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The relationship between meniscal pathology and osteoarthritis depends on the type of meniscal damage visible on magnetic resonance images: data from the Osteoarthritis Initiative

Open ArchivePublished:August 15, 2016DOI:https://doi.org/10.1016/j.joca.2016.08.004

      Summary

      Objective

      To determine the association of different types of meniscal pathology with knee pain, bone marrow lesion (BML) volume, and end-stage knee osteoarthritis (esKOA).

      Design

      Participants were selected from an ancillary project to the Osteoarthritis Initiative (OAI) who had at least one knee with symptomatic osteoarthritis. Baseline magnetic resonance images (MRI) were evaluated for meniscal pathology using a modified International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine (ISAKOS) classification system. We collapsed 10 types of meniscal pathology into five categories: normal, intrameniscal signal, morphological deformity/extrusion (altered meniscal shape and/or extrusion but no apparent substance loss), tear, and maceration. Outcomes included Western Ontario and McMaster Universities osteoarthritis index (WOMAC) knee pain and BML volume at baseline and after 2 years. We defined the prevalence of esKOA based on a validated algorithm. We performed logistic regression and adjusted for age, sex, and body mass index (BMI).

      Results

      The 463 participants (53% male) included in the analysis had mean age 63 (9.2) years, BMI 29.6 (4.6) kg/m2, and 71% had Kellgren–Lawrence grade ≥2. Morphological deformity/extrusion and maceration, but no other types of meniscal pathology, were associated with BML volume (morphological deformity/extrusion odds ratio [OR] = 2.47, 95% CI: 1.49, 4.09, maceration OR = 5.85, 95% CI: 3.40, 10.06) and change in BML volume (morphological deformity/extrusion OR = 2.17, 95% CI: 1.37, 3.45, maceration OR = 3.12, 95% CI: 1.87, 5.19). Only maceration was associated with baseline WOMAC knee pain (OR = 2.82, 95% CI: 1.79, 4.43) and prevalence of esKOA (OR = 7.53, 95% CI: 4.25, 13.31).

      Conclusions

      Based on MRI, morphologic deformity/extrusion and maceration rather than intrameniscal signal or tear were associated with osteoarthritis severity and progression, which highlights the importance of differentiating distinct types of meniscal pathology.

      Keywords

      Introduction

      Meniscal damage is common among older adults
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      Incidental meniscal findings on knee MRI in middle-aged and elderly persons.
      and is an important risk factor for the incidence
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      Meniscal tear in knees without surgery and the development of radiographic osteoarthritis among middle-aged and elderly persons: the Multicenter Osteoarthritis Study.
      and progression of knee osteoarthritis (KOA)
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      Meniscal tear and extrusion are strongly associated with progression of symptomatic knee osteoarthritis as assessed by quantitative magnetic resonance imaging.
      . Damage to a meniscus can compromise its ability to absorb, transmit, and distribute mechanical stress over a large area of the joint cartilage
      • Walker P.S.
      • Erkman M.J.
      The role of the menisci in force transmission across the knee.
      . Meniscal pathology increases the risk for structural changes commonly associated with KOA (e.g., bone marrow lesions (BMLs)
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      • Guermazi A.
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      • 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.
      • Lo G.H.
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      • McAlindon T.E.
      Group OAII
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      , cartilage volume loss
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      , and altered subchondral bone mineral density
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      Meniscal damage associated with increased local subchondral bone mineral density: a Framingham study.
      ). However, there are different types of meniscal pathology, which range from subtle intrameniscal signal to tears (e.g., horizontal tear, radial tear) and maceration. Certain types of meniscal pathology (e.g., maceration) may alter joint loading more than other types of subtle meniscal pathology (e.g., intrameniscal signal). Hence, certain types of meniscal pathology, like maceration (meniscal destruction), may influence structural and clinical progression of KOA more than other types of meniscal pathology. Major meniscal pathology (comparable with maceration) is associated with BML progression
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      • 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.
      and knee pain
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      • et al.
      The association between meniscal and cruciate ligament damage and knee pain in community residents.
      among individuals without KOA. Furthermore, the presence of major meniscal pathology is more likely in knees that receive a knee replacement than among knees that do not
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      Can structural joint damage measured with MR imaging be used to predict knee replacement in the following year?.
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      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.
      . While only 5% of adults without KOA have meniscal destruction (e.g., maceration), one in four have at least one type of meniscal pathology, which suggests that certain types of meniscal pathology (e.g., tears) may not be a major catalyst for OA progression
      • Englund M.
      • Guermazi A.
      • Gale D.
      • Hunter D.J.
      • Aliabadi P.
      • Clancy M.
      • et al.
      Incidental meniscal findings on knee MRI in middle-aged and elderly persons.
      . It is important to determine if certain types of meniscal pathology are associated with structural and symptomatic changes because this could help us more efficiently identify individuals at risk for progression.
      We aimed to determine the association of different types of meniscal pathology with common measures of OA severity and progression. Specifically, we evaluated knee pain, change in knee pain over 2 years, BML volume, and change in BML volume over 2 years because these measures of OA severity and progression have been previously associated with meniscal pathology in studies that did not account for different types of meniscal pathology
      • 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.
      • Lo G.H.
      • Hunter D.J.
      • Nevitt M.
      • Lynch J.
      • McAlindon T.E.
      Group OAII
      Strong association of MRI meniscal derangement and bone marrow lesions in knee osteoarthritis: data from the osteoarthritis initiative.
      • Kim H.A.
      • Kim I.
      • Song Y.W.
      • Kim D.H.
      • Niu J.
      • Guermazi A.
      • et al.
      The association between meniscal and cruciate ligament damage and knee pain in community residents.
      • Englund M.
      • Niu J.
      • Guermazi A.
      • Roemer F.W.
      • Hunter D.J.
      • Lynch J.A.
      • et al.
      Effect of meniscal damage on the development of frequent knee pain, aching, or stiffness.
      • Ding C.
      • Martel-Pelletier J.
      • Pelletier J.P.
      • Abram F.
      • Raynauld J.P.
      • Cicuttini F.
      • et al.
      Meniscal tear as an osteoarthritis risk factor in a largely non-osteoarthritic cohort: a cross-sectional study.
      . We also tested the association of different types of meniscal pathology with a validated definition of end-stage KOA (esKOA), which is a unique outcome that accounts for radiographic disease severity and self-reported knee pain and function
      • Riddle D.L.
      • Jiranek W.A.
      • Hayes C.W.
      Use of a validated algorithm to judge the appropriateness of total knee arthroplasty in the United States: a multicenter longitudinal cohort study.
      . We hypothesize that only certain types of meniscal pathology that severely alter meniscal function (i.e., maceration, change in meniscal shape [morphological deformity/extrusion]) relate to common measures of KOA severity and progression.

      Materials and methods

      Study sample

      We selected a convenience sample of the Osteoarthritis Initiative (OAI) Progression Cohort (n = 1390) who attended an OAI visit between August 2007 and April 2009 and consented to participate in the Bone Ancillary Study (n = 629). The primary aim of the Bone Ancillary Study was to investigate the influence of bone in the structural progression of OA. The inclusion criteria were a willingness to undergo additional knee imaging (i.e., additional magnetic resonance [MR] scans and dual-energy X-ray absorptiometry). Participants with contraindication for MR imaging were excluded. For the Bone Ancillary Study analyses, the 24-month OAI visit was considered baseline and the 48-month visit was considered as the 2 year follow-up. At baseline, these participants had clinical data and MR images that were assessed for meniscal pathology (n = 463) and BML volume (n = first 386 knees based on ID as a convenience). At the follow-up visit, 463 participants had clinical data and 386 participants had MR images that were assessed for BML volume. The reduced sample size was due to time and personnel constraints.
      We selected one knee per participant. We used the primary OAI imaging knee as the index knee unless there was a contraindication for MR imaging. According to protocol, the primary OAI imaging knee was the right knee, which underwent a complete set of OAI MR sequences. The contralateral knee had an abbreviated MR scan to reduce participant burden. While everyone in this study sample had at least one knee with symptomatic OA, the primary OAI imaging knee was not always the knee with symptomatic OA.
      This study received ethical approval from each OAI clinical site (Memorial Hospital of Rhode Island Institutional Review Board, The Ohio State University's Biomedical Sciences Institutional Review Board, University of Pittsburgh Institutional Review Board, and University of Maryland Baltimore–Institutional Review Board), the OAI coordinating center (Committee on Human Research at University of California, San Francisco), and the Institutional Review Board at Tufts Medical Center and Tufts University Health Sciences Campus. All participants provided informed consent to the OAI and the Bone Ancillary Study.

      MR imaging

      MR images were acquired at the 24- and 48-month OAI visits with one of four identical Siemens (Erlangen, Germany) Trio 3-T MR systems and a USA Instruments (Aurora, OH, USA) quadrature transmit–receive knee coil at the four OAI clinical sites
      • Peterfy C.G.
      • Schneider E.
      • Nevitt M.
      The osteoarthritis initiative: report on the design rationale for the magnetic resonance imaging protocol for the knee.
      . For purposes of the Bone Ancillary Study these MR images were considered baseline and 2 year follow-up. The following sequence was used for BML evaluation: sagittal intermediate-weighted, turbo spin echo, fat-suppressed MR sequences (field of view = 160 mm, slice thickness = 3 mm, skip = 0 mm, flip angle = 180°, echo time = 30 ms, recovery time = 3200 ms, 313 × 448 matrix (interpolated to 512 × 512), phase encode superior/inferior, x resolution = 0.357 mm, and y resolution = 0.511 mm). We scored menisci using the same sequences used to evaluate BMLs in addition to the coronal intermediate-weighted 2D turbo spin echo, recovery time of 3850 ms, echo time of 29 ms, slice thickness of 3 mm, and field of view of 140 mm. All images are publicly available (https://oai.epi-ucsf.org).

      Meniscal pathology scoring

      A single experienced fellowship trained musculoskeletal radiologist (RJW) reviewed the baseline MR images for meniscal pathology by location (i.e., anterior horn, body, and posterior horn) within the medial and lateral menisci using a modified International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine (ISAKOS) meniscal tear classification system
      • Anderson A.F.
      • Irrgang J.J.
      • Dunn W.
      • Beaufils P.
      • Cohen M.
      • Cole B.J.
      • et al.
      Interobserver reliability of the International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine (ISAKOS) classification of meniscal tears.
      . The original ISAKOS scoring was based on viewing of videos of arthroscopy to evaluate the meniscal tear based on the tear depth, location, tear pattern, length, quality of tissue, and percent of meniscus excised. This was modified to focus on the radiological aspect of MR imaging and 10 classifications were made: normal, intrameniscal signal, morphological deformity/extrusion (shape change including meniscal extrusion but no apparent substance loss), horizontal tear, horizontal flap tear, longitudinal-vertical tear, radial tear, vertical flap tear, complex tear, and maceration (destruction). The presence of these 10 pathologies was evaluated systematically in each region of the meniscus and each region was assigned only one pathology. Intrameniscal signal was defined as an increase in signal intensity within a region without other pathologic features. The reader indicated a type of tear when it was the only tear in a region. Meniscal morphological deformity/extrusion referred to the major loss of meniscal integrity with loss of normal contour and no obvious tear as defined by no linear hyperintense signal extending to an articular surface (Supplementary Fig. 1). Morphological deformity may occur with displacement [Fig. 1(c)]. Other types of pathologies, with the exception of intrameniscal signal, were absent in this category. Hence, if a region had morphological deformity/extrusion and intrameniscal signal change then the region was characterized as morphological deformity/extrusion. The inter-observer agreement (kappa) of the MRI-based ISAKOS scoring system ranged from 0.56 to 0.92. The intra-observer agreement was kappa >0.81.
      Fig. 1
      Fig. 1Different types of meniscal pathologies used in the modified ISAKOS scoring system. (a) Intrameniscal signal, (b) Tear (complex), (c) Morphological deformity/extrusion (often occurs with displacement), (d) Maceration.

      BML volume evaluation

      A semi-automated segmentation method was used to determine BML volume from baseline and follow-up MR images of the Bone Ancillary Study. We focused on BMLs in the medial and lateral tibia because we hypothesized these regions would be influenced by meniscal pathology more than the femoral regions, which could have BMLs secondary to patellofemoral OA. A detailed description of the segmentation method is published elsewhere
      • Pang J.
      • Driban J.B.
      • Destenaves G.
      • Miller E.
      • Lo G.H.
      • Ward R.J.
      • et al.
      Quantification of bone marrow lesion volume and volume change using semi-automated segmentation: data from the osteoarthritis initiative.
      . In brief, two readers measured BML volume by using a graphic user interface (MATLAB; MathWorks, Inc., Natick, MA, USA) to identify the crude boundaries of the tibia and femur in each slice of the MR sequence. The program automatically refined the initial bone border and applied a thresholding and curve evolution process twice to segment the areas of high signal intensity, which represent a probable BML. Based on common standards for defining BMLs
      • Roemer F.W.
      • Frobell R.
      • Hunter D.J.
      • Crema M.D.
      • Fischer W.
      • Bohndorf K.
      • et al.
      MRI-detected subchondral bone marrow signal alterations of the knee joint: terminology, imaging appearance, relevance and radiological differential diagnosis.
      , the software detected subchondral BMLs (i.e., the distance between a BML and the articular surface should be ≤10 mm
      • Roemer F.W.
      • Frobell R.
      • Hunter D.J.
      • Crema M.D.
      • Fischer W.
      • Bohndorf K.
      • et al.
      MRI-detected subchondral bone marrow signal alterations of the knee joint: terminology, imaging appearance, relevance and radiological differential diagnosis.
      ) that appear on more than one image. Using this criteria, BMLs have been associated with the presence of meniscal pathology
      • Lo G.H.
      • Hunter D.J.
      • Nevitt M.
      • Lynch J.
      • McAlindon T.E.
      Group OAII
      Strong association of MRI meniscal derangement and bone marrow lesions in knee osteoarthritis: data from the osteoarthritis initiative.
      , knee pain
      • Lo G.H.
      • McAlindon T.E.
      • Niu J.
      • Zhang Y.
      • Beals C.
      • Dabrowski C.
      • et al.
      Bone marrow lesions and joint effusion are strongly and independently associated with weight-bearing pain in knee osteoarthritis: data from the osteoarthritis initiative.
      • Driban J.B.
      • Price L.
      • Lo G.H.
      • Pang J.
      • Hunter D.J.
      • Miller E.
      • et al.
      Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker–longitudinal relationships with pain and structural changes: data from the Osteoarthritis Initiative.
      , and structural progression
      • Driban J.B.
      • Price L.
      • Lo G.H.
      • Pang J.
      • Hunter D.J.
      • Miller E.
      • et al.
      Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker–longitudinal relationships with pain and structural changes: data from the Osteoarthritis Initiative.
      • Driban J.B.
      • Tassinari A.
      • Lo G.H.
      • Price L.L.
      • Schneider E.
      • Lynch J.A.
      • et al.
      Bone marrow lesions are associated with altered trabecular morphometry.
      .
      Validity of this method with OAI images was previously demonstrated
      • Pang J.
      • Driban J.B.
      • Destenaves G.
      • Miller E.
      • Lo G.H.
      • Ward R.J.
      • et al.
      Quantification of bone marrow lesion volume and volume change using semi-automated segmentation: data from the osteoarthritis initiative.
      . We found a moderate-to-good intra-reader (intraclass correlation coefficient (ICC3,1) = 0.79–0.99) and inter-reader reliability (ICC2,1 = 0.59–0.93) for BML volume change
      • Shrout P.E.
      • Fleiss J.L.
      Intraclass correlations: uses in assessing rater reliability.
      . A third reader assessed the accuracy and consistency of all segmentations.

      Knee pain evaluation

      Knee-specific pain was assessed using the well validated Western Ontario and McMaster Universities osteoarthritis index (WOMAC) pain score
      • Bellamy N.
      • Buchanan W.W.
      • Goldsmith C.H.
      • Campbell J.
      • Stitt L.W.
      Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
      , which was assessed at baseline and 2 year follow-up visits. WOMAC pain scale is based on five questions of knee pain over the past 7 days when performing different activities (e.g., walking, climbing stairs, lying down). These pain questions were assessed with a 5-point Likert scale (0 = no pain and 4 = severe pain), which were summed for a total WOMAC pain score (range 0–20). WOMAC pain scores are publicly available (Files: AllClinical##_SAS [version 3.2 and 6.2]).

      esKOA calculation

      We adopted a strategy to define esKOA based on a modified validated algorithm for defining an individual's appropriateness for a total knee arthroplasty (TKA)
      • Riddle D.L.
      • Jiranek W.A.
      • Hayes C.W.
      Use of a validated algorithm to judge the appropriateness of total knee arthroplasty in the United States: a multicenter longitudinal cohort study.
      • Escobar A.
      • Quintana J.M.
      • Arostegui I.
      • Azkarate J.
      • Guenaga J.I.
      • Arenaza J.C.
      • et al.
      Development of explicit criteria for total knee replacement.
      . We defined the state of esKOA at the 36- and/or 48-month OAI visits (1 year and/or 2 year follow-up). The modified algorithm accounts for a participant's radiographic severity, localization of OA (i.e., patellofemoral, medial or lateral tibiofemoral, multiple compartments), knee symptoms, range of motion, and varus/valgus laxity assessments. Radiographic severity and localization were based on Kellgren–Lawrence scoring and OARSI joint space narrowing scores, respectively. Central readers provided the scoring based on bilateral posterior-anterior weight-bearing knee X-rays (Files: kXR_SQ_BU##[version 3.5 and 6.3]). One reader (JL) read MR images to determine the presence of patellofemoral OA (a definite osteophyte with a definite cartilage lesion at the patella or anterior femur
      • Hunter D.J.
      • Arden N.
      • Conaghan P.G.
      • Eckstein F.
      • Gold G.
      • Grainger A.
      • et al.
      Definition of osteoarthritis on MRI: results of a Delphi exercise.
      ) when the algorithm needed to account for the number of affected compartments. Knee pain and knee function status in participants were assessed with the sum of the WOMAC pain and function scales. We then collapsed the sum of the WOMAC pain and function scales into four categories to reflect the slight (scores 0–11), moderate (scores 12–22), intense (scores 23–33) and severe (scores ≥34) symptomatology. Patients were classified as having limited mobility or increased instability when they either had a flexion contracture of ≥5° or were graded as having moderate or severe medial or lateral laxity during valgus or varus stress testing with the knee flexed to 20°. All measures were collected following the OAI protocol, which is publicly available (https://oai.epi-ucsf.org; Files: allclinical## [version 1.5, 3.5, 5.5]).

      Clinical data

      At baseline, study staff asked participants: “Have you ever injured your right knee badly enough to limit your ability to walk for at least 2 days?”. A similar question was asked for the left knee. At each annual visit study staff asked a follow-up question: “Since your last annual visit to the OAI clinic about 12 months ago, have you injured your right knee badly enough to limit your ability to walk for at least 2 days?”. A similar question was asked for the left knee. We defined a history of injury as anyone who reported a history of injury at the baseline, 12-month, or 24-month OAI visits. A similar question was asked for the surgery status of knee and was followed up over the visits. Self-reported physical activity during the previous 7 days was measured using the Physical Activity Scale for the Elderly (PASE). PASE scores from 24-month OAI visit were used to determine physical activity groups from lowest to highest activity levels.
      Age, sex, and body mass index (BMI), were recorded based on a standardized protocol (https://oai.epi-ucsf.org). All OAI clinical data are publicly available.

      Data analysis

      Some types of meniscal pathologies had a low prevalence; therefore, for analyses, we collapsed the 10 original ISAKOS categories into normal, intrameniscal signal, morphological deformity/extrusion, tear (i.e., horizontal, horizontal flap, vertical–longitudinal, radial, radial–longitudinal, complex tear), and maceration. Each of these five categories was dichotomized as present or absent. As a secondary post hoc analysis, we also counted the number of regions of the knee with maceration (0–6), which represented the most severe type of meniscal pathology.
      To assess the association with types of meniscal pathology and structural progression we assessed BML volumes in 386 knees. Since the BML segmentation program detected small areas of signal intensity on every knee we used a classification and regression tree (CART) to identify a meaningful BML volume cut-off value using medial joint space narrowing progression as outcome as we previously published
      • Driban J.B.
      • Price L.
      • Lo G.H.
      • Pang J.
      • Hunter D.J.
      • Miller E.
      • et al.
      Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker–longitudinal relationships with pain and structural changes: data from the Osteoarthritis Initiative.
      . A total tibial BML volume less than 1 cm
      • 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.
      was identified as the volume that cannot be classified as meaningful BML. For cross-sectional analysis, we collapsed the baseline BML volume into three categories: (1) no meaningful BML volume (<1 cm3), (2) small BML volume: below median value of meaningful BML volumes (1.00–2.15 cm3), and (3) large BML volume: above median value of meaningful BML volume (>2.15 cm3). Longitudinally, the change in BML volume was collapsed to four groups based on the presence of a meaningful BML volume and quartiles of BML volume change: (1) no meaningful BML volume (<1 cm3) at both time points, (2) regression of meaningful BML volume: baseline BML volume ≥1.00 cm3 & BML volume change ≤−0.75 cm3, (lowest quartile of change), (3) no BML volume change: middle two quartiles of the BML volume change (baseline BML volume ≥1.00 cm3 & BML volume change >−0.75 cm3 & ≤1.00 cm3), and (4) progression of meaningful BML volume: (baseline BML volume ≥1.00 cm3 & BML volume change >1.00 cm3). Ordinal logistic regression was performed to determine the association of baseline meniscal pathology with BML volume and change in BML volume.
      A large percentage of knees had a WOMAC knee pain score of zero and our analyses failed to meet the assumptions for linear regression modelling; therefore, WOMAC knee pain at baseline was collapsed into three categories for cross-sectional analysis: (1) no or little pain (WOMAC pain score 0–1, reference category), (2) mild pain (WOMAC pain score 2–3), (3) moderate–severe pain (WOMAC pain score >3). Longitudinally, we collapsed the change in WOMAC knee pain between the baseline and 2 year follow-up visits into three categories based on the presence or absence of pain and a clinically meaningful change in pain (absolute change of two or relative change of 40%)
      • Pham T.
      • Van Der Heijde D.
      • Lassere M.
      • Altman R.D.
      • Anderson J.J.
      • Bellamy N.
      • et al.
      Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria.
      : (1) no pain or a meaningful decrease in pain (reference category), (2) pain but no change over time, and (3) meaningful increase in pain. Ordinal logistic regression was performed to determine the association of baseline meniscal pathology with knee pain and change in knee pain over 2 years.
      To assess whether the type of meniscal pathology was associated with esKOA we adapted the previously published decision rule
      • Riddle D.L.
      • Jiranek W.A.
      • Hayes C.W.
      Use of a validated algorithm to judge the appropriateness of total knee arthroplasty in the United States: a multicenter longitudinal cohort study.
      and collapsed the inconclusive and inappropriate category into one category that is not esKOA. We defined the original appropriate category as esKOA. Logistic regression was performed to determine the association between baseline meniscal pathology and esKOA. We completed secondary analyses by further adjusting for history of knee injury or surgery, BML and PASE in multivariable analyses.
      All parameter estimates were adjusted for age, sex, and BMI. In addition, indicator variables for intrameniscal signal, morphological deformity/extrusion, maceration, and tear were all included in models to explore the independent association of each type of meniscal pathology on structural and clinical progression of KOA. All statistical analyses were performed on SAS 9.4 (Cary, NC, USA).

      Results

      463 participants from the baseline visit of Bone Ancillary Study were included in the analysis with mean (standard deviation) age of 63 (9) years, 53% male, BMI 29.6 (4.6) kg/m2, and 86% had any type of meniscal pathology at baseline. 55% participants had intrameniscal signal, 30% morphological deformity/extrusion, 20% maceration and 47% any tear. Prevalence of baseline any knee pain was 73%, baseline BML was 27 %, and the esKOA was 15%. The sample included a wide range of radiographic severity with 14%, 15%, 34%, 28%, and 8% with Kellgren–Lawrence grades 0, 1, 2, 3, 4; respectively. There were 168 (36%) knees with a history of knee injury and 102 (22%) knees with a history of knee surgery.

      Types of meniscal pathology and BML volume

      Table I provides the cross-sectional associations between types of meniscal pathology and baseline BML volume. Table II presents the longitudinal associations between types of meniscal pathology and BML volume change. Overall, the presence of a meniscal pathology, regardless of type, was associated with BML volume (odds ratio [OR] = 3.91, 95% confidence interval [95% CI] = 1.36, 11.24). Morphological deformity/extrusion and maceration were consistently associated with BML volume and change in BML volume. Intrameniscal signal and any tear were not significantly associated with BML volume or change in BML volume.
      Table IAssociation between different types of meniscal pathology and total tibial BML volume at baseline (24-month OAI visit)
      Menisci (Overall n = 386)No BML
      No BML: BML volume below 1.00 cm3.
      n (%)
      Small BML
      Small BML: Below median of meaningful BML volume: BML volume >1.00 cm3 & <2.15 cm3.
      n (%)
      Large BML
      Large BML: Above median of meaningful BML volume: BML volume >2.15 cm3.
      n (%)
      Univariable OR (95% CI)Multivariable
      Ordinal regression models were used and adjusted for age, gender and BMI.
      OR (95% CI)
      Type of pathology
      Types of pathology were further adjusted for each other in multivariable analysis.
       Intrameniscal signal (n = 212)154 (73)31 (15)27 (13)1.09 (0.69, 1.71)1.25 (0.76, 2.08)
       Morphological deformity/extrusion (n = 117)68 (58)25 (21)24 (21)2.80 (1.76, 4.47)2.47 (1.49, 4.09)
       Maceration (n = 77)33 (43)12 (16)32 (42)7.04 (4.22, 11.76)
      Analyses failed to meet the proportional odds assumptions for ordinal logistic regression.
      5.85 (3.40, 10.06)
       Any tear (n = 183)137 (75)26 (14)20 (11)0.85 (0.54, 1.33)0.95 (0.58, 1.58)
      Maceration: number of regions affected
      Types of pathology were further adjusted for each other in multivariable analysis.
       0 (n = 309)251 (81)39 (13)19 (6)ReferenceReference
       1 (n = 37)20 (54)6 (16)11 (30)4.18 (2.12, 8.23)3.86 (1.94, 7.68)
       2 (n = 22)8 (36)3 (14)11 (50)10.09 (4.36, 23.29)8.19 (3.48, 19.29)
       3 and above (n = 18)5 (28)3 (17)10 (56)13.89 (5.42, 35.59)14.48 (5.56, 37.66)
      OR = odds ratio, 95% CI = 95% confidence interval.
      Bold denotes statistical significance at P < 0.05.
      All multivariable models remained statistically significant after further adjustments for injury or surgery and PASE.
      No BML: BML volume below 1.00 cm3.
      Small BML: Below median of meaningful BML volume: BML volume >1.00 cm3 & <2.15 cm3.
      Large BML: Above median of meaningful BML volume: BML volume >2.15 cm3.
      § Ordinal regression models were used and adjusted for age, gender and BMI.
      Types of pathology were further adjusted for each other in multivariable analysis.
      Analyses failed to meet the proportional odds assumptions for ordinal logistic regression.
      Table IIAssociation between different types and combination of meniscal pathology at baseline and total tibial BML volume change over 2 years
      Menisci (Overall n = 386)No BML at both times
      No BML at both times: BML volume below 1.00 cm3 at baseline and follow-up.
      n (%)
      Regression of BMLs
      Regression of BMLs: BML volume change lowest quartile: BML volume >1.00 cm3 at both times & BML volume change ≤−0.75 cm3.
      n (%)
      No change in BMLs
      No Change in BMLs: BML volume change middle two quartile: BML volume >1.00 cm3 at both times & BML volume change >−0.75 cm3 & ≤1.00 cm3.
      n (%)
      Progression of BMLs
      Progression of BMLs: BML volume change highest quartile: BML volume >1.00 cm3 at both times & BML volume change >1.00 cm3.
      n (%)
      Univariable OR (95% CI)Multivariable
      Ordinal logistic regression models were used and adjusted for age, gender and BMI.
      OR (95% CI)
      Type of pathology
      Types of pathology were further adjusted for each other in multivariable analysis.
       Intrameniscal signal (n = 212)138 (65)19 (9)34 (16)21 (10)1.09 (0.72, 1.64)1.21 (0.77, 1.90)
       Morphological deformity/extrusion (n = 117)60 (51)13 (11)30 (26)14 (12)2.33 (1.52, 3.60)2.17 (1.37, 3.45)
       Maceration (n = 77)26 (34)17 (22)24 (31)10 (13)3.81 (2.39, 6.07)
      Analyses failed to meet the proportional odds assumptions for ordinal logistic regression. Bold denotes statistical significance at P < 0.05.
      3.12 (1.87, 5.19)
       Any tear (n = 183)116 (63)17 (9)34 (19)16 (9)1.19 (0.79, 1.79)1.19 (0.76, 1.87)
      Maceration: number of regions affected
      Types of pathology were further adjusted for each other in multivariable analysis.
       0 (n = 309)227 (73)17 (6)43 (14)22 (7)ReferenceReference
       1 (n = 37)17 (46)8 (22)8 (22)4 (11)2.58 (1.37, 4.87)
      Analyses failed to meet the proportional odds assumptions for ordinal logistic regression. Bold denotes statistical significance at P < 0.05.
      2.29 (1.17, 4.47)
       2 (n = 22)6 (27)4 (18)10 (45)2 (9)4.49 (2.12, 9.53)
      Analyses failed to meet the proportional odds assumptions for ordinal logistic regression. Bold denotes statistical significance at P < 0.05.
      3.28 (1.45, 7.43)
       3 and above (n = 18)3 (17)5 (28)6 (33)4 (22)6.40 (2.719, 14.68)
      Analyses failed to meet the proportional odds assumptions for ordinal logistic regression. Bold denotes statistical significance at P < 0.05.
      6.62 (2.72, 16.13)
      OR = odds ratio, 95% CI = 95% confidence interval.
      All multivariable models remained statistically significant after further adjustments for injury or surgery and PASE.
      No BML at both times: BML volume below 1.00 cm3 at baseline and follow-up.
      Regression of BMLs: BML volume change lowest quartile: BML volume >1.00 cm3 at both times & BML volume change ≤−0.75 cm3.
      No Change in BMLs: BML volume change middle two quartile: BML volume >1.00 cm3 at both times & BML volume change >−0.75 cm3 & ≤1.00 cm3.
      § Progression of BMLs: BML volume change highest quartile: BML volume >1.00 cm3 at both times & BML volume change >1.00 cm3.
      Ordinal logistic regression models were used and adjusted for age, gender and BMI.
      Types of pathology were further adjusted for each other in multivariable analysis.
      # Analyses failed to meet the proportional odds assumptions for ordinal logistic regression. Bold denotes statistical significance at P < 0.05.
      Having more meniscal regions affected with maceration was associated with greater BML volume than those with a normal meniscus. Further adjusting for surgery or injury cases did not change our conclusion. We did not report the association between BML volume change and any type of meniscal pathology because our analyses failed to meet the assumption for proportional odds.

      Types of meniscal pathology and knee pain

      Table III, Table IV provide the cross-sectional and longitudinal associations between meniscal pathology and knee pain, respectively. Overall, the presence of a meniscal pathology, regardless of type, was not significantly associated with knee pain (OR = 1.30, 95% CI = 0.78, 2.18) or change in knee pain (OR = 0.89, 95% CI = 0.54, 1.48). When we assessed the types of meniscal pathology, meniscal maceration was significantly associated with greater knee pain but not with increase in knee pain in longitudinal analysis. Morphological deformity/extrusion was not significantly associated with knee pain cross-sectionally, but showed a trend (P = 0.059) towards an increase in knee pain over 2 years. Further adjusting for any history of surgery or injury cases, BMLs and PASE yielded largely similar results.
      Table IIIAssociation between different types of meniscal pathology and total WOMAC knee pain at baseline (24-month OAI visit)
      Menisci (n = 463)No-little pain
      No-Little Pain: total WOMAC pain score ≤1.
      n (%)
      Mild Pain
      Mild Pain: total WOMAC pain score 2 or 3.
      n (%)
      Moderate to severe Pain
      Moderate to Severe Pain: total WOMAC pain score >3.
      n (%)
      Univariable OR (95% CI)Multivariable
      Ordinal logistic regression models were used and adjusted for age, gender and BMI.
      OR (95% CI)
      Type of pathology
      Types of pathology were further adjusted for each other.
       Intrameniscal signal (n = 259)100 (39)57 (22)102 (39)1.10 (0.79, 1.55)1.12 (0.79, 1.60)
       Morphological deformity/extrusion (n = 142)48 (34)34 (24)62 (42)1.34 (0.93, 1.93)1.13 (0.78, 1.67)
       Maceration (n = 100)23 (23)24 (24)53 (53)2.35 (1.54, 3.58)2.82 (1.79, 4.43)
       Any tear (n = 222)86 (39)51 (23)85 (38)1.02 (0.73, 1.44)1.30 (0.91, 1.86)
      Maceration: number of regions affected
      Types of pathology were further adjusted for each other.
       0 (n = 363)154 (42)89 (24)121 (33)ReferenceReference
       1 (n = 49)11 (22)9 (18)29 (59)2.83 (1.58, 5.08)2.99 (1.65, 5.42)
       2 (n = 27)7 (26)7 (26)13 (48)1.97 (0.94, 4.11)2.55 (1.20, 5.34)
      All multivariable models remained statistically significant after further adjustments for injury or surgery, BML and PASE except.
       3 and above (n = 51)5 (21)8 (33)11 (46)2.03 (0.93, 4.42)2.54 (1.15, 5.60)
      All multivariable models remained statistically significant after further adjustments for injury or surgery, BML and PASE except.
      OR = odds ratio, 95% CI = 95% confidence interval.
      Bold denotes statistical significance at P < 0.05.
      No-Little Pain: total WOMAC pain score ≤1.
      Mild Pain: total WOMAC pain score 2 or 3.
      Moderate to Severe Pain: total WOMAC pain score >3.
      § All multivariable models remained statistically significant after further adjustments for injury or surgery, BML and PASE except.
      Ordinal logistic regression models were used and adjusted for age, gender and BMI.
      Types of pathology were further adjusted for each other.
      Table IVAssociation between types of meniscal pathology at baseline and total WOMAC knee pain change over 2 years
      Menisci (n = 463)No pain or decreased pain n (%)Pain but no change n (%)Increase in pain n (%)Univariable OR (95% CI)Multivariable
      Ordinal logistic regression models were used and adjusted for age, gender and BMI.
      OR (95% CI)
      Type of pathology
      Types of pathology were further adjusted for each other in multivariable analysis.
       Intrameniscal signal (n = 259)114 (44)61 (24)84 (32)1.19 (0.84, 1.67)1.24 (0.87, 1.76)
       Morphological deformity/extrusion (n = 142)54 (38)39 (27)49 (35)1.44 (1.00, 2.08)1.44 (0.99, 2.09)
       Maceration (n = 100)41 (41)30 (30)29 (29)1.10 (0.73, 1.66)1.02 (0.66, 1.57)
       Any tear (n = 222)105 (47)56 (25)61 (27)0.82 (0.58, 1.15)0.82 (0.58, 1.17)
      Maceration: number of regions affected
      Types of pathology were further adjusted for each other in multivariable analysis.
       0 (n = 363)166 (46)89 (25)108 (30)ReferenceReference
       1 (n = 49)24 (49)13 (27)12 (24)0.84 (0.48, 1.47)0.84 (0.47, 1.47)
       2 (n = 27)8 (30)10 (37)9 (33)1.53 (0.74, 3.14)1.57 (0.75, 3.27)
       3 and above (n = 24)9 (38)7 (29)8 (33)1.30 (0.61, 2.79)1.32 (0.61, 2.85)
      OR = odds ratio, 95% CI = 95% confidence interval.
      Decrease or increase in pain: total WOMAC pain absolute change of two or relative change of 40%.
      Bold denotes statistical significance at P < 0.05.
      All multivariable models remained statistically significant after further adjustments for injury or surgery, BML and PASE.
      Ordinal logistic regression models were used and adjusted for age, gender and BMI.
      Types of pathology were further adjusted for each other in multivariable analysis.

      Types of meniscal pathology and esKOA

      Table V presents the association of meniscal pathology type with the prevalence of esKOA at the 36- or 48-month OAI visit. Overall, there was no statistically significant association between the presence of meniscal pathology, regardless of type, and the prevalence of esKOA (OR = 1.50, 95% CI = 0.64, 3.54). However, maceration was associated with esKOA. Having more meniscal regions affected with maceration was associated with greater odds of having esKOA than those with a normal meniscus. Intrameniscal signal and any tear were not associated with esKOA.
      Table VAssociation between different types of meniscal pathology at baseline and prevalence of esKOA at 1 year and 2 year follow-up (36 and 48 month OAI visits) using an OAI adapted version of Escobar
      • Bellamy N.
      • Buchanan W.W.
      • Goldsmith C.H.
      • Campbell J.
      • Stitt L.W.
      Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
      algorithm
      Menisci (n = 461)End-stage KOA
      Proxy for end-stage KOA: a proxy measure for prediction of end-stage KOA based on adapted Escobar algorithm.
      Univariable OR (95% CI)Multivariable
      Binary logistic regression models were used and adjusted for age, gender and BMI.
      OR (95% CI)
      Absent n (%)Present n (%)
      Type of pathology
      Types of pathology were further adjusted for each other in multivariable analysis.
       Intrameniscal signal (n = 258)213 (83)45 (16)1.14 (0.69, 1.87)1.21 (0.69, 2.12)
       Morphological deformity/extrusion (n = 142)107 (75)35 (25)2.15 (1.31, 3.56)1.57 (0.90, 2.76)
       Maceration (n = 99)55 (56)44 (44)7.98 (4.67, 13.60)7.53 (4.25, 13.31)
       Any tear (n = 221)186 (85)35 (15)0.89 (0.54, 1.45)1.17 (0.67, 2.03)
      Maceration: number of regions affected
      Types of pathology were further adjusted for each other in multivariable analysis.
       0 (n = 362)329 (91)33 (9)ReferenceReference
       1 (n = 48)30 (63)18 (38)5.98 (3.01, 11.87)5.64 (2.81, 11.35)
       2 (n = 27)13 (48)14 (52)10.74 (4.66, 24.76)10.80 (4.52, 25.77)
       3 and above (n = 24)12 (50)12 (50)9.97 (4.15, 23.95)10.61 (4.34, 25.91)
      OR = odds ratio, 95% CI = 95% confidence interval.
      Bold denotes statistical significance at P < 0.05.
      All multivariable models remained statistically significant after further adjustments for injury or surgery, BML and PASE.
      Proxy for end-stage KOA: a proxy measure for prediction of end-stage KOA based on adapted Escobar algorithm.
      Binary logistic regression models were used and adjusted for age, gender and BMI.
      Types of pathology were further adjusted for each other in multivariable analysis.

      Discussion

      This is the first study to determine the association between different types of meniscal pathology based on the detailed ISAKOS scoring system and common measures of OA severity and progression. We found that meniscal maceration and an altered meniscal shape including meniscal extrusion (morphological deformity/extrusion) rather than intrameniscal signal or tears were associated with structural changes. Our results also suggest that meniscal maceration is associated with greater knee pain and esKOA.
      Abnormalities that severely disrupt load distribution of a meniscus such as altered shape and maceration were associated with BML volume and change in BML volume. Presence and larger number of regions with meniscal maceration was also associated with BML and esKOA suggesting that both number and type of pathology may be important in predicting KOA progression. Roemer et al. found that presence of maceration of the meniscal body and medial posterior horn was more likely in knees that received knee replacement than in control knees
      • Roemer F.W.
      • Kwoh C.K.
      • Hannon M.J.
      • Hunter D.J.
      • Eckstein F.
      • Wang Z.
      • et al.
      Can structural joint damage measured with MR imaging be used to predict knee replacement in the following year?.
      . Our findings also suggest that severe disruptive pathologies of menisci are associated with structural KOA progression.
      Prevalent intrameniscal signal and tear were not associated with BML presence or BML progression or esKOA in our study. The present finding concurs with a previous study, which found that the rate of medial meniscus lesions (tear or intrameniscal signal) was not higher in those who developed incident radiographic KOA compared with control participants
      • Badlani J.T.
      • Borrero C.
      • Golla S.
      • Harner C.D.
      • Irrgang J.J.
      The effects of meniscus injury on the development of knee osteoarthritis: data from the osteoarthritis initiative.
      . Hence, these pathologies are less disruptive and may not be detrimental in KOA progression over 2 years and conservative treatment can be considered for these pathologies; however, these findings may not be generalizable to acute meniscal tears. In fact, acute meniscal tears in younger athletic populations are key risk factors for incident KOA
      • Oiestad B.E.
      • Engebretsen L.
      • Storheim K.
      • Risberg M.A.
      Knee osteoarthritis after anterior cruciate ligament injury: a systematic review.
      • Lohmander L.S.
      • Englund P.M.
      • Dahl L.L.
      • Roos E.M.
      The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis.
      .
      The presence of a tear alone does not qualify as KOA
      • Hunter D.J.
      • Arden N.
      • Conaghan P.G.
      • Eckstein F.
      • Gold G.
      • Grainger A.
      • et al.
      Definition of osteoarthritis on MRI: results of a Delphi exercise.
      . A recent consensus-based OA definition noted that the presence of a tear must be accompanied by an osteophyte or full thickness cartilage defect and at least one of the following: BML/cyst, partial thickness cartilage loss, or bone attrition. Similarly, intrameniscal signal alone is not KOA despite representing early degenerative changes in the meniscus and being common among adults
      • Englund M.
      • Guermazi A.
      • Gale D.
      • Hunter D.J.
      • Aliabadi P.
      • Clancy M.
      • et al.
      Incidental meniscal findings on knee MRI in middle-aged and elderly persons.
      • Ludman C.N.
      • Hough D.O.
      • Cooper T.G.
      • Gottschalk A.
      Silent meniscal abnormalities in athletes: magnetic resonance imaging of asymptomatic competitive gymnasts.
      .
      We found that meniscal maceration was associated with higher knee pain cross-sectionally but not longitudinally. It is possible that maceration is associated with a severe pain that may not change over time. We found no other associations with knee pain including tears. Further prospective studies are warranted to determine if tear incidence is related to acute knee pain and if a subset of knees can then function without pain. The fact that only meniscal maceration is related to pain in our study may explain discordant findings in prior studies
      • Englund M.
      • Guermazi A.
      • Gale D.
      • Hunter D.J.
      • Aliabadi P.
      • Clancy M.
      • et al.
      Incidental meniscal findings on knee MRI in middle-aged and elderly persons.
      • Kim H.A.
      • Kim I.
      • Song Y.W.
      • Kim D.H.
      • Niu J.
      • Guermazi A.
      • et al.
      The association between meniscal and cruciate ligament damage and knee pain in community residents.
      • Ding C.
      • Martel-Pelletier J.
      • Pelletier J.P.
      • Abram F.
      • Raynauld J.P.
      • Cicuttini F.
      • et al.
      Meniscal tear as an osteoarthritis risk factor in a largely non-osteoarthritic cohort: a cross-sectional study.
      • Bhattacharyya T.
      • Gale D.
      • Dewire P.
      • Totterman S.
      • Gale M.E.
      • McLaughlin S.
      • et al.
      The clinical importance of meniscal tears demonstrated by magnetic resonance imaging in osteoarthritis of the knee.
      . Inconsistencies among prior studies may be due to the absence of clear-cut definition of different types of meniscal pathology. This highlights the need to differentiate meniscal maceration from other types of prevalent meniscal pathology.
      The strength of our study was the use of an algorithm to predict the esKOA, which incorporates measures of pain, function and structural severity. This measure is preferable to TKA, which is a common KOA endpoint, because various factors influence the patient's willingness to undergo TKA; including, financial situations
      • Hawker G.A.
      • Guan J.
      • Croxford R.
      • Coyte P.C.
      • Glazier R.H.
      • Harvey B.J.
      • et al.
      A prospective population-based study of the predictors of undergoing total joint arthroplasty.
      .
      There was no major difference in the association between meniscal pathology and knee pain after further adjustment for BMLs. There was a significant reduction in the effect size of the association between meniscal pathology and esKOA after further adjustment for BMLs suggesting a potential mediation. However, these associations remained statistically significant, indicating the independent association of meniscal pathology. BMLs may fall in the causal pathway of the association between meniscal pathology and knee pain or esKOA.
      An important limitation is that we did not measure the meniscal pathology at the follow-up visit; therefore, we cannot assess if change in meniscal pathology is associated with change in KOA. Furthermore, we evaluated meniscal pathology with a modified arthroscopy-based scoring system, and we could not measure the meniscal extrusion in this cohort and therefore cannot comment on the influence of extrusion on KOA progression. However, numerous studies have evaluated the importance of meniscal extrusion
      • 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.
      • 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.
      • 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.
      • Kawaguchi K.
      • Enokida M.
      • Otsuki R.
      • Teshima R.
      Ultrasonographic evaluation of medial radial displacement of the medial meniscus in knee osteoarthritis.
      . While our scoring system enabled us to assess different types of meniscal tears in various regions we unfortunately needed to summarize them as tears because each tear type had a low prevalence. Hence, we could not analyse the specific types of tears nor compartment-specific effect of meniscal pathology on BMLs and knee pain. Furthermore, we did not specifically measure the radial root tear, but they were included in the radial tear category. We are unable to determine the importance of the severity of a tear. We believe this may be important for future studies because our findings suggest that the least severe pathology (intrameniscal signal) is not associated with KOA or KOA progression while more severe types of pathology (meniscal maceration) are. We did not record insufficiency fractures in these subjects and therefore not included in the analyses. This cohort had a large number of KOA cases, which limits our ability to generalize to general population. Despite this limitation, this study provides important insights about meniscal findings that may be associated with changes within the next 2 years. Further longitudinal studies are required to confirm the effect of different meniscal pathologies on the other structural progression markers such as articular cartilage.

      Conclusions

      Among the five categories of meniscal pathologies, disruptive pathology (i.e., morphologic deformity/extrusion or maceration) rather than intrameniscal signal or tear was associated with knee pain and structural changes. Meniscal maceration is also associated with a later clinical state that is proxy for esKOA. This suggests that not all meniscal pathology has the same impact on KOA outcomes and therefore, it is important for future studies to differentiate distinct types of meniscal pathology. Similarly, clinicians should be wary of pathologies that impair normal load distribution properties of meniscus because they may relate to KOA severity and progression.

      Authors' contributions

      Antony had full access to the data in the study and contributed to the conception and design, analysis and interpretation of data, drafting/revisions of the article, as well as final approval of the article. Study design: Driban JB, Lo GH, Nevitt MC, Lynch J, Eaton CB, McAlindon TE; Data Collection: Driban JB, Lo GH, Ward RJ, McAlindon TE; Analysis and interpretation of data: Antony B, Driban JB, Price LL, Lo GH, Ward RJ, Nevitt MC, Lynch J, Eaton CB, Ding C, McAlindon TE; Statistical analysis: Antony B, Driban JB, Price LL, Ding C, McAlindon TE. All authors read and approved the final manuscript.

      Financial disclosure

      NIH/NIAMS (grant 1R01AR054938). The OAI is a public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, 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. This manuscript was prepared using an OAI public use data set and does not necessarily reflect the opinions or views of the OAI investigators, the NIH, or the private funding partners. Dr Lo is supported by K23 AR062127, an NIH/NIAMS funded mentored award. This work is also supported in part with resources at the VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413), at the Michael E. DeBakey VA Medical Center, Houston, TX. This manuscript does not reflect the views of the US government or the Veterans Administration.

      Competing interests

      The authors declare that they have no competing interests.

      Acknowledgements

      Special thanks go to the subjects who made this study possible. The Role of Bone in Knee Osteoarthritis Progression is supported by NIH/NIAMS (grant 1R01AR054938). The OAI is a public-private partnership comprising five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Pfizer, Inc.; Novartis Pharmaceuticals Corporation; Merck Research Laboratories; and GlaxoSmithKline. Private-sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript has received the approval of the OAI Publications Committee based on a review of its scientific content and data interpretation. This work was supported in part by the Emerging Researchers in Ageing (ERA) 2013 Exchange Program (supported by Australian Research Council's Centre for Excellence in Population Ageing Research (CEPAR)). We would like to acknowledge Geoffroy Destenaves and Jincheng Pang for their contribution to BML measurements.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:
      Supplementary Fig. 1
      Supplementary Fig. 1Morphological deformity/extrusion (often occurs with displacement) at the (a) anterior horn, (b) body, (c) posterior horn of medial meniscus.

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