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There exist no large-series human data linking contact stress exposure to an articular joint's propensity for developing osteoarthritis because contact stress analysis for large numbers of subjects remains impractical. The speed and simplicity of discrete element analysis (DEA) for estimating contact stresses makes its application to this problem highly attractive, but to date DEA has been used to study only a small numbers of cases. This is because substantial issues regarding its use in population-wide studies have not been addressed. Chief among them are developing fast and robust methods for model derivation and the selection of boundary conditions, establishing accuracy of computed contact stresses, and including capabilities for modeling in-series structural elements (e.g., a meniscus). This article describes an implementation of DEA that makes it feasible to perform subject-specific modeling in articular joints in large population-based studies.

PURPOSE: Advancing age is one of the strongest risk factors for osteoarthritis (OA). DNA methylation-based measures of epigenetic age acceleration may provide insights into mechanisms underlying OA. METHODS: We analyzed data from the Multicenter Osteoarthritis Study in a subset of 671 participants ages 45-69 years with no or mild radiographic knee OA. DNA methylation was assessed with the Illumina Infinium MethylationEPIC 850K array. We calculated predicted epigenetic age according to Hannum, Horvath, PhenoAge, and GrimAge epigenetic clocks, then regressed epigenetic age on chronological age to obtain the residuals. Associations between the residuals and knee, hand, and multi-joint OA were assessed using logistic regression, adjusted for chronological age, sex, clinical site, smoking status, and race. RESULTS: Twenty-three percent met criteria for radiographic hand OA, 25% met criteria for radiographic knee OA, and 8% met criteria for multi-joint OA. Mean chronological age (SD) was 58.4 (6.7) years. Mean predicted epigenetic age (SD) according to Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks was 64.9 (6.4), 68.6 (5.9), 50.5 (7.7), and 67.0 (6.2), respectively. Horvath epigenetic age acceleration was not associated with an increased odds of hand OA, odds ratio (95% confidence intervals) = 1.03 (0.99-1.08), with similar findings for knee and multi-joint OA. We found similar magnitudes of associations for Hannum epigenetic age, PhenoAge, and GrimAge acceleration compared to Horvath epigenetic age acceleration. CONCLUSIONS: Epigenetic age acceleration as measured by various well-validated epigenetic clocks based on DNA methylation was not associated with increased risk of knee, hand, or multi-joint OA independent of chronological age.

PURPOSE: Hip osteoarthritis (OA) is a major cause of pain and disability worldwide. Lack of effective therapies may reflect poor knowledge on its aetiology and risk factors, and result in the management of end-stage hip OA with costly joint replacement. The Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) consortium was established to pool and harmonise individual participant data from prospective cohort studies. The consortium aims to better understand determinants and risk factors for the development and progression of hip OA, to optimise and automate methods for (imaging) analysis, and to develop a personalised prediction model for hip OA. PARTICIPANTS: World COACH aimed to include participants of prospective cohort studies with ≥200 participants, that have hip imaging data available from at least 2 time points at least 4 years apart. All individual participant data, including clinical data, imaging (data), biochemical markers, questionnaires and genetic data, were collected and pooled into a single, individual-level database. FINDINGS TO DATE: World COACH currently consists of 9 cohorts, with 38 021 participants aged 18-80 years at baseline. Overall, 71% of the participants were women and mean baseline age was 65.3±8.6 years. Over 34 000 participants had baseline pelvic radiographs available, and over 22 000 had an additional pelvic radiograph after 8-12 years of follow-up. Even longer radiographic follow-up (15-25 years) is available for over 6000 of these participants. FUTURE PLANS: The World COACH consortium offers unique opportunities for studies on the relationship between determinants/risk factors and the development or progression of hip OA, by using harmonised data on clinical findings, imaging, biomarkers, genetics and lifestyle. This provides a unique opportunity to develop a personalised hip OA risk prediction model and to optimise methods for imaging analysis of the hip.

BackgroundObesity influences the development of osteoarthritis via low-grade inflammation. Progression of local inflammation (= synovitis) increased with weight gain in overweight and obese women compared to stable weight. Synovitis could be associated with subcutaneous fat (SCF) around the knee. Purpose of the study was to investigate the effect of weight loss on synovitis progression and to assess whether SCF around the knee mediates the relationship between weight loss and synovitis progression.MethodsWe included 234 overweight and obese participants (body mass index [BMI] ≥ 25 kg/m2) from the Osteoarthritis Initiative (OAI) with > 10% weight loss (n = 117) or stable overweight (

ObjectiveTo assess (i) the impact of changes in body weight on changes in joint-adjacent subcutaneous fat (SCF) and cartilage thickness over 4 years and (ii) the relation between changes in joint-adjacent SCF and knee cartilage thickness.DesignIndividuals from the Osteoarthritis Initiative (total=399) with > 10% weight gain (n=100) and > 10% weight loss (n=100) over 4 years were compared to a matched control cohort with less than 3% change in weight (n=199). 3.0T Magnetic Resonance Imaging (MRI) of the right knee was performed at baseline and after 4 years to quantify joint-adjacent SCF and cartilage thickness. Linear regression models were used to evaluate the associations between the (i) weight change group and 4-year changes in both knee SCF and cartilage thickness, and (ii) 4-year changes in knee SCF and in cartilage thickness. Analyses were adjusted for age, sex, baseline body mass index (BMI), tibial diameter (and weight change group in analysis (ii)).ResultsIndividuals who lost weight over 4-years had significantly less joint-adjacent SCF (beta range, medial/lateral joint sides: 2.2-4.2 mm, p

BackgroundMedial meniscus root tears (RTs) are associated with the development and worsening of knee osteoarthritis (OA), but little is known about their progression when compared with meniscal tears that spare the root (nonroot tears; NRTs).PurposeTo compare radiographic worsening of OA in knees with RTs versus NRTs and to identify factors associated with radiographic worsening of OA in knees with RTs.Study designCohort study; Level of evidence, 3.MethodsUsing the Osteoarthritis Initiative database, we included knees with medial meniscus RTs and NRTs present at the baseline visit (baseline tears) and new RTs and NRTs observed at 12- to 48-month annual follow-up visits (incident tears). Worsening of radiographic OA was defined for baseline tears as an increase in Kellgren-Lawrence grade (KLG) during the subsequent 12 months of follow-up; for incident tears, worsening was defined as either concurrent (increase in KLG over the 12 months preceding tear appearance on magnetic resonance imaging) or subsequent (increase in KLG during the 12 months after tear appearance). Odds ratios (ORs), adjusted for covariates, were calculated for the association of worsening by type of tear.ResultsIncluded were 39 knees with baseline RTs, 633 knees with baseline NRTs, 33 knees with incident RTs, and 234 knees with incident NRTs. Radiographic OA worsening subsequent to meniscal tear identification was no different for baseline RTs (15%) or baseline NRTs (14%; adjusted OR, 1.34; 95% CI, 0.52-3.47), nor did subsequent worsening differ for incident RTs (19%) versus incident NRTs (18%; adjusted OR, 0.52; 95% CI, 0.15-1.83). Concurrent radiographic OA worsening was seen at a significantly higher rate for incident RTs (64%) versus incident NRTs (21%; adjusted OR, 3.00; 95% CI, 1.21-7.47). Incident RTs in knees without radiographic OA (KLG 0-1) before the tear had a high rate of worsening (94%, n = 16) and were more likely to worsen than those in knees with radiographic OA (KLG ≥2) present before the tear.ConclusionCompared with NRTs, incident RTs were associated with a significantly increased risk of worsening radiographic OA over a 12-month period concurrent with the appearance of the tear. Incident RTs in knees without radiographic OA at baseline had a high rate of worsening.

OBJECTIVE: The aim of this work was to report the prevalence of computed tomography (CT)-detected intra-articular mineralization. DESIGN: We included participants from the Multicenter Osteoarthritis (MOST) Study. At the 12th year visit of the MOST study, bilateral knee CTs were first obtained. All participants also had posteroanterior and lateral radiographs of bilateral knees and completed standard questionnaires. Knee radiographs were assessed for Kellgren & Lawrence grade (KLG) and radiographic evidence of intra-articular mineralization. CT images were scored using the Boston University Calcium Knee Score (BUCKS) for cartilage, menisci, ligaments, capsule, and vasculature. Prevalence of intra-articular mineralization was computed for the total sample, and stratified by age, sex, race, Body Mass Index (BMI), presence of frequent knee pain, and KLG. We also determined distribution of mineralization in the cartilage and meniscus, and co-localization. RESULTS: 4140 bilateral knees from 2070 participants were included (56.7% female, mean age 61.1 years, mean BMI: 28.8 kg/m2). On radiographs 240 knees (5.8%) had intraarticular mineralization, while CT-detected mineralization was present in 9.8% of knees. Prevalence of hyaline articular and meniscus mineralization increased with age and KL grade, and was similar by sex, BMI categories, and comparable in subjects with and without frequent knee pain. Mineralization tended to be ubiquitous in the joint, most commonly involving all three (medial/lateral tibiofemoral and patellofemoral) compartments (3.1%), while the patellofemoral compartment was the most involved compartment in isolation (1.4%). CONCLUSIONS: CT of the knee provides greater visualization of intra-articular mineralization than radiographs and allows better localization of the crystal deposition within the joint. Further studies should focus on the co-localization of intra-articular crystal deposition and corresponding magnetic resonance imaging (MRI)-features of knee osteoarthritis (OA).

ObjectiveTo assess the effects of weight loss and weight gain on hip and knee radiographic changes, pain, and joint replacement over 4 years.MethodsParticipants (n = 2,752) from the Osteoarthritis Initiative were classified as those with weight gain (more than 5% gain), weight loss (more than -5% loss), or as controls (-3% to 3% change) over 4 years. Generalized estimating equations (adjusted for age, sex, and body mass index) were used to assess the relationship between the weight-change group and 4-year changes in knee radiographic osteoarthritis (OA) (Kellgren/Lawrence [K/L] grade), hip OA (Croft summary grade), joint space narrowing (JSN), and joint pain.ResultsFor radiographic knee OA, weight loss was associated with significantly lower odds of K/L grade worsening over 4 years (odds ratio [OR] 0.69 [95% confidence interval (95% CI) 0.53-0.91], P = 0.009), and weight gain was significantly associated with higher odds of medial knee JSN (OR 1.29 [95% CI 1.01-1.64], P = 0.038) compared to controls. For knee pain, weight loss was significantly associated with knee pain resolution over 4 years (OR 1.40 [95% CI 1.06-1.86], P = 0.019) while weight gain was associated with knee pain development (OR 1.34 [95% CI 1.08-1.67], P = 0.009) compared to controls. For all hip outcomes, no significant associations (P > 0.05) were found with weight-change groups. The associations between the weight-change group and total hip or total knee replacement were not significant (P > 0.05).ConclusionThis large, longitudinal study (n = 2,752 with 4-year follow-up) suggests that weight loss may protect against, and weight gain may exacerbate, radiographic and symptomatic knee OA, while weight change (at a 5% threshold) does not have significant effects on hip OA.

OBJECTIVE: Radiographic joint space width (JSW) has been a standard for measuring knee osteoarthritis (OA) structural change. Limitations in the responsiveness of this approach might be overcome by instead measuring 3D JSW on weight-bearing CT (WBCT). This study compared the responsiveness of 3D JSW measurements using WBCT with the responsiveness of radiographic 2D JSW. DESIGN: Standing, fixed-flexion knee radiographs (XR) and WBCT were acquired ancillary to the 144- and 168-month Multicenter Osteoarthritis Study visits. Tibiofemoral JSW was measured on both XR and WBCT. Responsiveness to change was defined by the standardized response mean (SRM) for change in JSW (1) at predetermined mediolateral locations (JSWx) on both modalities and (2) in the following subregions measured on WBCT images: central medial and lateral femur (CMF/CLF) and tibia (CMT/CLT), and anterior and posterior tibia (AMT/ALT, PMT/MLT). RESULTS: Baseline and 24-month follow-up JSWx measurements were completed for 265 participants (58.1% women). Responsiveness of 3D JSWx for medial tibiofemoral compartment on coronal WBCT (SRM range: -0.18, -0.24) exceeded that for 2D JSWx (-0.10, -0.16). Responsiveness of 3D JSW subregional mean (-0.06, -0.36) and maximal (-1.14, -1.75) CMF and CMT and maximal CLF/CLT 3D JSW changes were statistically significantly greater in comparison with respective medial and lateral 2D JSWx (P ≤ 0.002). CONCLUSIONS: Subregional 3D JSW on WBCT is substantially more responsive to 24-month changes in tibiofemoral joint structure compared to radiographic measurements. Use of subregional 3D JSW on WBCT could enable improved detection of OA structural progression over a 24-month duration in comparison with measurements made on XR.

ObjectiveOsteoarthritis (OA) is highly heterogeneous and has both biomechanical and systemic components that may not have the same etiology. We therefore aimed to identify specific knee OA phenotypes that may be more strongly associated with hand OA to refine the criteria used to define multi-joint OA.DesignWe assessed data from the Multicenter Osteoarthritis Study (MOST). We ascertained hand OA from bilateral hand photographs; scores for each joint row were summed to yield an aggregate hand OA score. Knee OA was ascertained from bilateral posteroanterior knee radiographs read for Kellgren-Lawrence grade and individual radiographic features. We tested associations between hand and knee OA with phenotypes including symptomatic OA, hyper- and atrophic knee OA, and one excluding post-traumatic OA. Associations between hand and knee OA were assessed with logistic regression, adjusted for age.ResultsWe studied 2493 participants with hand and knee OA measures. Median age was 63 years with 57% women. 55% had an aggregate hand OA score ≥2; frequency of knee OA phenotypes ranged from 8% to 34%. The age-adjusted odds ratio (OR) was 1.14 (95% confidence interval (CI) ​= ​1.04-1.26) for knee OA per standard deviation of the hand OA aggregate score. Hand OA associations with symptomatic knee OA and knee OA excluding post-traumatic knee OA were OR ​= ​1.16 (95% CI ​= ​1.03-1.31) and OR ​= ​1.21 (95% CI ​= ​1.08-1.35), respectively. No other knee OA phenotype reached statistical significance.ConclusionsAge-adjusted associations between hand and knee OA were modest and were largely similar across knee OA phenotypes.

BackgroundSynovial inflammation is a risk factor for osteoarthritis (OA). But to date, there is limited information on how inflammation impacts progression of knee OA.PurposeTo investigate how sustained synovitis, assessed with semi-quantitative magnetic resonance imaging (MRI) scores, impacts progression of knee degenerative changes over 4 years.Study typeRetrospective cohort study.SubjectsIn 249 participants (N = 132 women [53%]), from the Osteoarthritis Initiative (OAI) two definitions for synovitis were used resulting in two groups of participants with sustained synovitis at baseline, 2-year, and 4-year follow-up (N = 80 and N = 132), and two groups without synovitis at all three time points (N = 81 and N = 47).Field strength/sequence3 T intermediate-weighted (IW) turbo spin-echo (TSE) sequence and three-dimensional (3D) dual-echo steady-state (DESS) sequence.AssessmentSynovitis was scored semi-quantitatively using the Anterior Cruciate Ligament Osteoarthritis Score (ACLOAS), MRI Osteoarthritis Knee Score (MOAKS), and synovial proliferation score (SPS). Two MRI-based definitions of synovitis were used: (i) score ≥2 based on cumulative score of MOAKS and ACLOAS, and (ii) score ≥3 based on the cumulative score of ACLOAS, MOAKS, and SPS. Changes in structural abnormalities from baseline to year 4 measured using the whole-organ MRI score (WORMS) were defined as outcomes.Statistical testsLinear regression models were used to compare the differences in longitudinal changes in WORMS scores between participants with and without sustained synovitis for each definition of sustained synovitis. A P-value of

BackgroundTo assess the compound effects of BMI and sustained depressive symptoms on changes in knee structure, cartilage composition, and knee pain over 4 years using statistical interaction analyses.MethodsOne thousand eight hundred forty-four individuals from the Osteoarthritis Initiative Database were analyzed at baseline and 4-year follow-up. Individuals were categorized according to their BMI and presence of depressive symptoms (based on the Center for Epidemiological Studies Depression Scale (threshold≥16)) at baseline and 4-year follow-up. 3 T MRI was used to quantify knee cartilage T2 over 4 years, while radiographs were used to assess joint space narrowing (JSN). Mixed effects models examined the effect of BMI-depressive symptoms interactions on outcomes of cartilage T2, JSN, and knee pain over 4-years.ResultsThe BMI-depressive symptoms interaction was significantly associated with knee pain (p

ObjectiveThe lack of strong association between knee osteoarthritis (OA) structural features and pain continues to perplex researchers and clinicians. Evaluating the patellofemoral joint in addition to the tibiofemoral joint alone has contributed to explaining this structure-pain discordance, hence justifying a more comprehensive evaluation of whole-knee OA and pain. The present study, therefore, was undertaken to evaluate the association between patellofemoral and tibiofemoral OA features with localized anterior knee pain (AKP) using 2 study designs.MethodsUsing cross-sectional data from the Multicenter Osteoarthritis Study, our first approach was a within-person, knee-matched design in which we identified participants with unilateral AKP. We then assessed magnetic resonance imaging (MRI)-derived OA features (cartilage damage, bone marrow lesions [BMLs], osteophytes, and inflammation) in both knees and evaluated the association of patellofemoral and tibiofemoral OA features to unilateral AKP. In our second approach, MRIs from 1 knee per person were scored, and we evaluated the association of OA features to AKP in participants with AKP and participants with no frequent knee pain.ResultsUsing the first approach (n = 71, 66% women, mean ± SD age 69 ± 8 years), lateral patellofemoral osteophytes (odds ratio [OR] 5.0 [95% confidence interval (95% CI) 1.7-14.6]), whole-knee joint effusion-synovitis (OR 4.7 [95% CI 1.3-16.2]), and infrapatellar synovitis (OR 2.8 [95% CI 1.0-7.8]) were associated with AKP. Using the second approach (n = 882, 59% women, mean ± SD age 69 ± 7 years), lateral and medial patellofemoral cartilage damage (prevalence ratio [PR] 2.3 [95% CI 1.3-4.0] and PR 1.9 [95% CI 1.1-3.3], respectively) and lateral patellofemoral BMLs (PR 2.6 [95% CI 1.5-4.7]) were associated with AKP.ConclusionPatellofemoral but not tibiofemoral joint OA features and inflammation were associated with AKP.

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.

ObjectiveTo determine the optimal combination of imaging and biochemical biomarkers for use in the prediction of knee osteoarthritis (OA) progression.MethodsThe present study was a nested case-control trial from the Foundation of the National Institutes of Health OA Biomarkers Consortium that assessed study participants with a Kellgren/Lawrence grade of 1-3 who had complete biomarker data available (n = 539 to 550). Cases were participants' knees that had radiographic and pain progression between 24 and 48 months compared to baseline. Radiographic progression only was assessed in secondary analyses. Biomarkers (baseline and 24-month changes) that had a P value of

ObjectiveTo examine whether knee subchondral cysts, measured on magnetic resonance imaging (MRI), are associated with incident knee osteoarthritis (OA) outcomes.MethodsWe used longitudinal data from the Multicenter Osteoarthritis Study, a community-based cohort of subjects with risk factors for knee OA. Participants without a history of knee surgery and/or inflammatory arthritis (i.e., rheumatoid arthritis and gout) were followed up for 84 months for the following incident outcomes: 1) radiographic knee OA (Kellgren/Lawrence grade ≥2), 2) symptomatic radiographic knee OA (radiographic knee OA and frequent knee pain), and 3) frequent knee pain (with or without radiographic knee OA). In a subset of participants, subchondral cysts were scored on baseline MRIs of 1 knee. Multiple logistic regression, with adjustment for participant characteristics and other baseline knee MRI findings, was used to assess whether subchondral cysts were predictive of incident outcomes.ResultsAmong the participants with knees eligible for analyses of outcomes over 84 months, incident radiographic knee OA occurred in 22.8% of knees with no baseline radiographic knee OA, symptomatic radiographic knee OA occurred in 17.0% of knees with no baseline symptomatic radiographic knee OA, and frequent knee pain (with or without radiographic knee OA) occurred in 28.8% of knees with no baseline radiographic knee OA and 43.7% of knees with baseline radiographic knee OA. With adjustment for age, sex, and body mass index, the presence of subchondral cysts was not associated with incident radiographic knee OA but was associated with increased odds of incident symptomatic radiographic knee OA (odds ratio 1.92 [95% confidence interval 1.16-3.19]) and increased odds of incident frequent knee pain in those who had radiographic knee OA at baseline (odds ratio 2.11 [95% confidence interval 0.87-5.12]). Stronger and significant associations were observed for outcomes based on consistent reports of frequent knee pain within ~1 month of the study visit.ConclusionSubchondral cysts are likely to be a secondary phenomenon, rather than a primary trigger, of radiographic knee OA, and may predict symptoms in knees with existing disease.

ObjectiveTo determine reliability among four experienced and calibrated readers in cross-sectional and longitudinal semi-quantitative MRI assessments of knee osteoarthritis (OA) in the Multicenter Osteoarthritis (MOST) study.DesignFrom all MOST participants with at least one knee with readable 60-month and 84-month paired knee MRIs (1.0 ​T extremity systems), we selected 10 subjects having a spectrum of baseline disease severity of cartilage, bone marrow lesions, and meniscal damage and a spectrum of longitudinal changes in severity at 24 months follow-up. MRIs were independently assessed using the WORMS grading system by four musculoskeletal radiologists with the chronological sequence known to the readers. Kappa statistics were used to determine agreement between each pair of readers and Kendall's coefficient of concordance to determine average agreement across readers.ResultsFor most features, cross-sectional reliability was substantial to almost perfect. Regarding longitudinal reliability (detection of longitudinal change), inter-reader reliability as weighted kappa values ranged from 0.62 to 0.78 for cartilage damage, 0.75-0.88 for bone marrow lesions, 0.75-0.92 for meniscal tears, 0.67-0.95 for meniscal extrusion, 0.51-0.77 for bone attrition, 0.43-0.76 for osteophytes, 0.31-0.70 for Hoffa-synovitis, and 0.47-0.85 for effusion-synovitis. Kendall's coefficient ranged from 0.65 to 0.98.ConclusionHigh levels of cross-sectional reliability and moderate to high longitudinal reliability was achieved using four experienced readers in semiquantitative MRI-assessment of most knee OA features.

BackgroundOpioids are frequently prescribed for pain control in knee osteoarthritis patients, despite recommendations by current guidelines. Previous studies have investigated the chondrotoxicity of different opioid subtypes. However, the impact opioids may have on progression of osteoarthritis in vivo remains unknown. The aim of this study was thus to describe the associations between opioid use and knee structural changes and clinical outcomes, over 4 years.MethodsParticipants with baseline opioid use (n=181) and who continued use for ≥1 year between baseline and 4-year follow-up (n=79) were included from the Osteoarthritis Initiative cohort and frequency matched with non-users (controls) (1:2). Whole-Organ Magnetic Resonance Imaging Scores (WORMS) were obtained, including a total summation score (WORMS total, range 0-96) and subscores for cartilage (0-36), menisci (0-24), and bone marrow abnormalities and subchondral cyst-like lesions (0-18, respectively). Knee Injury Osteoarthritis Outcomes score (KOOS) symptoms, quality of life (QOL), and pain were also obtained at baseline and follow-up (range 0-100; lower scores indicate worse outcomes). Using linear regression models, associations between baseline and longitudinal findings were investigated. As pain may modify observations, a sensitivity analysis was performed for longitudinal findings. All analyses were adjusted for sex, BMI, age, race, and Kellgren-Lawrence grade.ResultsOpioid users had greater structural degeneration at baseline (WORMS total: Coef. [95% CI], P; 7.1 [5.5, 8.8],

Background Imaging of structural disease in osteoarthritis has traditionally relied on MRI and radiography. Joint space mapping (JSM) can be used to quantitatively map joint space width (JSW) in three dimensions from CT images. Purpose To demonstrate the reproducibility, repeatability, and feasibility of JSM of the knee using weight-bearing CT images. Materials and Methods Two convenience samples of weight-bearing CT images of left and right knees with radiographic Kellgren-Lawrence grades (KLGs) less than or equal to 2 were acquired from 2014 to 2018 and were analyzed retrospectively with JSM to deliver three-dimensional JSW maps. For reproducibility, images of three sets of knees were used for novice training, and then the JSM output was compared against an expert's assessment. JSM was also performed on 2-week follow-up images in the second cohort, yielding three-dimensional JSW difference maps for repeatability. Statistical parametric mapping was performed on all knee imaging data (KLG, 0-4) to show the feasibility of a surface-based analysis in three dimensions. Results Reproducibility (in 20 individuals; mean age, 58 years ± 7 [standard deviation]; mean body mass index, 28 kg/m2 ± 6; 14 women) and repeatability (in nine individuals; mean age, 53 years ± 6; mean body mass index, 26 kg/m2 ± 4; seven women) reached their lowest performance at a smallest detectable difference less than ±0.1 mm in the central medial tibiofemoral joint space for individuals without radiographically demonstrated disease. The average root mean square coefficient of variation was less than 5% across all groups. Statistical parametric mapping (33 individuals; mean age, 57 years ± 7; mean body mass index, 27 kg/m2 ± 6; 23 women) showed that the central-to-posterior medial joint space was significantly narrower by 0.5 mm for each incremental increase in the KLG (threshold P < .05). One knee (KLG, 2) demonstrated a baseline versus 24-month change in its three-dimensional JSW distribution that was beyond the smallest detectable difference across the lateral joint space. Conclusion Joint space mapping of the knee using weight-bearing CT images is feasible, demonstrating a relationship between the three-dimensional joint space width distribution and structural joint disease. It is reliably learned by novice users, can be personalized for disease phenotypes, and can be used to achieve a smallest detectable difference that is at least 50% smaller than that reported to be achieved at the highest performance level in radiography. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Roemer in this issue.

ObjectiveThe aim of this study was to investigate the associations between weight cycling and knee joint degeneration in individuals with overweight or obesity with different patterns of weight change over 4 years.MethodsA total of 2,271 individuals from the Osteoarthritis Initiative database were assessed (case-control study). Linear regression models using annual BMI measurements over 4 years were used to classify participants as weight cyclers or noncyclers. 3-T magnetic resonance imaging was used to quantify knee cartilage transverse relaxation time (T2) and cartilage thickness annually over 4 years in all subjects. Whole-Organ Magnetic Resonance Imaging Scores (WORMS) were obtained for cartilage, meniscus, and bone-marrow abnormalities in 958 subjects at baseline and at the 4-year follow-up. The longitudinal differences in cartilage T2 and thickness between weight cyclers and noncyclers were assessed using general estimating equations, whereas the differences in WORMS outcomes were compared using general linear models.ResultsNo significant differences in the rate of change of cartilage thickness or T2 were found between weight cyclers and noncyclers. However, increases in maximum cartilage WORMS (P = 0.0025) and bone-marrow abnormalities (P = 0.04) were significantly greater in weight cyclers than in noncyclers.ConclusionsAlthough participants' intent for weight cycling in this study was unknown, weight cyclers had significantly greater increases in cartilage and bone-marrow abnormalities over 4 years than noncyclers, independent of weight gain and loss.

ObjectivesTo study the natural history of new horizontal meniscal tears and their association with progression of cartilage degeneration in individuals at risk for or with mild to moderate knee osteoarthritis over 4 years.MethodsIndividuals who developed a new meniscal tear in the right knee over 2 years were selected from the Osteoarthritis Initiative 3T MRI studies. Knee structural changes were analyzed at the time of tear appearance (baseline), and after 4 years using a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). Meniscal tears were classified as either horizontal tears or non-horizontal tears. Individuals without a meniscal tear were 1:3 frequency matched according to BMI, gender, race, and age and served as the control group. Linear regression analysis was used to compare cross-sectional and longitudinal changes in cartilage WORMS scores.ResultsForty-one subjects developed horizontal tears, including one indiviudal who developed a tear in both menisci, and 34 developed non-horizonal tears. We found that (29/41 (70.7%)) of horizontal and (20/34 (58.8%)) of non-horizonatal tears were stable during follow-up (p = 0.281). Although knees with an incident tear had higher than controls WORMS MAX total knee scores at baseline (coef. = 0.47, p = 0.044, 95% CI = 0.01 to 0.93), there were no significant differences between the horizontal subgroup and knees without tears in overall cartilage scores at baseline and in progression over 4 years of follow-up.ConclusionsNew horizontal meniscal tears tended to be stable over 4 years and presented no significant differences in progression of cartilage degeneration when compared with knees without tears.Key points• Most of horizonal meniscal tears were stable over 4 years. • There were no statistically significant differences in overall progression of cartilage degenerative changes between knees with horizonal meniscal tears and control knees without tears • Horizontal tears most often occurred at the posterior horn of the medial meniscus and at the body of the lateral meniscus.

PurposeLower limb malalignment is a strong predictor of progression in knee osteoarthritis. The purpose of this study is to identify the individual alignment variables that predict progression in early to moderate osteoarthritis of the knee.MethodA longitudinal cohort study using data from the Osteoarthritis Initiative. In total, 955 individuals (1329 knees) with early to moderate osteoarthritis (Kellgren-Lawrence grade 1, 2 or 3) were identified. All subjects had full-limb radiographs analysed using the Osteotomy module within Medicad® Classic (Hectec GMBH) to give a series of individual alignment variables relevant to the coronal alignment of the lower limb. Logistic regression models, with generalised estimating equations were used to identify which of these individual alignment variables predict symptom worsening (WOMAC score > 9 points) and or structural progression (joint space narrowing progression in the medial compartment > 0.7mm) over 24 months.ResultsIndividual alignment variable were associated with both valgus and varus alignment (mechanical Lateral Distal Femoral Angle, Medial Proximal Tibial Angle and mechanical Lateral Distal Tibial Angle). Only the Medial Proximal Tibial Angle was significantly associated with structural progression and none of the variables was associated with symptom progression. The odds of joint space narrowing progression in the medial compartment occurring at 24 months increased by 21% for every one degree decrease (more varus) in Medial Proximal Tibial Angle (p < 0.001) CONCLUSIONS: Our results suggest that the risk of structural progression in the medial compartment is associated with greater varus alignment of the proximal tibia.Level of evidenceLevel III, retrospective cohort study.

ObjectiveTo determine the cross-sectional and longitudinal associations of vitamin C and D intake with magnetic resonance imaging (MRI) measures of cartilage composition (T2) and joint structure (cartilage, meniscus, and bone marrow) using data from the Osteoarthritis Initiative (OAI) cohort.MethodsA total of 1,785 subjects with radiographic Kellgren/Lawrence knee grades 0-3 in the right knee were selected from the OAI database. Vitamins C and vitamin D intake (diet, supplements, and total) were assessed using the Block Brief 2000 Food Frequency Questionnaire at baseline. The MRI analysis protocol included 3T cartilage T2 quantification and semiquantitative joint morphology gradings (Whole-Organ Magnetic Resonance Imaging Score [WORMS]) at baseline and 4 years. Linear regression was used to assess the association between standardized baseline vitamin intake and both baseline WORMS scores and standardized cartilage T2 values.ResultsHigher vitamin C intake was associated with lower average cartilage T2 values, medial tibia T2 values, and medial tibia WORMS scores (standardized coefficient range -0.07 to -0.05, P < 0.05). Higher vitamin D intake was associated with a lower cartilage WORMS sum score and medial femur WORMS score (standardized coefficient range -0.24 to -0.09, P < 0.05). Consistent use of vitamin D supplements of 400 IU at least once a week over 4 years was associated with significantly less worsening of cartilage, meniscus, and bone marrow abnormalities (odds ratio range 0.40-0.56, P < 0.05).ConclusionSupplementation with vitamin D over 4 years was associated with significantly less progression of knee joint abnormalities. Given the observational nature of this study, future longitudinal randomized controlled trials of vitamin D supplementation are warranted.

BACKGROUND: Knee osteoarthritis (OA) is more common in females than in males; however, the biological mechanisms for the difference in sex in patients with knee OA are not well understood. Knee shape is associated with OA and with sex, but the patterns of change in the bones shape over time and their relation to sex and OA are unknown and may help inform how sex is associated with shape and OA and whether the effect is exerted early or later in life.Questions/purposes (1) Does knee shape segregate stably into different groups of trajectories of change (groups of knees that share similar patterns of changes in bone shape over time)? (2) Do females and males have different trajectories of bone shape changes? (3) Is radiographic OA at baseline associated with trajectories of bone shape changes? METHODS: We used data collected from the NIH-funded Osteoarthritis Initiative (OAI) to evaluate a cohort of people aged 45 to 79 years at baseline who had either symptomatic knee OA or were at high risk of having it. The OAI cohort included 4796 participants (58% females; n = 2804) at baseline who either had symptomatic knee OA (defined as having radiographic tibiofemoral knee OA and answering positively to the question have you had pain, aching or stiffness around the knee on most days for at least one month during the past 12 months) or were at high risk of symptomatic knee OA (defined as having knee symptoms during the prior 12 months along with any of the following: overweight; knee injury; knee surgery other than replacement; family history of total knee replacement for OA; presence of Heberdens nodes; daily knee bending activity) or were part of a small nonexposed subcohort. From these participants, we limited the eligible group to those with radiographs available and read at baseline, 2 years, and 4 years, and randomly selected participants from each OAI subcohort in a manner to enrich representation in the study of the progression and nonexposed subcohorts, which were smaller in number than the OA incidence subcohort. From these patients, we randomly sampled 473 knees with radiographs available at baseline, 2 years, and 4 years. We outlined the shape of the distal femur and proximal tibia on radiographs at all three timepoints using statistical shape modelling. Five modes (each mode represents a particular type of knee bone shape variation) were derived for the proximal tibia and distal femurs shape, accounting for 78% of the total variance in shape. Group-based trajectory modelling (a statistical approach to identify the clusters of participants following a similar progression of change of bone shape over time, that is, trajectory group) was used to identify distinctive patterns of change in the bone shape for each mode. We examined the association of sex and radiographic OA at baseline with the trajectories of each bone shape mode using a multivariable polytomous regression model while adjusting for age, BMI, and race. RESULTS: Knee bone shape change trajectories segregated stably into different groups. In all modes, three distinct trajectory groups were derived, with the mean posterior probabilities (a measure of an individuals probability of being in a particular group and often used to characterize how well the trajectory model is working to describe the population) ranging from 84% to 99%, indicating excellent model fitting. For most of the modes of both the femur and tibia, the intercepts for the three trajectory groups were different; however, the rates of change were generally similar in each mode. Females and males had different trajectories of bone shape change. For Mode 1 in the femur, females were more likely to be in trajectory Groups 3 (odds ratio 30.2 [95% CI 12.2 to 75.0]; p < 0.001) and 2 than males (OR 4.1 [95% CI 2.3 to 7.1]; p < 0.001); thus, females had increased depth of the intercondylar fossa and broader shaft width relative to epicondylar width compared with males. For Mode 1 in the tibia, females were less likely to be in trajectory Group 2 (OR 0.5 [95% CI 0.3 to 0.9]; p = 0.01) than males (that is, knees of females were less likely to display superior elevation of tibial plateau or decreased shaft width relative to head width). Radiographic OA at baseline was associated with specific shape-change trajectory groups. For Mode 1 in the femur, knees with OA were less likely to be in trajectory Groups 3 (OR 0.4 [95% CI 0.2 to 0.8]; p = 0.008) and 2 (OR 0.6 [95% CI 0.3 to 1.0]; p = 0.03) than knees without OA; thus, knees with OA had decreased depth of the intercondylar fossa and narrower shaft width relative to epicondylar width compared with knees without OA. For Mode 1 in the tibia, knees with OA were not associated with trajectory. CONCLUSIONS: The shapes of the distal femur and proximal tibia did not change much over time. Sex and baseline knee radiographic OA status are associated with the trajectory of change in the bones shape, suggesting that both may contribute earlier in life to the associations among trajectories observed in older individuals. Future studies might explore sex-related bone shape change earlier in life to help determine when the sex-specific shapes arise and also the degree to which these sex-related shapes are alterable by injury or other events. LEVEL OF EVIDENCE: Level III, prognostic study.

Knee osteoarthritis (OA) is a leading cause of chronic disability worldwide, but no diagnostic or prognostic biomarkers are available. Increasing evidence supports epigenetic dysregulation as a contributor to OA pathogenesis. In this pilot study, we investigated epigenetic patterns in peripheral blood mononuclear cells (PBMCs) as models to predict future radiographic progression in OA patients enrolled in the longitudinal Osteoarthritis Initiative (OAI) study. PBMC DNA was analyzed from baseline OAI visits in 58 future radiographic progressors (joint space narrowing at 24 months, sustained at 48 months) compared to 58 non-progressors. DNA methylation was quantified via Illumina microarrays and beta- and M-values were used to generate linear classification models. Data were randomly split into a 60% development and 40% validation subsets, models developed and tested, and cross-validated in a total of 40 cycles. M-value based models outperformed beta-value based models (ROC-AUC 0.81 ± 0.01 vs. 0.73 ± 0.02, mean ± SEM, comparison p = 0.002), with a mean classification accuracy of 73 ± 1% (mean ± SEM) for M- and 69 ± 1% for beta-based models. Adjusting for covariates did not significantly alter model performance. Our findings suggest that PBMC DNA methylation-based models may be useful as biomarkers of OA progression and warrant additional evaluation in larger patient cohorts.

BackgroundKnee bone shape differs between men and women and the incidence of knee osteoarthritis (OA) is higher in women than in men. Therefore, the purpose of the present study was to determine whether the observed difference in the incidence of knee radiographic OA (ROA) between men and women is mediated by bone shape.MethodsWe randomly sampled 304 knees from the OAI with incident ROA (i.e., development of Kellgren/Lawrence grade ≥ 2 by month 48) and 304 knees without incident ROA. We characterized distal femur and proximal tibia shape on baseline radiographs using Statistical Shape Modeling. If a specific bone shape was associated with the risk of incident ROA, marginal structural models were generated to assess the mediation effect of that bone shape on the relation of sex and risk of incident knee ROA adjusting for baseline covariates.ResultsCase and control participants were similar by age, sex and race, but case knees were from higher body mass index (BMI) participants (29.4 vs. 27.0; p

OBJECTIVE:Osteoarthritis (OA) is a disease with a substantial public health burden. Quantitative assessments of periarticular bone may be a biomarker capable of monitoring early disease progression. The purpose of this study was to evaluate whether measures of periarticular bone associate with longitudinal structural progression. METHODS:We conducted a 12-18 months longitudinal study using the Osteoarthritis Initiative (OAI). Participants received knee dual-energy x-ray absorptiometry (DXA), trabecular magnetic resonance (MR) imaging, and x-rays. Knee DXAs generated proximal tibial medial:lateral periarticular bone mineral density (paBMD) measures. Proximal tibial trabecular MR images were assessed for trabecular morphometry: apparent bone volume fraction (BVF), trabecular number, thickness, and spacing. Weight-bearing x-rays were assessed for medial tibiofemoral joint space narrowing (JSN). Chi-squared analyses assessed whether periarticular bone measures were predictive of worsening medial tibiofemoral JSN, adjusted for age, sex, and BMI. RESULTS:In all, 444 participants, mean age 64.2 ± 9.2 years, BMI 29.5 ± 4.6kg/m2, and 52% male at baseline. Medial JSN (radiographic progression) occurred in 40 participants (9%). Higher baseline medial:lateral paBMD, apparent BVF, trabecular number and thickness, and lower baseline and decreased trabecular spacing were all associated with more progression of JSN in the medial compartment. From lowest to highest baseline medial:lateral paBMD quartile groups, 2%, 5%, 11%, and 18% had medial JSN progression, respectively, between the 36- and 48-month visits, p-values = 0.001 and 0.002 unadjusted and adjusted. The rate of change in medial:lateral paBMD, apparent BVF, and spacing were associated with more medial JSN. For rate of medial:lateral paBMD change from lowest to highest quartile, the proportion of each group that experienced medial JSN progression were 5%, 5%, 11%, and 18%, with an unadjusted and adjusted p-value of 0.005. CONCLUSION:Baseline and most rates of periarticular bone change associate with knee OA structural progression, highlighting the close relationship between subchondral bone and JSN. Future studies should focus on developing these measures as predictive and pathophysiological biomarkers, and evaluating their deployment in clinical trials testing bone-targeted therapeutics.

BackgroundOsteoarthritis (OA), a multifactorial disease causing joint degeneration, often leads to severe disability. The rising rates of disability highlight the need for implementing preventative measures at early stages of the disease, which would especially benefit subjects at high risk for OA development.PurposeTo develop a risk prediction tool for moderate-severe OA (TOARP) over 8 years based on subject characteristics, knee radiographs, and MRI data at baseline using data from the Osteoarthritis Initiative (OAI).Study typeRetrospective.Subjects641 subjects with no/mild radiographic OA (Kellgren-Lawrence [KL] 0-2) and no clinically significant symptoms (Western Ontario and McMaster Universities Arthritis Index [WOMAC] 0-1) were selected from the OAI.Field strength/sequenceMR images were obtained using 3.0T.AssessmentCompartment-specific cartilage and meniscus morphology and cartilage T2 were assessed. Baseline subject demographics, risk factors, KL score, cartilage WORMS score, presence of meniscus tear, and cartilage T2 were used to predict the development of moderate/severe OA (KL = 3-4 or WOMAC pain ≥5 or total knee replacement [TKR]) over 8 years.Statistical testsBest subsets variable selection followed by cross-validation were used to assess which combinations of variables best predict moderate/severe OA.ResultsModel 1 included KL score, previous knee injury in the last 12 months, age, gender, and BMI. Model 2 included all variables in Model 1 plus presence of cartilage defects in the lateral femur and patella, and presence of a meniscal tear. Model 3 included all variables in Models 1 and 2, plus cartilage T2 in the medial tibia and medial femur. Compared to Model 1 (cross-validated AUC = 0.67), Model 3 performed significantly better (AUC = 0.72, P = 0.04), while Model 2 showed a statistical trend (AUC = 0.71, P = 0.08).Data conclusionWe established a risk calculator for the development of moderate/severe knee OA over 8 years that includes radiographic and MRI data. The inclusion of MRI-based morphological abnormalities and cartilage T2 significantly improved model performance.Level of evidence2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1517-1526.

Purpose To determine the relationship of patellofemoral joint alignment and trochlear morphology to superolateral Hoffa fat pad (SHFP) edema on magnetic resonance (MR) images in older adults with or at risk for osteoarthritis of the knee. Materials and Methods Institutional review board approval and written informed consent were obtained from all subjects. The Multicenter Osteoarthritis Study is a prospective cohort study of older adults with or at risk for osteoarthritis of the knee. Subjects were recruited from Birmingham, Alabama, and Iowa City, Iowa. In this cross-sectional study, patellofemoral joint alignment (bisect offset, patellar tilt angle, and Insall-Salvati ratio), trochlear morphology (sulcus angle, lateral and medial trochlear inclination, and trochlear angle) and SHFP edema were assessed on MR images of the knee. Measures of alignment and morphology were divided into quartiles, and SHFP was determined to be present or absent. Separate logistic regression models were used to determine the relationship of each measure of alignment and morphology to the presence of SHFP edema, with adjustments for age, sex, and body mass index. Results SHFP edema was present in 152 (13.4%) of the 1134 knees that were included. When compared with knees with measurements in the lowest quartile, knees with measurements in the highest quartile for trochlear angle, bisect offset, and Insall-Salvati ratios were 1.6 (95% confidence interval [CI]: 1.0, 2.6), 2.3 (95% CI: 1.3, 4.0), and 8.9 (95% CI: 4.7, 16.9) times more likely to show SHFP edema, respectively. No relationship was found between other measures and SHFP edema. Conclusion A more anterior trochlear facet, a more laterally displaced patella, and knees with patella alta were significantly associated with SHFP edema on MR images in subjects with or at risk for osteoarthritis of the knee. © RSNA, 2017.

ObjectivesTo evaluate the ability of different MRI sequences to detect chondrocalcinosis within knee cartilage and menisci, and to analyze the association with joint degeneration.MethodsSubjects with radiographic knee chondrocalcinosis (n = 90, age 67.7 ± 7.3 years, 50 women) were selected from the Osteoarthritis Initiative and matched to controls without radiographic chondrocalcinosis (n = 90). Visualization of calcium-containing crystals (CaC) was compared between 3D T1-weighted gradient-echo (T1GE), 3D dual echo steady-state (DESS), 2D intermediate-weighted (IW), and proton density (PD)-weighted fast spin-echo (FSE) sequences obtained with 3T MRI and correlated with a semiquantitative CaC score obtained from radiographs. Structural abnormalities were assessed using Whole-Organ MRI Score (WORMS) and logistic regression models were used to compare cartilage compartments with and without CaC.ResultsCorrelations between CaC counts of MRI sequences and degree of radiographic calcifications were highest for GE (rT1GE = 0.73, P  0.05). Meniscus WORMS was significantly higher in subjects with chondrocalcinosis compared to controls (P = 0.005). Cartilage defects were significantly more frequent in compartments with CaC than without (patella: P = 0.006; lateral tibia: P

BackgroundTo describe the scoring methodology and MRI assessments used to evaluate the cross-sectional features observed in cases and controls, to define change over time for different MRI features, and to report the extent of changes over a 24-month period in the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium study nested within the larger Osteoarthritis Initiative (OAI) Study.MethodsWe conducted a nested case-control study. Cases (n = 406) were knees having both radiographic and pain progression. Controls (n = 194) were knee osteoarthritis subjects who did not meet the case definition. Groups were matched for Kellgren-Lawrence grade and body mass index. MRIs were acquired using 3 T MRI systems and assessed using the semi-quantitative MOAKS system. MRIs were read at baseline and 24 months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. We provide the definition and distribution of change in these biomarkers over time.ResultsSeventy-three percent of the cases had subregions with BML worsening (vs. 66 % in controls) (p = 0.102). Little change in osteophytes was seen over 24 months. Twenty-eight percent of cases and 10 % of controls had worsening in meniscal scores in at least one subregion (p

We described a definition of end-stage knee osteoarthritis (esKOA) and evaluated its association with health outcomes and osteoarthritis risk factors. We included Osteoarthritis Initiative participants with or at risk for knee osteoarthritis who had complete baseline data. We defined esKOA by adapting a validated appropriateness algorithm for total knee replacement based on data from baseline and the first four follow-up visits. We performed person-based analyses, including both knees from all participants. Participants met the definition of esKOA at the visit at which ≥1 knee reached the esKOA criteria. We assessed differences in individual characteristics between groups at baseline and over time and tested if incident esKOA (outcome) was associated with osteoarthritis risk factors (e.g., age, maximum adult weight, and quadriceps strength). The cohort consisted of 3916 participants with mean age of 61 (SD = 9) years and mean body mass index of 28.4 (4.7) kg/m(2); 59 % were female and 9.7 % developed incident esKOA. Those with incident esKOA had poorer health outcomes at baseline and greater declines in health outcomes, with the exception of SF-12 mental health score. Five out of nine tested risk factors were associated with incident esKOA in unadjusted analyses, with older age (≥65 years; odds ratio = 1.44, 95 % confidence interval = 1.19 to 1.83) and quadriceps weakness (odds ratio = 0.78, 95 % confidence interval = 0.71 to 0.86) remaining significant in adjusted models. Older age and quadriceps weakness predicted esKOA. esKOA is also characterized by poor health-related outcomes. This definition of esKOA could be a new clinically relevant outcome measure for osteoarthritis research.

ObjectiveTo determine the association between changes in semiquantitative magnetic resonance imaging (MRI) biomarkers over 24 months and radiographic and pain progression over 48 months in knees with mild-to-moderate osteoarthritis (OA).MethodsWe undertook a nested case-control study as part of the Foundation for the National Institutes of Health Biomarkers Consortium Project. We used multivariable logistic regression models to examine the association between change over 24 months in semiquantitative MRI markers and radiographic and pain progression in knee OA. MRIs were read according to the MRI OA Knee Score system. We focused on changes in cartilage, osteophytes, meniscus, bone marrow lesions, Hoffa-synovitis, and effusion-synovitis.ResultsThe most parsimonious model included changes in cartilage thickness and surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology (C statistic 0.740). Compared with no worsening, worsening in cartilage thickness in ≥3 subregions was associated with 2.8-fold (95% confidence interval [95% CI] 1.3-5.9) greater odds of being a case, and worsening in cartilage surface area in ≥3 subregions was associated with 2.4-fold (95% CI 1.3-4.4) greater odds of being a case. Worsening of meniscal morphology in any region was associated with 2.2-fold (95% CI 1.3-3.8) greater odds of being a case. Worsening effusion-synovitis and Hoffa-synovitis were also associated with a greater odds of being a case (odds ratios 2.7 and 2.0, respectively).ConclusionTwenty-four-month changes in cartilage thickness, cartilage surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology were independently associated with OA progression, suggesting that these factors may serve as efficacy biomarkers in clinical trials of disease-modifying interventions for knee OA.

ObjectiveTo investigate the relationship of step length to the sex-specific prevalence and worsening of magnetic resonance imaging (MRI)-detected structural damage in the patellofemoral (PF) joint among a cohort of older women and men with or at risk of knee osteoarthritis (OA).MethodsThe Multicenter Osteoarthritis Study is a cohort study of persons ages 50-79 years with or at risk of knee OA. Step length was assessed using the GAITRite walkway (CIR Systems) at the 60-month visit, and cartilage damage and bone marrow lesions (BMLs) were graded on MRI at the 60- and 84-month visits. Step length was divided into sex-specific quintiles, and the relationship of step length to the prevalence and worsening of cartilage damage and BMLs in the PF joint was examined using logistic regression, adjusting for age, body mass index (BMI), leg length, and tibiofemoral joint structural damage.ResultsIn 1,053 knees, 4,094 and 4,083 PF joint subregions were studied for the cartilage and BML analyses, respectively. Mean ± SD age was 65.6 ± 8.1 years and mean ± SD BMI was 29.1 ± 4.7 kg/m(2) ; 62% of participants were female. In women, compared to those with the shortest step length, those with the longest step length had 0.62 (95% confidence interval [95% CI] 0.43-0.88) and 0.59 (95% CI 0.40-0.87) times the odds of cartilage damage and BMLs, respectively. There was no cross-sectional association in men, and no longitudinal association in either sex.ConclusionWomen with PF joint structural damage may adapt their gait by shortening their step length, but this may not be sufficient to reduce the risk of worsening damage over time.

ObjectiveHip shape by statistical shape modeling (SSM) is associated with hip radiographic osteoarthritis (rOA). We examined associations between hip shape and knee rOA given the biomechanical interrelationships between these joints.MethodsBilateral baseline hip shape assessments [for those with at least 1 hip with a Kellgren-Lawrence arthritis grading scale (KL) 0 or 1] from the Johnston County Osteoarthritis Project were available. Proximal femur shape was defined on baseline pelvis radiographs and evaluated by SSM, producing mean shape and continuous variables representing independent modes of variation (14 modes = 95% of shape variance). Outcomes included prevalent [baseline KL ≥ 2 or total knee replacement (TKR)], incident (baseline KL 0/1 with followup ≥ 2), and progressive knee rOA (KL increase of ≥ 1 or TKR). Limb-based logistic regression models for ipsilateral and contralateral comparisons were adjusted for age, sex, race, body mass index (BMI), and hip rOA, accounting for intraperson correlations.ResultsWe evaluated 681 hips and 682 knees from 342 individuals (61% women, 83% white, mean age 62 yrs, BMI 29 kg/m(2)). Ninety-nine knees (15%) had prevalent rOA (4 knees with TKR). Lower modes 2 and 3 scores were associated with ipsilateral prevalent knee rOA, and only lower mode 3 scores were associated with contralateral prevalent knee rOA. No statistically significant associations were seen for incident or progressive knee rOA.ConclusionVariations in hip shape were associated with prevalent, but not incident or progressive, knee rOA in this cohort, and may reflect biomechanical differences between limbs, genetic influences, or common factors related to both hip shape and knee rOA.

ObjectiveTo determine the diagnostic performance of standing computerized tomography (SCT) of the knee for osteophytes and subchondral cysts compared with fixed-flexion radiography, using MRI as the reference standard.MethodsTwenty participants were recruited from the Multicenter Osteoarthritis Study. Participants' knees were imaged with SCT while standing in a knee-positioning frame, and with postero-anterior fixed-flexion radiography and 1T MRI. Medial and lateral marginal osteophytes and subchondral cysts were scored on bilateral radiographs and coronal SCT images using the OARSI grading system and on coronal MRI using Whole Organ MRI Scoring. Imaging modalities were read separately with images in random order. Sensitivity, specificity and accuracy for the detection of lesions were calculated and differences between modalities were tested using McNemar's test.ResultsParticipants' mean age was 66.8 years, body mass index was 29.6 kg/m(2) and 50% were women. Of the 160 surfaces (medial and lateral femur and tibia for 40 knees), MRI revealed 84 osteophytes and 10 subchondral cysts. In comparison with osteophytes and subchondral cysts detected by MRI, SCT was significantly more sensitive (93 and 100%; p < 0.004) and accurate (95 and 99%; p < 0.001 for osteophytes) than plain radiographs (sensitivity 60 and 10% and accuracy 79 and 94%, respectively). For osteophytes, differences in sensitivity and accuracy were greatest at the medial femur (p = 0.002).ConclusionsIn comparison with MRI, SCT imaging was more sensitive and accurate for detection of osteophytes and subchondral cysts than conventional fixed-flexion radiography. Additional study is warranted to assess diagnostic performance of SCT measures of joint space width, progression of OA features and the patellofemoral joint.

ObjectiveTo evaluate whether T2 relaxation time measurements obtained at 3 T MRI predict the onset of radiographic knee osteoarthritis (OA).Materials and methodsWe performed a nested case-control study of incident radiographic knee OA in the Osteoarthritis Initiative cohort. Cases were 50 knees with baseline Kellgren-Lawrence (KL) grade of 0 that developed KL grade of 2 or more over a 4-year period. Controls were 80 knees with KL grade of 0 after 4 years of follow-up. Baseline T2 relaxation time measurements and laminar analysis of T2 in deep and superficial layers were performed in all knee compartments. The association of T2 values with incident OA was assessed with logistic regression and differences in T2 values by case-control status with linear regression, adjusting for age, sex, body mass index (BMI) and other covariates.ResultsBaseline T2 values in all compartments except the medial tibia were significantly higher in knees that developed OA compared with controls and were particularly elevated in the superficial cartilage layers in all compartments. There was an increased likelihood of incident knee OA associated with higher baseline T2 values, particularly in the patella, adjusted OR per 1 SD increase in T2 (3.37 (95% CI 1.72 to 6.62)), but also in the medial femur (1.90 (1.07 to 3.39)), lateral femur (2.17 (1.11 to 4.25)) and lateral tibia (2.23 (1.16 to 4.31)).ConclusionsThese findings suggest that T2 values assessed when radiographic changes are not yet apparent may be useful in predicting the development of radiological tibiofemoral OA.

BackgroundTo develop a semi-quantitative MR-based hip osteoarthritis (OA) evaluation system (Scoring hip osteoarthritis with MRI, SHOMRI), and to test its reproducibility and face validity.MethodsThe study involved 98 subjects with informed consent. Three-Tesla MR imaging of hip was performed in three planes with intermediate-weighted fat saturated FSE sequences. Two radiologists assessed cartilage loss, bone marrow edema pattern, subchondral cyst in 10 subregions, and assessed labrum in 4 subregions. In addition, presence or absence of ligamentum teres integrity, paralabral cysts, intra-articular body, and effusion in the hip joint were analyzed using the SHOMRI system. The reproducibility was assessed with intra-class correlation coefficient (ICC), Cohen's Kappa values and percent agreement. SHOMRI scores were correlated with radiographic Kellgren-Lawrence (KL) and OARSI atlas gradings, and clinical parameters, the hip osteoarthritis outcome score (HOOS) and hip range of motion (ROM), using Spearman's rank correlation and ordinal logistic regression.ResultsICC values were in the excellent range, 0.91 to 0.97. Cohen's Kappa values and percent agreement ranged from 0.55 to 0.79 and 66 to 99%, respectively. SHOMRI demonstrated significant correlations with KL and OARSI gradings as well as with clinical parameters, HOOS and ROM (P < 0.05). Among the SHOMRI features, subchondral cyst and bone marrow edema pattern showed the highest correlation with HOOS and ROM.ConclusionSHOMRI demonstrated moderate to excellent reproducibility and significant correlation with radiographic gradings and clinical parameters.

PurposeTo assess whether changes in knee cartilage MR-based T2 relaxation times are associated with weight loss in individuals with risk factors for knee osteoarthritis (OA) compared with controls with stable weight.Materials and methodsOne hundred twenty-seven individuals with risk factors for knee OA were studied: 62 subjects had a body mass index (BMI) decrease≥10% over 48 months and 65 controls had a BMI change

PurposeTo describe a scoring system for quantification of cartilage lesions (Cartilage Lesion Score [CaLS]), to determine its reproducibility, to examine the association of CaLS-detected longitudinal change with known risk factors for osteoarthritis (OA) progression by comparing a group of subjects with OA risk factors with a group of subjects without OA risk factors, and to compare the CaLS system with the established semiquantitative Whole-Organ Magnetic Resonance Imaging Score (WORMS) and Boston-Leeds Osteoarthritis Knee Score (BLOKS) systems in terms of detection of cartilage defect progression.Materials and methodsAll subjects provided written informed consent, and the local institutional review board approved this HIPAA-compliant study. Fifty-two subjects with and 25 subjects without risk factors for knee OA were randomly selected from the Osteoarthritis Initiative. Inclusion criteria were age of 45-60 years, body mass index of 19-27 kg/m(2), and no knee pain or OA on radiographs at baseline. Baseline and 24-month follow-up right knee 3-T magnetic resonance images were analyzed with WORMS, BLOKS, and CaLS systems. Progression of cartilage lesions with each scoring system was compared by using multilevel mixed-effects linear-regression models. κ values were calculated to determine reliability.ResultsIntraclass coefficient values for inter- and intraobserver reliability of the CaLS system were 0.86 and 0.91, respectively. Interobserver κ value range for individual features was 0.81-0.94. The CaLS system enabled significantly higher detection of cartilage lesion progression than did WORMS or BLOKS systems (P < .001); 51.8% (56 of 108), 17.6% (19 of 108), and 13.0% (14 of 108) of the lesions progressed when analyzed with the CaLS, WORMS, and BLOKS systems, respectively. With the CaLS system, subjects with OA risk factors had significantly higher odds of progression than did subjects without risk factors (odds ratio, 2.78; P = .005).ConclusionThe CaLS system is a reproducible scoring system for cartilage lesions that yields an improved detection rate for monitoring progression when compared with detection rates of semiquantitative WORMS and BLOKS systems.

ObjectiveTo examine the cross-sectional association of whole-knee synovitis assessed by contrast-enhanced magnetic resonance imaging (CEMRI) with radiographic tibiofemoral osteoarthritis (OA), non-CEMRI-assessed cartilage damage, and meniscal status.MethodsMulticenter Osteoarthritis Study (MOST) is a cohort study of people with or at high risk of knee OA. Subjects are a subset of MOST who volunteered for both CEMRI and non-CEMRI. Using CEMRI, synovitis was assessed at 11 sites and graded 0-2 at each site. Presence of "whole-knee synovitis" was defined as the synovitis score of ≥ 1 at any site from each knee. Cartilage and meniscal damage was evaluated using non-CEMRI based on the Whole Organ MRI Score. Logistic regression was used to assess associations of synovitis with radiographic OA (Kellgren-Lawrence grade ≥ 2), widespread cartilage damage, and meniscal damage, adjusting for age, sex, and body mass index (BMI). Additional analyses were performed excluding subjects who had chondrocalcinosis on radiography and those taking antiinflammatory medications.ResultsFour hundred four subjects were included (mean age 58.8 ± 7.0 yrs, BMI 29.6 ± 4.9 kg/m(2), 45.5% women). On CEMRI, the maximum synovitis score across 11 sites in each knee was 0 in 106 knees (26.2%), 1 in 135 (33.4%), and 2 in 163 (40.4%). Synovitis was associated with radiographic OA [adjusted OR (aOR) 3.25, 95% CI 1.98-5.35] and widespread cartilage damage (aOR 1.91, 95% CI 1.24-2.92). Severe meniscal damage showed a borderline significant association with synovitis (aOR 1.74, 95% CI 0.99-3.04). Additional analyses as described did not notably change the results.ConclusionCEMRI-detected synovitis is strongly associated with tibiofemoral radiographic OA and MRI-detected widespread cartilage damage.

ObjectiveTo investigate hip shape by active shape modeling (ASM) as a potential predictor of incident radiographic hip osteoarthritis (RHOA) and symptomatic hip osteoarthritis (SRHOA).MethodsAll hips developing RHOA from baseline (Kellgren/Lawrence [K/L] grade 0/1) to mean 6-year followup (K/L grade ≥2, 190 hips) and 1:1 control hips (K/L grade 0/1 at both times, 192 hips) were included. Proximal femur shape was defined on baseline anteroposterior pelvis radiographs and submitted to ASM, producing a mean shape and continuous variables representing independent modes of shape variation. Mode scores (n = 14, explaining 95% of shape variance) were simultaneously included in logistic regression models with incident RHOA and SRHOA as dependent variables, adjusted for intraperson correlations, sex, race, body mass index (BMI), baseline K/L grade, and/or symptoms.ResultsWe evaluated 382 hips from 342 individuals: 61% women and 83% white, with mean age 62 years and mean BMI 29 kg/m(2) . Several modes differed by sex and race, but no modes were associated with incident RHOA overall. Among men only, modes 1 and 2 were significantly associated (for a 1-SD decrease in mode 1 score: odds ratio [OR] 1.7 [95% confidence interval (95% CI) 1.1-2.5] and for a 1-SD increase in mode 2 score: OR 1.5 [95% CI 1.0-2.2]) with incident RHOA. A 1-SD decrease in mode 2 or 3 score increased the odds of SRHOA by 50%.ConclusionThis study confirms other reports that variations in proximal femur shape have a modest association with incident hip OA. The observation of proximal femur shape associations with hip symptoms requires further investigation.

PurposeTo study the natural evolution of cartilage T2 relaxation times in knees with various extents of morphological cartilage abnormalities, assessed with 3 Tesla MRI from the Osteoarthritis Initiative.Materials and methodsRight knee MRIs of 245, 45- to 60-year-old individuals without radiographic osteoarthritis (OA) were included. Cartilage was segmented and T2 maps were generated in five compartments (patella, medial and lateral femoral condyle, medial, and lateral tibia) at baseline and 2-year follow-up. We examined the association of T2 values and 2-year change of T2 values with various Whole-Organ MR Imaging Scores (WORMS). Statistical analysis was performed with analysis of variance and Students t-tests.ResultsHigher baseline T2 was associated with more severe cartilage defects at baseline and subsequent cartilage loss (P

ObjectiveTo evaluate trochlear morphology as a potential risk factor for patellofemoral osteoarthritis, determined by morphological and quantitative measurements of cartilage degeneration using 3-T magnetic resonance imaging (MRI) of the knee.Materials and methodsMRI of the right knees of 304 randomly selected subjects, aged 45-60 years, from the Osteoarthritis Initiative (OAI) progression cohort were screened for trochlear dysplasia, defined by an abnormal trochlear depth. Out of 304 subjects, n = 85 demonstrated a shallow trochlea (depth ≤3 mm; 28 %). In these, and also in a random sample of controls with normal trochlear depth (n = 50), the facet ratio and the sulcus angle were calculated and knee structural abnormalities were assessed by using a modified Whole Organ MR Imaging Score (WORMS). Cartilage segmentation was performed and T2 relaxation times and patellar cartilage volume were determined. ANOVA and multivariate regression models were used for statistical analysis of the association of MRI structural measures and trochlear morphology.ResultsKnees with a shallow trochlea showed higher patellofemoral degeneration (WORMS mean ± standard deviation, 11.2 ± 0.5 versus 5.7 ± 0.6; multivariate regression, P 170°) also showed increased WORMS scores (12.2 ± 1.1 versus 8.6 ± 0.6; P = 0.003). T2 values at the patella were significantly lower in the dysplasia group with a shallow trochlea. However, significance was lost after adjustment for cartilage volume (P = 0.673).ConclusionTrochlear dysplasia, defined by a shallow trochlea, was associated with higher WORMS scores and lower cartilage volume, indicating more advanced osteoarthritis at the patellofemoral joint.

ObjectiveTo evaluate the association of baseline frequent knee bending activities with the prevalence and progression of cartilage and meniscal abnormalities over 3 years and to assess the effect of frequent knee bending on the different knee compartments with 3T magnetic resonance imaging (MRI).MethodsWe studied 115 subjects without radiographic knee osteoarthritis (OA) but with risk factors for OA from the Osteoarthritis Initiative database. The inclusion criteria at baseline were age 45-55 years, body mass index of 19-27 kg/m(2) , Western Ontario and McMaster Universities Osteoarthritis Index pain score of 0, and Kellgren/Lawrence grade

PurposeTo assess the association of meniscal root tear with the development or worsening of tibiofemoral cartilage damage.Materials and methodsInstitutional review board approval and written informed consent from all subjects were obtained. A total of 596 knees with radiographically depicted osteoarthritis were randomly selected from the Multicenter Osteoarthritis study cohort. Cartilage damage was semiquantitatively assessed by using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system (grades 0-6). Subjects were separated into three groups: root tear only, meniscal tear without root tear, and neither meniscal nor root tear. A log-binomial regression model was used to calculate the relative risks for knees to develop incident or progressing cartilage damage in the root tear group and the meniscal tear group, with the no tear group serving as a reference.ResultsIn the medial tibiofemoral joint, there were 37 knees with isolated medial posterior root tear, 294 with meniscal tear without root tear, and 264 without meniscal or root tear. There were only two lateral posterior root tears, and no anterior root tears were found. Thus, the focus was on the medial posterior root tear. The frequency of severe cartilage damage (WORMS ≥ 5) was higher in the group with root tear than in the group without root or meniscal tear (76.7% vs 19.7%, P < .0001) but not in the group with meniscal but no root tear (76.7% vs 65.2%, P = .055). Longitudinal analyses included 33 knees with isolated medial posterior root tear, 270 with meniscal tear, and 245 with no tear. Adjusted relative risk of cartilage loss was 2.03 (95% confidence interval [CI]: 1.18, 3.48) for the root tear group and 1.84 (95% CI: 1.32, 2.58) for the meniscal tear group.ConclusionIsolated medial posterior meniscal root tear is associated with incident and progressive medial tibiofemoral cartilage loss.

ObjectiveTo better understand the relationship between knee pain and bilateral knee lesions, we compared focal knee lesions in knee pairs of subjects with no, unilateral, and bilateral knee pain, and risk factors for knee osteoarthritis (OA), but no radiographic knee OA.Materials and methodsWe examined both knees of 120 subjects from the Osteoarthritis Initiative database. We randomly selected 60 subjects aged 45-55 years with OA risk factors, no knee pain (WOMAC pain score=0) and no radiographic OA (KL-score ≤1) in both knees. We also selected two comparison groups with OA risk factors and no radiographic OA in both knees, but with knee pain (WOMAC pain score ≥5): 30 subjects with right only knee pain and 30 subjects with bilateral knee pain. All subjects underwent 3T MRI of both knees and focal knee lesions were assessed.ResultsStatistically significant associations between prevalence of focal lesions in the right and left knee with odds ratios up to 13.5 were found in all three subject groups. Focal knee lesions were generally not associated with pain in analyses comparing knee pairs of subjects with unilateral knee pain (p>0.05). The prevalence and severity of focal knee lesions were not significantly different in knee pairs of subjects with no knee pain and those with bilateral knee pain (p>0.05).ConclusionFocal knee lesions in the right and left knee of subjects with OA risk factors were positively associated with each other independent of knee pain status, and were not statistically significant different between knees in subjects with unilateral knee pain.

ObjectiveSynovitis is thought to be a secondary phenomenon in the osteoarthritis (OA) process and the menisci might be triggers of localized synovitis. The aim was to assess the cross-sectional associations of posterior horn meniscal damage with perimeniscal synovitis, and with synovitis posterior to the posterior cruciate ligament (PCL) using contrast enhanced (CE) MRI.DesignThe Multicenter Osteoarthritis (MOST) Study is a longitudinal observational study of subjects with or at risk for knee OA. Subjects are a subset of MOST who were examined with 1.5T CE MRI and had semiquantitative synovitis (scored from 0 to 2 at 11 locations) and meniscal readings (scored with WORMS from 0 to 4) available. Logistic regression was used to assess the association of posterior meniscal damage and perimeniscal synovitis in the same compartment, and between posterior meniscal damage and synovitis posterior to the PCL.ResultsThree hundred and seventy seven knees were included (mean age 61.1 years±6.9, mean BMI 29.6±4.9, 44.3% women). The odds for ipsi-compartmental perimeniscal synovitis were increased for knees with medial posterior horn meniscal damage (adjusted odds ratio [aOR] 2.5, 95% confidence intervals [95% CI] 1.3,4.8), but not for lateral damage (aOR 1.7, 95% CI 0.4,6.6). No positive associations were found for meniscal damage and presence of synovitis posterior to the PCL (aOR 0.9, 95% CI 0.6,1.5).ConclusionsMeniscal damage of the posterior horns is associated with ipsi-compartmental perimensical synovitis. No associations were found for posterior horn meniscal damage with synovitis posterior to the PCL, which suggests that synovitis posterior to the PCL is likely to be triggered by different pathomechanisms.