Michael J. Wald

Effect of testosterone replacement on trabecular architecture in hypogonadal men.

We evaluated the effect of testosterone treatment on trabecular architecture by μMRI in 10 untreated severely hypogonadal men. After 2 years, μMRI parameters of trabecular connectivity improved significantly, suggesting the possibility that testosterone improves trabecular architecture.

Accuracy of High-Resolution In Vivo Micro Magnetic Resonance Imaging for Measurements of Microstructural and Mechanical Properties of Human Distal Tibial Bone

Micro magnetic resonance imaging (µMRI) is an in vivo imaging method that permits 3D quantification of cortical and trabecular bone microstructure. µMR images can also be used for building microstructural finite element (µFE) models to assess bone stiffness, which highly correlates with bones resistance to fractures. In order for µMRI‐based microstructural and µFE analyses to become standard clinical tools for assessing bone quality, validation with a current gold standard, namely, high‐resolution micro computed tomography (µCT), is required. Microstructural measurements of 25 human cadaveric distal tibias were performed for the registered µMR and µCT images, respectively. Next, whole bone stiffness, trabecular bone stiffness, and elastic moduli of cubic subvolumes of trabecular bone in both µMR and µCT images were determined by voxel‐based µFE 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 µMRI showed strong correlations with µCT measurements (r2 = 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 (r2 = 0.33 to 0.51). Each of these measurements also contributed to one or many of the µFE‐predicted mechanical properties. However, model‐independent trabecular thickness (Tb.Th*) based on µMRI had no correlation with the µCT measurement and did not contribute to any mechanical measurement. Furthermore, the whole bone and trabecular bone stiffness based on µMRI were highly correlated with those of µCT images (r2 = 0.86 and 0.96), suggesting that µMRI‐based µFE analyses can directly and accurately quantify whole bone mechanical competence. In contrast, the elastic moduli of the µMRI trabecular bone subvolume had significant but only moderate correlations with their gold standards (r2 = 0.40 to 0.58). We conclude that most microstructural and mechanical properties of the distal tibia can be derived efficiently from µMR images and can provide additional information regarding bone quality.

Trabecular structure quantified with the MRI-based virtual bone biopsy in postmenopausal women contributes to vertebral deformity burden independent of areal vertebral BMD.

In postmenopausal women with a wide range of vertebral deformities, MRI‐based structural measures of topology and scale at the distal radius are shown to account for as much as 30% of vertebral deformity, independent of integral vertebral BMD.

Spatial autocorrelation and mean intercept length analysis of trabecular bone anisotropy applied to in vivo magnetic resonance imaging

Osteoporosis is characterized by bone loss and deterioration of the trabecular bone (TB) architecture that leads to impaired overall mechanical strength of the bone. Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry is currently the standard clinical metric assessing bone integrity but it fails to capture the structural changes in the TB. Recent research suggests that structure contributes to bone strength in a manner complementary to BMD. Besides parameters of scale such as the mean TB thickness and mean bone volume fraction, parameters describing the anisotropy of the trabecular architecture play an important role in the characterization of TB since trabeculae are preferentially oriented along the direction of local loading. Therefore, the degree of structural anisotropy is of pivotal importance to the bones mechanical competence. The most common method for measuring structural anisotropy of TB is the mean-intercept length (MIL). In this work we present a method, based on the three-dimensional spatial autocorrelation function (ACF), for mapping of the full structural anisotropy ellipsoid of both TB thickness and spacing and we examine its performance as compared to that of MIL. Not only is the ACF method faster by several orders of magnitude, it is also considerably more robust to noise. Further, it is applicable at lower spatial resolution and is relatively insensitive to image shading. The chief reason for ACFs superior performance is that it does not require binarization, which is difficult to achieve in the limited spatial regime of in vivo magnetic resonance imaging. MIL and ACF have been applied to high-resolution magnetic resonances images of the tibia in a group of ten healthy postmenopausal women by comparing the structural anisotropy and principal direction of the computed fabric tensor for each method. While there is fair agreement between the two methods, ACF analysis yielded greater anisotropy than MIL for both TB thickness and spacing. There was good agreement between the two techniques as far as the eigenvectors of the fabric ellipsoids were concerned, which parallel the bones macroscopic axis.

Computational biomechanics of the distal tibia from high-resolution MR and micro-CT images

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.

Structural and mechanical parameters of trabecular bone estimated from in vivo high-resolution magnetic resonance images at 3 tesla field strength

To evaluate the performance of a new 3 Tesla (T) high‐resolution trabecular bone (TB) imaging technique at two resolution regimens in terms of serial reproducibility and sensitivity.

Performance of the MRI-based virtual bone biopsy in the distal radius: Serial reproducibility and reliability of structural and mechanical parameters in women representative of osteoporosis study populations

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 Youngs 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.

Reduced bone mineral density is not associated with significantly reduced bone quality in men and women practicing long-term calorie restriction with adequate nutrition.

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.

Spin-echo micro-MRI of trabecular bone using improved 3D fast large-angle spin-echo (FLASE)†

Fast large‐angle spin echo (FLASE) is a common pulse sequence designed for quantitative imaging of trabecular bone (TB) microarchitecture. However, imperfections in the nonselective phase‐reversal pulse render it prone to stimulated echo artifacts. The problem is further exacerbated at isotropic resolution. Here, a substantially improved RF‐spoiled FLASE sequence (sp‐FLASE) is described and its performance is illustrated with data at 1.5T and 3T. Additional enhancements include navigator echoes for translational motion sensing applied in a slice parallel to the imaging slab. Whereas recent work suggests the use of fully‐balanced FLASE (b‐FLASE) to be advantageous from a signal‐to‐noise ratio (SNR) point of view, evidence is provided here that the greater robustness of sp‐FLASE may outweigh the benefits of the minor SNR gain of b‐FLASE for the target application of TB imaging in the distal extremities, sites of exclusively fatty marrow. Results are supported by a theoretical Bloch equation analysis and the pulse sequence dependence of the effective T2 of triglyceride protons. Last, sp‐FLASE images are shown to provide detailed and reproducible visual depiction of trabecular networks in three dimensions at both anisotropic (137 × 137 × 410 μm3) and isotropic (160 × 160 × 160 μm3) resolutions in the human distal tibia in vivo. Magn Reson Med, 2009.

Performance of μMRI-Based virtual bone biopsy for structural and mechanical analysis at the distal tibia at 7T field strength

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 (μMRI)‐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.