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Eckstein F.,Paracelsus Medical University | Eckstein F.,Chondrometrics GmbH | Hellio Le Graverand M.P.,Pfizer | Charles H.C.,Duke University | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective: To examine the relationship of baseline clinical, radiographic, molecular and MRI measures with structural progression (subregional MRI-based femorotibial cartilage loss) in knee osteoarthritis (OA). Methods: Single knees of 75 female participants with radiographic knee OA (and 77 healthy control participants) were examined over 24 months using MRI. Subregional femorotibial cartilage thickness was determined at baseline and follow-up. Baseline clinical, radiographic, molecular (n=16) and quantitative MRI-based measures of the meniscus and cartilage, including delayed gadolinium-enhanced MRI (dGEMRIC) and T2, were obtained. Differences in these baseline measures between radiographic osteoarthritic knees with longitudinal cartilage thinning (or thickening) and those with no significant change were evaluated by receiver operator characteristic analyses and Wilcoxon rank sum tests. Results: The relatively strongest predictors of longitudinal cartilage thinning were reduced baseline cartilage thickness in the medial femur (area under the curve (AUC)=0.81), varus malalignment (AUC=0.77), reduced minimum joint space width and a greater radiographic joint space narrowing (JSN) score (both AUC=0.74). These remained significant after adjusting for multiple comparisons using false discovery rates. Reduced bone resorption (C-terminal telopeptide of type I collagen; AUC=0.65) and a low dGEMRIC index (reflecting low proteoglycan content) in the medial tibia (AUC=0.68) were associated with longitudinal cartilage thinning, but failed to reach statistical significance after correction for multiple testing in this (small) sample. Conclusions: This exploratory study indicates that baseline molecular or MRI cartilage compositional markers may not provide better discrimination between knees with cartilage thinning and those without longitudinal change than simple radiographic measures, such as greater JSN score. Source

Buck R.J.,StatAnswers Consulting LLC | Dreher D.,Merck Serono SA | Dreher D.,Totzke and Dreher Scientific SA | Eckstein F.,Paracelsus Medical University | Eckstein F.,Chondrometrics GmbH
Cartilage | Year: 2012

Objective: To describe the distribution of longitudinal femorotibial cartilage thickness annualized rate of change (ΔThCtAB) from quasi-population-based studies, and to construct a reference distribution for men and women without signs, symptoms, or risk factors of knee osteoarthritis (OA). Methods: Segmented baseline and 1-year follow-up MRI from 43 men and 69 women of the Osteoarthritis Initiative (OAI) asymptomatic control cohort without risk factors and also baseline and 2-year follow-up data from 77 asymptomatic women of the Pfizer A9001140 study were included. The mean, standard deviation (SD), and correlation of ΔThCtAB in medial and lateral femorotibial subregions were estimated; distributions were tested for normality and for differences between cohorts and gender. Results: Distributions of femorotibial ΔThCtAB rates were consistent between cohorts and were normally distributed, with rates <0.7%/y. Subregion ΔThCtAB SDs were correlated with mean baseline cartilage thickness (ratio = 3%-5%). However, ΔThCtAB SD did not increase with baseline thickness when estimated for different tertiles of any given subregion, indicating the relationship may rather be due to spatial location than to baseline thickness. Conclusions: Distributions of (subregional) longitudinal cartilage thickness rates of change appear to be normally distributed, not significantly different from zero, and similar for different cohorts of asymptomatic subjects. Given the spatial heterogeneity of subregional cartilage change observed in OA knees, the proposed reference distribution of subregional cartilage thickness change, ΔThCtAB may be used to describe and identify structural progression (i.e., cartilage loss) in individual OA knees with greater accuracy and sensitivity than conventional approaches, such as minimal detectable difference.© The Author(s) 2012. Source

Buck R.J.,StatAnswers Consulting LLC | Wyman B.T.,Pfizer | Graverand M.-P.H.L.,Pfizer | Wirth W.,Chondrometrics GmbH | And 2 more authors.
Magnetic Resonance in Medicine | Year: 2010

The relationship between three-dimensional, MRI-based morphologic measurements commonly taken of knee cartilage was examined to determine whether a subset of variables fully reflects differences observed in cartilage in cross-sectional and longitudinal studies. The benefits of a subset of measures include increased statistical power due to reduced multiple comparisons, improved understanding of relationships between the morphologic measures of articular knee cartilage, and greater efficiency in reporting results. One hundred fifty-two women (77 healthy and 75 with knee osteoarthritis) had coronal 3-T MR images of the knee acquired at baseline and at 24 months. Measures of femorotibial cartilage morphology (surface area, thickness, volume, etc.) were determined in the medial and lateral tibia and femur. Cartilage thickness (mean cartilage thickness over the total area of the [subchondral] bone), total subchondral bone area, and percentage of denuded area of the subchondral bone were found to explain over 90% of the cross-sectional and longitudinal variation observed in other measures of cartilage morphology commonly reported in knee osteoarthritis. Hence, these three measures of cartilage morphology explain nearly all variation in a larger set of common cartilage morphology measures both cross-sectionally and longitudinally, both in healthy and in osteoarthritic knees. These variables hence define an efficient subset for describing structural status and change in osteoarthritic cartilage. © 2010 Wiley-Liss, Inc. Source

Wirth W.,Chondrometrics GmbH | Wirth W.,Paracelsus Medical University | Buck R.,StatAnswers Consulting LLC | Nevitt M.,University of California at San Francisco | And 12 more authors.
Osteoarthritis and Cartilage | Year: 2011

Objective: The sensitivity to change of quantitative analysis of cartilage in knee osteoarthritis using magnetic resonance imaging (MRI) is compromised by the spatial heterogeneity of cartilage loss. We explore whether extended (medial-lateral) " ordered values" (OVs) are superior to conventional approaches of analyzing subregional cartilage thickness loss and to radiography, in differentiating rates of progression in knees with and without joint space narrowing (JSN). Methods: 607 Osteoarthritis Initiative (OAI) participants (308 without and 299 with baseline JSN at baseline) were studied over 12 months. Subregional femorotibial cartilage loss was determined in all knees, and changes in minimum joint space width (mJSW) in a subset of 290 knees. Subregional thickness changes in medial and lateral tibial and femoral cartilages were sorted in ascending order (OV1-16). A Wilcoxon rank-sum test was used to compare rates of change in knees with and without JSN. Results: JSN-knees displayed greater cartilage loss than those without JSN, with minimal P-values of 0.008 for femorotibial subregions, 3.3×10-4 for medial OV1, and 5.4×10-7 for extended (medial and lateral) OV1. mJSW measurements (n=290) did not discriminate between longitudinal rates of change in JSN vs no-JSN knees (P=0.386), whereas medial OV1 (P=5.1×10-4) and extended OV1 did (P=2.1×10-5). Conclusion: Extended OVs showed higher sensitivity to detecting differences in longitudinal rates of cartilage loss in knees with and without baseline JSN than anatomical (sub)regions and radiography. The OV technique also circumvents challenges of selecting particular regions " a priori" in clinical trials and may thus provide a powerful tool in studying risk factors or treatment efficacy in osteoarthritis. © 2011 Osteoarthritis Research Society International. Source

Buck R.J.,StatAnswers Consulting LLC | Wirth W.,Paracelsus Medical University | Wirth W.,Chondrometrics GmbH | Dreher D.,Merck Serono SA | And 3 more authors.
Osteoarthritis and Cartilage | Year: 2013

Objective: Estimate the frequency and spatial location of rapid femorotibial cartilage thinning or thickening in knees with, or at risk of, osteoarthritis (OA) and examine their association with clinical and radiographic covariates. Design: Knee cartilage thickness change over 12 months was measured using magnetic resonance imaging in the right knee of 757 Osteoarthritis Initiative (OAI) participants that had radiographic findings of osteophytes or joint space narrowing (JSN). Thickness changes in individual knees were classified as having rapid thinning or thickening or no detectable OA-related change when compared to asymptomatic OAI Control cohort knees. Results: Cartilage thinning, found in 18.5% of subjects, was more frequent in knees with OAI calculated Kellgren-Lawrence grade (cKLG) > 2 (P < 0.001) and with frequent pain (P = 0.047). No link was found between body mass index, sex, and age and cartilage thinning (P > 0.15). The percent of knees with thickening was small (4.4%), but greater in knees with frequent pain (P = 0.02). Rapid thinning was most common in the central (36.4%) and external (32.1%) subregions of the medial weight-bearing femur. Mean cartilage loss in rapidly thinning subregions ranged from 11.2%/y to 24.6%/y. Knees with cKLG > 2, but classified as having no detectable OA-related change had mean cartilage loss rates significantly >0 (0.4%/y-1.3%/y) in 10 subregions. Conclusion: Most observed subregional changes in OA knees were indistinguishable from changes found in an asymptomatic cohort, but a fraction of subregions showed rapid progression. The relative frequency of rapid thinning increases when cKLG > 2, a classification closely associated with JSN and/or frequent knee pain are present. © 2012 Osteoarthritis Research Society International. Source

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