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Objective: The aim of the study was to determine whether tibiofemoral contact stress predicts risk for worsening knee pain over 84 ms in adults aged 50-79 yrs with or at elevated risk for knee osteoarthritis., Design: Baseline tibiofemoral contact stress was estimated using discrete element analysis. Other baseline measures included weight, height, hip-knee-ankle alignment, Kellgren-Lawrence grade, and Western Ontario and McMaster Universities Osteoarthritis Index pain subscale. Logistic regression models assessed the association between baseline contact stress and 84-mo worsening of Western Ontario and McMaster Universities Osteoarthritis Index pain subscale., Results: Data from the dominant knee (72.6% Kellgren-Lawrence grade 0/1 and 27.4% Kellgren-Lawrence grade ≥ 2) of 208 participants (64.4% female, mean ± SD body mass index = 29.6 ± 5.1 kg/m 2 ) were analyzed. Baseline mean and peak contact stress were 3.3 ± 0.9 and 9.4 ± 4.3 MPa, respectively. Forty-seven knees met the criterion for worsening pain. The highest tertiles in comparison with the lowest tertiles of mean (odds ratio [95% confidence interval] = 2.47 [1.03-5.95], P = 0.04) and peak (2.49 [1.03-5.98], P = 0.04) contact stress were associated with worsening pain at 84 mos, after adjustment for age, sex, race, clinic site, and baseline pain. Post hoc sensitivity analyses including adjustment for body mass index and hip-knee-ankle alignment attenuated the effect., Conclusions: These findings suggest that elevated tibiofemoral contact stress can predict the development of worsening of knee pain., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess whether quantitative changes in the meniscus predict progression from early knee osteoarthritis (OA) to knee replacement (KR)., Methods: A nested case-control study was conducted among Osteoarthritis Initiative participants: all 35 case knees with baseline Kellgren/Lawrence (K/L) grade ≤2 that had KR between 36 and 60 months were matched 1:1 by age, sex, and baseline K/L grade to 35 control knees without subsequent KR. Quantitative 3-dimensional medial meniscus position and morphologic measures were determined from magnetic resonance imaging at the visit just before KR and 2 years before. Paired t-tests and case-control odds ratios (ORs, standardized per SD of change in controls) were used to compare changes between groups., Results: Cases (52% women, age 65 ± 7 years, body mass index [BMI] 30 ± 4 kg/m 2 , K/L grades 0/1/2: 5/8/22 participants, respectively) and controls (52% women, age 64 ± 7 years, BMI 30 ± 5 kg/m 2 , K/L grades 0/1/2: 9/4/22 participants, respectively) were similar. Compared to control knees, KR case knees displayed longitudinal changes, specifically, a decrease in tibial plateau coverage, an increase in meniscal extrusion, and a decrease in meniscal width. The odds for KR increased with greater reduction in the percentage of tibial plateau coverage (OR 2.28 [95% CI confidence interval (95% CI) 1.43, 3.64]), a greater increase in maximal extrusion (OR 1.40 [95% CI 1.12, 1.75]), and a greater reduction of mean meniscal width (OR 2.01 [95% CI 1.23, 3.26]). The odds for KR increased with medial compartment cartilage thickness loss (OR 2.86 [95% CI 1.51, 5.41]) for comparison., Conclusion: Quantitative measures of meniscal position and morphology are associated with subsequent KR in knees with rapidly progressing knee OA. These findings show that structural changes of the meniscus are related to an important clinical and economic outcome of knee OA., (© 2020, American College of Rheumatology.)

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 (β = -4.72 [95% confidence interval (95% CI) -7.22, -2.23]) and worse NRS pain (β = 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 (β = -3.49 [95% CI -4.73, -2.25]), SF-12 MCS (β = -1.42 [95% CI -2.57, -0.26]), and CES-D (β = 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., (© 2020 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To compare 5-year change in femorotibial cartilage thickness in 121 young, active adults with an acute anterior cruciate ligament (ACL) tear randomized to a strategy of structured rehabilitation plus early ACL reconstruction (ACLR) or structured rehabilitation plus optional delayed ACLR., Design: 62 patients were randomized to early ACLR, 59 to optional delayed ACLR. Magnetic resonance imaging (MRI) was acquired within 4 weeks of injury, at two- and 5-years follow-up. Main outcome was 5-year change in overall femorotibial cartilage thickness. Secondary outcomes included the location-independent cartilage ChangeScore, summarizing thinning and thickening in 16 femorotibial subregions. An exploratory as-treated comparison was performed additionally., Results: Baseline and at least one follow-up MRI were available for 117 patients. Over 5 years, a comparable increase in overall femorotibial cartilage thickness was observed for patients randomized to early ACLR (n = 59) and patients randomized to optional delayed ACLR (n = 58, adjusted mean difference: -5 μm, 95% CI: [-118, 108]μm). However, the location-independent cartilage ChangeScore was greater in those treated with early ACLR than in patients treated with optional delayed ACLR (adjusted mean difference: 403 μm [119, 687]μm). As-treated analysis showed no between-group differences for the main outcome, while the location-independent cartilage ChangeScore was greater for patients treated with early (adjusted mean difference: 632 μm [268, 996]μm) or delayed ACLR (adjusted mean difference: 449 μm [108, 791]μm) than for patients treated with rehabilitation alone., Conclusions: In young active adults with acute ACL-injury, choice of treatment strategy for the injured ACL did not modify the magnitude of 5-year change in overall femorotibial cartilage thickness., Trial Registration: ISRCTN84752559., (Copyright © 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Sprifermin is under investigation as a potential disease-modifying osteoarthritis drug. Previously, 2-year results from the FORWARD study showed significant dose-dependent modification of cartilage thickness in the total femorotibial joint (TFTJ), medial and lateral femorotibial compartments (MFTC, LFTC), and central medial and lateral TFTJ subregions, by quantitative magnetic resonance imaging (qMRI) using manual segmentation., Objective: To determine whether qMRI findings from FORWARD could be reproduced by an independent method of automated segmentation using an identical dataset and similar anatomical regions in a post-hoc analysis., Method: Cartilage thickness was assessed at baseline and 6, 12, 18 and 24 months, using automated cartilage segmentation with active appearance models, a supervised machine learning method. Images were blinded for treatment and timepoint. Treatment effect was assessed by observed and adjusted changes using a linear mixed model for repeated measures., Results: Based on automated segmentation, statistically significant, dose-dependent structural modification of cartilage thickness was observed over 2 years with sprifermin vs placebo for TFTJ (overall treatment effect and dose response, both P < 0.001), MFTC (P = 0.004 and P = 0.044), and LFTC (both P < 0.001) regions. For highest dose, in the central medial tibial (P = 0.008), central lateral tibial (P < 0.001) and central lateral femoral (P < 0.001) regions., Conclusions: Cartilage thickness assessed by automated segmentation provided a consistent dose response in structural modification compared with manual segmentation. This is the first time that two independent quantification methods of image analysis have reached the same conclusions in an interventional trial, strengthening the conclusions that sprifermin modifies structural progression in knee osteoarthritis., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Magnetic resonance imaging (MRI) under mechanical loading, commonly referred to as stress MRI, allows the evaluation of functional properties of intra- and periarticular tissues non-invasively beyond static assessment. Quantitative MRI can identify physiological and pathological responses to loading as indication of, potentially treatable, early degeneration and load transmission failure. Therefore, we have developed and validated an MRI-compatible pressure-controlled axial loading device to compress human knee specimens under variable loading intensity and axis deviation. Ten structurally intact human knee specimens (mean age 83.2 years) were studied on a 3.0T scanner (Achieva, Philips). Proton density-weighted fat-saturated turbo spin-echo and high-resolution 3D water selective 3D gradient-echo MRI scans were acquired sequentially at 10° joint flexion in seven configurations: unloaded and then at approximately half and full body weight loading in neutral, 10° varus and 10° valgus alignment, respectively. Following manual segmentation in both femorotibial compartments, cartilage thickness (ThC) was determined as well as meniscus extrusion (ExM). These measures were compared to computed tomography scans, histological grading (Mankin and Pauli scores), and biomechanical properties (Instantaneous Young's Modulus). Compartmental, regional and subregional changes in ThC and ExM were reflective of loading intensity and joint alignment, with the greatest changes observed in the medial compartment during varus and in the lateral compartment during valgus loading. These were not significantly associated with the histological tissue status or biomechanical properties. In conclusion, this study explores the physiological in-situ response of knee cartilage and meniscus, based on stress MRI, and as a function of loading intensity, joint alignment, histological tissue status, and biomechanical properties, as another step towards clinical implementation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To describe associations of body composition, physical activity and physical performance with knee cartilage thickness and subchondral bone area in young adults., Methods: Body composition, physical activity and physical performance were measured 4-5 years prior to knee MRI. Cartilage thickness and bone area were measured quantitatively from MRI. Associations were assessed using linear regression analysis, with mediators being identified using mediation analysis., Results: Participants (n = 186) were 31-41 years of age when the MRI was acquired and 48% were female. Greater lean mass was positively associated with cartilage thickness [β = 6.52 μm/kg (95% CI 0.86, 12.18)] and bone area [β = 13.37 mm2/kg (95% CI 5.43, 21.31)]. Physical performance measures were positively associated with cartilage thickness [long jump: β = 2.44 μm/cm (95% CI 0.70, 4.18); hand grip strength: 7.74 μm/kg (95% CI 1.50, 13.98); physical work capacity: 1.07 μm/W (95% CI 0.29, 1.85)] and bone area [long jump: β = 3.99 mm2/cm (95% CI 0.64, 7.34); hand grip strength: 19.06 mm2/kg (95% CI 7.21, 30.92); leg strength: 3.18 mm2/kg (95% CI 1.09, 5.28); physical work capacity: 3.15 mm2/W (95% CI 1.70, 4.60)]. Mediation analysis suggested these associations were mediated by lean mass (effect mediated: 27-95%)., Conclusion: Greater lean mass and better physical performance measured 4-5 years prior were associated with greater knee cartilage thickness and subchondral bone area in young adults, and the associations of physical performance were largely mediated by lean mass. These findings suggest lean mass may play an important role in maintaining knee joint health in young adults., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The aim of the study was to investigate whether muscle strength declines before or concurrent with incident knee pain in subjects with and without radiographic knee osteoarthritis., Design: Osteoarthritis initiative participants with incident knee pain (occurrence of infrequent/frequent knee pain during the past 12 mos at two consecutive follow-up time points (either years Y3 + Y4 or Y4 + Y5) were compared with controls (no incident knee pain) with 2-yr changes in knee extensor strength during BL➔Y2 (before) and Y2➔Y4 (concurrent)., Results: Two hundred two knees (49% women, 40% radiographic knee osteoarthritis) displayed incident pain, and 439 did not (46% women, 23% radiographic knee osteoarthritis). Women with radiographic knee osteoarthritis displayed a significantly greater (P = 0.04) reduction in knee extensor strength concurrent with incident pain compared with controls (mean = -17.6 N vs. +4.5 N), but men did not. A similar trend was observed in women without radiographic knee osteoarthritis, but this was not statistically significant (P = 0.08). There was no significant relationship with change in extensor strength before incident pain (P ≥ 0.43)., Conclusions: These results suggest that in women, incident knee pain is accompanied by a concurrent reduction in knee extensor strength, whereas loss in strength does not precede incident knee pain. The findings encourage interventional studies that attempt to attenuate a decline in extensor strength once knee symptoms occur.

Objectives: To test PEEK implant-associated MRI artifacts, a method for blinding MRI readers, the repeatability of cartilage thickness measures before and 6 weeks after high tibial osteotomy (HTO), and the sensitivity to change of cartilage thickness 12 months after HTO., Materials and Methods: Ten patients underwent HTO using a PEEK implant and 3 T-MRI before, 6 weeks and 12 months after surgery. Masks were applied to hide implant visibility on 48 MRI pairs, which were assessed by 7 readers (blinded to time). One blinded reader measured femorotibial cartilage thickness from masked MRIs., Results: No artifacts were produced. Readers were unable to identify scans by time greater than by chance. Cartilage thickness before and 6 weeks after surgery was not significantly different and indicated excellent repeatability. Medial cartilage thickness increases 12 M postoperatively approached statistical significance (p = 0.06), with no lateral changes observed. Half of the participants had an increase in medial cartilage thickness at 12 M that exceeded the minimal detectable change. Standardized response mean values were moderate-to-large., Discussion: Postoperative measures of cartilage thickness are repeatable, consistent and sensitive to change when artifact is eliminated, and a validated blinding technique is used. These results provide proof of concept for accurately measuring increases in medial knee articular cartilage after medial opening wedge HTO.

Objective: To develop a model of early osteoarthritis, by examining whether radiographically normal knees with contralateral joint space narrowing (JSN), but without contralateral trauma history, display greater longitudinal cartilage composition change (transverse relaxation time; T2) than subjects with bilaterally normal knees., Methods: 120 radiographically normal knees (Kellgren Lawrence grade [KLG] 0) from the Osteoarthritis Initiative were studied. 60 case knees displayed definite contralateral radiographic knee osteoarthritis (KLG ≥ 2) whereas 60 reference subjects were bilaterally KLG0, and were matched 1:1 to cases based on age, sex, and BMI. All had multi-echo spin-echo MRI acquired at year (Y) 1 and 4 follow-up, with cartilage T2 being determined in superficial and deep cartilage layers across 16 femorotibial subregions. T2 across all regions was considered the primary analytic focus., Results: Of 60 KLG0 case knees (30 female, age: 65.0 ± 8.8 y, BMI: 27.6 ± 4.4 kg/m 2 ), 21/22/13/4 displayed contralateral JSN 0/1/2/3, respectively. The longitudinal increase in the deep layer cartilage T2 between Y1 and Y4 was significantly greater (P = 0.03; Cohen's D 0.50) in the 39 KLG0 case knees with contralateral JSN (1.2 ms; 95% confidence interval [CI] [0.4, 2.0]) than in matched KLG0 reference knees (0.1 ms; 95% CI [-0.5, 0.7]). No significant differences were identified in superficial T2 change. T2 at Y1 was significantly greater in case than in reference knees, particularly in the superficial layer of the medial compartment., Conclusions: Radiographically normal knees with contralateral, non-traumatic JSN represent an applicable model of early osteoarthritis, with deep layer cartilage composition (T2) changing more rapidly than in bilaterally normal knees. CLINICALTRIALS., Gov Identification: NCT00080171., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Purpose: To evaluate whether baseline MRI-defined structural abnormalities are associated with subsequent change in laminar femorotibial cartilage transverse relaxation time (T2) of participants without radiographic signs, symptoms or risk factors for knee osteoarthritis (OA)., Method: We studied all right knees with longitudinal MRI data of the refined Osteoarthritis Initiative Healthy Reference cohort. Baseline osteophytes, effusion-synovitis, Hoffa-synovitis, bone marrow lesions, cartilage lesions, and meniscus morphology and - extrusion were scored semiquantitatively from MR images by an expert reader. Deep and superficial layer cartilage T2 was computed in the medial and lateral femorotibial compartment (MFTC/LFTC) at baseline and at 1- and 4-year follow-up from multi-echo spin-echo MR images. Statistical analyses were performed using UNIANOVA., Results: 82 participants (age 54.1 ± 7.2y, BMI 24.2 ± 3.0 kg/m²; 61% women, bilateral Kellgren-Lawrence 0) were studied. Number of baseline MRI pathologies was not significantly associated with longitudinal change in MFTC or LFTC cartilage T2 over 1 or 4 years. Feature-specific analyses suggested that presence of baseline MFTC osteophytes may be associated with prolongation in superficial MFTC cartilage T2 over one (0.8 vs. 0.0 ms, p = 0.02) and four years (2.3 vs. 0.9 ms, p = 0.01), and that MFTC meniscal damage or extrusion may be associated with prolongation in deep layer T2 times over the first year (0.7 vs. 2.1 ms, p = 0.02)., Conclusions: Our study does not provide evidence that, in knees without radiographic OA, baseline structural MRI abnormalities are strongly related to compositional progression during normal aging and/or the potentially earliest phases of the disease as measured by cartilage T2., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To describe the associations of childhood and adulthood adiposity measures with knee cartilage thickness, volume and bone area in young adults., Methods: Childhood and adulthood adiposity measures (weight, height, waist circumference and hip circumference) of 186 participants were collected in 1985 (aged 7-15 years) and during 2004-2006 (aged 26-36 years). Knee magnetic resonance imaging was conducted during 2008-2010 (aged 31-41 years) and cartilage thickness, volume and bone area were measured using a quantitative approach (Chondrometrics, Germany). Linear regressions were used to examine the above associations., Results: The prevalence of overweight was 7.6% in childhood and 42.1% in adulthood. Childhood weight (β = - 5.57 mm 2 /kg) and body mass index (BMI) (β = - 11.55 mm 2 /kg/m 2 ) were negatively associated with adult patellar bone area, whereas adult weight was positively associated with bone area in medial femorotibial compartment (MFTC) (β = 3.37 mm 2 /kg) and lateral femorotibial compartment (LFTC) (β = 2.08 mm 2 /kg). Adult waist-hip ratio (WHR) was negatively associated with cartilage thickness (MFTC: β = - 0.011; LFTC: β = - 0.012 mm/0.01 unit), volume (Patella: β = - 20.97; LFTC: β = - 21.71 mm 3 /0.01 unit) and bone area (Patella: β = - 4.39 mm 2 /0.01 unit). The change in WHR z-scores from childhood to adulthood was negatively associated with cartilage thickness (MFTC: β = - 0.056 mm), volume (patella: - 89.95; LFTC: - 93.98 mm 3 ), and bone area (patella: - 20.74 mm 2 ). All p-values < 0.05., Conclusions: Childhood weight and BMI were negatively but adult weight was positively associated with adult bone area. Adult WHR and the change in WHR from childhood to adulthood were negatively associated with cartilage thickness, volume, and bone area. These suggest early-life adiposity measures may affect knee structures in young adults.

Objective: To test whether radiographically normal knees with contralateral radiographic knee osteoarthritis (OA), but without contralateral trauma history, display greater cartilage thickness loss than knees from subjects with bilaterally radiographically normal knees., Methods: 828 radiographically normal knees (Kellgren Lawrence grade [KLG] 0) from the Osteoarthritis Initiative [OAI] were studied; 150 case knees displayed definite radiographic knee OA (KLG ≥ 2) contralaterally, and had MRI double echo steady state (DESS) images available at 12 and 48 month follow-up. 678 reference knees displayed KLG0 at the contralateral side. Cartilage thickness change was determined in femorotibial subregions and location-independent cartilage thinning scores were computed. Case and reference knees were compared using ANCOVA., Results: Of the 150 KLG0 case knees, 108 had a contralateral KLG2 knee (50 without, and 58 with joint space narrowing [JSN]), 31 a KLG3 and 11 a KLG4 knee. The cartilage thinning score tended to be greater in case than reference knees; the cartilage thinning score in KLG0 case knees with contralateral radiographic JSN (-858 μm; [95% confidence interval -1016, -701 μm]) was significantly greater (P = 0.0012) than that in bilaterally KLG0 reference knees (-634 μm; [-673, -596 μm]), whereas KLG0 knees with contralateral KLG2 without JSN only showed relatively small thinning scores (-530 μm, [-631, -428 μm]). Region-specific analysis suggested greater rates of cartilage loss in case than in reference knees in the lateral, rather than medial, femorotibial compartment., Conclusions: Radiographically normal knees with contralateral JSN may serve as a human model of early OA, for testing disease modifying drugs in clinical trials designed to prevent cartilage loss before the onset of radiographic change. CLINICALTRIALS., Gov Identification: NCT00080171., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Contralateral knee pain has been suggested to be associated with muscle weakness in a pain-free knee, potentially through a mechanism of central nervous inhibition. Whether contralateral knee pain also affects muscle strength in a painful knee, however, is unknown. Here we study the extent to which isometric muscle strength differs between matched painful limbs of people with unilateral knee pain vs. matched painful limbs people with bilateral knee pain. To that end, 163 participants with unilateral knee pain were identified from the Osteoarthritis Initiative. Unilaterally painful (UP) limbs were defined as having numerical rating scale (NRS) ≥4/10, infrequent/frequent pain in the painful limb, while contralateral pain-free limbs were defined by NRS=0-1, no/infrequent pain and Western Ontario and McMaster Universities Arthritis Index (WOMAC) ≤1. The comparator group were matched bilaterally painful (BP) limbs. Maximum isometric muscle strength (N) was compared between 1:1 matched BP and UP limbs. Extensor strength was found to be lower in BP limbs than in UP limbs, (-2.9%; p=0.39) but this difference was not statistically significant. Extensor strength was significantly lower in the UP vs. contralateral pain-free limbs (-6.2%; p<0.001). No differences were observed between BP and contralateral painful limbs (0.6%; p=0.87). In conclusion, the current results identify a slight reduction of maximum knee extensor strength in a painful limb, when the contralateral knee is also painful. In contrast to pain-free limbs, this effect did not reach statistical significance, but the overall findings support the concept of central nervous inhibition of muscle strength by contralateral knee pain., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Objective: To assess structural progression in knees with no/mild radiographic osteoarthritis (OA) (i.e., Kellgren/Lawrence [K/L] grades 0-2) that will undergo knee replacement during a 5-year period; to assess differences in structural damage on magnetic resonance imaging (MRI) in knees with no/mild radiographic OA versus those with severe radiographic OA (i.e., K/L grades 3 and 4) at baseline; and to assess differences in pain levels between those groups., Methods: All participants who underwent knee replacement from baseline to 60 months were drawn from the Osteoarthritis Initiative. MRIs were assessed for bone marrow lesions (BMLs), Hoffa synovitis, and effusion synovitis (i.e., hyperintensity signal changes in the fat pad and abnormal amount of capsular distension due to intraarticular joint fluid and/or synovial thickening) at baseline and at the time point before knee replacement (T0). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score (KOOS) pain were used for pain characterization. WOMAC activities of daily living and KOOS quality of life were applied to characterize functional status of the included participants. Logistic regression was used to assess the association of no/mild radiographic OA with these MRI features and pain., Results: Based on inclusion criteria, 181 knees were selected. Participants were predominantly female (57.8%) with a mean age of 64.4 years. A total of 51 knees (28.2%) had no/mild radiographic OA at baseline. Of these, 51.0% progressed to severe radiographic OA. No/mild radiographic OA knees showed higher odds of BMLs in the patellofemoral joint at baseline (odds ratio [OR] 7.92 [95% confidence interval (95% CI) 3.45-18.16]) and T0 (OR 9.44 [95% CI 4.00-22.28]) compared to severe radiographic OA knees. In addition, no/mild radiographic OA knees were associated with change from no pain to pain from baseline to T0 (adjusted OR 5.48 [95% CI 1.25-24.00])., Conclusion: More than half of the knees with no/mild radiographic OA before knee replacement progressed to severe radiographic OA during 4 years of follow-up. BMLs in the patellofemoral joint were more often seen among knees that had no/mild radiographic OA. Worsening pain status may contribute to knee replacement in knees with no/mild radiographic OA., (© 2018, American College of Rheumatology.)

Objective: To determine whether 3D meniscal measures had similar sensitivity to longitudinal change as cartilage thickness; to what extent these measures are associated with longitudinal joint space width (JSW) change; and whether the latter associations differ between minimum (mJSW) and fixed-location JSW., Methods: Two-year changes in medial meniscal position and morphology, cartilage thickness (MRI) and minimum and fixed-location JSW (radiography) were determined in 35 Osteoarthritis Initiative knees [12 men, age: 67 (51-77) years; 23 women, age: 65 (54-78) years], progressing from baseline Kellgren-Lawrence grade ≤2 to knee replacement within 3-5 years. Multiple linear regression assessed the features contributing to JSW change., Results: Meniscal measures, cartilage thickness and JSW displayed similar sensitivity to change (standardised response mean≤|0.76|). Meniscal changes were strongly associated with JSW change (r≤|0.66|), adding ≤20% to its variance in addition to cartilage thickness change. Fixed-location JSW change (multiple r 2 =72%) was more strongly related to cartilage and meniscal change than mJSW (61%). Meniscal morphology explained more of fixed-location JSW and meniscal position more of mJSW., Conclusion: Meniscal measures provide independent information in explaining the variance of radiographic JSW change. Fixed-location JSW appears to be more reflective of structural change than mJSW and, hence, a potentially superior measure of structural progression., Key Points: • 3D positional/morphological meniscal measures change in rapidly progressing knees. • Similar sensitivity to 2-year change of quantitative meniscal/cartilage measures in rapid progression. • Changes in meniscal measures are strongly associated with radiographic JSW change. • Meniscal change provides information to explain JSW variance independent of cartilage. • Fixed-location JSW reflects structural disease stage more closely than minimum JSW.

Objective: To determine whether loss in thigh muscle strength prior to knee replacement is caused by reductions of muscle strength in the anatomic cross-sectional area or by reductions of specific strength., Methods: All 100 of the participants in the Osteoarthritis Initiative who underwent knee replacement and whose medical records included data on thigh isometric muscle strength and magnetic resonance imaging (MRI) (58 women, and 42 men, mean ± SD age 65 ± 8 years, mean ± SD body mass index [BMI] 29 ± 5 kg/m 2 ) were matched with a control (no knee replacement) for age, sex, height, BMI, and radiographic severity. Thigh muscle anatomic cross-sectional area was determined by MRI at the research visit before knee replacement (time 0) and 2 years before time 0 (time -2). Specific strength (strength/anatomic cross-sectional area) was calculated, and the measures were compared by conditional logistic regression (i.e., odds ratio [OR] per standard deviation). ORs adjusted for pain (OR adj ) and 95% confidence intervals (95% CIs) were also calculated., Results: Knee replacement cases had significantly smaller extensor (but not flexor) anatomic cross-sectional areas than controls at time 0 (women, OR adj 1.89 [95% CI 1.05-3.90]; men, OR adj 2.22 [95% CI 1.04-4.76]), whereas no significant differences were found at time -2. Women who had knee replacement showed lower levels of extensor specific strength than controls at time 0 (OR 1.59 [95% CI 1.02-2.50]), although this difference was not observed in men and did not maintain significance after adjustment for pain (OR adj 1.22 [95% CI 0.71-2.08]). Female cases lost significantly more extensor specific strength between time -2 and time 0 than controls (OR adj 3.76 [95% CI 1.04-13.60]), whereas no significant differences were noted at time -2, or in men., Conclusion: Prior to knee replacement, a significant reduction in knee extensor strength appears to occur in women through 2 mechanisms: one driven by pain (loss of specific strength) and one independent of pain (loss of muscle anatomic cross-sectional area). Men who underwent knee replacement showed significantly reduced levels of extensor anatomic cross-sectional area, but not significantly lower strength or specific strength., (© 2017, American College of Rheumatology.)

Introduction: In knee osteoarthritis, local increase and decrease in cartilage thickness has been observed over short time intervals. Hence, averaging cartilage change across large regions may not capture the complexity of structural alterations in disease progression. This study aims to examine the relative performance of different metrics of cartilage thickness change for different clinical studies scenarios., Materials and Methods: Metrics for assessing cartilage thickness change were characterized by conventional measures of change versus absolute values (the magnitude) of change, and by different methods of summarizing change over (sub-) regions. Sample sizes for these metrics were derived for 6-24-month observation periods, and for different treatment efficacies. Treatment effects were derived from an observational trial with 6-, 12-, and 24-month follow-up, ranging from slowing cartilage loss to stimulating cartilage growth., Results: Projected sample sizes ranged from 10 to >10,000 patients/arm (median = 164), depending on metric choice, treatment efficacy, and observation period. The smallest sample sizes for metrics using magnitude of change typically were half the size of those using conventional measures of change. Extreme values, e.g., minimum change or average of last four-ordered values of absolute change, required smaller sample sizes than metrics averaging over one or more regions., Conclusions: Metrics using extreme magnitudes of change were most efficient in detecting differences between treatment and placebo, i.e., involved the smallest sample sizes across different DMOAD study lengths and treatment efficacies. Ancillary metrics can be used to clarify whether differences between treatment and placebo indicate structural benefit when needed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The infra-patellar fat pad (IPFP) has been proposed to represent an endocrine link between obesity and knee osteoarthritis (OA). The purpose of the current study has been to explore the extent to which IPFP volume is related to body mass index (BMI). A total of 152 participants (age 56±7 years) without knee OA were studied. These consisted of 19 men and 19 women of normal weight (BMI 18.5-25), 19/19 pre-obese (BMI 25-30), 19/19 obese class I (BMI 30-35) and 19/19 obese class II (BMI 35-40), who were matched 1:1 for age and height. The IPFP volume was manually segmented from sagittal fat-suppressed magnetic resonance images (MRI). An ANOVA of repeated measures was used to assess whether IPFP volume was related to BMI. The IPFP volume differed significantly between the BMI strata (ANOVA: p=0.001): It was 27.1±6.7cm 3 (mean±SD) in normal weight, 29.3±6.9cm 3 in pre-obese, 31.0±6.9cm 3 in obese class I, and 30.4±6.6cm 3 in obese class II participants; the difference in IPFP volume (and body weight) relative to normal weight subjects was 10% (18%) in pre-obese, 17% (39%) in obese class I, and 15% (59%) in obese class II participants. Stratification by sex showed similar results. In conclusion, IPFP volume is shown to be related to BMI, albeit the relative increase (compared with normal weight) does not appear to be proportional to that in body weight. Nonetheless, these findings support the hypothesis that the IPFP may represent a potential endocrine link between obesity and OA, with more intra-articular adipose tissue potentially releasing greater amounts of adipokines., (Copyright © 2017. Published by Elsevier GmbH.)

Objective: To cross-sectionally determine the quantitative relationship of age-adjusted, sex-specific isometric knee extensor and flexor strength to patient-reported knee pain., Methods: Difference of thigh muscle strength by age, and that of age-adjusted strength per unit increase on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain scale, was estimated from linear regression analysis of 4553 Osteoarthritis Initiative (OAI) participants (58% women). Strata encompassing the minimal clinically important difference (MCID) in knee pain were compared to evaluate a potentially non-linear relationship between WOMAC pain levels and muscle strength., Results: In OAI participants without pain, the age-related difference in isometric knee extensor strength was -9.0%/-8.2% (women/men) per decade, and that of flexor strength was -11%/-6.9%. Differences in age-adjusted strength values for each unit of WOMAC pain (1/20) amounted to -1.9%/-1.6% for extensor and -2.5%/-1.7% for flexor strength. Differences in torque/weight for each unit of WOMAC pain ranged from -3.3 to -2.1%. There was no indication of a non-linear relationship between pain and strength across the range of observed WOMAC values, and similar results were observed in women and men., Conclusion: Each increase by 1/20 units in WOMAC pain was associated with a ∼2% lower age-adjusted isometric extensor and flexor strength in either sex. As a reduction in muscle strength is known to prospectively increase symptoms in knee osteoarthritis (KOA) and as pain appears to reduce thigh muscle strength, adequate therapy of pain and muscle strength is required in KOA patients to avoid a vicious circle of self-sustaining clinical deterioration., (Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To explore to what extent three-dimensional measures of the meniscus and femorotibial cartilage explain the variation in medial and lateral femorotibial radiographic joint space width (JSW), in healthy men and women., Methods: The right knees of 87 Osteoarthritis Initiative healthy reference participants (no symptoms, radiographic signs or risk factors of osteoarthritis; 37 men, 50 women; age 55.0±7.6; BMI 24.4±3.1) were assessed. Quantitative measures of subregional femorotibial cartilage thickness and meniscal position and morphology were computed from segmented magnetic resonance images. Minimal and medial/lateral fixed-location JSW were determined from fixed-flexion radiographs. Correlation and regression analyses were used to explore the contribution of demographic, cartilage and meniscal parameters to JSW in healthy subjects., Results: The correlation with (medial) minimal JSW was somewhat stronger for cartilage thickness (0.54≤r≤0.67) than for meniscal (-0.31≤r≤0.50) or demographic measures (-0.15≤r≤0.48), in particular in men. In women, in contrast, the strength of the correlations of cartilage thickness and meniscal measures with minimal JSW were in the same range. Fixed-location JSW measures showed stronger correlations with cartilage thickness (r≥0.68 medially; r≥0.59 laterally) than with meniscal measures (r≤|0.32| medially; r≤|0.32| laterally). Stepwise regression models revealed that meniscal measures added significant independent information to the total variance explained in minimal JSW (adjusted multiple r 2 =58%) but not in medial or lateral fixed-location JSW (r 2 =60/51%, respectively)., Conclusions: In healthy subjects, minimal JSW was observed to reflect a combination of cartilage and meniscal measures, particularly in women. Fixed-location JSW, in contrast, was found to be dominated by variance in cartilage thickness in both men and women, with somewhat higher correlations between cartilage and JSW in the medial than lateral femorotibial compartment. The significant contribution of the meniscus' position on minimal JSW reinforces concerns over validity of JSW as an indirect measure of hyaline cartilage., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The infrapatellar fat pad (IPFP) represents intra-articular adipose tissue that may contribute to intra-articular inflammation and pain by secretion of proinflammatory cytokines. Here we examined the impact of weight loss by diet and/or exercise interventions on the IPFP volume., Methods: Intensive Diet and Exercise for Arthritis (IDEA) was a single-blinded, single-center, 18-month, prospective, randomized controlled trial that enrolled 454 overweight and obese older adults with knee pain and radiographic osteoarthritis. Participants were randomized to 1 of 3 groups: exercise-only control (E), diet-induced weight loss (D), and diet-induced weight loss + exercise (D+E). In a subsample (n = 106; E: n = 36, D: n = 35, and D+E: n = 35), magnetic resonance images were acquired at baseline and at the 18-month follow-up, from which we analyzed IPFP volume, surface areas, and thickness in this secondary analysis., Results: The average weight loss amounted to 1.0% in the E group, 10.5% in the D group, and 13.0% in the D+E group. A significant (p < 0.01) reduction in IPFP volume was observed in the E (2.1%), D (4.0%), and D+E (5.2%) groups. The IPFP volume loss in the D+E group was significantly greater than that in the E group (p < 0.05) when not adjusting for parallel comparisons. Across intervention groups, there were significant correlations between IPFP volume change, individual weight loss (r = 0.40), and change in total body fat mass (dual-energy X-ray absorptiometry; r = 0.44, n = 88) and in subcutaneous thigh fat area (computed tomography; r = 0.32, n = 82)., Conclusions: As a potential link between obesity and knee osteoarthritis, the IPFP was sensitive to intervention by diet and/or exercise, and its reduction was correlated with changes in weight and body fat., (© 2017 S. Karger AG, Basel.)

Background: Knee joint distraction (KJD) is a surgical joint-preserving treatment in which the knee joint is temporarily distracted by an external frame. It is associated with joint tissue repair and clinical improvement. Initially, patients were submitted to an eight-week distraction period, and currently patients are submitted to a six-week distraction period. This study evaluates whether a shorter distraction period influences the outcome., Methods: Both groups consisted of 20 patients. Clinical outcome was assessed by WOMAC questionnaires and VAS-pain. Cartilaginous tissue repair was assessed by radiographic joint space width (JSW) and MRI-observed cartilage thickness., Results: Baseline data between both groups were comparable. Both groups showed an increase in total WOMAC score; 24±4 in the six-week group and 32±5 in the eight-week group (both p<0.001). Mean JSW increased 0.9±0.3mm in the six-week group and 1.1±0.3mm in the eight-week group (p=0.729 between groups). The increase in mean cartilage thickness on MRI was 0.6±0.2mm in the eight-week group and 0.4±0.1mm in the six-week group (p=0.277)., Conclusions: A shorter distraction period does not influence short-term clinical and structural outcomes statistically significantly, although effect sizes tend to be smaller in six week KJD as compared to eight week KJD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: A recent publication on efficacy of Sprifermin for knee osteoarthritis (OA) using quantitatively MRI-defined central medial tibio-femoral compartment cartilage thickness as the structural primary endpoint reported no statistically significant dose response. However, Sprifermin was associated with statistically significant, dose-dependent reductions in loss of total and lateral tibio-femoral cartilage thickness. Based on these preliminary promising data a post-hoc analysis of secondary assessment and endpoints was performed to evaluate potential effects of Sprifermin on semi-quantitatively evaluated structural MRI parameters. Aim of the present analysis was to determine effects of sprifermin on several knee joint tissues over a 12 month period., Methods: 1.5 T or 3 T MRIs were acquired at baseline and 12 months follow-up using a standard protocol. MRIs were read according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) scoring system (in 14 articular subregions) by four muskuloskeletal radiologists independently. Analyses focused on semiquantitative changes in the 100 μg subgroup and matching placebo of multiple MRI-defined structural alterations. Analyses included a delta-subregional and delta-sum approach for the whole knee and the medial and lateral tibio-femoral (MTFJ, LTFJ), and patello-femoral (PFJ) compartments, taking into account number of subregions showing no change, improvement or worsening and changes in the sum of subregional scores. Mann-Whitney - Wilcoxon tests assessed differences between groups., Results: Fifty-seven and 18 patients were included in the treatment and matched placebo subgroups. Less worsening of cartilage damage was observed from baseline to 12 months in the PFJ (0.02, 95 % confidence interval (CI) (-0.04, 0.08) vs. placebo 0.22, 95 % CI (-0.05, 0.49), p = 0.046). For bone marrow lesions (BMLs), more improvement was observed from 6 to 12 months for whole knee analyses (-0.14, 95 % CI (-0.48, 0.19) vs. placebo 0.44, 95 % CI (-0.15, 1.04), p = 0.042) although no significant effects were seen from the baseline visit, or in Hoffa-synovitis, effusion-synovitis, menisci and osteophytes., Conclusions: In this post-hoc analysis cartilage showed less worsening from baseline to 12 months in the PFJ, and BMLs showed more improvement from 6 to 12 months for the whole knee., Trial Registration: ClinicalTrials.gov identifier: NCT01033994 .

Objective: To evaluate whether change in fixed-location measures of radiographic joint space width (JSW) and cartilage thickness by MRI predict knee replacement., Methods: Knees replaced between 36 and 60 months' follow-up in the Osteoarthritis Initiative were each matched with one control by age, sex and radiographic status. Radiographic JSW was determined from fixed flexion radiographs and subregional femorotibial cartilage thickness from 3 T MRI. Changes between the annual visit before replacement (T0) and 2 years before T0 (T-2) were compared using conditional logistic regression., Results: One hundred and nineteen knees from 102 participants (55.5 % women; age 64.2 ± 8.7 [mean ± SD] years) were studied. Fixed-location JSW change at 22.5 % from medial to lateral differed more between replaced and control knees (case-control [cc] OR = 1.57; 95 % CI: 1.23-2.01) than minimum medial JSW change (ccOR = 1.38; 95 % CI: 1.11-1.71). Medial femorotibial cartilage loss displayed discrimination similar to minimum JSW, and central tibial cartilage loss similar to fixed-location JSW. Location-independent thinning and thickening scores were elevated prior to knee replacement., Conclusions: Discrimination of structural progression between knee pre-placement cases versus controls was stronger for fixed-location than minimum radiographic JSW. MRI displayed similar discrimination to radiography and suggested greater simultaneous cartilage thickening and loss prior to knee replacement., Key Points: • Fixed-location JSW predicts surgical knee replacement more strongly than minimum JSW. • MRI predicts knee replacement with similar accuracy to radiographic JSW. • MRI reveals greater cartilage thinning and thickening prior to knee replacement.

Objective: To determine whether thigh muscle strength predicts the risk of undergoing knee replacement surgery, independent of radiographic severity of osteoarthritis and pain., Methods: Participants in the Osteoarthritis Initiative study who had received a knee replacement between the 12-month and 60-month follow-up visits (cases) were each matched with 1 control subject (who did not receive a knee replacement over 60 months) for age, sex, height, body mass index, baseline radiographic stage, and location of joint space narrowing. Isometric knee extensor and flexor strength was recorded biennially. The strength examination prior to knee replacement (≤2 years) was termed time 0, that 2 years prior to time 0 was termed time -2, and that 4 years prior to time 0 was termed time -4. Muscle strength in patients and controls was compared using paired t-tests and conditional logistic regression analysis adjusted for pain., Results: One hundred thirty-six participants (60% women, mean ± SD age 65 ± 9 years, body mass index 29 ± 4 kg/m(2) ) received a knee replacement during follow-up, had strength data for at least time 0, and had a matched control. Knee extensor strength at time 0 (primary outcome measure) was significantly lower in female patients compared with controls (P < 0.001, pain-adjusted odds ratio [ORadj ] 1.72, 95% confidence interval 1.16-2.56), but no significant difference was observed in men. Results were similar for knee flexor strength at time 0 and for longitudinal change in extensor and flexor strength between time -2 and time 0. Thigh muscle strength at time -2 or time -4, or change between time -4 and time -2, did not predict the risk of undergoing knee replacement surgery in men or women., Conclusion: Thigh muscle strength predicted the risk of undergoing knee replacement surgery in women, but not in men. The results of this study may identify a window during which the risk of undergoing knee replacement surgery in women can be modified., (© 2016, American College of Rheumatology.)

Objective: To investigate whether a clinically relevant change in knee function in patients with or at risk for osteoarthritis (OA) of the knee is associated with concurrent or prior change in thigh muscle strength., Methods: Participants in the Osteoarthritis Initiative (n = 2,675 [1,485 women and 1,190 men]) with available measurements of isometric muscle strength at baseline, 2-year follow-up, and 4-year follow-up were grouped into those with greater than minimum clinically important worsening (score of ≥6 [of a possible 68] on the Western Ontario and McMaster Universities Osteoarthritis Index function subscale) between 2-year follow-up and 4-year follow-up, those with greater than minimum clinically important improvement, and those without relevant change. Changes in isometric muscle strength concurrent with function change (between 2-year follow-up and 4-year follow-up) and preceding function change (between baseline and 2-year follow-up), with 95% confidence intervals (95% CIs), were determined, and differences between groups were assessed by analysis of covariance., Results: Concurrent loss in extensor muscle strength in participants with worsening knee function during the 2-year follow-up-4-year follow-up period differed significantly from that in participants without change in knee function (-4.6% [95% CI -6.8, -2.4] and -2.2% [95% CI -3.0, -1.4], respectively; P = 0.03), as did the concurrent increase in strength among those with functional improvement (2.2% [95% CI -0.3, 4.7]; P < 0.0001). This increase in strength among subjects with improved function remained significantly different from the change in subjects with no change in function after adjustment for covariates, but was preceded by a greater loss in strength (-7.7% [95% CI -10.3, -5.0], P = 0.02) during the baseline-year 2 period compared to those without change in function during the year 2-year 4 period (-4.3% [95% CI -5.2, -3.4]). The decrease in strength during the baseline-year 2 period in those with worsening knee function during the year 2-year 4 period (-4.5% [95% CI -6.9, -2.2]) did not differ significantly from that in patients without a change in function (P = 0.87). No differences in changes in flexor muscle strength were observed between groups., Conclusion: These findings suggest that there is a positive concurrent longitudinal association between change in extensor muscle strength and worsening/improvement in knee function in patients with knee OA. However, a corresponding change in thigh muscle strength preceding the change in function was not observed., (© 2016, American College of Rheumatology.)

Objective: To determine how frontal plane lower limb alignment obtained using a new femorotibial angle (FTA) measurement and non-radiographic handheld goniometry, predict femorotibial cartilage thickness loss in varus and valgus knees, compared with the gold standard mechanical axis (hip-knee-ankle [HKA])., Methods: 934 Osteoarthritis (OA) Initiative knees with radiographic OA had the above alignment measures and 3T knee MRIs acquired. The new FTA measure was compared to the gold standard, with and without adjusting FTA for the sex-specific varus shift. Changes in medial (MFTC) and lateral femorotibial (LFTC) cartilage thickness were quantified over 1-year and 2-years. Adjusted odds ratios (adjORs) were used to compare how the different alignment measures predict medial and lateral cartilage loss in varus and valgus knees., Results: Pearson correlation coefficients between 2-year MFTC/LFTC cartilage loss and alignment measures were small to moderate, and were similar for FTA (r = 0.28/-0.30) and for HKA (r = 0.28/-0.29). Using the adjusted FTA measure, varus and valgus predicted MFTC progression (adjOR = 3.73) and LFTC progression (adjOR = 2.55) as well as HKA (adjOR = 3.16 and 2.31) over 1-year, and this relationship was also observed over 2-years. Goniometry was a weak predictor for MFTC and LFTC progression (adjOR1-year = 1.65 and 1.71; adjOR2-year = 0.68 and 1.24)., Conclusions: After adjustment, the new FTA measure obtained from short (fixed-flexion) knee films was as good as the gold standard in predicting medial and lateral cartilage loss over 1- or 2-years, without need for obtaining long-limb radiographs for determining the mechanical axis. Goniometry and non-adjusted FTA measures, in contrast, were poor predictors of cartilage loss., (Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To test the hypothesis that quantitative measures of meniscus extrusion predict incident radiographic knee osteoarthritis (KOA), prior to the advent of radiographic disease., Methods: 206 knees with incident radiographic KOA (Kellgren Lawrence Grade (KLG) 0 or 1 at baseline, developing KLG 2 or greater with a definite osteophyte and joint space narrowing (JSN) grade ≥1 by year 4) were matched to 232 control knees not developing incident KOA. Manual segmentation of the central five slices of the medial and lateral meniscus was performed on coronal 3T DESS MRI and quantitative meniscus position was determined. Cases and controls were compared using conditional logistic regression adjusting for age, sex, BMI, race and clinical site. Sensitivity analyses of early (year [Y] 1/2) and late (Y3/4) incidence was performed., Results: Mean medial extrusion distance was significantly greater for incident compared to non-incident knees (1.56 mean ± 1.12 mm SD vs 1.29 ± 0.99 mm; +21%, P < 0.01), so was the percent extrusion area of the medial meniscus (25.8 ± 15.8% vs 22.0 ± 13.5%; +17%, P < 0.05). This finding was consistent for knees restricted to medial incidence. No significant differences were observed for the lateral meniscus in incident medial KOA, or for the tibial plateau coverage between incident and non-incident knees. Restricting the analysis to medial incident KOA at Y1/2 differences were attenuated, but reached significance for extrusion distance, whereas no significant differences were observed at incident KOA in Y3/4., Conclusion: Greater medial meniscus extrusion predicts incident radiographic KOA. Early onset KOA showed greater differences for meniscus position between incident and non-incident knees than late onset KOA., (Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the association of cartilage thickness change over 24 months, as determined by magnetic resonance imaging (MRI), with knee osteoarthritis (OA) progression at 24-48 months., Methods: This nested case-control study included 600 knees with a baseline Kellgren/Lawrence (K/L) grade of 1-3 from 600 Osteoarthritis Initiative (OAI) participants. Case knees (n = 194) had both medial tibiofemoral radiographic joint space loss (≥0.7 mm) and a persistent increase in the Western Ontario and McMaster Universities Osteoarthritis Index pain score (≥9 on a 0-100 scale) 24-48 months from baseline. Control knees (n = 406) included 200 with neither radiographic nor pain progression, 103 with radiographic progression only, and 103 with pain progression only. Medial and lateral femorotibial cartilage was segmented from sagittal 3T MRIs at baseline, 12 months, and 24 months. Logistic regression was used to assess the association of change in cartilage thickness, with a focus on the central medial femorotibial compartment, and OA progression., Results: Central medial femorotibial compartment thickness loss was significantly associated with case status, with an odds ratio (OR) of 1.9 (95% confidence interval [95% CI] 1.6-2.3) (P < 0.0001). Association with case status reached P < 0.05 for both the central femur (OR 1.8 [95% CI 1.5-2.2]) and the central tibia (OR 1.6 [95% CI 1.3-1.9]). Lateral femorotibial compartment cartilage thickness loss, in contrast, was not significantly associated with case status. A reduction in central medial femorotibial compartment cartilage thickness was strongly associated with radiographic progression (OR 4.0 [95% CI 2.9-5.3]; P < 0.0001) and only weakly associated with pain progression (OR 1.3 [95% CI 1.1-1.6]; P < 0.01)., Conclusion: Our findings indicate that loss of medial femorotibial cartilage thickness over 24 months is associated with the combination of radiographic and pain progression in the knee, with a stronger association for radiographic progression., (© 2015, American College of Rheumatology.)

Objective: To evaluate the extent to which the current designs of clinical trials in knee osteoarthritis (OA) permit detection of a therapeutic effect of disease-modifying OA drugs (DMOADs) on the incidence of knee replacement, and to provide estimates of the required sample sizes., Methods: We selected distinct subcohorts of the Osteoarthritis Initiative (OAI), based on available information on eligibility criteria for clinical knee OA trials (ClinicalTrials.gov) and additional subcohorts stratified for age, sex, and the severity of radiographic OA. The observed incidence of knee replacement in these OAI subcohorts was used to estimate the expected incidence of knee replacement in the control group of a clinical trial. Based on this estimate, the sample sizes required to detect hypothetical treatment effects on the incidence of knee replacement were calculated, assuming observation periods of 2, 5, or 7 years., Results: The cumulative knee replacement incidence rates in the OAI subcohorts ranged from 0.9% to 12.9%. The corresponding sample sizes required to detect 50% improvement by the DMOAD, with a power of 80% and 95% confidence, were 5,459 and 362, respectively. Including only women with advanced age and radiographic OA increased the incidence of knee replacement and decreased the required sample size., Conclusion: The sample sizes that are commonly used in clinical trials do not enable the effects of a DMOAD on incident knee replacement to be detected with sufficient power and confidence. The estimated incidence rates of knee replacement and the corresponding sample sizes are important for informing the design of trials for disease course-modifying effects as well as for socioeconomic evaluation of a DMOAD in terms of preventing knee replacement., (© 2015, American College of Rheumatology.)

Objectives: To explore cross-sectional relationships between a new radiographic measure of the femorotibial angle (FTA), the hip-knee-ankle angle (HKA), and the goniometry; to quantify sex differences between measures; and to evaluate the sensitivity of these measures to medial and lateral joint space narrowing (JSN)., Methods: Concurrent validity was evaluated in 2123 knees from the osteoarthritis (OA) initiative using Pearson correlation coefficients (r) and Bland-Altman plots (offsets). Diagnostic validity with respect to JSN was evaluated using areas under the receiver-operating characteristic curves (AUC) and standardized mean differences (SMD). Analyses were stratified by sex and JSN., Results: JSN and sex contributed significantly to regression models predicting offsets between measures (p < 0.001), after controlling for age, BMI, and OA severity. There were weak correlations between FTA vs. goniometry (r: 0.16-0.22), and moderate correlations between FTA vs. HKA (r: 0.25-0.53) and HKA vs. goniometry (r: 0.40-0.67). The offset between the new FTA measure and HKA was larger in females than males (p < 0.001). Offsets between radiographic measures and goniometry also varied by sex and JSN (FTA: 2.9°-7.6°; HKA: 0.5°-2.4°). AUC (0.74-0.91) and SMD (0.53-3.80) between JSN strata were largest for FTA, whereas diagnostic validity was moderate for HKA (AUC: 0.69-0.80; SMD: 0.43-2.04) and weakest for handheld goniometry (AUC: 0.56-0.63; SMD: 0.07-0.90)., Conclusions: Compared to HKA, goniometry demonstrated poor diagnostic validity with respect to JSN. The new FTA measure, in contrast, represented a reasonable surrogate of radiographic disease severity (JSN). The new FTA measure was skewed in the varus direction when compared to HKA and more so in females. This requires cautious interpretation when measurements are related to previous studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To determine whether an anabolic drug (sprifermin) is capable of reducing cartilage loss wherever it occurs in a given knee, using a subject-specific, location-independent analysis of cartilage change in patients with knee osteoarthritis (OA)., Methods: Study participants (n = 168; ages ≥40 years, 69% women) had symptomatic femorotibial OA not confined to the medial compartment. Sprifermin (10, 30, or 100 μg) or placebo was injected intraarticularly 3 times over 3 weeks, both after randomization (baseline) and 3 months later. Coronal magnetic resonance images were acquired at baseline and 3, 6, and 12 months after treatment. The femorotibial cartilage of each subject was segmented, and changes in cartilage thickness were computed across 16 subregions. Location-independent post hoc analysis was used to compute summary scores of negative and positive changes in the subregions, summarized as the total cartilage thinning sum score (ThCTnS) and the total cartilage thickening sum score (ThCTkS), capturing change in either direction in each knee. Ordered values of the magnitude of subject-specific subregional changes in thickness were determined. The ThCTnS and ThCTkS in each sprifermin dose group at 12 months of followup were compared with the values in the matched placebo groups, using the Wilcoxon-Mann-Whitney test., Results: The mean ± SD ThCTnS was -591 ± 617 μm (median -360 μm, Q1/Q3 = -820/-200 μm) in patients treated with 100 μg sprifermin (n = 57), and -921 ± 777 μm (median -745 μm, Q1/Q3 = -1,190/-380 μm) in patients given placebo (n = 18). The mean difference in the ThCTnS between the 100-μg sprifermin group and the placebo group was 331 μm (95% confidence interval [95% CI] 24, 685), a difference that was statistically significant (P = 0.03). The mean difference in the ThCTkS in the 100-μg sprifermin group compared with the placebo group was 237 μm (95% CI 34, 440), also a statistically significant difference (P = 0.028)., Conclusion: Sprifermin not only increases cartilage thickness, but also reduces cartilage loss. Subject-specific, location-independent analysis of both cartilage thinning and thickening represents a sensitive and informative approach for studying the effects of disease-modifying OA drugs., (© 2015, American College of Rheumatology.)

Objective: Knee pain and muscle weakness confer risk for knee osteoarthritis incidence and progression. The purpose of this study was to determine whether unilateral knee pain influences contralateral thigh muscle strength., Design: Of 4796 Osteoarthritis Initiative participants, 224 (mean ± SD age, 63.9 ± 8.9 yrs) cases could be matched to a control. Cases were defined as having unilateral knee pain (numerical rating scale, ≥ 4/10; ≥infrequent pain) and one pain-free knee (numerical rating scale, 0-1; ≤infrequent pain; Western Ontario and McMaster Universities Arthritis Index, ≤ 1). Controls were defined as having bilaterally pain-free knees (numerical rating scale, 0-1; ≤infrequent pain; Western Ontario and McMaster Universities Arthritis Index, ≤ 1). Maximal isometric muscle strength (N) was compared between limbs in participants with unilateral pain (cases) as well as between pain-free limbs of cases and controls., Results: Knee extensor/flexor strength in pain-free limbs of the cases was lower than that in bilaterally pain-free controls (-5.5%/-8.4%; P = 0.043/P = 0.022). Within the cases, maximum extensor/flexor strength was significantly lower in the painful limb than in the pain-free limb (-6.3%/4.1%; P < 0.0001/P = 0.015)., Conclusions: These results suggest that strength in limbs without knee pain is associated with the pain status of the contralateral knee. The strength difference between unilateral pain-free cases and matched bilateral pain-free controls was similar to that between limbs in persons with unilateral knee pain. Lower strength caused by contralateral knee pain might be centrally mediated.

Objective: Test the hypothesis that greater baseline peak external knee adduction moment (KAM), KAM impulse, and peak external knee flexion moment (KFM) during the stance phase of gait are associated with baseline-to-2-year medial tibiofemoral cartilage damage and bone marrow lesion progression, and cartilage thickness loss., Methods: Participants all had knee OA in at least one knee. Baseline peak KAM, KAM impulse, and peak KFM (normalized to body weight and height) were captured and computed using a motion analysis system and six force plates. Participants underwent MRI of both knees at baseline and 2 years later. To assess the association between baseline moments and baseline-to-2-year semiquantitative cartilage damage and bone marrow lesion progression and quantitative cartilage thickness loss, we used logistic and linear regressions with generalized estimating equations (GEE), adjusting for gait speed, age, gender, disease severity, knee pain severity, and medication use., Results: The sample consisted of 391 knees (204 persons): mean age 64.2 years (SD 10.0); BMI 28.4 kg/m(2) (5.7); 156 (76.5%) women. Greater baseline peak KAM and KAM impulse were each associated with worsening of medial bone marrow lesions, but not cartilage damage. Higher baseline KAM impulse was associated with 2-year medial cartilage thickness loss assessed both as % loss and as a threshold of loss, whereas peak KAM was related only to % loss. There was no relationship between baseline peak KFM and any medial disease progression outcome measures., Conclusion: Findings support targeting KAM parameters in an effort to delay medial OA disease progression., (Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess whether the presence of structural osteoarthritis (OA) features over as many as 4 years prior to incident radiographic OA increases the risk of radiographic OA in a nested, case-control design., Methods: We studied 355 knees from the Osteoarthritis Initiative cohort that developed radiographic OA before the 48-month visit. They were matched one-to-one by sex, age, and contralateral knee radiographic status with a control knee. Magnetic resonance images (MRIs) were read for bone marrow lesions (BMLs), cartilage damage, meniscal damage (including tears and extrusion), Hoffa synovitis, and effusion synovitis. Conditional logistic regression was applied to assess the risk of radiographic OA with regard to the presence of BMLs (score ≥2), cartilage lesions (score ≥1.1), meniscal damage (any) and extrusion of ≥3 mm ± (score ≥2), and Hoffa and effusion synovitis (any). Time points were defined as incident radiographic OA visit (P0), 1 year prior to the detection of radiographic OA (P -1), 2 years prior to the detection of radiographic OA (P -2), etc., Results: The presence of Hoffa synovitis (hazard ratio [HR] 1.76 [95% confidence interval (95% CI) 1.18-2.64]), effusion synovitis (HR 1.81 [95% CI 1.18-2.78]), and medial meniscal damage (HR 1.83 [95% CI 1.17-2.89]) at P -2 predicted radiographic OA incidence. At P -1, all features but meniscal extrusion predicted radiographic OA, with highest odds for medial BMLs (HR 6.50 [95% CI 2.27-18.62]) and effusion synovitis (HR 2.50 [95% CI 1.76-3.54]). The findings at P -3 and P -4 did not reach statistical significance., Conclusion: Our findings indicate that the presence of specific structural features of MRI-detected joint damage 2 years prior to incident radiographic OA increases the risk of incident radiographic OA. However, 1 year prior to radiographic OA, the presence of almost any abnormal morphologic feature increases the risk of radiographic OA in the subsequent year., (© 2015, American College of Rheumatology.)

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., (Copyright © 2015 by the American College of Rheumatology.)

Purpose: To assess whether magnetic resonance (MR) imaging-based cross-sectional measures of structural joint damage can be used to predict knee replacement during the following year., Materials and Methods: Participants were drawn from the Osteoarthritis Initiative, a longitudinal observational study that includes 4796 participants who have knee osteoarthritis or are at risk. The HIPAA-compliant protocol was approved by the institutional review boards of all participating centers, and written informed consent was obtained from all participants. During the 5 years of follow-up, 199 knees underwent knee replacement and were matched with 199 control knees that did not undergo knee replacement. Knees were matched according to radiographic disease stage and patient sex and age. All knees that underwent knee replacement and had MR images available from the year before surgery were included. MR images were assessed for cartilage damage, bone marrow lesions, meniscal damage, meniscal extrusion, synovitis, and effusion prior to reported knee replacement. Conditional logistic regression was applied to assess the risk of knee replacement. Analyses were performed on a compartmental and knee level., Results: Participants had a mean age ± standard deviation of 64.2 years ± 8.4 (range, 47-82 years) and were predominantly women (232 of 398 participants, 58.3%). Risk for knee replacement was significantly increased for knees that exhibited two or more subregions with severe cartilage loss (odds ratio [OR], 16.5; 95% confidence interval [CI]: 3.96, 68.76), more than two subregions with bone marrow lesions (OR, 4.00; 95% CI: 1.75, 9.16), medial meniscal maceration (OR, 1.84; 95% CI: 1.13, 2.99), effusion (OR, 4.75; 95% CI: 2.55, 8.85), or synovitis (OR, 2.17; 95% CI: 1.33, 3.56), but not extrusion (OR, 1.00; 95% CI: 0.60,1.67), when compared with knees that did not exhibit these features as the reference standard., Conclusion: Apart from meniscal extrusion, all features of tissue abnormalities at MR imaging were related to clinical prognosis and could be used to predict knee replacement in the following year.

Objective: Anterior cruciate ligament (ACL) rupture involves an increased risk of osteoarthritis. The purpose of this study was to explore changes in cartilage thickness over 5 years after ACL rupture., Methods: A total of 121 young active adults (ages 18-35 years; 26% women) from the Knee ACL, Nonsurgical versus Surgical Treatment (KANON) study, who had acute traumatic rupture of the ACL were studied. Sagittal magnetic resonance images were acquired within 4 weeks of ACL rupture (baseline) and at the 2-year and 5-year followup assessments. Medial and lateral femorotibial cartilage was segmented (with blinding to acquisition order), and the mean cartilage thickness was computed across 16 femorotibial subregions. Total femorotibial cartilage thickness change was the primary analytic focus. Maximal subregional mean cartilage thickness loss (ordered value 1 [OV1]) and gain (ordered value 16 [OV16]), independent of its specific location in individual knees, were the secondary analytic focus., Results: Overall femorotibial cartilage thickness increased by 31 μm/year over 5 years (95% confidence interval 18, 44). The increase was similar in men and women and was significantly greater in those younger, as compared with those older, than the median age (25.3 years). The rate of total cartilage thickness change did not differ significantly between the first 2 years and the later 3 years. However, the maximal annualized subregional cartilage loss (OV1) and gain (OV16) were both significantly greater (P < 0.001 and P < 0.05, respectively) during the earlier interval than during the later interval (-115 versus -54 μm [OV1] and 116 versus 69 μm [OV16])., Conclusion: Cartilage thickening was observed over 5 years following ACL injury, particularly in the medial femorotibial compartment and in younger subjects. Major perturbations in cartilage homeostasis were seen over the first 2 years after ACL rupture, with simultaneous subregional thinning and thickening occurring within the same cartilage plate or compartment., (Copyright © 2015 by the American College of Rheumatology.)

Objective: To determine the association between changes in the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) index over 2 years as a measure of cartilage proteoglycan concentration, with changes in cartilage thickness in the medial tibiofemoral compartment of knees in middle-aged women., Methods: One hundred and forty-eight women (one knee for each subject) aged ≥40 years were included. 3.0 T MR images of the knee were acquired at baseline, 1 year and 2 years. Three-dimensional (3D) spoiled gradient recalled echo (SPGR) sequences (for cartilage thickness) and 3D inversion recovery-prepared SPGR sequences after dGEMRIC were acquired. Segmentation was performed in the medial central (weight-bearing) femur and tibia to determine cartilage proteoglycan concentration and thickness. The association of change in the dGEMRIC indices between baseline and 1-year follow-up with (a) concomitant changes in cartilage thickness and (b) change in cartilage thickness between 1 and 2 years was assessed using linear regression., Results: In the whole-sample model, a decrease in dGEMRIC indices over time at the central medial femur significantly predicted an increase in cartilage thickness at both the central medial femur (p=0.008) and the medial tibia (p=0.04)., Conclusions: A decrease in dGEMRIC indices was associated with an increase in cartilage thickness in the medial compartment. Our results suggest that an increase in cartilage thickness may also be related to a decrease in proteoglycan concentration, which may represent swelling of cartilage in early stages of degeneration., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Knee replacement (KR) represents a clinically important endpoint of knee osteoarthritis (KOA). Here we examine the 4-year trajectory of femoro-tibial cartilage thickness loss prior to KR vs non-replaced controls., Methods: A nested case-control study was performed in Osteoarthritis Initiative (OAI) participants: Cases with KR between 12 and 60 month (M) follow-up were each matched with one control (without KR through 60M) by age, sex, and baseline radiographic stage. Femoro-tibial cartilage thickness was measured quantitatively using magnetic resonance imaging (MRI) at the annual visit prior to KR occurrence (T0), and at 1-4 years prior to T0 (T-1 to T-4). Cartilage loss between cases and controls was compared using paired t-tests and conditional logistic regression., Results: One hundred and eighty-nine knees of 164 OAI participants [55% women; age 64 ± 8.7; body mass index (BMI) 29 ± 4.5] had KR and longitudinal cartilage data. Comparison of annualized slopes of change across all time points revealed greater loss in the central medial tibia (primary outcome) in KRs than in controls [94 ± 137 vs 55 ± 104 μm; P = 0.0017 (paired t); odds ratio (OR) 1.36 (95% confidence interval (CI): 1.08-1.70)]. The discrimination was stronger for T-2 → T0 [OR 1.61 (1.33-1.95), n = 127] than for T-1 → T0, and was not statistically significant for intervals prior to T-2 [i.e., T-4 → T-2, OR 0.97 (0.67-1.41), n = 60]. Results were similar for total medial femoro-tibial cartilage loss (secondary outcome), and when adjusting for pain and BMI., Conclusions: In knees with subsequent replacement, cartilage loss accelerates in the 2 years, and particularly in the year prior to surgery, compared with controls. Whether slowing this cartilage loss can delay KR remains to be determined., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Imaging in clinical trials is used to evaluate subject eligibility, and/or efficacy of intervention, supporting decision making in drug development by ascertaining treatment effects on joint structure. This review focusses on imaging of bone and cartilage in clinical trials of (knee) osteoarthritis. We narratively review the full-text literature on imaging of bone and cartilage, adding primary experience in the implementation of imaging methods in clinical trials. Aims and constraints of applying imaging in clinical trials are outlined. The specific uses of semi-quantitative and quantitative imaging biomarkers of bone and cartilage in osteoarthritis trials are summarized, focusing on radiography and magnetic resonance imaging (MRI). Studies having compared both imaging methodologies directly and those having established a relationship between imaging biomarkers and clinical outcomes are highlighted. To make this review of practical use, recommendations are provided as to which imaging protocols are ideal for capturing specific aspects of bone and cartilage tissue, and pitfalls in their usage are highlighted. Further, the longitudinal sensitivity to change, of different imaging methods is reported for various patient strata. From these power calculations can be accomplished, provided the strength of the treatment effect is known. In conclusion, current imaging methodologies provide powerful tools for scoring and measuring morphological and compositional aspects of most articular tissues, capturing longitudinal change with reasonable to excellent sensitivity. When employed properly, imaging has tremendous potential for ascertaining treatment effects on various joint structures, potentially over shorter time scales than required for demonstrating effects on clinical outcomes., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the rate and sensitivity to change of quantitative cartilage thickness change with magnetic resonance imaging (MRI) across specific radiographic strata of knee osteoarthritis (KOA) from central expert readings of the Osteoarthritis Initiative (OAI). Specifically, we explored whether Kellgren Lawrence grade (KLG) 2 knees with radiographic joint space narrowing (JSN) displayed greater cartilage loss than those without JSN, and whether knees with medial JSN grade2 had greater loss than those with grade1., Methods: One-year femorotibial cartilage thickness change was obtained for 836 knees, 112 without, and 724 with definite radiographic KOA based on baseline site readings. The maximum subregional cartilage loss, and cartilage thickness change in the total femorotibial joint (FTJ) and medial femorotibial compartment (MFTC) were analyzed across different radiographic strata (central vs site readings)., Results: The maximum subregional rate of change was significantly greater in central&#95;KLG2 knees with than in those without JSN (172 ± 152 vs 134 ± 100 μm; P = 0.03). In contrast, the rate did not differ significantly between central&#95;KLG1 knees with and without JSN. MFTC cartilage loss in central&#95;medial&#95;grade2 JSN knees was substantially and significantly greater than in grade1 knees (-70 ± 159 vs -31 ± 126 μm; P = 0.02). For comparison, the loss in grade3 knees was -72 ± 122 μm., Conclusions: In KLG2 knees, presence of radiographic JSN was associated with significantly and substantially greater rates of subregional cartilage loss. Differentiating knees with mild vs moderate medial JSN, and definite radiographic OA knees with vs without JSN is important in predicting structural progression of KOA, and for planning clinical trials testing the efficacy of disease modifying drugs (DMOADs)., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Cartilage spin-spin magnetic resonance imaging (MRI) relaxation time (T2) represents a promising imaging biomarker of "early" osteoarthritis (OA) known to be associated with cartilage composition (collagen integrity, orientation, and hydration). However, no longitudinal imaging studies have been conducted to examine cartilage maturation in healthy subjects thus far. Therefore, we explore T2 change in the deep and superficial cartilage layers at the end of adolescence., Methods: Twenty adolescent and 20 mature volleyball athletes were studied (each 10 men and 10 women). Multi-echo spin-echo (MESE) images were acquired at baseline and 2-year follow-up. After segmentation, cartilage T2 was calculated in the deep and superficial cartilage layers of the medial tibial (MT) and the central, weight-bearing part of the medial femoral condyle (cMF), using five echoes (TE 19.4-58.2 ms)., Results: 16 adolescent (6 men, 10 women, baseline age 15.8 ± 0.5 years) and 17 mature (nine men, eight women, age 46.5 ± 5.2 years) athletes had complete baseline and follow-up images of sufficient quality to compute T2. In adolescents, a longitudinal decrease in T2 was observed in the deep layers of MT (-2.0 ms; 95% confidence interval (CI): [-3.4, -0.6] ms; P < 0.01) and cMF (-1.3 ms; [-2.4, -0.3] ms; P < 0.05), without obvious differences between males and females. No significant change was observed in the superficial layers, or in the deep or superficial layers of the mature athletes., Conclusion: In this first pilot study on quantitative imaging of cartilage maturation in healthy, athletic subjects, we find evidence of cartilage compositional change in deep cartilage layers of the medial femorotibial compartment in adolescents, most likely related to organizational changes in the collagen matrix., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine whether thigh muscle strength differs between symptomatic and asymptomatic knees, and/or different radiographic strata of knee osteoarthritis (KOA)., Methods: Isometric extensor and flexor strength were analyzed in 3,809 Osteoarthritis Initiative participants (2,201 women and 1,608 men) with central radiographic Kellgren/Lawrence (K/L) grade readings. Isometric strength measurements were stratified by radiographic disease status (K/L grades 0, 1, 2, and 3/4) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores. Age-adjusted, separate-slopes analysis of covariance models was used to compare strength between "symptomatic" (WOMAC score range 5-20) and "asymptomatic" (WOMAC score = 0) legs within and across K/L grade strata. Exploratory analyses focused on strength normalized to body weight and symptom frequency., Results: Isometric strength was significantly lower in symptomatic than in asymptomatic legs: -11 to -13% for extensor strength and -7 to -16% for flexor strength (P < 0.0001 for both) in men, and -9 to -17% (P = 0.029) for extensor strength, and -10 to -21% (P = 0.049) for flexor strength in women. Similar observations were made for pain frequency strata. Extensor and flexor strength were not significantly different across K/L grade strata in asymptomatic legs in either sex (P ≥ 0.12). However, strength normalized to body weight was lower at higher K/L grades in both sexes (P ≤ 0.02) because the body mass index was greater in participants with more advanced radiographic disease., Conclusion: Knee symptoms (i.e., pain) appear to be the relevant determinant of isometric knee extensor and flexor strength in KOA, whereas no direct association between strength and radiographic severity was observed. These findings suggest that the reduction in thigh muscle strength in KOA is related to pain but not to the structural (radiographic) disease status., (Copyright © 2014 by the American College of Rheumatology.)

The Osteoarthritis Initiative (OAI) is a multicentre, prospective, observational, cohort study of knee osteoarthritis (OA) that began recruitment in 2004. The OAI provides public access to clinical and image data, enabling researchers to examine risk factors/predictors and the natural history of knee OA incidence and progression, and the qualification of imaging and other biomarkers. In this narrative review, we report imaging findings and lessons learned 10 years after enrolment has started. A literature search for full text articles published from the OAI was performed up to 31 December 2013 using Pubmed and the OAI web page. We summarise the rationale, design and imaging protocol of the OAI, and the history of OAI publications. We review studies from early partial, and later full OAI public data releases. The latter are structured by imaging method and tissue, reviewing radiography and then MRI findings on cartilage morphology, cartilage lesions and composition (T2), bone, meniscus, muscle and adipose tissue. Finally, analyses directly comparing findings from MRI and radiography are summarised. Ten years after the first participants were enrolled and first papers published, the OAI has become an invaluable resource to the OA research community. It has fuelled novel methodological approaches of analysing images, and has provided a wealth of information on OA pathophysiology. Continued collection and public release of long-term observations will help imaging measures to gain scientific and regulatory acceptance as 'prognostic' or 'efficacy of intervention' biomarkers, potentially enabling shorter and more efficient clinical trials that can test structure-modifying therapeutic interventions (NCT00080171)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To determine the predictive value of unicompartimental joint space narrowing (JSN) for MRI-based cartilage thickness loss in the narrowed and the non-narrowed femorotibial compartment., Methods: 922 knees from 922 Osteoarthritis Initiative (OAI) participants (62.2 ± 9.0 years, 61% females) with radiographic OA (158 without JSN [noJSN], 175 with lateral JSN [latJSN], 589 with medial JSN [medJSN]) were analyzed using 3 T MRI. One-year cartilage thickness change was determined in the lateral (LFTC) and medial femorotibial compartment (MFTC), and in femorotibial subregions. The probability of subsequent cartilage loss was calculated using predefined thresholds. The predictive value of JSN for the probability and magnitude of cartilage loss was compared between latJSN, medJSN and noJSN knees using Fisher's exact and Mann-Whitney-U tests., Results: The probability of cartilage loss was greater in the narrowed compartment of latJSN/medJSN knees (34.9%/32.4%) than in noJSN knees (13.3%/12.7%, P ≤ 6.4 × 10(-6)) and so was the magnitude of cartilage thickness change (P ≤ 8.2 × 10(-6)). No significant differences were observed between the narrowed compartments of latJSN vs. medJSN knees (probability: P = 0.58, magnitude: P = 0.19) or between the non-narrowed compartment of latJSN/medJSN vs. noJSN knees (probability: P ≥ 0.35, magnitude: P = ≥0.23). These results were confirmed by the location-independent ordered value (OV) analyses of femorotibial subregions., Conclusion: The predictive value of latJSN for lateral compartment cartilage loss was comparable to that of medJSN for medial compartment cartilage loss, whereas cartilage loss in the non-narrowed compartment was similar to that in noJSN knees. These findings provide important clues to predicting progression of knee OA, and in tailoring inclusion criteria for clinical trials., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Conflicting associations between imaging biomarkers and pain in knee osteoarthritis (OA) have been reported. A relation between pain and denuded areas of subchondral bone (dABs) has been suggested and this study explores this relationship further by relating the presence, phenotype, location and size of dABs to different measures of knee pain., Methods: 633 right knees from the Osteoarthritis Initiative (OAI) (250 men, age 61.7 ± 9.6 yrs, BMI 29.4 ± 4.7 kg/m(2)) were included. Manual segmentation of the femorotibial cartilage plates was performed on 3 T coronal fast low angle shot with water excitation (FLASHwe) images. dABs were defined as areas where the subchondral bone was uncovered by cartilage. The following measures of pain were used: weightbearing-, non-weightbearing-, moderate-to-severe-, infrequent- and frequent knee pain., Results: Using pain measures from subjects without dABs as a reference, those with at least one dAB had a 1.64-fold higher prevalence ratio [PR, 95% confidence interval (CI) 1.24-2.18] to have frequent and 1.45-fold higher for moderate-to-severe knee pain (95% CI 1.13-1.85). Subjects with dABs in central subregions had a 1.53-fold increased prevalence of having weightbearing pain (95% CI 1.20-1.97), especially when the central subregion was moderately (>10%) denuded (PR 1.81, 95% CI 1.35-2.42). Individuals with cartilage-loss-type dABs had a slightly higher prevalence (PR 1.13, 95% CI 1.00-1.27) of having frequent knee pain compared to individuals with intra-chondral-osteophyte-type dABs., Conclusion: This study supports a positive relation between femorotibial dABs and knee pain, especially when the dABs are located centrally (i.e., in weightbearing regions) or when the respective central subregion is moderately denuded., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Unlabelled: The sixth Osteoarthritis Research Society International (OARSI) Workshop on Imaging in Osteoarthritis combined with the third osteoarthritis (OA) Biomarkers Workshop is the first to bring together the imaging and molecular biomarker communities to focus on clinical validation and qualification of OA biomarkers. The workshop was held in Hilton Head, SC, USA, from June 12-14, 2012; 138 attendees participated, including representatives from academia, pharmaceutical and magnetic resonance imaging (MRI) industries, Food and Drug Administration (FDA), and National Institutes of Health (NIH). Presentations and discussions raised awareness, consolidated knowledge, and identified strategies to overcome challenges for the development and application of imaging and biochemical biomarkers in OA research studies and clinical trials., Conclusion: The OA research communities need to work alongside regulatory agencies across the world, to qualify and validate new chemical and imaging biomarkers for future research and clinical trials., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Introduction: Meniscal extrusion is thought to be associated with less meniscus coverage of the tibial surface, but the association of radiographic disease stage with quantitative measures of tibial plateau coverage is unknown. We therefore compared quantitative and semi-quantitative measures of meniscus position and morphology in individuals with bilateral painful knees discordant on medial joint space narrowing (mJSN)., Methods: A sample of 60 participants from the first half (2,678 cases) of the Osteoarthritis Initiative cohort fulfilled the inclusion criteria: bilateral frequent pain, Osteoarthritis Research Society International (OARSI) mJSN grades 1-3 in one, no-JSN in the contra-lateral (CL), and no lateral JSN in either knee (43 unilateral mJSN1; 17 mJSN2/3; 22 men, 38 women, body mass index (BMI) 31.3 ± 3.9 kg/m(2)). Segmentation and three-dimensional quantitative analysis of the tibial plateau and meniscus, and semi-quantitative evaluation of meniscus damage (magnetic resonance imaging (MRI) osteoarthritis knee score = MOAKS) was performed using coronal 3T MR images (MPR DESSwe and intermediate-weighted turbo spin echo (IW-TSE) images). CL knees were compared using paired t-tests (between-knee, within-person design)., Results: Medial tibial plateau coverage was 36 ± 9% in mJSN1 vs 45 ± 8% in CL no-JSN knees, and was 31 ± 9% in mJSN2/3 vs 46 ± 6% in no-JSN knees (both P < 0.001). mJSN knees showed greater meniscus extrusion and damage (MOAKS), but no significant difference in meniscus volume. No significant differences in lateral tibial coverage, lateral meniscus morphology or position were observed., Conclusions: Knees with medial JSN showed substantially less medial tibial plateau coverage by the meniscus. We suggest that the less meniscal coverage, i.e., less mechanical protection may be a reason for greater rates of cartilage loss observed in JSN knees., (Copyright © 2012 Osteoarthritis Research Society International. All rights reserved.)