Kartogenin treatment prevented joint degeneration in a rodent model of osteoarthritis: A pilot study.

Osteoarthritis (OA) is a major degenerative joint disease characterized by progressive loss of articular cartilage, synovitis, subchondral bone changes, and osteophyte formation. Currently there is no treatment for OA except temporary pain relief and end-stage joint replacement surgery. We performed a pilot study to determine the effect of kartogenin (KGN, a small molecule) on both cartilage and subchondral bone in a rat model of OA using multimodal imaging techniques. OA was induced in rats (OA and KGN treatment group) by anterior cruciate ligament transection (ACLT) surgery in the right knee joint. Sham surgery was performed on the right knee joint of control group rats. KGN group rats received weekly intra-articular injection of 125 µM KGN 1 week after surgery until week 12. All rats underwent in vivo magnetic resonance imaging (MRI) at 3, 6, and 12 weeks after surgery. Quantitative MR relaxation measures (T1ρ and T2 ) were determined to evaluate changes in articular cartilage. Cartilage and bone turnover markers (COMP and CTX-I) were determined at baseline, 3, 6, and 12 weeks. Animals were sacrificed at week 12 and the knee joints were removed for micro-computed tomography (micro-CT) and histology. KGN treatment significantly lowered the T1ρ and T2 relaxation times indicating decreased cartilage degradation. KGN treatment significantly decreased COMP and CTX-I levels indicating decreased cartilage and bone turnover rate. KGN treatment also prevented subchondral bone changes in the ACLT rat model of OA. Thus, kartogenin is a potential drug to prevent joint deterioration in post-traumatic OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1780-1789, 2016.

Improving bone strength prediction in human proximal femur specimens through geometrical characterization of trabecular bone microarchitecture and support vector regression.

We investigate the use of different trabecular bone descriptors and advanced machine learning tech niques to complement standard bone mineral density (BMD) measures derived from dual-energy x-ray absorptiometry (DXA) for improving clinical assessment of osteoporotic fracture risk. For this purpose, volumes of interest were extracted from the head, neck, and trochanter of 146 ex vivo proximal femur specimens on multidetector computer tomography. The trabecular bone captured was characterized with (1) statistical moments of the BMD distribution, (2) geometrical features derived from the scaling index method (SIM), and (3) morphometric parameters, such as bone fraction, trabecular thickness, etc. Feature sets comprising DXA BMD and such supplemental features were used to predict the failure load (FL) of the specimens, previously determined through biomechanical testing, with multiregression and support vector regression. Prediction performance was measured by the root mean square error (RMSE); correlation with measured FL was evaluated using the coefficient of determination R2. The best prediction performance was achieved by a combination of DXA BMD and SIM-derived geometric features derived from the femoral head (RMSE: 0.869 ± 0.121, R2: 0.68 ± 0.079), which was significantly better than DXA BMD alone (RMSE: 0.948 ± 0.119, R2: 0.61 ± 0.101) (p < 10-4). For multivariate feature sets, SVR outperformed multiregression (p < 0.05). These results suggest that supplementing standard DXA BMD measurements with sophisticated femoral trabecular bone characterization and supervised learning techniques can significantly improve biomechanical strength prediction in proximal femur specimens.

Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial.

BACKGROUND: Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health. METHODS: In this nested safety substudy of the MAP.3 trial (a randomised, placebo-controlled, double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer), we included postmenopausal women from five centres who were eligible to participate in MAP.3, not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip, and femoral neck T-scores above -2·0. The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius by high-resolution peripheral quantitative CT. The primary analysis was per protocol using a non-inferiority margin. This analysis was done earlier than originally planned because of the impending announcement of MAP.3 results and subsequent unmasking of patients to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT01144468, and has been extended to 5 years of unmasked follow-up. FINDINGS: 351 women (176 given exemestane, 175 given placebo; median age 61·3 years [IQR 59·2-64·9]) met our inclusion criteria and completed baseline assessment. At the time of clinical cutoff, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). From baseline to 2 years, the mean percent change in total volumetric BMD at the distal radius was -6·1% (95% CI -7·0 to -5·2) in the exemestane group and -1·8% (-2·4 to -1·2) in the placebo group (difference -4·3%, 95% CI -5·3 to -3·2; p<0·0001). The lower limit of the 95% CI was lower than our non-inferiority margin of negative 4% (one-sided test for non-inferiority p=0·70), meaning the hypothesis that exemestane was inferior could not be rejected. At the distal tibia, the mean percent change in total volumetric BMD from baseline to 2 years was -5·0% (95% CI -5·5 to -4·4) in the exemestane group and -1·3% (-1·7 to -1·0) in the placebo group (difference -3·7%, 95% CI -4·3 to -3·0; p<0·0001). The mean percent change in cortical thickness was -7·9% (SD 7·3) in the exemestane group and -1·1% (5·7) in the placebo group at the distal radius (difference -6·8%, 95% CI -8·5 to -5·0; p<0·0001) and -7·6% (SD 5·9) in the exemestane group and -0·7% (4·9) in the placebo group at the distal tibia (difference -6·9%, -8·4 to -5·5; p<0·0001). Decline in areal BMD, as measured by dual-energy x-ray absorptiometry, in the exemestane group compared with the placebo group occurred at the lumbar spine (-2·4% [95% CI -3·1 to -1·7] exemestane vs -0·5% [-1·1 to 0·2] placebo; difference -1·9%, 95% CI -2·9 to -1·0; p<0·0001), total hip (-1·8% [-2·3 to -1·2] exemestane vs -0·6% [-1·1 to -0·1] placebo; difference -1·2%, -1·9 to -0·4; p=0·004), and femoral neck (-2·4% [-3·2 to -1·7] exemestane vs -0·8% [-1·5 to 0·1] placebo; difference -1·6%, -2·7 to -0·6; p=0·002). INTERPRETATION: 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation. Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits. For women taking exemestane, regular bone monitoring plus adequate calcium and vitamin D supplementation are important. To assess the effect of our findings on fracture risk, long-term follow-up is needed. FUNDING: Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society).

Trabecular bone structure obtained from multislice spiral computed tomography of the calcaneus predicts osteoporotic vertebral deformities.

PURPOSE: To compare multislice computed tomography (MSCT)-derived parameters of the trabecular bone structure of the calcaneus with bone mineral density (BMD) in their ability to differentiate between donors with and without osteoporotic fractures of the spine and to optimize CT scan protocols. METHODS: Forty-two postmortem calcanei (81.2 +/- 10 years) were imaged with a 16-detector row MSCT system using 4 different scan protocols varying spatial resolution (12-24 lp/cm) and radiation dose. Structural parameters of trabecular bone were derived from these images, and BMDs of the calcanei were determined using dual x-ray absorptiometry. Vertebral deformities of the spine were radiographically classified using the Spinal Fracture Index. Diagnostic performance in differentiation between donors with and without vertebral fractures was assessed using receiver operating characteristic (ROC) analysis. RESULTS: There were significant case-control differences for many of the structural parameters measured (P < 0.05). The highest ROC values were found for apparent trabecular thickness using the high-resolution and high-dose protocols. Statistically significant correlations were found between most structure parameters and BMD (up to r = 0.85, P < 0.01). CONCLUSION: Structural parameters of trabecular bone as obtained from high-resolution MSCT images of the calcaneus can be used to differentiate between donors with and without osteoporotic vertebral fractures, using a high-resolution and high-dose CT protocol.

In vivo application of 3D-line skeleton graph analysis (LSGA) technique with high-resolution magnetic resonance imaging of trabecular bone structure.

Over the last several years magnetic resonance (MR) imaging has emerged as a means of measuring in vivo 3D trabecular bone structure. In particular, MR based diagnosis could be used to complement standard bone mineral density (BMD) methods for assessing osteoporosis and evaluating longitudinal changes. The aim of this study was to demonstrate the feasibility of using the 3D-LSGA technique for the evaluation of trabecular bone structure of high-resolution MR images, particularly for assessing longitudinal changes, in vivo. First, the reproducibility of topological 3D-LSGA based measurements was evaluated in a set of seven volunteers, and coefficients of variations ranged from 3.5% to 6%. Second, high-resolution MR images of the radius in 30 postmenopausal women from a placebo controlled drug study (Idoxifene), divided into placebo ( n=9) and treated ( n=21) groups, were obtained at baseline (BL) and after 1 year of treatment (follow-up, FU). In addition, dual X-ray absorptiometry (DXA) measures of BMD were obtained in the distal radius. Standard morphological measurements based on the mean intercept length (MIL) technique as well as 3D-LSGA based measurements were applied to the 3D MR images. Significant changes from BL to FU were detected, in the treated group, using the topological 3D-LSGA based measurements, morphological measures of volume of connected trabeculae and App Tb.N from MIL analysis. The duration of the study was short, and the number of patients remaining in the study was small, hence these results cannot be interpreted with regard to a true therapeutic response. Furthermore, the site (wrist) and the drug (idoxifene) are not optimal for follow-up study. However, this paper demonstrated the feasibility of using 3D-LSGA based evaluation coupled with in vivo high-resolution MR imaging as a complementary approach for the monitoring of trabecular bone changes in individual subjects.