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Meniscal extrusion and bone marrow lesions are associated with incident and progressive knee osteoarthritis

  • A.J. Teichtahl
    Correspondence
    Address correspondence and reprint requests to: A.J. Teichtahl, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital Melbourne, VIC 3004, Australia. Fax: 61-3-9903-0556.
    Affiliations
    Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia

    Baker IDI Heart and Diabetes Institute, Commercial Road, Melbourne, VIC 3004, Australia
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  • F.M. Cicuttini
    Affiliations
    Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia
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  • F. Abram
    Affiliations
    Medical Imaging Research & Development, ArthroLab Inc., Montreal, Quebec, Canada
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  • Y. Wang
    Affiliations
    Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia
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  • J.-P. Pelletier
    Affiliations
    Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada
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  • P. Dodin
    Affiliations
    Medical Imaging Research & Development, ArthroLab Inc., Montreal, Quebec, Canada
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  • J. Martel-Pelletier
    Affiliations
    Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada
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Open ArchivePublished:February 12, 2017DOI:https://doi.org/10.1016/j.joca.2017.02.792

      Summary

      Objective

      Whether meniscal extrusion and bone marrow lesions (BMLs) are independently associated with the risk of knee osteoarthritis (OA) is unknown.

      Methods

      Data was extracted from the Osteoarthritis Initiative (OAI) cohort. Participants were grouped according to the absence (Kellgren–Lawrence (KL) grade ≤ 1, n = 2120) or presence (KL ≥ 2, n = 2249) of radiographic OA (ROA). Baseline meniscal extrusion and tibial BMLs were assessed. Tibial plateau cartilage volume was assessed at baseline and 72 months, while radiographic disease was assessed at baseline and 48 months. Total knee replacement (TKR) was assessed at 72 months.

      Results

      In those with ROA, the presence of a baseline meniscal extrusion (independent of BMLs) was associated with accelerated cartilage volume loss (medial tibia: −2.1%/annum vs −1.5%; lateral: −2.6%/annum vs −1.6%; both P < 0.001), progressive ROA and TKR (Odds ratio (OR) range 1.4–1.8; 95% CI range 1.1–2.9). The presence of a baseline BML was associated with accelerated cartilage volume loss (medial tibia: −2.1%/annum vs −1.6%; lateral: −1.9%/annum vs −1.6%; P ≤ 0.02), progressive ROA and joint replacement (OR range 1.5–2.4; 95% CI range 1.1–3.4). In those with no ROA, a baseline medial meniscal extrusion was associated with accelerated cartilage volume loss (medial tibia: −2.1%/annum vs −1.2%, P < 0.001), and a baseline medial BML with incident ROA (OR 1.7, 95% CI 1.1 to 2.9).

      Conclusions

      The presence of baseline meniscal extrusion and BMLs are associated with incident and progressive knee of each other (OA) and represent important structural targets for the treatment and prevention of knee OA.

      Keywords

      • While meniscal extrusion and BMLs increase the risk of progressive knee OA, previous studies have been limited by examining
        • i)
          the medial rather than the lateral knee joint
        • ii)
          established rather than incident knee OA
        • iii)
          one primary endpoint (e.g., radiographic progression)
      • Another limitation of previous data has been the failure to distinguish whether meniscal extrusion or BMLs are associated with progressive disease independent OA
      • We show that the presence of baseline meniscal extrusion and BMLs are associated with incident and progressive knee OA (independent of each other).

      Introduction

      Meniscal extrusion and bone marrow lesions (BMLs) are magnetic resonance imaging (MRI) detected abnormalities that increase the risk for knee osteoarthritis (OA)
      • Roemer F.W.
      • Zhang Y.
      • Niu J.
      • Lynch J.A.
      • Crema M.D.
      • Marra M.D.
      • et al.
      Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study.
      • Sharma L.
      • Eckstein F.
      • Song J.
      • Guermazi A.
      • Prasad P.
      • Kapoor D.
      • et al.
      Relationship of meniscal damage, meniscal extrusion, malalignment, and joint laxity to subsequent cartilage loss in osteoarthritic knees.
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Berthiaume M.J.
      • Beaudoin G.
      • Choquette D.
      • Haraoui B.
      • et al.
      Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes.
      • Ding C.
      • Martel-Pelletier J.
      • Pelletier J.P.
      • Abram F.
      • Raynauld J.P.
      • Cicuttini F.
      • et al.
      Knee meniscal extrusion in a largely non-osteoarthritic cohort: association with greater loss of cartilage volume.
      • Berthiaume M.J.
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Labonte F.
      • Beaudoin G.
      • Bloch D.A.
      • et al.
      Meniscal tear and extrusion are strongly associated with progression of symptomatic knee osteoarthritis as assessed by quantitative magnetic resonance imaging.
      • Driban J.B.
      • Lo G.H.
      • Lee J.Y.
      • Ward R.J.
      • Miller E.
      • Pang J.
      • et al.
      Quantitative bone marrow lesion size in osteoarthritic knees correlates with cartilage damage and predicts longitudinal cartilage loss.
      • Dore D.
      • Quinn S.
      • Ding C.
      • Winzenberg T.
      • Zhai G.
      • Cicuttini F.
      • et al.
      Natural history and clinical significance of MRI-detected bone marrow lesions at the knee: a prospective study in community dwelling older adults.
      • Roubille C.
      • Martel-Pelletier J.
      • Raynauld J.P.
      • Abram F.
      • Dorais M.
      • Delorme P.
      • et al.
      Meniscal extrusion promotes knee osteoarthritis structural progression: protective effect of strontium ranelate treatment in a phase III clinical trial.
      • Roemer F.W.
      • Kwoh C.K.
      • Hannon M.J.
      • Green S.M.
      • Jakicic J.M.
      • Boudreau R.
      • et al.
      Risk factors for magnetic resonance imaging-detected patellofemoral and tibiofemoral cartilage loss during a six-month period: the joints on glucosamine study.
      • Pelletier J.P.
      • Raynauld J.P.
      • Berthiaume M.J.
      • Abram F.
      • Choquette D.
      • Haraoui B.
      • et al.
      Risk factors associated with the loss of cartilage volume on weight-bearing areas in knee osteoarthritis patients assessed by quantitative magnetic resonance imaging: a longitudinal study.
      • Kothari A.
      • Guermazi A.
      • Chmiel J.S.
      • Dunlop D.
      • Song J.
      • Almagor O.
      • et al.
      Within-subregion relationship between bone marrow lesions and subsequent cartilage loss in knee osteoarthritis.
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Haraoui B.
      • Choquette D.
      • Dorais M.
      • Wildi L.M.
      • et al.
      Risk factors predictive of joint replacement in a 2-year multicentre clinical trial in knee osteoarthritis using MRI: results from over 6 years of observation.
      • Tanamas S.K.
      • Wluka A.E.
      • Pelletier J.P.
      • Pelletier J.M.
      • Abram F.
      • Berry P.A.
      • et al.
      Bone marrow lesions in people with knee osteoarthritis predict progression of disease and joint replacement: a longitudinal study.
      . Meniscal extrusion is a structural abnormality that occurs when the meniscus is displaced away from or uncovers the tibial articular cartilage, while BMLs are subchondral lesions that may include areas of sclerosis
      • Zanetti M.
      • Bruder E.
      • Romero J.
      • Hodler J.
      Bone marrow edema pattern in osteoarthritic knees: correlation between MR imaging and histologic findings.
      , increased bone volume fraction and trabecular thickness
      • Hunter D.J.
      • Gerstenfeld L.
      • Bishop G.
      • Davis A.D.
      • Mason Z.D.
      • Einhorn T.A.
      • et al.
      Bone marrow lesions from osteoarthritis knees are characterized by sclerotic bone that is less well mineralized.
      .
      While prospective cohort studies have shown that both meniscal extrusion and BMLs increase the risk of progressive knee OA, defined by cartilage volume loss
      • Roemer F.W.
      • Zhang Y.
      • Niu J.
      • Lynch J.A.
      • Crema M.D.
      • Marra M.D.
      • et al.
      Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study.
      • Sharma L.
      • Eckstein F.
      • Song J.
      • Guermazi A.
      • Prasad P.
      • Kapoor D.
      • et al.
      Relationship of meniscal damage, meniscal extrusion, malalignment, and joint laxity to subsequent cartilage loss in osteoarthritic knees.
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Berthiaume M.J.
      • Beaudoin G.
      • Choquette D.
      • Haraoui B.
      • et al.
      Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes.
      • Ding C.
      • Martel-Pelletier J.
      • Pelletier J.P.
      • Abram F.
      • Raynauld J.P.
      • Cicuttini F.
      • et al.
      Knee meniscal extrusion in a largely non-osteoarthritic cohort: association with greater loss of cartilage volume.
      • Berthiaume M.J.
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Labonte F.
      • Beaudoin G.
      • Bloch D.A.
      • et al.
      Meniscal tear and extrusion are strongly associated with progression of symptomatic knee osteoarthritis as assessed by quantitative magnetic resonance imaging.
      • Driban J.B.
      • Lo G.H.
      • Lee J.Y.
      • Ward R.J.
      • Miller E.
      • Pang J.
      • et al.
      Quantitative bone marrow lesion size in osteoarthritic knees correlates with cartilage damage and predicts longitudinal cartilage loss.
      • Dore D.
      • Quinn S.
      • Ding C.
      • Winzenberg T.
      • Zhai G.
      • Cicuttini F.
      • et al.
      Natural history and clinical significance of MRI-detected bone marrow lesions at the knee: a prospective study in community dwelling older adults.
      • Roubille C.
      • Martel-Pelletier J.
      • Raynauld J.P.
      • Abram F.
      • Dorais M.
      • Delorme P.
      • et al.
      Meniscal extrusion promotes knee osteoarthritis structural progression: protective effect of strontium ranelate treatment in a phase III clinical trial.
      • Roemer F.W.
      • Kwoh C.K.
      • Hannon M.J.
      • Green S.M.
      • Jakicic J.M.
      • Boudreau R.
      • et al.
      Risk factors for magnetic resonance imaging-detected patellofemoral and tibiofemoral cartilage loss during a six-month period: the joints on glucosamine study.
      • Pelletier J.P.
      • Raynauld J.P.
      • Berthiaume M.J.
      • Abram F.
      • Choquette D.
      • Haraoui B.
      • et al.
      Risk factors associated with the loss of cartilage volume on weight-bearing areas in knee osteoarthritis patients assessed by quantitative magnetic resonance imaging: a longitudinal study.
      • Kothari A.
      • Guermazi A.
      • Chmiel J.S.
      • Dunlop D.
      • Song J.
      • Almagor O.
      • et al.
      Within-subregion relationship between bone marrow lesions and subsequent cartilage loss in knee osteoarthritis.
      or the requirement for total knee replacement (TKR)
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Haraoui B.
      • Choquette D.
      • Dorais M.
      • Wildi L.M.
      • et al.
      Risk factors predictive of joint replacement in a 2-year multicentre clinical trial in knee osteoarthritis using MRI: results from over 6 years of observation.
      • Tanamas S.K.
      • Wluka A.E.
      • Pelletier J.P.
      • Pelletier J.M.
      • Abram F.
      • Berry P.A.
      • et al.
      Bone marrow lesions in people with knee osteoarthritis predict progression of disease and joint replacement: a longitudinal study.
      , the predominance of these studies have focused on the medial rather than the lateral knee joint, and have examined people with established knee OA. It remains unclear whether these structural abnormalities predate incident knee OA. Moreover, previous studies have examined only one, rather than a combination of primary endpoints for disease, such as cartilage volume loss, incident and progressive radiographic OA (ROA) and TKR. This is presumably because the follow-up periods in prior studies have been of a 2-year maximum duration, which is inadequate to capture the full spectrum of disease progression. Another limitation of previous data has been the failure to distinguish whether meniscal extrusion or BMLs independently are associated with progressive disease. Meniscal extrusion and BMLs may be interrelated, since meniscal pathology has been shown to increase the risk for BMLs
      • Englund M.
      • Guermazi A.
      • Roemer F.W.
      • Yang M.
      • Zhang Y.
      • Nevitt M.C.
      • et al.
      Meniscal pathology on MRI increases the risk for both incident and enlarging subchondral bone marrow lesions of the knee: the MOST study.
      . Understanding whether meniscal extrusion and BMLs are independently associated with knee OA may have important ramifications, as either lesion may independently be a structure whereby disease modifying OA therapies could be targeted to reduce the incidence and progression of disease.
      The National Institutes of Health Osteoarthritis Initiative (OAI) is the largest knee OA observational cohort, providing an unprecedented opportunity to address these important questions
      • Jungmann P.M.
      • Kraus M.S.
      • Alizai H.
      • Nardo L.
      • Baum T.
      • Nevitt M.C.
      • et al.
      Association of metabolic risk factors with cartilage degradation assessed by T2 relaxation time at the knee: data from the osteoarthritis initiative.
      • Martel-Pelletier J.
      • Roubille C.
      • Abram F.
      • Hochberg M.C.
      • Dorais M.
      • Delorme P.
      • et al.
      First-line analysis of the effects of treatment on progression of structural changes in knee osteoarthritis over 24 months: data from the osteoarthritis initiative progression cohort.
      • Lin W.
      • Alizai H.
      • Joseph G.B.
      • Srikhum W.
      • Nevitt M.C.
      • Lynch J.A.
      • et al.
      Physical activity in relation to knee cartilage T2 progression measured with 3 T MRI over a period of 4 years: data from the osteoarthritis initiative.
      .
      The aim of this 72 month longitudinal study was to examine whether compartmental baseline meniscal extrusion and BMLs were associated with incident and progressive knee OA, as measured by (1) cartilage volume loss, (2) incident or progressive ROA, and (3) TKR.

      Methods

      OAI

      Data were extracted from the OAI, a publicly available multicentre population-based observational cohort study of knee OA (available for public access at http://www.oai.uscf.edu/). The OAI comprises data of participants aged 45–79 years at baseline. Participants were excluded from the OAI if they had inflammatory arthritis, severe joint space narrowing in both knees, unilateral knee joint replacement and severe joint space narrowing in the contralateral knee, inability to undergo MRI or to provide a blood sample, required use of walking aids excepting a single straight cane ≤50% of the time, or were unwilling to provide informed consent. Participants were recruited at four clinical sites, and the study was approved by the institutional review boards at each of the sites. All participants gave informed consent. The follow-up retention rate at 48 months was 78.8%, and 66.5% by 72 months.

      Participants of the current study

      Bilateral standing posteroanterior fixed-flexion knee radiographs
      • Nevitt M.C.
      • Peterfy C.
      • Guermazi A.
      • Felson D.T.
      • Duryea J.
      • Woodworth T.
      • et al.
      Longitudinal performance evaluation and validation of fixed-flexion radiography of the knee for detection of joint space loss.
      were obtained at baseline for Kellgren–Lawrence (KL) grading (0–4) and group stratification. The data for these readings were obtained from the OAI database (http://www.oai.ucsf.edu/). If the participant did not have evidence of ROA, then the dominant knee, defined by leg used to kick a ball, was included for analyses as the target knee. In participants with radiographic knee OA, the knee with the highest KL grade was chosen. When the radiographic severity was equal between sides, the most painful knee (highest WOMAC pain score) was selected as the target knee for analyses. In the case of pain in both knees being equal, the dominant knee was selected.
      Participants were then divided into two groups based on their baseline KL grade: the first included participants without ROA at baseline (i.e., the incidence cohort), defined by a KL grade ≤1 (n = 2120), and the other included participants with ROA at baseline (i.e., the progression cohort), defined by a KL grade ≥2 at baseline (n = 2249) (Fig. 1).
      Body mass index (BMI) (kg m−2) were retrieved from the OAI database.

      Knee MRI acquisition

      Knee MRI acquisitions were performed for the target knee using 3T apparatus (Magnetom Trio, Siemens, Erlangen, Germany) at the four OAI clinical centres. MR images were acquired using DESS imaging and 2D-TSE with sagittal slices, as described in the OAI protocol
      • Peterfy C.G.
      • Gold G.
      • Eckstein F.
      • Cicuttini F.
      • Dardzinski B.
      • Stevens R.
      MRI protocols for whole-organ assessment of the knee in osteoarthritis.
      .

      MRI cartilage assessments

      Cartilage volume was measured using the DESS sequence and automatic human cartilage segmentation (ArthroLab, Montreal, Quebec, Canada), as previously described and validated
      • Martel-Pelletier J.
      • Roubille C.
      • Abram F.
      • Hochberg M.C.
      • Dorais M.
      • Delorme P.
      • et al.
      First-line analysis of the effects of treatment on progression of structural changes in knee osteoarthritis over 24 months: data from the osteoarthritis initiative progression cohort.
      • Dodin P.
      • Pelletier J.P.
      • Martel-Pelletier J.
      • Abram F.
      Automatic human knee cartilage segmentation from 3D magnetic resonance images.
      . Cartilage volume was analysed for the medial and lateral tibial compartments. The MR images were registered using the previously described method
      • Dodin P.
      • Pelletier J.P.
      • Martel-Pelletier J.
      • Abram F.
      Automatic human knee cartilage segmentation from 3D magnetic resonance images.
      , allowing a precise correspondence of the images in the subsequent MRI of the same patient. The change in knee cartilage volume over time was obtained by subtracting the baseline volume (mm3) from the 72 month follow-up volume, and divided by the baseline volume, in percentage values. An annual rate was determined by dividing the percentage value by six. The test–retest revealed an excellent measurement error of 0.3 ± 1.6% as described
      • Dodin P.
      • Pelletier J.P.
      • Martel-Pelletier J.
      • Abram F.
      Automatic human knee cartilage segmentation from 3D magnetic resonance images.
      , which corresponds to a measurement error of 30.3 ± 126.2 mm3.

      MRI meniscal extrusion assessment

      Meniscal extrusion was assessed with both DESS and 2D-TSE imaging and scored as absence or presence of partial or complete extrusion, as previously described
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Berthiaume M.J.
      • Beaudoin G.
      • Choquette D.
      • Haraoui B.
      • et al.
      Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes.
      . In brief, the extent of meniscal extrusion on the medial or lateral edges of the femoral tibial joint space, not including the osteophytes, was evaluated for the anterior, body, and posterior horn of the menisci in which 0 = no extrusion, 1 = partial meniscal extrusion, and 2 = complete meniscal extrusion with no contact with the joint space. The presence of any meniscal extrusion was defined as any score ≥1. The intra-reader correlation coefficient ranged from 0.85 to 0.92.

      MRI BMLs assessment

      BMLs were quantified at baseline using a fully automated system as described
      • Dodin P.
      • Abram F.
      • Pelletier J.P.
      • Martel-Pelletier J.
      A fully automated system for quantification of knee bone marrow lesions using MRI and the osteoarthritis initiative cohort.
      . In brief, the automated BML quantification first characterises the bone and cartilage domain in the DESS sequence, then proceeds to the BML quantification which was developed as a four-stage process: selection of structured and bright areas corresponding to BMLs, geometric filtering of unrelated structures, segmentation of the BML, and quantification of BML proportion within bone regions obtained by the ratio of the number of voxels in the BML object over those in the bone region examined. Data are expressed as the percentage of BML size in the medial and lateral tibial compartments. The presence of a BML was identified by a percentage of 1% of greater.

      X-ray: incident and progressive ROA

      Incident ROA was defined by a baseline KL grade of 0 or 1 changing to KL grade 2 or greater by 48 month follow-up (the latest radiographic data available in the OAI database until March 2016). Progressive ROA was defined by a baseline KL grade of 2 or 3 changing to a higher grade by 48 month follow-up.

      TKR

      TKR status was confirmed by the 72 month follow-up visit. It was defined as any knee with patient-reported TKR which was confirmed on subsequent radiograph between baseline and 72 month follow-up visit.

      Statistical analyses

      All of the data were systematically entered into a computerized database, after which descriptive statistics for participant characteristics were tabulated. Baseline characteristics are presented as mean ± standard deviation (SD) or percentage (%) where appropriate. We compared the demographic and clinical characteristics of participants with and without ROA at baseline using independent samples t tests for continuous data and Pearson's chi-square test for categorical data. The associations between baseline BMLs and meniscal extrusion for the outcome of cartilage volume loss were examined using F-test (general linear model) with estimated marginal means adjusted for gender, baseline age, BMI and either meniscal extrusion or BML as potential confounders. The associations between baseline BMLs and meniscal extrusion, for the outcomes of incident or progressive ROA, as well as joint replacement, were examined using binary logistic regression analyses, adjusting for gender, baseline age, BMI and either meniscal extrusion or BMLs. Odds ratio (OR) approximated relative risk (RR), given that the prevalence of BMLs and meniscal extrusions were low. All tests were two-sided and a P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS statistical package (standard version 20.0, Chicago, IL, USA).

      Results

      Study population (Table I)

      Participant characteristics at baseline and their structural changes over follow-up are shown in Table I. At baseline, 2120 participants had no ROA (KL ≤ 1), while 2249 participants had ROA (KL ≥ 2). Those with ROA were older (62.7 years vs 59.9 years, P < 0.001) and had greater BMI (29.8 kgm−2 vs 27.6 kgm−2, P < 0.001). People with ROA also had a higher prevalence of baseline meniscal extrusions (medial: 36.3% vs 9.9%; lateral: 9.5% vs 0.1%; both P < 0.001) and tibial BMLs (medial: 26.7% vs 8.9%; lateral: 20.9% vs 15.5%; both P < 0.001) than people without ROA, as well as less lateral (1934 mm3 vs 2003 mm3, P = 0.001) but not medial tibial cartilage volume (1407 mm3 vs 1384 mm3, P = 0.20). Moreover, people with ROA had a greater annual percentage loss of medial (1.7% vs 1.3%, P < 0.001) and lateral (1.7% vs 1.4%, P < 0.001) tibial cartilage volume, as well as a significantly greater incidence of joint replacement surgery (9.6% vs 0.4%, P < 0.001). There was a weak correlation between meniscal extrusion and BMLs for both the medial (r = 0.22, P <0.001) and lateral (r = 0.15, P < 0.001) tibia.
      Table IParticipants characteristics
      No radiographic disease (KL 0/1) N = 2120Radiographic disease (KL 2/3/4) N = 2249P
      Baseline data
      Age (years)59.9 (9.1)62.7 (9.0)<0.001
      Gender (% female)1224 (57.7)1311 (58.3)0.71
      BMI (kg.m−2)27.6 (4.5)29.8 (4.8)<0.001
      Meniscal extrusion, n (%)
      Medial207 (9.9)771 (36.3)<0.001
      Lateral3 (0.1)201 (9.5)<0.001
      BMLs, n (%)
      Medial182 (8.9)557 (26.7)<0.001
      Lateral316 (15.5)436 (20.9)<0.001
      Change data
      Annual % change in tibial cartilage volume (72 months)
      Medial−1.3 (1.5)−1.7 (1.8)<0.001
      Lateral−1.4 (1.3)−1.7 (1.5)<0.001
      Incident ROA (48 months), n (%)165 (9.6)
      Progressive ROA (48 months), n (%)272 (17.8)
      Knee replacement surgery (72 months), n (%)8 (0.4)215 (9.6)<0.001
      Results displayed as mean (SD) unless otherwise stated.

      The associations between baseline meniscal extrusion and cartilage volume (Table II)

      Among people with no ROA, those with a medial meniscal extrusion had a greater rate of medial tibial cartilage volume loss compared with those without a medial meniscal extrusion (2.1%/annum vs 1.2%/annum, P < 0.001). Moreover, among people with ROA, the presence of a medial or lateral meniscal extrusion was associated with significantly greater rates of cartilage volume loss in that respective tibial compartment (Medial extrusion: 2.1%/annum vs 1.5%/annum, P < 0.001; Lateral extrusion 2.6%/annum vs 1.6%/annum, P < 0.001). Results for the total population are presented in Supplementary Table 1.
      Table IIThe estimated marginal means of tibial cartilage volume (baseline to 72 months) according to the presence or absence of baseline meniscal extrusion or BMLs
      KL 0/1KL 2/3/4
      Meniscal extrusion
      Medial meniscal extrusion
      Present N = 207Absent N = 1878PPresent N = 770Absent N = 1354P
      Annual % medial tibial change−2.1 (0.14)−1.2 (0.04)<0.001−2.1 (0.10)−1.5 (0.07)<0.001
      Lateral meniscal extrusion
      Present N = 3Absent N = 2082PPresent N = 201Absent N = 1923P
      Annual % lateral tibial change−2.6 (0.16)−1.6 (0.04)<0.001
      BMLs
      Medial tibial BML
      Present N = 182Absent N = 1860PPresent N = 557Absent N = 1531P
      Annual % medial tibial change−1.2 (0.14)−1.3 (0.04)0.61−2.1 (0.11)−1.6 (0.06)<0.001
      Lateral tibial BML
      Present N = 316Absent N = 1726PPresent N = 436Absent N = 1653P
      Annual % lateral tibial change−1.5 (0.10)−1.4 (0.04)0.71−1.9 (0.10)−1.6 (0.05)0.02
      Results displayed as Estimated Marginal Mean (Standard Error of the Mean).
      Annual % change results adjusted for age, gender and BMI and either same compartment meniscal extrusion or BML.

      The associations between baseline BML and cartilage volume (Table II)

      Among people with ROA, the presence of a medial or lateral BML was associated with significantly greater rates of cartilage volume loss in that respective tibial compartment (Medial BML: 2.1%/annum vs 1.6%/annum, P < 0.001; Lateral BML 1.9%/annum vs 1.6%/annum, P = 0.02). Results for the total population are presented in Supplementary Table 3.

      The associations of baseline meniscal extrusion with incident and progressive ROA and knee replacement (Table III)

      The presence of a baseline medial meniscal extrusion was not significantly associated with the risk of incident ROA (OR 1.2, 95% CI 0.7 to 2.1, P = 0.51). In those with baseline ROA, the presence of a medial meniscal extrusion at baseline was associated with an increased risk of progressive ROA (OR 1.4, 95% CI 1.1 to 1.9, P = 0.02) and knee joint replacement surgery (OR 1.8, 95% CI 1.3 to 2.5, P = 0.001). Likewise, the presence of a lateral meniscal extrusion at baseline was associated with an increased risk of progressive ROA (OR 1.8, 95% CI 1.1 to 2.9, P = 0.01) and knee joint replacement surgery (OR 1.6, 95% CI 1.1 to 2.6, P = 0.04). Results for the total population are presented in Supplementary Table 2. A dose–response relationship is demonstrated in Table IV.
      Table IIIThe association between baseline meniscal extrusion and BMLs and the risk of incident or progressive ROA by 48 months and joint replacement by 72 months
      Meniscal extrusion
      Risk of incident ROA at 48 months among participants with a baseline score of KL 0/1
      n = 1642 with 156 incident cases of ROA.
      Risk of progressive ROA at 48 months among participants with baseline score of KL2/3
      n = 1405 with 253 cases of radiographic progression.
      Univariate OR (95% CI)PMultivariable OR (95% CI)PUnivariate OR (95% CI)PMultivariable OR (95% CI)P
      Medial1.1 (0.7, 1.9)0.671.2 (0.7, 2.1)0.511.5 (1.2, 2.1)0.0031.4 (1.1, 1.9)0.02
      Lateral2.1 (1.3, 3.3)0.0021.8 (1.1, 2.9)0.01
      Risk of knee joint replacement at 72 months among participants with a baseline score of KL 0/1Risk of knee joint replacement at 72 months among participants with a baseline score of KL/2/3/4
      n = 2015 with 169 cases of knee joint replacement.
      Univariate OR (95% CI)PMultivariable OR (95% CI)PUnivariate OR (95% CI)PMultivariable OR (95% CI)P
      Medial2.2 (1.6, 3.0)<0.0011.8 (1.3, 2.5)0.001
      Lateral1.9 (1.2, 2.9)0.0061.6 (1.1, 2.6)0.04
      BMLs
      Risk of incident ROA at 48 months among participants with a baseline score of KL 0/1
      n = 1642 with 156 incident cases of ROA.
      Risk of progressive ROA at 48 months among participants with baseline score of KL2/3
      n = 1405 with 253 cases of radiographic progression.
      Univariate OR (95% CI)PMultivariable OR (95% CI)PUnivariate OR (95% CI)PMultivariable OR (95% CI)P
      Medial1.8 (1.1, 2.9)0.031.7 (1.1, 2.9)0.031.9 (1.4, 2.5)<0.0011.8 (1.3, 2.4)<0.001
      Lateral1.2 (0.8, 1.8)0.461.1 (0.7, 1.8)0.551.8 (1.3, 2.5)<0.0011.7 (1.2, 2.4)0.001
      Risk of knee joint replacement at 72 months among participants with a baseline score of KL 0/1Risk of knee joint replacement at 72 months among participants with a baseline score of KL/2/3/4
      n = 2015 with 169 cases of knee joint replacement.
      Univariate OR (95% CI)PMultivariable OR (95% CI)PUnivariate OR (95% CI)PMultivariable OR (95% CI)P
      Medial2.7 (2.0, 3.7)<0.0012.4 (1.7, 3.4)<0.001
      Lateral1.7 (1.2, 2.4)0.0031.5 (1.1, 2.2)0.02
      Meniscal extrusion analysis adjusted for age, gender, BMI and respective compartment specific tibial BML at baseline.
      BMLs analysis adjusted for age, gender, BMI and respective compartment specific meniscal extrusion at baseline.
      n = 1642 with 156 incident cases of ROA.
      n = 1405 with 253 cases of radiographic progression.
      n = 2015 with 169 cases of knee joint replacement.
      Table IVThe dose response relationship between baseline meniscal extrusion (grade 0–2) and the risk of incident or progressive ROA by 48 months and joint replacement by 72 months
      Risk of incident ROA at 48 months among participants with a baseline score of KL 0/1
      In people with KL 0/1 at baseline (far left column), the frequency of grade 2 meniscal extrusion was low in the medial (n = 9, 0.4%), and absent in the lateral (n = 0) compartments, precluding further analyses.
      Risk of progressive ROA at 48 months among participants with baseline score of KL2/3
      In people with KL 2–4 at baseline (far right column) the frequency of grade 2 meniscal extrusion was 273 (12.1%) in the medial and 132 (5.9%) lateral compartments, enabling dose–response analyses.
      Multivariable OR (95% CI)PMultivariable OR (95% CI)P
      Medial1.41 (1.15, 1.74)0.001
      Lateral1.40 (1.05, 1.86)0.02
      Risk of knee joint replacement at 72 months among participants with a baseline score of KL/2/3/4
      In people with KL 2–4 at baseline (far right column) the frequency of grade 2 meniscal extrusion was 273 (12.1%) in the medial and 132 (5.9%) lateral compartments, enabling dose–response analyses.
      Multivariable OR (95% CI)PMultivariable OR (95% CI)P
      Medial1.62 (1.31, 1.99)<0.001
      Lateral1.41 (1.10, 1.82)0.007
      Multivariable analysis adjusted for age, gender, BMI and respective compartment specific tibial BML at baseline.
      In people with KL 0/1 at baseline (far left column), the frequency of grade 2 meniscal extrusion was low in the medial (n = 9, 0.4%), and absent in the lateral (n = 0) compartments, precluding further analyses.
      In people with KL 2–4 at baseline (far right column) the frequency of grade 2 meniscal extrusion was 273 (12.1%) in the medial and 132 (5.9%) lateral compartments, enabling dose–response analyses.

      The associations between baseline BMLs, incident and progressive ROA and knee replacement (Table III)

      The presence of a baseline medial (OR 1.7, 95% CI 1.1 to 2.9, P = 0.03) but not lateral (OR 1.1, 95% CI 0.7 to 1.8, P = 0.55) BML was significantly associated with an increased risk of incident ROA. In those with baseline ROA, the presence of a baseline medial BML was associated with an increased risk of progressive ROA (OR 1.8, 95% CI 1.3 to 2.4, P < 0.001) and knee joint replacement surgery (OR 2.4, 95% CI 1.7 to 3.4, P < 0.001). Likewise, the presence of a lateral BML at baseline was associated with an increased risk of progressive ROA (OR 1.7, 95% CI 1.2 to 2.4, P = 0.001) and knee joint replacement surgery (OR 1.5, 95% CI 1.1 to 2.2, P = 0.02). Results for the total population are presented in Supplementary Table 4. A dose–response relationship is demonstrated in Table V.
      Table VThe dose response relationship between baseline BMLs and the risk of incident or progressive ROA by 48 months and joint replacement by 72 months
      Risk of incident ROA at 48 months among participants with a baseline score of KL 0/1Risk of progressive ROA at 48 months among participants with baseline score of KL2/3
      Multivariable OR (95% CI)PMultivariable OR (95% CI)P
      Medial1.03 (0.98, 1.09)0.261.05 (1.03, 1.08)<0.001
      Lateral1.00 (0.97, 1.04)0.941.02 (0.99, 1.05)0.26
      Risk of knee joint replacement at 72 months among participants with a baseline score of KL/2/3/4
      Multivariable OR (95% CI)PMultivariable OR (95% CI)P
      Medial1.05 (1.02, 1.08)<0.001
      Lateral1.01 (0.96, 1.06)0.76
      Multivariable analysis adjusted for age, gender, BMI and respective compartment specific meniscal extrusion at baseline.

      Discussion

      This study has demonstrated that among those with ROA, the presence of baseline meniscal extrusion or BMLs (independent of each other) were associated with disease progression, measured by accelerated cartilage volume loss, radiographic progression and joint replacement surgery. Among people with no ROA, the presence of a baseline medial meniscal extrusion was associated with accelerated cartilage volume loss, while a baseline medial BML was associated with incident ROA. Taken together, these data identify important structural targets to help delay or avert the incidence and progression of knee OA.
      Meniscal extrusion is a structural abnormality where the meniscus is displaced away from or uncovers the tibial articular cartilage, and are common among people with knee OA. In this study, we have shown that among people with ROA, the presence of a meniscal extrusion was associated with compartment specific cartilage volume loss, progressive ROA and joint replacement surgery, independent of the presence of BMLs. To our knowledge, this is the first study to demonstrate associations between meniscal extrusion and joint changes over the entire spectrum of joint disease, within the same prospective cohort, and independent of BMLs (see supplementary Tables 1 and 2). This has been possible because of the large sample size and long duration of follow-up of the OAI so that the entire spectrum of disease progression can be captured, ranging from cartilage loss, through to progressive ROA and joint replacement. Moreover, most previous studies have predominantly focussed on the medial knee compartment. For instance, a considerably smaller study (n = 161) with a modest incidence of knee joint replacement surgery (n = 18) demonstrated that medial meniscal extrusion was a risk factor for surgery over a 2 year period
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Haraoui B.
      • Choquette D.
      • Dorais M.
      • Wildi L.M.
      • et al.
      Risk factors predictive of joint replacement in a 2-year multicentre clinical trial in knee osteoarthritis using MRI: results from over 6 years of observation.
      . A recent 36-month MRI study of people with knee OA found that individuals with medial meniscal extrusion had more joint space width and cartilage volume loss
      • Roubille C.
      • Martel-Pelletier J.
      • Raynauld J.P.
      • Abram F.
      • Dorais M.
      • Delorme P.
      • et al.
      Meniscal extrusion promotes knee osteoarthritis structural progression: protective effect of strontium ranelate treatment in a phase III clinical trial.
      , a finding corroborated elsewhere
      • Roemer F.W.
      • Zhang Y.
      • Niu J.
      • Lynch J.A.
      • Crema M.D.
      • Marra M.D.
      • et al.
      Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study.
      • Sharma L.
      • Eckstein F.
      • Song J.
      • Guermazi A.
      • Prasad P.
      • Kapoor D.
      • et al.
      Relationship of meniscal damage, meniscal extrusion, malalignment, and joint laxity to subsequent cartilage loss in osteoarthritic knees.
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Berthiaume M.J.
      • Beaudoin G.
      • Choquette D.
      • Haraoui B.
      • et al.
      Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes.
      • Ding C.
      • Martel-Pelletier J.
      • Pelletier J.P.
      • Abram F.
      • Raynauld J.P.
      • Cicuttini F.
      • et al.
      Knee meniscal extrusion in a largely non-osteoarthritic cohort: association with greater loss of cartilage volume.
      • Berthiaume M.J.
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Labonte F.
      • Beaudoin G.
      • Bloch D.A.
      • et al.
      Meniscal tear and extrusion are strongly associated with progression of symptomatic knee osteoarthritis as assessed by quantitative magnetic resonance imaging.
      • Roemer F.W.
      • Kwoh C.K.
      • Hannon M.J.
      • Green S.M.
      • Jakicic J.M.
      • Boudreau R.
      • et al.
      Risk factors for magnetic resonance imaging-detected patellofemoral and tibiofemoral cartilage loss during a six-month period: the joints on glucosamine study.
      • Pelletier J.P.
      • Raynauld J.P.
      • Berthiaume M.J.
      • Abram F.
      • Choquette D.
      • Haraoui B.
      • et al.
      Risk factors associated with the loss of cartilage volume on weight-bearing areas in knee osteoarthritis patients assessed by quantitative magnetic resonance imaging: a longitudinal study.
      . Since we have a longer follow-up period (72 months) and a considerably larger sample, we have been able to demonstrate both medial and lateral meniscal extrusion were associated with progressive joint disease, independent of BMLs. Moreover, we have extended these previous works by demonstrating that a medial meniscal extrusion was associated with accelerated medial tibial cartilage volume loss in people with no ROA.
      BMLs are subchondral lesions that may include areas of sclerosis
      • Zanetti M.
      • Bruder E.
      • Romero J.
      • Hodler J.
      Bone marrow edema pattern in osteoarthritic knees: correlation between MR imaging and histologic findings.
      , increased bone volume fraction and trabecular thickness, despite reduced bone mineral density
      • Hunter D.J.
      • Gerstenfeld L.
      • Bishop G.
      • Davis A.D.
      • Mason Z.D.
      • Einhorn T.A.
      • et al.
      Bone marrow lesions from osteoarthritis knees are characterized by sclerotic bone that is less well mineralized.
      . Akin to meniscal extrusion, no previous study has examined how BMLs relate to the primary outcomes of cartilage loss, radiographic progression and joint replacement surgery, within the same prospective cohort and independent of meniscal extrusion. In this study, we have demonstrated that the presence of BMLs were associated with accelerated cartilage volume loss, progressive ROA and joint replacement surgery among people with ROA, independent of meniscal extrusion. In smaller prospective studies of shorter duration, BMLs were associated with an increased risk for joint replacement surgery
      • Raynauld J.P.
      • Martel-Pelletier J.
      • Haraoui B.
      • Choquette D.
      • Dorais M.
      • Wildi L.M.
      • et al.
      Risk factors predictive of joint replacement in a 2-year multicentre clinical trial in knee osteoarthritis using MRI: results from over 6 years of observation.
      • Tanamas S.K.
      • Wluka A.E.
      • Pelletier J.P.
      • Pelletier J.M.
      • Abram F.
      • Berry P.A.
      • et al.
      Bone marrow lesions in people with knee osteoarthritis predict progression of disease and joint replacement: a longitudinal study.
      . Moreover, previous studies have shown BMLs to be associated with cartilage loss in the same subregion
      • Driban J.B.
      • Lo G.H.
      • Lee J.Y.
      • Ward R.J.
      • Miller E.
      • Pang J.
      • et al.
      Quantitative bone marrow lesion size in osteoarthritic knees correlates with cartilage damage and predicts longitudinal cartilage loss.
      • Dore D.
      • Quinn S.
      • Ding C.
      • Winzenberg T.
      • Zhai G.
      • Cicuttini F.
      • et al.
      Natural history and clinical significance of MRI-detected bone marrow lesions at the knee: a prospective study in community dwelling older adults.
      • Kothari A.
      • Guermazi A.
      • Chmiel J.S.
      • Dunlop D.
      • Song J.
      • Almagor O.
      • et al.
      Within-subregion relationship between bone marrow lesions and subsequent cartilage loss in knee osteoarthritis.
      . To our knowledge, no study has examined the relationships between BMLs and the risk of incident ROA, while only one previous smaller study (n = 223 at follow-up) has demonstrated that BMLs conferred a compartment specific risk for the progression of ROA
      • Felson D.T.
      • McLaughlin S.
      • Goggins J.
      • LaValley M.P.
      • Gale M.E.
      • Totterman S.
      • et al.
      Bone marrow edema and its relation to progression of knee osteoarthritis.
      .
      Taken together, these data implicate meniscal extrusion and BMLs as structural abnormalities that could be targeted in an attempt to reduce the onset and progression of knee OA. Previous works have shown that modifiable factors such as obesity and joint trauma were associated with meniscal extrusion
      • Ding C.
      • Martel-Pelletier J.
      • Pelletier J.P.
      • Abram F.
      • Raynauld J.P.
      • Cicuttini F.
      • et al.
      Knee meniscal extrusion in a largely non-osteoarthritic cohort: association with greater loss of cartilage volume.
      • Englund M.
      • Felson D.T.
      • Guermazi A.
      • Roemer F.W.
      • Wang K.
      • Crema M.D.
      • et al.
      Risk factors for medial meniscal pathology on knee MRI in older US adults: a multicentre prospective cohort study.
      , while weight loss reduced cartilage volume loss and improved knee pain in people with, but not without meniscal pathology
      • Teichtahl A.J.
      • Wluka A.E.
      • Wang Y.
      • Strauss B.J.
      • Proietto J.
      • Dixon J.B.
      • et al.
      The longitudinal relationship between changes in body weight and changes in medial tibial cartilage, and pain among community-based adults with and without meniscal tears.
      . Obesity and strenuous physical activity were also shown to be risk factors for increasing BML size
      • Foong Y.C.
      • Khan H.I.
      • Blizzard L.
      • Ding C.
      • Cicuttini F.
      • Jones G.
      • et al.
      The clinical significance, natural history and predictors of bone marrow lesion change over eight years.
      • Davies-Tuck M.L.
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      • Wang Y.
      • English D.R.
      • Giles G.G.
      • Cicuttini F.
      The natural history of bone marrow lesions in community-based adults with no clinical knee osteoarthritis.
      . Pharmacological interventions such as zolendronic acid have shown promise as a therapeutic option to reduce BML size
      • Laslett L.L.
      • Dore D.A.
      • Quinn S.J.
      • Boon P.
      • Ryan E.
      • Winzenberg T.M.
      • et al.
      Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial.
      . Disease modifying OA therapies may be well served by targeting meniscal extrusion and BMLs as important structural endpoints.
      The present study has several strengths. The OAI offers a unique opportunity to study the disease profile of a large number of participants with and without ROA and explore the impact of meniscal extrusion and BMLs on disease progression throughout a disease spectrum ranging from cartilage loss to incident and progressive ROA, and ultimately joint replacement surgery. Until now, the assessment of cartilage thickness/volume change by qMRI had been done mostly using manual or semiautomated technologies, which have the intrinsic limitation of variability in results with respect to human intervention. This, in turn, imposed limitations with regard to a complete analysis of the OAI cohort. The recent validation of fully automated technology to assess OA joint structural changes including cartilage thickness/volume
      • Dodin P.
      • Pelletier J.P.
      • Martel-Pelletier J.
      • Abram F.
      Automatic human knee cartilage segmentation from 3D magnetic resonance images.
      greatly improved the capacity and reliability of the analysis of the OAI MRI dataset. Nevertheless, this study has several potential limitations. We aimed to examine whether baseline meniscal extrusion and BMLs are associated with the incidence and progression of knee OA. We have not examined people with and without clinical knee OA, as we have not stratified the participants according to the presence of knee pain at baseline. Rather, we have stratified our baseline groups according to the presence (KL grade 2–4) or absence (KL grade 0 and 1) of ROA. We have limited our BML analyses to those present in the subchondral region of the proximal tibia. Accordingly, we have measured cartilage specific to the tibial region, rather than the global knee, as an outcome. Tibial and femoral cartilage volumes are strongly correlated in cross-sectional analyses
      • Cicuttini F.M.
      • Wluka A.E.
      • Stuckey S.L.
      Tibial and femoral cartilage changes in knee osteoarthritis.
      and in longitudinal work
      • Cicuttini F.M.
      • Wluka A.E.
      • Wang Y.
      • Stuckey S.L.
      Longitudinal study of changes in tibial and femoral cartilage in knee osteoarthritis.
      . A measure of tibial cartilage volume loss is therefore reflective of change occurring within the tibiofemoral compartment. Nevertheless, we cannot be sure that this is reflective of all the different structural components of the knee joint, measured at varying points in the natural history of OA. Bias phenomenon, caused by association with other variables could also confound our associations. We have however adjusted all multivariable analyses for age, gender and BMI, arguably the three most important determinants of cartilage volume loss and incident/progressive knee OA. Nevertheless, other structural lesions such as synovitis, have not been accounted for. We have also adjusted for BMLs when meniscal lesions were the exposure of interest, and adjusted for meniscal lesions when BMLs were the exposure of interest. Although residual confounding may still exist, we rectified this further in stratified analyses (see Supplementary Tables 2 and 3). This provides strong evidence that each structural abnormality is associated with deleterious outcomes independent of the other lesion. Despite our large cohort, the prevalence of baseline lateral meniscal extrusion was low among people with no ROA (n = 3, 0.1%). Finally, it is possible that among those with baseline ROA, co-existing meniscal extrusions and or BMLs represented a more diseased knee joint which is at higher risk for progression (cartilage volume loss, progressive ROA and joint replacement surgery).
      This study has demonstrated that the presence of baseline meniscal extrusion and BML are associated with incident and progressive knee OA, characterised by accelerated cartilage volume loss, increased incidence and progression of ROA and the risk of joint replacement surgery. Meniscal extrusion and BMLs therefore represent important structural targets to help reduce the burden of knee OA.

      Contributorship

      Teichtahl A – design of the study, data analyses, writing, manuscript preparation.
      Cicuttini F – design of the study, data analyses, manuscript preparation.
      Abram F – data acquisition, manuscript preparation.
      Wang Y – data analyses, manuscript preparation.
      Pelletier JP – data acquisition, manuscript preparation.
      Dodin P – data acquisition, manuscript preparation.
      Martel-Pelletier J – design of the study, data acquisition, data analyses, manuscript preparation.

      Competing interests

      Drs Teichtahl, Wang and Prof Cicuttini have no conflict of interest. Drs Martel-Pelletier and Pelletier, F Abram and P Dodin are not part of the OAI investigative team. Drs Martel-Pelletier and Pelletier are shareholders in ArthroLab Inc. F Abram and P Dodin are employees of ArthroLab Inc.

      Funding

      The OAI is a public-private partnership comprised of five contracts ( NO1-AR-2-2258 ; NO1-AR-2-2259 ; NO1-AR-2-2260 ; NO1-AR-2-2261 ; NO1-AR-2-2262 ) funded by the National Institutes of Health , a branch of the Department of Health and Human Services, in four clinical sites (University of Maryland School of Medicine and Johns Hopkins University, Baltimore, MD; Ohio State University, Columbus, OH; University of Pittsburgh, PA; Memorial Hospital of Rhode Island, Pawtucket, RI) and conducted by the OAI study investigators. Private funding partners include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline, and Pfizer Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. The study was funded in part by grants from the Osteoarthritis Research Unit (Montreal, Quebec, Canada). A.J.T is the recipient of the National Health and Medical Research Council (NHMRC) Early Career Fellowship (ID 1073284). Y.W and is the recipient of NHMRC Career Development Fellowship (Clinical Level 1 #1065464).

      Acknowledgements

      We would like to thank the OAI participants and Coordinating Center for their work in generating the clinical and radiological data of the OAI cohort and for making them publicly available.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

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