Efficacy and cost-effectiveness of Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis: protocol for a randomised placebo-controlled trial (the SCUlpTOR trial).

INTRODUCTION: Knee osteoarthritis (KOA) is a highly prevalent disabling joint disease. Intra-articular stem cell therapy is increasingly being used for treating KOA with little high-quality evidence to support its use. The aim of this study is to investigate the efficacy, safety and cost-effectiveness of allogeneic mesenchymal stem cells (Cymerus MSCs) for treating symptomatic tibiofemoral KOA and improving knee structure over 24 months. METHODS AND ANALYSIS: The Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis study is a phase III, multi-centre, parallel, superiority, randomised, double-blind, placebo-controlled trial, which will be conducted in Sydney and Hobart, Australia. 440 participants (220 per arm) aged over 40 years with painful KOA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) with medial minimum joint space width between 1 and 4 mm in the study knee will be recruited from the community and randomly allocated to receive either intra-articular MSCs or saline at baseline, week 3 and week 52. The coprimary outcomes will be the proportion of participants achieving patient-acceptable symptom state for knee pain at 24 months and quantitative central medial femorotibial compartment cartilage thickness change from baseline to 24 months. Main secondary outcomes include change in knee pain, Patient Global Assessment, physical function, quality of life and other structural changes. Additional data for cost-effectiveness analysis will also be recorded. Adverse events will be monitored throughout the study. The primary analysis will be conducted using modified intention-to-treat. ETHICS AND DISSEMINATION: This protocol has been approved by The University of Sydney (USYD) Human Research Ethics Committee (HREC) #: 2020/119 and The University of Tasmania (UTAS) HREC #: H0021868. All participants will be required to provide informed consent. Dissemination will occur through conferences, social media, and scientific publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trials Registry (ACTRN12620000870954); U1111-1234-4897.

Impact of Diabetes Mellitus on Knee Osteoarthritis Pain and Physical and Mental Status: Data From the Osteoarthritis Initiative.

OBJECTIVE: Diabetes mellitus (DM) appears to increase osteoarthritic knee pain, which may be related to greater adiposity and more advanced disease status often observed in individuals with osteoarthritis (OA) and DM. We aimed to assess whether OA knee pain and health status are worse in individuals with OA and DM, independent of these potential confounders. METHODS: We included 202 OA participants with DM and 2,279 without DM from the Osteoarthritis Initiative. Knee pain was evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and a numeric rating scale (NRS). Physical and mental status were assessed by the Medical Outcomes Study Short Form 12 (SF-12) questionnaire, physical component summary (PCS) score and mental component summary (MCS) score, and by the Center for Epidemiologic Studies Depression Scale (CES-D). Linear regression models assessed the influence of DM, adjusted for age, sex, body mass index (BMI), and radiographic severity. RESULTS: OA participants with DM reported worse knee pain and greater physical and mental issues compared with participants without DM. Individuals with DM had worse KOOS pain (ß = -4.72 [95% confidence interval (95% CI) -7.22, -2.23]) and worse NRS pain (ß = 0.42 [95% CI 0.04, 0.80]) independent of BMI, OA severity, age, and sex. The negative influence of DM was also apparent for SF-12 PCS (ß = -3.49 [95% CI -4.73, -2.25]), SF-12 MCS (ß = -1.42 [95% CI -2.57, -0.26]), and CES-D (ß = 1.08 [95% CI 0.08, 2.08]). CONCLUSION: Individuals with knee OA experience on average higher pain intensity and a worse physical and mental health status if they have DM. Linear regression models show that DM is a risk factor for higher pain, in addition to and independent of greater BMI and radiographic OA severity.

Five-minute knee MRI for simultaneous morphometry and T2 relaxometry of cartilage and meniscus and for semiquantitative radiological assessment using double-echo in steady-state at 3T.

BACKGROUND: Biomarkers for assessing osteoarthritis activity necessitate multiple MRI sequences with long acquisition times. PURPOSE: To perform 5-minute simultaneous morphometry (thickness/volume measurements) and T2 relaxometry of both cartilage and meniscus, and semiquantitative MRI Osteoarthritis Knee Scoring (MOAKS). STUDY TYPE: Prospective. SUBJECTS: Fifteen healthy volunteers for morphometry and T2 measurements, and 15 patients (five each Kellgren-Lawrence grades 0/2/3) for MOAKS assessment. FIELD STRENGTH/SEQUENCE: A 5-minute double-echo steady-state (DESS) sequence was evaluated for generating quantitative and semiquantitative osteoarthritis biomarkers at 3T. ASSESSMENT: Flip angle simulations evaluated tissue signals and sensitivity of T2 measurements. Morphometry and T2 reproducibility was compared against morphometry-optimized and relaxometry-optimized sequences. Repeatability was assessed by scanning five volunteers twice. MOAKS reproducibility was compared to MOAKS derived from a clinical knee MRI protocol by two readers. STATISTICAL TESTS: Coefficients of variation (CVs), concordance confidence intervals (CCI), and Wilcoxon signed-rank tests compared morphometry and relaxometry measurements with their reference standards. DESS MOAKS positive percent agreement (PPA), negative percentage agreement (NPA), and interreader agreement was calculated using the clinical protocol as a reference. Biomarker variations between Kellgren-Lawrence groups were evaluated using Wilcoxon rank-sum tests. RESULTS: Cartilage thickness (P = 0.65), cartilage T2 (P = 0.69), and meniscus T2 (P = 0.06) did not significantly differ from their reference standard (with a 20° DESS flip angle). DESS slightly overestimated meniscus volume (P < 0.001). Accuracy and repeatability CVs were <3.3%, except the meniscus T2 accuracy (7.6%). DESS MOAKS had substantial interreader agreement and high PPA/NPA values of 87%/90%. Bone marrow lesions and menisci had slightly lower PPAs. Cartilage and meniscus T2 , and MOAKS (cartilage surface area, osteophytes, cysts, and total score) was higher in Kellgren-Lawrence groups 2 and 3 than group 0 (P < 0.05). DATA CONCLUSION: The 5-minute DESS sequence permits MOAKS assessment for a majority of tissues, along with repeatable and reproducible simultaneous cartilage and meniscus T2 relaxometry and morphometry measurements. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1328-1341.

Contralateral knee effect on self-reported knee-specific function and global functional assessment: data from the Osteoarthritis Initiative.

OBJECTIVE: To analyze the effect of contralateral knee pain on sensitivity of patient-reported outcomes and objectively measured functional performance tests in subjects with knee osteoarthritis (OA). METHODS: Subjects with discordant knee pain status (i.e., 1 knee being painful [≥4 on a numeric pain rating scale (NPRS)], with the contralateral knee being pain free [NPRS 0]) were selected from the Osteoarthritis Initiative and matched to subjects with bilaterally pain-free and painful knees by age, sex, body mass index, and radiographic knee OA. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function score, the global Physical Activity Scale for the Elderly (PASE), and objective functional performance tests were cross-sectionally compared in a matched case-control design. RESULTS: A total of 378 subjects with discordant knee pain status were matched to 359 controls with bilaterally pain-free knees and to 323 controls with bilaterally painful knees. WOMAC scores in pain-free knees of discordant knee pain cases significantly differed compared to scores of bilaterally pain-free knees (P = 0.003). Likewise, scores in painful knees of discordant knee pain cases significantly differed compared to scores of bilaterally painful knees (P < 0.001). PASE levels between these groups were not significantly different (P > 0.68). Functional performance tests differed in subjects with discordant knee pain compared to subjects with bilaterally pain-free knees and when compared to subjects with bilaterally painful knees, with the chair stand test showing the strongest effect size (standardized response mean 0.28 and 0.33, respectively). CONCLUSION: The WOMAC physical function score, although knee specific, is impacted by the contralateral knee pain status. The repeated chair stand test appears to be the most sensitive assessment in differentiation between groups with different status of knee pain.

The susceptibility of the femoral neck to fracture: an assessment incorporating the effects of age-remodeling and stress reduction.

Age-related bone remodeling may cause fragility of the femoral neck, thereby increasing fracture risk in elderly populations. We investigated the effects of age-remodeling and stress-reduction on the femoral neck region using the Finite Strip Method (FSM). We verified the possibility that the femoral neck is likely to undergo fracture through two mechanisms: yielding and local buckling. We hypothesized that the femoral necks of young subjects are more prone to fracture by yielding, whereas those of elderly subjects are more susceptible to fracture initiated by local buckling. The slices from the CT-scans of 15 subjects corresponding to the lowest area moment of inertia were segregated into cortex and trabeculae. Geometric and material properties for each strip were obtained from the CT-scans. The FSM, proposed here as an approximation to the better-known Finite Element Method (FEM), was implemented on a model comprising both cortex and trabeculae. Finite strip (FS) analyses were performed on models that incorporated the effects of age-related bone remodeling, as well as a reduction in physiological stress on the bone (as a result of weight loss). Comparisons were made with similar FS analyses performed on only the cortical shell, in order to ascertain the contributions of the trabeculae to femoral neck strength. We observed that the femoral necks of simulated young subjects manifested a marked predisposition to undergo yielding, whereas the femoral neck models of simulated elderly subjects were more prone to buckling before yielding. The trabecular degradation and cortical thinning involved in aging render the femoral neck more susceptible to failure by buckling.

Multiplanar reconstruction recovers morphological cartilage assessment reproducibility from maloriented coronal MRI scans.

The study's purpose was to assess the effect of multiplanar reconstruction on precision of weight-bearing medial and lateral femoral cartilage (cMF, cLF) morphometry in maloriented coronal MR images. Twenty knees were scanned four times with a 1.0 Tesla extremity imager using a fat-suppressed T1-weighted three-dimensional spoiled gradient recalled echo sequence; twice with "best as" double bull's-eye orientation of the femoral condyles, and once each with 5° internal and external rotation. Multiplanar reconstruction was applied to maloriented scans to recover double bull's-eye orientation. Medial and lateral femoral cartilages were segmented and precision of bone area, cartilage volume and thickness (ThCtAB) evaluated for all scans. Test-retest precision (RMSCV%) of the double bull's-eye scans was 1.1% for total bone area and 4.1% for cartilage volume. Differences in precision between double bull's-eye and maloriented images were assessed. Higher precision errors were observed in malorientated images for all outcomes (1.7-4.8% for internally rotation scans; 1.7-4.8% for external rotation scans). Precision generally improved with multiplanar reconstruction correction (1.7-5.6% for internally rotated scans; 1.2-3.5% for external rotation scans). Precision of femoral cartilage morphometry is generally reduced when maloriented images are acquired. Multiplanar reconstruction can correct malorientated scans and recover precision losses. Measurements are affected in a rotationally and compartmentally dependent manner.

Assessment of synovitis in the osteoarthritic knee: Comparison between manual segmentation, semiautomated segmentation, and semiquantitative assessment using contrast-enhanced fat-suppressed T1-weighted MRI.

Osteoarthritic joints regularly exhibit synovitis, which is ideally assessed on contrast-enhanced MRI. Manual segmentation is the reference standard for volumetric analysis but is labor intensive. The aim was to evaluate alternative semiautomated approaches of targeted thresholding and gaussian deconvolution. Volumetric and semiquantitative synovitis assessment was compared in addition. Thirty-two knees with osteoarthritis were scanned on a 1.5-T system. Synovitis volumes were plotted against each other and distributions fit with linear functions. The relationship between semiquantitative scores and synovitis volumes was assessed using Spearman's correlation coefficient. Semiautomated volume measurement was more time efficient than manual segmentation and showed a high correlation with manual analysis (R(2) = 0.88 and 0.82). Manual segmentation was correlated with summed and with maximum semiquantitative synovitis scores (rho = 0.71 and 0.47). In conclusion, semiautomated analysis provides comparable quantitative results when compared to manual segmentation but is approximately five times more time efficient. Semiquantitative assessment adds anatomic information on synovitis distribution.

Effect of exercise intervention on thigh muscle volume and anatomical cross-sectional areas--quantitative assessment using MRI.

The objective of this study was to evaluate the location-specific magnitudes of an exercise intervention on thigh muscle volume and anatomical cross-sectional area, using MRI. Forty one untrained women participated in strength, endurance, or autogenic training for 12 weeks. Axial MR images of the thigh were acquired before and after the intervention, using a T1-weighted turbo-spin-echo sequence (10 mm sections, 0.78 mm in-plane resolution). The extensor, flexor, adductor, and sartorius muscles were segmented between the femoral neck and the rectus femoris tendon. Muscle volumes were determined, and anatomical cross-sectional areas were derived from 3D reconstructions at 10% (proximal-to-distal) intervals. With strength training, the volume of the extensors (+3.1%), flexors (+3.5%), and adductors (+3.9%) increased significantly (P < 0.05) between baseline and follow-up, and with endurance training, the volume of the extensor (+3.7%) and sartorius (+5.1%) increased significantly (P < 0.05). No relevant or statistically significant change was observed with autogenic training. The greatest standardized response means were observed for the anatomical cross-sectional area in the proximal aspect (10-30%) of the thigh and generally exceeded those for muscle volumes. The study shows that MRI can be used to monitor location-specific effects of exercise intervention on muscle cross-sectional areas, with the proximal aspect of the thigh muscles being most responsive.

Assessment of the individual fracture risk of the proximal femur by using statistical appearance models.

PURPOSE: Standard diagnostic techniques to quantify bone mineral density (BMD) include dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography. However, BMD alone is not sufficient to predict the fracture risk for an individual patient. Therefore, the development of tools, which can assess the bone quality in order to predict individual biomechanics of a bone, would mean a significant improvement for the prevention of fragility fractures. In this study, a new approach to predict the fracture risk of proximal femora using a statistical appearance model will be presented. METHODS: 100 CT data sets of human femur cadaver specimens are used to create statistical appearance models for the prediction of the individual fracture load (FL). Calculating these models offers the possibility to use information about the inner structure of the proximal femur, as well as geometric properties of the femoral bone for FL prediction. By applying principal component analysis, statistical models have been calculated in different regions of interest. For each of these models, the individual model parameters for each single data set were calculated and used as predictor variables in a multilinear regression model. By this means, the best working region of interest for the prediction of FL was identified. The accuracy of the FL prediction was evaluated by using a leave-one-out cross validation scheme. Performance of DXA in predicting FL was used as a standard of comparison. RESULTS: The results of the evaluative tests demonstrate that significantly better results for FL prediction can be achieved by using the proposed model-based approach (R = 0.91) than using DXA-BMD (R = 0.81) for the prediction of fracture load. CONCLUSIONS: The results of the evaluation show that the presented model-based approach is very promising and also comparable to studies that partly used higher image resolutions for bone quality assessment and fracture risk prediction.

Magnetic resonance imaging-based semiquantitative and quantitative assessment in osteoarthritis.

Whole organ magnetic resonance imaging (MRI)-based semiquantitative (SQ) assessment of knee osteoarthritis (OA), based on reliable scoring methods and expert reading, has become a powerful research tool in OA. SQ morphologic scoring has been applied to large observational cross-sectional and longitudinal epidemiologic studies as well as interventional clinical trials. SQ whole organ scoring analyzes all joint structures that are potentially relevant as surrogate outcome measures of OA and potential disease modification, including cartilage, subchondral bone, osteophytes, intra- and periarticular ligaments, menisci, synovial lining, cysts, and bursae. Resources needed for SQ scoring rely on the MRI protocol, image quality, experience of the expert readers, method of documentation, and the individual scoring system that will be applied. The first part of this article discusses the different available OA whole organ scoring systems, focusing on MRI of the knee, and also reviews alternative approaches. Rheumatologists are made aware of artifacts and differential diagnoses when applying any of the SQ scoring systems. The second part focuses on quantitative approaches in OA, particularly measurement of (subregional) cartilage loss. This approach allows one to determine minute changes that occur relatively homogeneously across cartilage structures and that are not apparent to the naked eye. To this end, the cartilage surfaces need to be segmented by trained users using specialized software. Measurements of knee cartilage loss based on water-excitation spoiled gradient recalled echo acquisition in the steady state, fast low-angle shot, or double-echo steady-state imaging sequences reported a 1% to 2% decrease in cartilage thickness annually, and a high degree of spatial heterogeneity of cartilage thickness changes in femorotibial subregions between subjects. Risk factors identified by quantitative measurement technology included a high body mass index, meniscal extrusion and meniscal tears, knee malalignment, advanced radiographic OA grade, bone marrow alterations, and focal cartilage lesions.

Accuracy and precision of quantitative assessment of cartilage morphology by magnetic resonance imaging at 3.0T.

OBJECTIVE: Quantitative magnetic resonance imaging (MRI) of articular cartilage represents a powerful tool in osteoarthritis (OA) research, but has so far been confined to a field strength of 1.5T. The aim of this study was to evaluate the precision of quantitative MRI assessments of human cartilage morphology at 3.0T and to correlate the measurements at 3.0T with validated measurements at 1.5T. METHODS: MR images of the knee of 15 participants with OA and 15 healthy control subjects were acquired using Siemens 1.5T and 3.0T scanners. Double oblique coronal scans were obtained at 1.5T with a 1.5-mm partition thickness, at 3.0T with a 1.5-mm partition thickness, and at 3.0T with a 1.0-mm partition thickness. Cartilage volume, thickness, and surface area of the femorotibial cartilage plates were quantified using proprietary software. RESULTS: For 1.5-mm partition thickness at 1.5T, the precision error was 3.0% and 2.6% for cartilage volume and cartilage thickness, respectively. The error was smaller for a 1.5-mm partition thickness at 3.0T (2.6% and 2.5%) and still smaller for a 1.0-mm partition thickness at 3.0T (2.1% and 2.0%). Correlation coefficients between values obtained at 3.0T and 1.5T were high (r > or = 0.96), with no significant deviation between the two field strengths. CONCLUSION: Quantitative MRI measurement of cartilage morphology at 3.0T (partition thickness 1 mm) was found to be accurate and tended to be more reproducible than at 1.5T (partition thickness 1.5 mm). Imaging at 3.0T may therefore provide superior ability to detect changes in cartilage status over time and to determine responses to treatment with structure-modifying drugs.

Quantitative assessment of cartilage status in osteoarthritis by quantitative magnetic resonance imaging: technical validation for use in analysis of cartilage volume and further morphologic parameters.

OBJECTIVE: Quantitative diagnostic tools for osteoarthritis (OA) are important for evaluating the treatment response to structure-modifying drugs. This study was undertaken to test the technical validity (accuracy) of quantitative magnetic resonance imaging (qMRI) for reliable determination of the total bone interface area, percentage of cartilaginous (denuded) joint surface area, and cartilage thickness in OA. METHODS: High-resolution MRIs of femorotibial and patellar cartilage were acquired in 21 patients prior to total knee arthroplasty, using a T1-weighted gradient-echo sequence with water excitation. After segmentation of original bone interface areas (before disease onset) and the actual cartilage layer, the percentages of cartilaginous joint surface area, cartilage thickness, and cartilage volume were determined using proprietary software. During surgery, the patella and the medial and lateral tibia were resected. Results obtained with qMRI were compared with those obtained by direct image analysis of surface area, cartilage thickness, and cartilage volume of the surgically removed tissue. RESULTS: Pairwise differences between results obtained with qMRI and morphologic analysis were +/-4.6% for percentage of cartilaginous surface area, +/-8.9% for cartilage thickness, and +/-9.1% for cartilage volume. Correlation coefficients ranged from 0.92 (thickness) to 0.98 (volume). CONCLUSION: Quantitative MRI permits technically accurate and differential assessment of increases in eroded joint surface area and reductions in cartilage thickness in OA. The surrogate validity of these parameters requires testing in longitudinal studies. These parameters may be advantageous over determination of cartilage volume alone when diagnosing OA, exploring its progression, or testing responsiveness to new therapies.

Surface size, curvature analysis, and assessment of knee joint incongruity with MRI in vivo.

The purpose of this study was to develop an MR-based technique for quantitative analysis of joint surface size, surface curvature, and joint incongruity and to assess its reproducibility under in vivo imaging conditions. The surface areas were determined after 3D reconstruction of the joint by triangulation and the incongruity by Gaussian curvature analysis. The precision was tested by analyzing four replicated MRI datasets of human knees in 14 individuals. The algorithms were shown to produce accurate data in geometric test objects. The interscan precision was <4% (CV%) for surface area, 2.9-5.7 m(-1) (SD) for the mean principal curvature, and 4.1-7.4 m(-1) for congruence indices. Incongruity was highest in the femoropatellar joint (79.7 m(-1)) and lowest in the medial femorotibial joint (28.6 m(-1)). This technique will permit identification of the specific role of surface size, curvature, and incongruity as potential risk factors for osteoarthritis.