ABSTRACT: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.Introduction: Osteoporosis, characterized by low BMD and diminished bone quality, is a significant public health problem in men. Hypogonadal men have decreased BMD and deteriorated trabecular architecture compared with eugonadal men, and testosterone treatment improves their BMD. We tested the hypothesis that testosterone replacement in hypogonadal men would also improve their trabecular architecture. Materials and Methods: We selected 10 untreated severely hypogonadal men and treated them with a testosterone gel for 24 months to maintain their serum testosterone concentrations within the normal range. Each subject was assessed before and after 6, 12, and 24 months of testosterone treatment by magnetic resonance microimaging (MRI) of the distal tibia and by DXA of the spine and hip. The MRI parameters reflect the integrity of the trabecular network and include the ratio of all surface voxels (representing plates) to curve voxels (representing rods) and the topological erosion index, a ratio of topological parameters expected to increase on trabecular deterioration to those expected to decrease. The higher the surface-to-curve ratio and the lower the topological erosion index, the more intact the trabecular network. Results: Serum testosterone concentrations increased to midnormal after 3 months of treatment and remained normal thereafter. After 24 months of testosterone treatment, BMD of the spine increased 7.4% (p < 0.001), and of the total hip increased 3.8% (p ‫ס‬ 0.008). Architectural parameters assessed by MRI also changed: the surface-to-curve ratio increased 11% (p ‫ס‬ 0.004) and the topological erosion index decreased 7.5% (p ‫ס‬ 0.004). Conclusions: These results suggest the possibility that testosterone replacement of hypogonadal men improves trabecular architecture.

The mechanical properties of bone estimated by micro-finite element (µFE) analysis on the basis of in-vivo micro-MR images (µMRI) 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 µFE-derived mechanical parameters obtained from µMR images at 160 µm isotropic voxel size now achievable in vivo with those derived from 25 µm isotropic (reference) µCT images of thirty cadaveric tibiae from fifteen donors (4 females, 11 males, 55–84 yrs.). Elastic and shear moduli estimated from (5 mm)3 sub-volumes of trabecular bone (TB) derived from µMR images were significantly correlated with those derived from volume-matched reference µCT images (R2 = 0.60–0.67). Axial stiffness of whole-bone sections (including both cortical and trabecular compartments) derived from µMR-based models were highly correlated (R2 = 0.85) with those from high-resolution reference images. Further, µFE models generated from µCT images after downsampling to lower resolutions relevant to in-vivo µMRI (100–160 µm), showed mechanical parameters to be strongly correlated (R2 > 0.93) with those derived at reference resolution (25 µm). Incorporation of grayscale image information into the µMR-based µFE model yielded slopes closer to unity than binarized models (1.07±0.15 vs. 0.71±0.11) when correlated with reference sub-regional elastic and shear moduli. The work suggests that elastic properties of distal tibia can be reliably estimated by µFE analysis from µMR images obtainable at in-vivo resolution.

Micro magnetic resonance imaging (µMRI) is an in vivo imaging method which permits three dimensional (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 bone’s resistance to fractures. In order for µMR image-based microstructural and µFE analyses to become standard clinical tools for assessing bone quality, validation with a current gold standard, namely the high-resolution micro computed tomography (µCT) is required. Microstructural measurements of 25 human cadaveric distal tibiae were performed for the registered µMR and µCT images, respectively. Next, whole bone stiffness, trabecular bone stiffness, and elastic moduli of cubic sub-volumes 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) of µMRI showed strong correlations with µCT measurements (r2=0.67~0.97), and bone surface to volume ratio (BS/BV), connectivity density (Conn.D), and degree of anisotropy (DA) had significant but moderate correlations (r2=0.33~0.51). Each of these measurements also contributed to one or many of the µFE-predicted mechanical properties. However, model-independent trabecular thickness (Tb.Th*) of µMRI had no correlation with the µCT measurement and did not contribute to any mechanical measurement. Furthermore, the whole bone and trabecular bone stiffness of µMR images were highly correlated to 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 sub-volume had significant but only moderate correlations with their gold standards (r2=0.40~0.58). We conclude that most microstructural and mechanical properties of the distal tibia can be efficiently derived from µMR images and can provide additional information regarding bone quality.

Purpose: 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. Materials and Methods:The left distal tibial metaphysis of seven healthy volunteers was imaged at three timepoints using a FLASE (fast large-angle spin-echo) pulse sequence at 137 Â 137 Â 410 mm 3 and (160 mm) 3 voxel sizes. Image artifacts, motion degradation, and serial image volume misalignments were controlled to maximize reproducibility of image-derived measures of scale, topology, orientation in terms of structural anisotropy, and finite-element derived Young's and shear moduli. Coefficients of variation (CV) and intraclass correlation coefficients (ICC) for structural and mechanical parameters were evaluated as measures of reproducibility and reliability. The ability of structural and mechanical parameters to distinguish between subjects was tested by analysis of variance.Results: Reproducibility was generally higher in the anisotropic data (CVs 1-5% versus 1-9% for isotropic images). Anisotropic voxel size yielded greater measurement reliability (ICCs 0.75-0.99, mean ¼ 0.92 versus 0.62-0.99, mean ¼ 0.86) and better discrimination of the seven subjects (75% versus 50% of the possible comparisons were significantly different [P < 0.05]) except for measures of structural anisotropy and topology. Isotropic resolution improved detection of structural orientation and permitted visualization of small perforations in longitudinal trabecular plates not detected at anisotropic resolution.Conclusion: Improved image acquisition and processing techniques enhance reproducibility of structural and mechanical parameters derived from high-resolution MRI of metaphyseal bone in the distal tibia.

A randomized, double-blind, placebo-controlled, 52-week study (NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, for progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to gosuranemab (n=321) or placebo (n=165).Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6; P=0.85; primary endpoint) or secondary endpoints, resulting in discontinuation of the open-label long-term extension.Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P<0.0001). Incidences of AEs and deaths were similar between groups. This well-powered study suggests N-terminal tau neutralization does not translate to clinical efficacy.