Effects of Odanacatib on the Radius and Tibia of Postmenopausal Women: Improvements in Bone Geometry,Microarchitecture, and Estimated Bone Strength

The cathepsin K inhibitor odanacatib (ODN), currently in phase 3 development for postmenopausal osteoporosis, has a novel mechanism of action that reduces bone resorption while maintaining bone formation. In phase 2 studies, odanacatib increased areal bone mineral density (aBMD) at the lumbar spine and total hip progressively over 5 years. To determine the effects of ODN on cortical and trabecular bone and estimate changes in bone strength, we conducted a randomized, double‐blind, placebo‐controlled trial, using both quantitative computed tomography (QCT) and high‐resolution peripheral (HR‐p)QCT. In previously published results, odanacatib was superior to placebo with respect to increases in trabecular volumetric BMD (vBMD) and estimated compressive strength at the spine, and integral and trabecular vBMD and estimated strength at the hip. Here, we report the results of HR‐pQCT assessment. A total of 214 postmenopausal women (mean age 64.0 ± 6.8 years and baseline lumbar spine T‐score –1.81 ± 0.83) were randomized to oral ODN 50 mg or placebo, weekly for 2 years. With ODN, significant increases from baseline in total vBMD occurred at the distal radius and tibia. Treatment differences from placebo were also significant (3.84% and 2.63% for radius and tibia, respectively). At both sites, significant differences from placebo were also found in trabecular vBMD, cortical vBMD, cortical thickness, cortical area, and strength (failure load) estimated using finite element analysis of HR‐pQCT scans (treatment differences at radius and tibia = 2.64% and 2.66%). At the distal radius, odanacatib significantly improved trabecular thickness and bone volume/total volume (BV/TV) versus placebo. At a more proximal radial site, odanacatib attenuated the increase in cortical porosity found with placebo (treatment difference = –7.7%, p = 0.066). At the distal tibia, odanacatib significantly improved trabecular number, separation, and BV/TV versus placebo. Safety and tolerability were similar between treatment groups. In conclusion, odanacatib increased cortical and trabecular density, cortical thickness, aspects of trabecular microarchitecture, and estimated strength at the distal radius and distal tibia compared with placebo. © 2014 American Society for Bone and Mineral Research     

Investigation of the effect of dietary intake of omega-3 polyunsaturated fatty acids on trauma-induced white matter injury with quantitative diffusion MRI in mice

Previous studies suggest that long-term supplementation and dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) may have neuroprotective effects following brain injury. The objective of this study was to investigate potential neuroprotective effects of omega-3 PUFAs on white matter following closed-head trauma. The closed-head injury model of engineered rotational acceleration (CHIMERA) produces a reproducible injury in the optic tract and brachium of the superior colliculus in mice. Damage is detectable using diffusion tensor imaging (DTI) metrics, particularly fractional anisotropy (FA), with sensitivity comparable to histology. We acquired in vivo (n = 38) and ex vivo (n = 41) DTI data in mice divided into sham and CHIMERA groups with two dietary groups: one deficient in omega-3 PUFAs and one adequate in omega-3 PUFAs. We examined injury effects (reduction in FA) and neuroprotection (FA reduction modulated by diet) in the optic tract and brachium. We verified that diet did not affect FA in sham animals. In injured animals, we found significantly reduced FA in the optic tract and brachium (~10% reduction, p < 0.001), and Bayes factor analysis showed strong evidence to reject the null hypothesis. However, Bayes factor analysis showed substantial evidence to accept the null hypothesis of no diet-related FA differences in injured animals in the in vivo and ex vivo samples. Our results indicate no neuroprotective effect from adequate dietary omega-3 PUFA intake on white matter damage following traumatic brain injury. Since damage from CHIMERA mainly affects white matter, our results do not necessarily contradict previous findings showing omega-3 PUFA-mediated neuroprotection in gray matter.     

Mapping T2 relaxation time in the pediatric knee: feasibility with a clinical 1.5-T MR imaging system

PURPOSE: To determine the feasibility of mapping the spatial variation of cartilage T2 relaxation time in vivo in the pediatric knee with a 1.5-T clinical magnetic resonance (MR) imaging system and the manufacturer's body gradient coil. MATERIALS AND METHODS: Twenty-five children and adolescents (age range, 5-17 years; mean age, 11.8 years) underwent a multisection-multiecho MR sequence for T2 relaxation time mapping. Quantitative transverse T2 maps of the patellar cartilage were calculated for 15 of the subjects. Sagittal T2 maps were calculated for the remaining 10 subjects. T2 profiles were generated for the patellar and distal femoral weight- and non-weight-bearing unossified epiphyseal and articular hyaline cartilage and for the distal femoral and proximal tibial physes. The Mann-Whitney U test was used to test for differences between paired profiles. RESULTS: Femoral non-weight-bearing unossified epiphyseal and articular cartilage showed spatial variation similar to that of weight-bearing unossified epiphyseal and articular cartilage, but with increased T2 values (P <.001). T2 spatial variations of the distal femoral and proximal tibial physes were similar to those of epiphyseal and articular cartilage but had a different pattern and increased magnitude (P <.001). The highest T2 values were measured in the distal femoral physis. CONCLUSION: T2 spatial variation of patellar hyaline cartilage in children is similar to that of patellar articular cartilage in adults. Mapping of spatial variation of T2 relaxation time of cartilage in the pediatric knee in vivo is feasible with a clinical 1.5-T MR imaging system and a body gradient coil.     

Posterior distal femoral and proximal tibial metaphyseal stripes at MR imaging in children and young adults

PURPOSE: To determine the frequency and distribution of the hyperintense stripe seen along the posterior surface of distal femoral and proximal tibial metaphyses at magnetic resonance (MR) imaging. MATERIALS AND METHODS: One hundred forty-two MR imaging studies obtained in 139 children and young adults were reviewed. The authors recorded the presence and distribution of posterior distal femoral and proximal tibial metaphyseal stripes. Presence of stripe was correlated with patient age and sex and with patency of the adjacent physis. Fifty-nine studies of adults were reviewed similarly. Two-way analysis of variance was performed to compare mean patient age for sex among four different categories that were based on stripe presence and physeal patency. Orthogonal contrasts were used to determine whether a linear trend across the categories existed. In one cadaveric femur, imaging and histologic analysis were performed. RESULTS: A metaphyseal stripe was seen in all patients with a completely or partially open physis (110 femora, 102 tibiae) and in 56 femora and 60 tibiae in the patients with fused physes. Thirty-five femora and 35 tibiae showed no stripe; all patients were skeletally mature. Correlations between metaphyseal stripe visualization and physeal patency were significant (P <.001). Differences in mean patient age among the four categories were significant for both (femoral and tibial) locations (P <.001), and a linear trend with age (P <.001) was demonstrated. This linear trend was also observed in both sexes (P <.001). Histologic analysis revealed highly vascular loose fibrous tissue. CONCLUSION: A posterior metaphyseal stripe is seen at MR imaging of the skeletally immature knee and likely reflects normal bone growth.     

MR imaging and T2 mapping of femoral cartilage: in vivo determination of the magic angle effect

OBJECTIVE: The purpose of this study was to perform a quantitative evaluation of the effect of static magnetic field orientation on cartilage transverse (T2) relaxation time in the intact living joint and to determine the magnitude of the magic angle effect on in vivo femoral cartilage. MATERIALS AND METHODS: Quantitative T2 maps of the femoral-tibial joint were obtained in eight asymptomatic male volunteers using a 3-T magnet. Cartilage T2 profiles (T2 vs normalized distance from subchondral bone) were evaluated as a function of orientation of the radial zone of cartilage with the applied static magnetic field (B(0)). RESULTS: At a normalized distance of 0.3 from bone, cartilage T2 is 8.6% longer in cartilage oriented 55 degrees to B(0) compared with cartilage oriented parallel with B(0). Greater orientation variation is observed in more superficial cartilage. At a normalized distance of 0.6, cartilage T2 is 18.3% longer. The greatest orientation effect is observed near the articular surface where T2 is 29.1% longer at 55 degrees. CONCLUSION: The effect of orientation on cartilage T2 is substantially less than that predicted from prior ex vivo studies. The greatest variation in cartilage T2 is observed in the superficial 20% of cartilage. Given the small orientation effect, it is unlikely that the "magic angle effect" accounts for regional differences in cartilage signal intensity observed in clinical imaging. We hypothesize that regional differences in the degree of cartilage compression are primarily responsible for the observed regional differences in cartilage T2.     

Interphalangeal joint cartilage: high-spatial-resolution in vivo MR T2 mapping--a feasibility study

The purpose of this study was to evaluate feasibility of magnetic resonance (MR) T2 mapping of the proximal interphalangeal joint of the index finger. Cartilage T2 maps with an in-plane resolution of 39 microm were obtained from five asymptomatic subjects-four men and one woman, aged 24-45 years-by using a 3.0-T MR imager. Image acquisition time was 9.6 minutes. All cartilage T2 maps demonstrated spatial variation similar to that reported previously for knee cartilage, with T2 values increasing toward the articular surface. These results demonstrate the feasibility of acquiring cartilage T2 maps of small joints in the hand. Application of T2 mapping techniques to non-weight-bearing joints may provide a means for differentiation of local biomechanical and systemic factors that can affect cartilage T2 values.     

Three-dimensional MR microscopy of a transgenic mouse model of dilated cardiomyopathy

Background. Scientists are now able to alter the genetics of vertebrate embryos routinely to produce animal models of human developmental diseases. However, our understanding of structural changes in these animal models is limited by current methodologies. Histological techniques, although providing great anatomic detail, display only “static” data (one time point only) in two dimensions. Ultrasound may be used to generate continuous time course data, but is limited by interobserver variation, limited acoustic windows, and relatively low resolution.¶Objective. To apply the high resolution, non-destructive, and three-dimensional acquisition capabilities of magnetic resonance (MR) microscopy to compare the hearts of normal mice versus an established transgenic mouse model of dilated cardiomyopathy.¶Materials and methods. Transgenic mice exhibiting dilated cardiomyopathy were developed via the introduction of a mutated, heart-specific gene (myosin light chain). Post-mortem cardiac imaging was performed on the transgenic mice and normal controls. MR imaging was performed on a Bruker 3T imaging magnet using a custom radiofrequency coil following contrast perfusion of the atrial and ventricular chambers. Image resolution was 156 μm isotropic voxels. MR images were compared to gross pathologic specimens. Imaging data were post-processed using custom software to calculate the volumes of the atria and ventricles and to display the three-dimensional morphology of the chambers and myocardium.¶Results. Of the seven mice scanned, four exhibited normal right atrial (average = 14.8 μl ± 1.4), left atrial (average = 8.5 μl ± 0.3), right ventricular (average = 12.9 μl ± 2.7), and left ventricular (average 3.3 μl ± 0.5) volumes. Three mice exhibited dilatation of the right and left cardiac chambers (RA average = 23.9 μl ± 5.6; LA average = 15.9 μl ± 4.8; RV average = 32.5 μl ± 6.8; LV average 24.0 μl ± 1.4). The gross morphology was verified upon autopsy of the animals and correlated with the animal's genotype. The differences in volumes between the normal and dilated cardiomyopathy mice were statistically significant ¶(P values ranged from 0.001 to 0.024 for the different chambers).¶Conclusion. MR microscopy is a potentially useful tool for developmental biology research. The imaging of mouse hearts is feasible, and these methods provide quantitative and qualitative morphologic data of a mouse model of dilated cardiomyopathy not available using traditional methods.     

Knee in early juvenile rheumatoid arthritis: MR imaging findings

PURPOSE: To determine the magnetic resonance (MR) imaging findings in the knee in early juvenile rheumatoid arthritis. MATERIALS AND METHODS: MR imaging (1.5 T) was performed in the more symptomatic knee in 30 children with juvenile rheumatoid arthritis with a symptom duration 1 year or less. Conventional, fast spin-echo, three-dimensional gradient-echo, and gadolinium-enhanced T1-weighted images were assessed. Two radiologists independently read the images, and a third resolved disagreements. These images were compared with knee radiographs in 27 children. RESULTS: Mean maximal synovial thickness was 4.8 mm +/- 2.4 (SD). Mean synovial volume was 15.4 mL +/- 10.8. Suprapatellar joint effusions were seen in 26 (87%) of 30 knees, meniscal hypoplasia in 11 (37%) of 30 knees, and abnormal epiphyseal marrow in eight (27%) of 30 knees. Three knees had articular cartilage contour irregularity, fissures, and/or thinning. One knee had a bone erosion. Knee radiographs showed suprapatellar fullness in 78% of the knees, joint space narrowing in one knee, and no bone abnormalities. CONCLUSION: Synovial hypertrophy and joint effusions are the most frequent MR imaging findings of knees in early juvenile rheumatoid arthritis. Early in the disease, radiographically occult cartilage and bone erosions are uncommonly seen at MR imaging. The potential relationship of synovitis to cartilage abnormalities deserves further study.     

Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy

Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome c and AIF from mitochondria, cleavage of caspase-9 and -8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.     

Reproducibility of hepatic fat fraction measurement by magnetic resonance imaging

Purpose:

To evaluate the reproducibility of magnetic resonance imaging (MRI)‐determined hepatic fat fraction (%) across imaging sites with different magnet types and field strength. Reproducibility among MRI platforms is unclear, even though evaluating hepatic fat fractions (FFs) using MRI‐based methods is accurate against MR spectroscopy.

Materials and Methods:

Overweight subjects were recruited to undergo eight MRI examinations at five imaging centers with a range of magnet manufacturers and field strengths (1.5 and 3 T). FFs were estimated in liver and in fat‐emulsion phantoms using three methods: 1) dual‐echo images without correction (nominally out‐of‐phase [OP] and in‐phase [IP]); 2) dual‐dual‐echo images (two sequences) with T2* correction (nominally OP/IP and IP/IP); and 3) six‐echo images with spectral model and T2* correction, at sequential alternating OP and IP echo times (Methods 1, 2, and 3, respectively).

Results:

Ten subjects were recruited. For Methods 1, 2, and 3, respectively, hepatic FF ranged from ?2.5 to 27.0, 1.9 to 29.6, and 1.3 to 34.4%. Intraclass correlation coefficients were 0.85, 0.89, and 0.91 for each method, and within‐subject coefficients of variation were 18.5, 9.9, and 10.3%, respectively. Mean phantom FFs derived by Methods 2 and 3 were comparable to the known FF for each phantom. Method 1 underestimated phantom FF.

Conclusion:

Methods 2 and 3 accurately assess FF. Strong reproducibility across magnet type and strength render them suitable for use in multicenter trials and longitudinal assessments. J. Magn. Reson. Imaging 2013;37:1359–1370. © 2012 Wiley Periodicals, Inc.