentation to measure the mechanical properties of thin films supported on substrates where the Young's modulus of the film (E1) is substantially less than that of the Young's modulus of the substrate (E2) with modulus ratios from E1/E2 = 0.0001 to 1 is important for investigating materials such as soft polymers, cellulosic sheets, and biological materials. Most existing models for determining the elastic properties of films or sheets on substrates from indentation measurements were developed for the analysis of metal and dielectric films on semiconductor substrates and thus have been used in cases where E1/E2 is ~0.01 to ~10. In the present work, flat punch indentation of systems with E1/E2 = 0.0001 to 1 is investigated via finite element (FE) modeling and experiments. A FE parametric study in which E1/E2 was varied from 0.0001 to 1 was performed to quantify the effect of substrate stiffness on the measurement of the elastic film properties. A semi-analytical model that treats the thin film and substrate as two springs in series was fit to the FE results to allow for use of the results presented. Preliminary experiments, in which a series of film/substrate systems with various modulus mismatch (E1/E2 from ~0.0005 to ~1) were characterized using instrumented indentation, were performed to evaluate the effectiveness of the model for extracting films properties from indentation measurements. The results of the parametric FE study show that for very stiff substrates, the measured stiffness becomes insensitive to changes in substrate modulus. The analytical model and FE model agree to within 7% for E1/E2 values between 0.0001 to 1 and a/t ratios from 1 to 100. Comparison of the preliminary experimental results and FE model show reasonable agreement, but further investigation is required to obtain better correlation.

Rationale and Objectives: Subtle subject movement during high-resolution three-dimensional micro-magnetic resonance imaging of trabecular bone (TB) causes blurring, thereby rendering the data unreliable for quantitative analysis. In this work, the effects of translational and rotational motion displacements were evaluated qualitatively and quantitatively.Materials and Methods: In experiment 1, motion was induced by applying various simulated and previously observed in vivo trajectories as phase shifts to k-space or rotation angles to k-space segments of a virtually motion-free data set. In experiment 2, images that were visually free of motion artifacts from two groups of 10 healthy individuals, differing in age, were selected to probe the effects of motion on TB parameters. In both experiments, images were rated for motion severity, and the scores were compared to a focus criterion, the normalized gradient squared.Results: Strong correlations were observed between the motion quality scores and the corresponding normalized gradient squared values (R(2) = 0.52-0.64, P < .01). The results from experiment 1 demonstrated consistently lower image quality and alterations in structural parameters of 9% to 45% with increased amplitude of displacements. In experiment 2, the significant differences in structural parameter group means of the motion-free images were lost upon motion degradation. Autofocusing, a postprocessing correction method, partially recovered the sharpness of the original motion-free images in 13 of 20 subjects.Conclusions: Quantitative TB structural measures are highly sensitive to subtle motion-induced degradation, which adversely affects precision and statistical power. The results underscore the influence of subject movement in high-resolution three-dimensional micro-magnetic resonance imaging and its correction for TB structure analysis.

Introduction: Vertebral fractures are among the most common outcomes of osteoporosis [1]. Early detection of vertebral deformities is important because patients with such deformities are known to be at elevated risk for further vertebral fractures [2]. The less than satisfactory performance of DXA-based BMD measurements [3] in predicting vertebral fracture susceptibility has spurred the search for other markers of bone quality. The purpose of this study was to evaluate the performance of a custom-built software tool for quantitative morphometry of spine on the basis of mid-line sagittal MR images. Towards this goal, we evaluated the intra-reader reproducibility of computing spinal deformity indices and their associations with age and gender as part of an ongoing translational study.

The mechanical properties of bone estimated by micro-finite element (microFE) analysis on the basis of in vivo micro-MR images (microMRIs) of the distal extremities provide a new tool for direct assessment of the mechanical consequences of intervention. However, the accuracy of the method has not previously been investigated. Here, we compared microFE-derived mechanical parameters obtained from microMRIs at 160 microm isotropic voxel size now achievable in vivo with those derived from 25 microm isotropic (reference) microCT images of 30 cadaveric tibiae from 15 donors (4 females and 11 males, aged 55-84 years). Elastic and shear moduli estimated from 5mm(3) subvolumes of trabecular bone (TB) derived from microMRIs were significantly correlated with those derived from volume-matched reference microCT images (R(2)=0.60-0.67). Axial stiffness of whole-bone sections (including both cortical and trabecular compartments) derived from microMR-based models were highly correlated (R(2)=0.85) with those from high-resolution reference images. Further, microFE models generated from microCT images after downsampling to lower resolutions relevant to in vivo microMRI (100-160 microm) showed mechanical parameters to be strongly correlated (R(2)>0.93) with those derived at reference resolution (25 microm). Incorporation of grayscale image information into the microMR-based microFE model yielded slopes closer to unity than binarized models (1.07+/-0.15 vs. 0.71+/-0.11) when correlated with reference subregional elastic and shear moduli. This work suggests that elastic properties of distal tibia can be reliably estimated by microFE analysis from microMRIs obtainable at in vivo resolution.

Summary Calorie restriction (CR) reduces bone quantity but not bone quality in rodents. Nothing is known regarding the long‐term effects of CR with adequate intake of vitamin and minerals on bone quantity and quality in middle‐aged lean individuals. In this study, we evaluated body composition, bone mineral density (BMD), and serum markers of bone turnover and inflammation in 32 volunteers who had been eating a CR diet (∼35% less calories than controls) for an average of 6.8 ± 5.2 years (mean age 52.7 ± 10.3 years) and 32 age‐ and sex‐matched sedentary controls eating Western diets (WD). In a subgroup of 10 CR and 10 WD volunteers, we also measured trabecular bone (TB) microarchitecture of the distal radius using high‐resolution magnetic resonance imaging. We found that the CR volunteers had significantly lower body mass index than the WD volunteers (18.9 ± 1.2 vs. 26.5 ± 2.2 kg m −2 ; P = 0.0001). BMD of the lumbar spine (0.870 ± 0.11 vs. 1.138 ± 0.12 g cm −2 , P = 0.0001) and hip (0.806 ± 0.12 vs. 1.047 ± 0.12 g cm −2 , P = 0.0001) was also lower in the CR than in the WD group. Serum C‐terminal telopeptide and bone‐specific alkaline phosphatase concentration were similar between groups, while serum C‐reactive protein (0.19 ± 0.26 vs. 1.46 ± 1.56 mg L −1 , P = 0.0001) was lower in the CR group. Trabecular bone microarchitecture parameters such as the erosion index (0.916 ± 0.087 vs. 0.877 ± 0.088; P = 0.739) and surface‐to‐curve ratio (10.3 ± 1.4 vs. 12.1 ± 2.1, P = 0.440) were not significantly different between groups. These findings suggest that markedly reduced BMD is not associated with significantly reduced bone quality in middle‐aged men and women practicing long‐term calorie restriction with adequate nutrition.

Introduction: As the mechanical properties of trabecular bone (TB) vary according to test direction, a structure-based prediction of bone’s mechanical properties requires the knowledge of TB orientation. Assuming TB approximates an orthotropic material (i.e. has at least two planes of symmetry), its orientation can be captured by a second-rank fabric tensor in the form of a 3x3 matrix [1,2]. The invariants (e.g. eigenvalues) of the fabric tensor have been related to the elastic constants of TB by assuming a homogeneous tissue modulus and alignment of the principal fabric and mechanical axes [3]. On the basis of ex vivo images (e.g. optical reconstructions of specimen sections and μCT images), the addition of fabric measures have significantly improved the prediction of experimentally-determined [4] and micro finite element (μFE) derived TB elastic constants [5]. In this work, the contribution of fabric measures is investigated in micro-magnetic resonance (μMR) images of distal tibia specimens and tibia of live subjects. Fabric measures are derived from two techniques; the mean intercept length (MIL) [6] and spatial autocorrelation function (ACF) [7]; and elastic constants are determined from μFE simulations.

Micro magnetic resonance imaging (mu MRI) is an in vivo imaging method that permits 3D quantification of cortical and trabecular bone microstructure. mu MR images can also be used for building microstructural finite element (mu FE) models to assess bone stiffness, which highly correlates with bone's resistance to fractures. In order for mu MRI-based microstructural and mu FE analyses to become standard clinical tools for assessing bone quality, validation with a current gold standard, namely, high-resolution micro computed tomography (mu CT), is required. Microstructural measurements of 25 human cadaveric distal tibias were performed for the registered mu MR and mu CT images, respectively. Next, whole bone stiffness, trabecular bone stiffness, and elastic moduli of cubic subvolumes of trabecular bone in both mu MR and mu CT images were determined by voxel-based mu FE analysis. The bone volume fraction (BV/TV), trabecular number (Tb.N*), trabecular spacing (Tb.Sp*), cortical thickness (Ct.Th), and structure model index (SMI) based on mu MRI showed strong correlations with mu CT measurements (r(2) = 0.67 to 0.97), and bone surface-to-volume ratio (BS/BV), connectivity density (Conn.D), and degree of anisotropy (DA) had significant but moderate correlations (r(2) = 0.33 to 0.51). Each of these measurements also contributed to one or many of the mu FE-predicted mechanical properties. However, model-independent trabecular thickness (Tb.Th*) based on mu MRI had no correlation with the mu CT measurement and did not contribute to any mechanical measurement. Furthermore, the whole bone and trabecular bone stiffness based on mu MRI were highly correlated with those of mu CT images (r(2) = 0.86 and 0.96), suggesting that mu MRI-based mu FE analyses can directly and accurately quantify whole bone mechanical competence. In contrast, the elastic moduli of the mu MRI trabecular bone subvolume had significant but only moderate correlations with their gold standards (r(2) = 0.40 to 0.58). We conclude that most microstructural and mechanical properties of the distal tibia can be derived efficiently from mu MR images and can provide additional information regarding bone quality. (C) 2010 American Society for Bone and Mineral Research.

Figure 3: Representative co-registered axial images and cores of a 67-year old patient randomized to Zoledronic acid acquired with 3D FLASE at 3T (A, B) and 3D FSE-OSC at 7T (C-E). Figure 2: Comparison of BVF and TB axial stiffness in baseline data within 30 patients at 3T using 3D FLASE (A) and 5 patients at 7T with 3D FSE-OSC (B). Figure 1: Comparison of BVF (3T FLASE) and BMD measurements (pQCT) at the distal tibia in 30 patients. Initial Results from Baseline Structural and Computational Biomechanics μMRI Study in Postmenopausal Women

Recently, micro-magnetic resonance imaging (μMRI) in conjunction with micro-finite element analysis has shown great potential in estimating mechanical properties - stiffness and elastic moduli - of bone in patients at risk of osteoporosis. Due to limited spatial resolution and signal-to-noise ratio achievable in vivo, the validity of estimated properties is often established by comparison to those derived from high-resolution micro-CT (μCT) images of cadaveric specimens. For accurate comparison of mechanical parameters derived from μMR and μCT images, analyzed 3D volumes have to be closely matched. The alignment of the micro structure (and the cortex) is often hampered by the fundamental differences of μMR and μCT images and variations in marrow content and cortical bone thickness. Here we present an intensity cross-correlation based registration algorithm coupled with segmentation for registering 3D tibial specimen images acquired by μMRI and μCT in the context of finite-element modeling to assess the bone's mechanical constants. The algorithm first generates three translational and three rotational parameters required to align segmented μMR and CT images from sub regions with high micro-structural similarities. These transformation parameters are then used to register the grayscale μMR and μCT images, which include both the cortex and trabecular bone. The intensity crosscorrelation maximization based registration algorithm described here is suitable for 3D rigid-body image registration applications where through-plane rotations are known to be relatively small. The close alignment of the resulting images is demonstrated quantitatively based on a voxel-overlap measure and qualitatively using visual inspection of the micro structure.