Newark, CA, United States


Newark, CA, United States
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Genant H.K.,University of California at San Francisco | Genant H.K.,Synarc Inc. | Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center | Fuerst T.,Synarc Inc. | Fries M.,Glaxosmithkline
Osteoporosis International | Year: 2012

Summary Hip structural analysis (HSA) performed in a subset of participants from the STudy Researching Osteoporosis iN Guys (STRONG) demonstrated that 1 year of ibandronate treatment was associated with a significant improvement in some but not all parameters of hip geometry relative to placebo in men with low bone density. Introduction HSA was performed on dual-energy X-ray absorptiometry (DXA) images in a subset of participants from the STRONG to examine the impact of monthly ibandronate on geometric properties of the hip in men with low bone density. Methods This prespecified subgroup analysis evaluated men in the intent-to-treat population of STRONG with baseline and 12-month DXA data. Cross-sectional geometric parameters of the femoral shaft (FS), intertrochanter region (IT), and narrow neck (NN) were calculated from femoral DXA scans. All analyses were exploratory. Treatment differences were evaluated using analysis of covariance, which adjusted for baseline parameter value, testosterone level, and treatment. Results HSA was performed on DXA scans from 89 men (34 placebo; 55 monthly ibandronate). Significant increases in average cortical thickness and cross-sectional area and decreases (i.e., improvements) in the buckling ratio were observed at the FS and IT at 12 months for ibandronatetreated men compared with placebo-treated men. No significant differences were observed between ibandronate and placebo for any NN HSA parameters. Conclusions One year of ibandronate treatment was associated with a significant improvement in some but not all parameters of hip geometry relative to placebo in men with low bone density, suggesting that ibandronate may improve resistance to axial compressive forces and bending forces at the hip. © International Osteoporosis Foundation and National Osteoporosis Foundation 2011.

Fitzpatrick L.A.,Glaxosmithkline | Dabrowski C.E.,Glaxosmithkline | Cicconetti G.,Glaxosmithkline | Gordon D.N.,Glaxosmithkline | And 5 more authors.
Journal of Bone and Mineral Research | Year: 2012

Intermittent injections of parathyroid hormone have osteoanabolic effects that increase bone mineral density (BMD). Ronacaleret is an orally administered calcium-sensing receptor antagonist that stimulates endogenous parathyroid hormone release from the parathyroid glands. Our objective was to compare the effects of ronacaleret and teriparatide on volumetric BMD (vBMD) measured by quantitative computed tomography (QCT). We conducted a randomized, placebo-controlled, dose-ranging trial at 45 academic centers with 31 sites participating in the substudy. Patients included 569 postmenopausal women with low bone mineral density; vBMD was assessed at the spine and hip in a subset of 314 women. Patients were treated for up to 12 months with open-label teriparatide 20 μg subcutaneously once daily or randomly assigned in a double-blind manner to ronacaleret 100 mg, 200 mg, 300 mg, or 400 mg once daily, alendronate 70 mg once weekly, or matching placebos. Ronacaleret increased spine integral (0.49% to 3.9%) and trabecular (1.8% to 13.3%) vBMD compared with baseline, although the increments were at least twofold lower than that attained with teriparatide (14.8% and 24.4%, respectively) but similar or superior to that attained with alendronate (5.0% and 4.9%, respectively). There were small non-dose-dependent decreases in integral vBMD of the proximal femur with ronacaleret (-0.1 to -0.8%) compared with increases in the teriparatide (3.9%) and alendronate (2.7%) arms. Parathyroid hormone (PTH) elevations with ronacaleret were prolonged relative to that seen historically with teriparatide. Ronacaleret preferentially increased vBMD of trabecular bone that is counterbalanced by small decreases in BMD at cortical sites. The relative preservation of trabecular bone and loss at cortical sites are consistent with the induction of mild hyperparathyroidism with ronacaleret therapy. © 2012 American Society for Bone and Mineral Research.

Fan B.,University of California at San Francisco | Lu Y.,University of California at San Francisco | Genant H.,University of California at San Francisco | Genant H.,Synarc Inc. | And 2 more authors.
Osteoporosis International | Year: 2010

Summary: The standardized bone mineral density (sBMD) values, derived using universal standardized equations, were shown to be equivalent within 1.0% for hip but significantly different for spine for state-of-art fan-beam dual X-ray absorptiometry (DXA) Hologic and GE-Lunar systems. Spine L1-L4 and L2-L4 sBMD mean differences between the two systems were 0.042 g/cm 2 (4.1%) and 0.035 g/cm 2 (3.2%), respectively. Introduction: The objective of this study is to validate the 1994 pencil-beam DXA "universal standardization equations" for state-of-the-art fan-beam DXA systems. Methods: The spine and bilateral femurs of 87 postmenopausal women were scanned on both Hologic Delphi and GE-Lunar Prodigy DXA systems at three different clinical centers. The scans were analyzed using Hologic Apex and GE-Lunar EnCore software. The BMD results were converted to sBMD using the equations previously developed. Linear regression analysis was used to describe the relationship of the two systems' BMD results. Bland-Altman analysis was used to assess the differences in measures. Results: The Apex and Prodigy sBMD values were highly correlated (r ranged from 0.92 to 0.98). Spine L1-L4 and L2-L4 sBMD values had significant intercepts and slopes for Bland-Altman regression, with mean differences of 0.042 g/cm 2 (4.1%) and 0.035 g/cm 2 (3.2%), respectively. The total hip and neck sBMD showed no significant intercept and slope, except left total sBMD had a significant difference between the two systems of 0.009 g/cm 2 (1.0%). Conclusions: The sBMD values were shown to be equivalent within 1.0% for hip but were significantly different for spine on the two systems. Biases may persist in pooled sBMD data from different manufacturers, and further study is necessary to determine the cause. © The Author(s) 2009.

Engelke K.,Synarc Inc | Engelke K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Fuerst T.,Synarc Inc | Dardzinski B.,Uniformed Services University of the Health Sciences | And 4 more authors.
Journal of Bone and Mineral Research | Year: 2015

Odanacatib, a selective cathepsin K inhibitor, increases areal bone mineral density (aBMD) at the spine and hip of postmenopausal women. To gain additional insight into the effects on trabecular and cortical bone, we analyzed quantitative computed tomography (QCT) data of postmenopausal women treated with odanacatib using Medical Image Analysis Framework (MIAF; Institute of Medical Physics, University of Erlangen, Erlangen, Germany). This international, randomized, double-blind, placebo-controlled, 2-year, phase 3 trial enrolled 214 postmenopausal women (mean age 64 years) with low aBMD. Subjects were randomized to odanacatib 50mg weekly (ODN) or placebo (PBO); all participants received calcium and vitamin D. Hip QCT scans at 24 months were available for 158 women (ODN: n=78 women; PBO: n=80 women). There were consistent and significant differential treatment effects (ODN-PBO) for total hip integral (5.4%), trabecular volumetric BMD (vBMD) (12.2%), and cortical vBMD (2.5%) at 24 months. There was no significant differential treatment effect on integral bone volume. Results for bone mineral content (BMC) closely matched those for vBMD for integral and trabecular compartments. However, with small but mostly significant differential increases in cortical volume (1.0% to 1.3%) and thickness (1.4% to 1.9%), the percentage cortical BMC increases were numerically larger than those of vBMD. With a total hip BMC differential treatment effect (ODN-PBO) of nearly 1000 mg, the proportions of BMC attributed to cortical gain were 45%, 44%, 52%, and 40% for the total, neck, trochanter, and intertrochanter subregions, respectively. In postmenopausal women treated for 2 years, odanacatib improved integral, trabecular, and cortical vBMD and BMC at all femur regions relative to placebo when assessed by MIAF. Cortical volume and thickness increased significantly in all regions except the femoral neck. The increase in cortical volume and BMC paralleled the increase in cortical vBMD, demonstrating a consistent effect of ODN on cortical bone. Approximately one-half of the absolute BMC gain occurred in cortical bone. © 2014 American Society for Bone and Mineral Research.

Engelke K.,Synarc Inc | Engelke K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Nagase S.,Ono Pharma UK Ltd | Fuerst T.,Synarc Inc | And 5 more authors.
Journal of Bone and Mineral Research | Year: 2014

ONO-5334 (Ono Pharmaceutical Co., Ltd., Osaka, Japan) inhibits cathepsin K and has been shown to increase areal bone mineral density (BMD) at the hip and spine in postmenopausal osteoporosis. Quantitative computed tomography (QCT) allows the study of the cortical and trabecular bone separately and provides structural information such as cortical thickness. We investigated the impact of 2 years of cathepsin K inhibition on these different bone compartments with ONO-5334. The clinical study was a randomized, double-blind, placebo, and active controlled parallel group study conducted in 13 centers in six European countries. The original study period of 12 months was extended by another 12 months. A total of 147 subjects (age 55-75 years) of the QCT substudy who participated in the extension period were included. Subjects had been randomized into one of five treatment arms: placebo; ONO-5334 50 mg twice per day (BID); ONO-5334 100 mg once daily (QD); ONO-5334 300 mg QD; or alendronate 70 mg once weekly (QW). QCT was obtained to evaluate bone structure at the lumbar spine and proximal femur. After 24 months ONO-5334 showed statistically significant increases versus placebo for integral, trabecular, and cortical BMD at the spine and the hip (for ONO-5334 300 mg QD, BMD increases were 10.5%, 7.1%, and 13.4% for integral, cortical, and trabecular BMD at the spine, respectively, and 6.2%, 3.4%, and 14.6% for integral, cortical, and trabecular total femur BMD, respectively). Changes in cortical and trabecular BMD in the spine and hip were similar for alendronate as for ONO-5334. Integral volume did not demonstrate statistically significant changes under ONO-5334 treatment, thus there was no evidence of periosteal apposition, neither at the spine nor at the femur. Cortical thickness changes were not statistically significant for ONO-5334 in the spine and hip, with exception of a 2.1% increase after month 24 in the intertrochanter for ONO-5334 300 mg QD. Over 2 years ONO-5334 showed a statistically significant and persistent increase of trabecular and integral BMD at the spine and the hip. Cortical BMD also progressively increased but at a lower rate. Changes in bone size and of periosteal apposition were not observed. © 2014 American Society for Bone and Mineral Research.

Cheung A.M.,University of Toronto | Majumdar S.,University of California at San Francisco | Brixen K.,University of Southern Denmark | Chapurlat R.,French Institute of Health and Medical Research | And 8 more authors.
Journal of Bone and Mineral Research | Year: 2014

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 50mg 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 © 2014 American Society for Bone and Mineral Research.

Brixen K.,University of Southern Denmark | Chapurlat R.,University of Lyon | Cheung A.M.,University of Toronto | Keaveny T.M.,University of California at Berkeley | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Odanacatib, a cathepsin K inhibitor, increases spine and hip areal bone mineral density (BMD)in postmenopausal women with low BMD and cortical thickness in ovariectomized monkeys. Objective: The objective of the study was to examine the impact of odanacatib on the trabecular and cortical bone compartments and estimated strength at the hip and spine. Design: This was a randomized, double-blind, 2-year trial. Setting: The study was conducted at a private or institutional practice. Participants: Participants included 214 postmenopausal women with low areal BMD. Intervention: The intervention included odanacatib 50 mg or placebo weekly. Main Outcome Measures: Changes in areal BMD by dual-energy x-ray absorptiometry (primary end point, 1 year areal BMD change at lumbar spine), bone turnover markers, volumetric BMD by quantitative computed tomography (QCT), and bone strength estimated by finite element analysis were measured. Results: Year 1 lumbar spine areal BMD percent change from baseline was 3.5% greater with odanacatib than placebo (P<.001). Bone-resorption marker C-telopeptide of type 1 collagen was significantly lower with odanacatib vs placebo at 6 months and 2 years (P<.001). Bone-formation marker procollagen I N-terminal peptide initially decreased with odanacatib but by 2 years did not differ from placebo. After 6 months, odanacatib-treated women had greater increases in trabecular volumetric BMD and estimated compressive strength at the spine and integral and trabecular volumetric BMD and estimated strength at the hip (P<.001). At the cortical envelope of the femoral neck, bone mineral content, thickness, volume, and cross-sectional area also increased from baseline with odanacatib vs placebo (P<.001 at 24 months). Adverse experiences were similar between groups. Conclusions: Over 2 years, odanacatib decreased bone resorption, maintained bone formation, increased areal and volumetric BMD, and increased estimated bone strength at both the hip and spine. Copyright © 2013 by The Endocrine Society.

Imaging has been used in clinical trials for decades and has proven a useful biomarker in many disease states. Although imaging is not widely used in clinical practice for AD patient care, many pharmaceutical and biotech companies have relied on this technique for eligibility, safety and efficacy roles in their trials. In this overview, issues with standardization, validation and regulations will be discussed in order to gain a better understanding of the benefits, risks and impact on study conduct of adding imaging to Alzheimer's disease clinical trials.

Synarc Inc. | Date: 2011-05-25

A method for computer based analysis of a low field MR image including a trabecular region of bone for extracting from said image diagnostic information by applying a trained statistical classifier which has been trained on similar labelled according to the severity of a trabecular bone altering disease suffered at the time or later. For each image in the training set a region of interest (ROI) is defined, textural information relating to the intensities of voxels within the ROI is obtained, and combinations of features of said textural information are found which suitably classify the images according to said labelling. An image under study is treated similarly and features of said textural information for the voxels within the ROI of the image are combined as learnt in the training of the classifier to estimate a level of said trabecular bone altering disease or propensity to develop said bone altering disease or a level thereof associated with said image.

Synarc Inc. | Date: 2010-06-03

A method of manipulation of a representation of a 2-D shape for improving a General Procrustes Alignment process, comprising taking a starting 2-D shape defined by a set of landmarks derived from data representing a 2-D projection image of a body part such as a vertebra, in a suitably programmed computing device deriving for each landmark of the 2-D shape a probable relative depth by the application thereto of a statistical model based on a multiplicity of 3-D shapes defined by landmarks derived from 3-D images of similar said body parts, said landmarks having one depth and two spatial coordinates, said model relating the probable relative depth of each landmark in a 3-D-shape of a said body part to the spatial coordinates of the set of landmarks constituting a said shape, and based on the inferred relative depth of the landmarks of the starting 2-D shape deforming the starting 2-D shape to correct for apparent distortion caused by rotation about an axis parallel to the projection plane of the imaged body part, so producing a corrected 2-D shape.

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