Rates of change and sensitivity to change in cartilage morphology in healthy knees and in knees with mild, moderate, and end-stage radiographic osteoarthritis: Results from 831 participants from the osteoarthritis initiative

Authors

  • Felix Eckstein,

    Corresponding author
    1. Institute of Anatomy and Musculoskeletal Research, Paracelsus Medical University, Salzburg, Austria
    2. Chondrometrics GmbH, Ainring, Germany
    • Institute of Anatomy & Musculoskeletal Research, Paracelsus Medical University, Strubergasse 21, A5020 Salzburg, Austria
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    • Dr. Eckstein has received consultant fees, speaking fees, and/or honoraria (less than $10,000 each) from Merck, Genzyme, GSK, and Pfizer, and (more than $10,000 each) from Merck Sorono, Novartis, and Sanofi-Aventis, and owns stock and/or holds stock options in Chondrometrics GmbH.

  • Michael Nevitt,

    1. University of California, San Francisco
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  • Alberto Gimona,

    1. Novartis Pharma AG, Basel, Switzerland
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    • Dr. Gimona owns stock and/or holds stock options in Novartis Pharma AG.

  • Kristen Picha,

    1. Centocor Research and Development, Inc., Radnor, Pennsylvania
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    • Dr. Picha owns stock and/or holds stock options in Johnson & Johnson and has several patents pending from Centocor R&D.

  • Jennifer H. Lee,

    1. Wyeth Research, Collegeville, Pennsylvania
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    • Dr. Lee owns stock and/or holds stock options in Pfizer and Johnson & Johnson.

  • Richard Y. Davies,

    1. GlaxoSmithKline, Inc., Collegeville, Pennsylvania
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    • Dr. Davies owns stock and/or holds stock options in GSK.

  • Donatus Dreher,

    1. Merck Serono SA, Geneva, Switzerland
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  • Olivier Benichou,

    1. Eli Lilly & Co., Indianapolis, Indiana
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    • Dr. Benichou owns stock and/or holds stock options in Eli Lilly.

  • Marie-Pierre Hellio Le Graverand,

    1. Pfizer, Inc., New London, Connecticut
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  • Martin Hudelmaier,

    1. Institute of Anatomy and Musculoskeletal Research, Paracelsus Medical University, Salzburg, Austria
    2. Chondrometrics GmbH, Ainring, Germany
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  • Susanne Maschek,

    1. Institute of Anatomy and Musculoskeletal Research, Paracelsus Medical University, Salzburg, Austria
    2. Chondrometrics GmbH, Ainring, Germany
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    • Drs. Maschek and Wirth have received honoraria (more than $10,000) from Chondrometrics GmbH and own stock and/or hold stock options in Chondrometrics GmbH.

  • Wolfgang Wirth,

    1. Institute of Anatomy and Musculoskeletal Research, Paracelsus Medical University, Salzburg, Austria
    2. Chondrometrics GmbH, Ainring, Germany
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    • Drs. Maschek and Wirth have received honoraria (more than $10,000) from Chondrometrics GmbH and own stock and/or hold stock options in Chondrometrics GmbH.

  • Osteoarthritis Initiative Investigators Group


Abstract

Objective

To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (OA), specifically healthy knees and knees with end-stage radiographic OA.

Methods

One knee of 831 Osteoarthritis Initiative participants was examined: 112 healthy knees, without radiographic OA or risk factors for knee OA, and 719 radiographic OA knees (310 calculated Kellgren/Lawrence [K/L] grade 2, 300 calculated K/L grade 3, and 109 calculated K/L grade 4). Subregional change in thickness was assessed after segmentation of weight-bearing femorotibial cartilage at baseline and 1 year from coronal magnetic resonance imaging (MRI). Regional and ordered values (OVs) of change were compared by baseline radiographic OA status.

Results

Healthy knees displayed small changes in plates and subregions (±0.7%; standardized response mean [SRM] ±0.15), with OVs being symmetrically distributed close to zero. In calculated K/L grade 2 knees, changes in cartilage thickness were small (<1%; minimal SRM −0.22) and not significantly different from healthy knees. Knees with calculated K/L grade 3 showed substantial loss of cartilage thickness (up to −2.5%; minimal SRM −0.35), with OV1 changes being significantly (P < 0.05) greater than those in healthy knees. Calculated K/L grade 4 knees displayed the largest rate of loss across radiographic OA grades (up to −3.9%; minimal SRM −0.51), with OV1 changes also significantly (P < 0.05) greater than in healthy knees.

Conclusion

MRI-based cartilage thickness showed high rates of loss in knees with moderate and end-stage radiographic OA, and small rates (indistinguishable from healthy knees) in mild radiographic OA. From the perspective of sensitivity to change, end-stage radiographic OA knees need not be excluded from longitudinal studies using MRI cartilage morphology as an end point.

INTRODUCTION

Joint space width (JSW) in weight-bearing radiographs has been commonly used as an outcome measure of progression in osteoarthritis (OA) (1–3) and represents an end point for disease modification that is accepted by regulatory agencies. Radiographic studies for identification of OA risk factors and treatment efficacy have generally excluded knees with late- or end-stage radiographic OA at baseline (4–7), since no further reduction in JSW can be expected when its value approaches zero (bone-to-bone contact, Kellgren/Lawrence [K/L] grade 4). Therefore, no information on the structural progression of end-stage radiographic OA knees is currently available. However, K/L grade 4 knees may be of particular interest since they are likely to encounter total knee arthroplasty (TKA) in the near future, with TKA representing an important clinical end point (8).

The Osteoarthritis Initiative (OAI) is an ongoing multicenter study (online at http://www.oai.ucsf.edu) targeted at identifying sensitive (imaging) biomarkers for onset and progression of knee OA. A total of 4,674 participants with all grades of radiographic OA and 122 healthy knees without symptoms, signs, and risk factors of knee OA are studied using radiographs (3, 9) and magnetic resonance imaging (MRI) (10). MRI can be used to obtain technically validated, quantitative, structural outcomes in OA, including cartilage area, (subregional) cartilage thickness, and volume (11–15). Prior work showed that high rates of cartilage loss, measured quantitatively with MRI, were associated with an increased risk of having future TKA, whereas radiographic outcomes were not (16).

Although studies have shown that substantial amounts of cartilage are still present at end-stage radiographic OA (17) or when a TKA is performed (12, 18), longitudinal studies using MRI (19–30) have generally avoided the inclusion of such knees. To our knowledge, no prior study has compared the rate of (and sensitivity to) change in cartilage thickness in end-stage radiographic OA knees with that in knees with less severe radiographic OA grades, or in healthy reference OAI knees with that in radiographic OA OAI knees.

The objective of this study was therefore to study the 1-year rate of (and sensitivity to) change in femorotibial cartilage thickness in a large subset of OAI knees across a wide range of radiographic disease stages (17), specifically healthy reference knees and knees with end-stage radiographic OA. We tested the hypotheses that end-stage radiographic OA knees display a rate of change similar to knees with less severe stages of radiographic OA, and that all radiographic OA knees display larger rates of change than healthy knees. The overarching question was whether, from a perspective of sensitivity to change, knees with end-stage radiographic OA need to be excluded from longitudinal studies of OA progression. Answering the above questions can inform clinical trials with regard to sample size calculations per specific radiographic disease stages, including end-stage radiographic OA.

SUBJECTS AND METHODS

OAI cohort and MRI sequences.

OAI participants were ages 45–79 years, with or at risk of symptomatic knee OA in at least one knee. General exclusion criteria were rheumatoid or inflammatory arthritis, bilateral end-stage knee OA, inability to walk without aids, and MRI contraindications. The OAI also includes “non-exposed” healthy reference participants (n = 122) without clinical or radiographic signs of knee OA, and free of exposure to potential risk factors of knee OA. The following inclusion criteria applied to this cohort: 1) no pain, aching, or stiffness in either knee in the past year; 2) no radiographic femorotibial OA (Osteoarthritis Research Society International [OARSI] osteophyte grade 0 and joint space narrowing [JSN] grade 0) in either knee using the clinical site readings of the baseline bilateral fixed flexion radiographs (3); and 3) no risk factors for OA, including obesity, knee injury, knee surgery, a family history of TKA in a biologic parent or sibling, Heberden's nodes (defined as self-reported bony enlargements), or repetitive knee bending (defined as current daily activity).

Fixed flexion radiographs (3, 9) and 3T MRIs (using Magnetom Trio magnets [Siemens Erlangen] and quadrature transmit–receive knee coils [USA Instruments]) were acquired according to a standardized protocol (online at http://www.oai.ucsf.edu/datarelease/) (10, 31). The current longitudinal analysis was performed in a subsample of OAI knees analyzed by a consortium of industry partners, the OAI coordinating center at University of California, San Francisco (UCSF), and an image analysis company (Chondrometrics) (17). The analysis only included the knees that were imaged using the double oblique coronal fast low-angle shoot (FLASH) water excitation sequence (10).

Radiographic grading and sample selection.

The baseline calculated K/L grades, derived from OARSI atlas osteophyte and JSN grades (public-use data set 0.2.2) (32, 33), were used in this study because central readings were only available for a small part of the cohort. The calculated K/L grades were assigned by centrally trained and certified readers (1–3 validated radiologists in each of 4 clinical sites). Readers assessed each knee for the presence/absence of definite marginal osteophytes (OARSI atlas grade 1–3; any medial and lateral, tibial, and femoral osteophytes) and medial and lateral JSN grades 1 (OARSI atlas grades 1–2) or 2 (OARSI atlas grade 3). The calculated K/L grades were defined as: calculated K/L grade 0 = grade 0 for both osteophytes and JSN scores, calculated K/L grade 1 = questionable osteophyte and grade 0–1 JSN (or grade 0 osteophyte and grade 1 JSN), calculated K/L grade 2 = definite osteophyte and grade 0 JSN (or no/questionable osteophyte and grade 2 JSN), calculated K/L grade 3 = definite osteophyte and grade 1 JSN, and calculated K/L grade 4 = definite osteophyte and grade 2 JSN.

Grade 1 JSN in the OAI corresponds to “definite mild” and not to “possible or uncertain” JSN. Based on previous recommendations (34, 35), the OAI therefore graded knees with definite osteophytes and OARSI JSN grade 1 and 2 as calculated K/L grade 3. Six knees without definite osteophytes but with OARSI JSN grade 3 were also classified as calculated K/L grade 2 by the OAI (see above), but because these represented a distinct (and very small) group, they were eliminated from the analysis. OARSI JSN grade 3 (OAI JSN grade 2 = calculated K/L grade 4) ranged from a 67–100% reduction in JSW (100% = bone-on-bone contact).

A sample of 831 knees (825 right, 6 left, 1 per participant) was studied: 112 from the non-exposed healthy reference sample, 310 with calculated K/L grade 2, 300 with calculated K/L grade 3, and 109 with calculated K/L grade 4. Of the 122 participants in the non-exposed healthy reference sample (public-use data sets 0.F.1 and 1.F.1), 112 had usable coronal FLASH acquisitions at baseline and 1-year followup. The selection criteria of the entire cohort studied here have been reported in detail in a recent (cross-sectional) report (17). In brief, the radiographic OA subgroups comprised knees from 3 samples.

The first sample consisted of 139 knees from an age- and sex-stratified subsample from the progression subcohort (first release; public-use data sets 0.B.1 and 1.B.1) (26, 27). This subsample included participants with frequent symptoms and radiographic OA in at least 1 knee: 52 knees were calculated K/L grade 2, 68 knees were calculated K/L grade 3, and 19 knees were calculated K/L grade 4. Note that these radiographic grades deviate from the “centrally read” K/L grade readings used in previous publications (26, 27) for reasons explained above. Three calculated K/L grade 0 knees, 15 calculated K/L grade 1 knees (knees contralateral to those that qualified the participant to be in the progression subcohort), and 2 knees with unusable FLASH acquisitions were excluded from the current analysis.

The second sample included 490 knees with calculated K/L grade 2 or 3 (clinical site readings), selected by ascending OAI identifiers from the first half of the OAI cohort (public-use data sets 0.C.1 and 1.C.1), but excluding those described in the first sample. Only knees with definite radiographic OA, e.g., calculated K/L grade 2 or higher (but not calculated K/L grade 1), were selected because these are of particular relevance for clinical trials. At the time of sample selection, the imaging data of the second half of the cohort were not yet publicly available.

The third sample consisted of 90 knees from participants with calculated K/L grade 4. These represent all of the calculated K/L grade 4 knees from the first half of the OAI cohort with usable baseline and 1-year followup coronal FLASH acquisitions.

MRI analysis.

The baseline and 1-year followup MR images (10, 31) were shipped from the OAI coordinating center at UCSF to the image analysis center (Chondrometrics). After quality control of appropriate coverage, orientation, and absence of artifacts (MH), segmentation of paired baseline and 1-year followup images was performed by 7 operators, each with more than 3 years of experience in cartilage segmentation. The operators were blinded to the order of the acquisition and to the baseline radiographic status. The total area of subchondral bone (tAB) and cartilage surface (AC) were segmented manually in the medial tibia (MT) and lateral tibia (LT), and in the weight-bearing (central) part of the medial femoral condyle (cMF) and lateral femoral condyle (cLF). Each of these regions of interest was addressed as a cartilage “plate” throughout this study. From the MT and cMF, aggregate values were obtained for the medial femorotibial compartment, and from the LT and cLF, aggregate values were obtained for the lateral femorotibial compartment. The posterior aspects of the femoral condyles were not included because segmentation in these areas is not supported by the coronal imaging protocol and because the sensitivity to change in these regions was shown to be less than in the tibia and in the weight-bearing femoral regions (29). To minimize segmentation errors and deviations between readers, all of the segmentations were quality controlled by a single expert (SM). tAB or AC entries were corrected by the operators, if found necessary by the expert. The mean cartilage thickness over the tAB (ThCtAB), including denuded areas but excluding osteophytes, was determined in all of the cartilage plates. The subregional thickness was determined in the central, external, internal, anterior, and posterior aspect of the MT and LT, and in the central, external, and internal aspects of the cMF and cLF, as described previously (13). The test–retest precision of the methodology has also been previously reported (13, 36–38).

Statistical analysis.

The statistical analyses were performed using SPSS, version 17. The mean change and SD of the change in ThCtAB (μm) between baseline and 1-year followup were determined as a measure of progression. Percent changes were derived by relating the mean change in a group to the mean ThCtAB at baseline for the same group. The standardized response mean (SRM; defined as the mean change divided by the SD of change) was used as a measure of the sensitivity to change. An extended ordered values (OVs) approach (39, 40) was applied, comprising all 16 subregions in the femorotibial joint (5 each in the MT and LT and 3 each in the cMF and cLF). This approach sorts subregional changes (in ThCtAB) in each subject in ascending order, i.e., the subregion in each knee showing the largest decrease in ThCtAB is assigned to OV1, the subregion showing the second-largest decrease to OV2, and so forth, with the subregion showing the smallest decrease (or largest increase) assigned to OV16.

OV1 was defined as the primary outcome to evaluate whether the rate of subregional cartilage loss differed between K/L grades, independent of where it was located in the femorotibial joint. Exploratory and comparative tests were also performed for cartilage compartments, plates, subregions, and OV2 through OV16.

To test for potential differences in the rate of change (OV1) between healthy knees and knees with different calculated K/L grades, the Kruskal-Wallis test was applied. When this test revealed significant differences (P < 0.05), the Mann-Whitney U test and the t-test for unequal variances (Welch test) were used to compare rates of change of calculated K/L grade 2, calculated K/L grade 3, and calculated K/L grade 4 knees with non-exposed healthy knees, respectively. To correct for multiplicity of these 3 parallel tests (calculated K/L grade 2, calculated K/L grade 3, and calculated K/L grade 4 knees versus healthy knees), the required P value was set to less than 0.0167 to maintain a global error level of 5%. For exploratory reasons, the same series of tests were used for OV2 through OV16 and region-based results, with no adjustment for multiple testing of several OVs, plates, and subregions.

RESULTS

The demographic data of the non-exposed control participants and those of the participants with different calculated K/L grades are shown in Table 1.

Table 1. Demographic data for the 831 study participants, including non-exposed controls and participants with knees with definite radiographic osteoarthritis*
 Non-exposed controls (n = 112)Calculated K/L grade 2 (n = 310)Calculated K/L grade 3 (n = 300)Calculated K/L grade 4 (n = 109)
  • *

    Values are the mean ± SD unless otherwise indicated. K/L = Kellgren/Lawrence; BMI = body mass index.

  • Calculated K/L grade at baseline, obtained at the clinical sites from osteophyte and joint space narrowing readings in fixed flexion radiographs based on the Osteoarthritis Research Society International atlas.

Sex, M/F43/69113/197113/18755/54
Age, years55.0 ± 7.760.5 ± 9.064.2 ± 9.463.7 ± 9.0
Height, cm168 ± 86166 ± 87168 ± 94169 ± 89
Weight, kg68.6 ± 11.881.8 ± 15.384.4 ± 16.885.3 ± 15.3
BMI, kg/m224.3 ± 3.029.5 ± 4.629.8 ± 4.729.7 ± 4.9

In the non-exposed control knees, the rates of changes across the OVs were symmetrically distributed close to zero (OV1 = −121 μm, OV16 = +124 μm; 8 OVs with negative changes and 8 OVs with positive changes) (Table 2). In anatomic regions (Table 3), the changes were small and within ±0.3% for compartments and plates, and within ±0.7% for the subregions.

Table 2. Ordered values (OVs) of longitudinal subregional cartilage thickness changes over 1 year as measured with magnetic resonance imaging
 Non-exposed controls (n = 112)Calculated K/L grade 2 (n = 310)*Calculated K/L grade 3 (n = 300)*Calculated K/L grade 4 (n = 109)*Kruskal-Wallis test
Mean ± SD change, μmMean change, %Mean ± SD change, μmMean change, %Mean ± SD change, μmMean change, %Mean ± SD change, μmMean change, %
  • *

    Calculated Kellgren/Lawrence (K/L) grade at baseline, obtained at the clinical sites from osteophyte and joint space narrowing readings in fixed flexion radiographs based on the Osteoarthritis Research Society International atlas.

  • Ratio of the mean change in μm and average cartilage thickness at baseline in each group.

  • The Kruskal-Wallis test was used to test whether or not there were any significant differences in the rate of change between the different subcohorts.

  • §

    Rate of change significantly different from non-exposed healthy controls when applying a Mann-Whitney U test at P < 0.0167 (global error level = 5%, since 3 parallel tests are applied). Results obtained with the Welch test were very similar to those reported above for the Mann-Whitney U test.

OV1−121 ± 81−6.2−137 ± 104−6.6−180 ± 144§−9.4−200 ± 117§−12.55.54 × 10−14
OV2−80 ± 45−4.3−98 ± 80−5.3−126 ± 95§−7.3−139 ± 86§−8.76.03 × 10−13
OV3−60 ± 42−3.3−69 ± 50−3.7−95 ± 78§−5.4−108 ± 71§−7.34.01 × 10−13
OV4−46 ± 38−2.6−53 ± 43−2.9−73 ± 61§−4.2−85 ± 60§−6.38.43 × 10−11
OV5−31 ± 36−1.7−40 ± 40−2.1−57 ± 55§−3.2−68 ± 55§−4.81.06 × 10−9
OV6−20 ± 36−1.2−29 ± 39−1.6−43 ± 50§−2.5−53 ± 49§−3.86.21 × 10−9
OV7−11 ± 36−0.6−19 ± 37−1.0−31 ± 45§−1.8−40 ± 47§−2.89.12 × 10−8
OV8−1 ± 350.0−9 ± 36−0.5−19 ± 43§−1.1−27 ± 45§−1.82.95 × 10−6
OV98 ± 340.41 ± 340.0−7 ± 42§−0.4−16 ± 44§−1.27.88 × 10−6
OV1018 ± 341.010 ± 320.54 ± 43§0.2−6 ± 47§−0.34.12 × 10−5
OV1129 ± 341.620 ± 32§1.216 ± 431.06 ± 46§0.68.91 × 10−5
OV1237 ± 362.131 ± 311.728 ± 431.719 ± 46§1.20.001
OV1348 ± 372.844 ± 332.542 ± 442.533 ± 47§2.30.007
OV1465 ± 423.859 ± 373.361 ± 483.551 ± 543.60.021
OV1585 ± 484.479 ± 434.381 ± 554.778 ± 635.30.352
OV16124 ± 836.1112 ± 555.8116 ± 716.5118 ± 797.70.453
Table 3. Subregional cartilage thickness changes over 1 year as measured with magnetic resonance imaging*
 Non-exposed controls (n = 112)Calculated K/L grade 2 at baseline (n = 310)Calculated K/L grade 3 at baseline (n = 300)Calculated K/L grade 4 at baseline (n = 109)Kruskal-Wallis test§
 Mean change, μmSRMMean change, %Mean change, μmSRMMean change, %Mean change, μmSRMMean change, %Mean change, μmSRMMean change, %
  • *

    K/L = Kellgren/Lawrence; SRM = standardized response mean; MFTC = medial femorotibial compartment (MT + cMF); LFTC = lateral femorotibial compartment (LT + cLF); MT = medial tibia; cMF = central medial (weight-bearing) femoral condyle; LT = lateral tibia; cLF = central lateral (weight-bearing) femoral condyle.

  • Mean change divided by the SD of the change.

  • Ratio of the mean change in μm and average cartilage thickness at baseline in each group.

  • §

    The Kruskal-Wallis test was used to test whether or not there were any significant differences in the rate of change between the different subcohorts.

  • Rate of change significantly different from non-exposed healthy controls when applying a Mann-Whitney U test at P < 0.0167 (global error level = 5%, since 3 parallel tests are applied).

Cartilage components and plates
 MFTC20.020.1−13−0.13−0.3−40−0.31−1.2−55−0.38−2.08.89 × 10−5
 LFTC70.090.2−9−0.11−0.2−29−0.23−0.8−49−0.39−1.54.89 × 10−4
 MT20.050.1−2−0.05−0.1−10−0.18−0.6−27−0.42−1.92.64 × 10−4
 cMF00.000.0−11−0.14−0.6−30−0.32−1.8−28−0.28−2.10.001
 LT20.050.1−10−0.22−0.5−21−0.31−1.1−27−0.51−1.70.001
 cLF60.100.320.030.1−7−0.09−0.4−22−0.25−1.30.044
Cartilage subregions
 Central MT40.050.2−9−0.09−0.4−23−0.22−1.0−58−0.44−3.01.22 × 10−4
 External MT40.070.3−7−0.09−0.5−21−0.23−1.6−31−0.31−3.90.001
 Internal MT10.020.1−4−0.06−0.2−7−0.11−0.4−27−0.33−1.40.020
 Anterior MT100.150.730.050.230.040.2−12−0.13−0.80.153
 Posterior MT−6−0.10−0.410.020.1−7−0.12−0.5−15−0.24−1.20.037
 Central cMF−2−0.03−0.1−23−0.19−1.0−49−0.33−2.5−40−0.30−3.00.003
 External cMF50.080.4−4−0.04−0.3−22−0.21−1.7−8−0.09−1.00.013
 Internal cMF−2−0.03−0.1−7−0.10−0.4−22−0.25−1.2−35−0.29−2.10.007
 Central LT110.100.3−20−0.20−0.6−49−0.35−1.8−54−0.47−2.31.19 × 10−5
 External LT60.110.4−6−0.09−0.4−17−0.21−1.1−26−0.38−2.00.003
 Internal LT00.000.0−16−0.22−0.8−29−0.29−1.7−23−0.29−1.60.053
 Anterior LT−7−0.07−0.400.000.0−5−0.07−0.3−23−0.28−1.40.049
 Posterior LT20.020.1−11−0.12−0.6−11−0.10−0.6−15−0.19−1.00.740
 Central cLF100.110.510.010.0−14−0.11−0.6−31−0.23−1.50.073
 External cLF40.060.240.050.2−6−0.06−0.4−22−0.23−1.50.083
 Internal cLF30.060.200.000.0−4−0.05−0.3−16−0.15−0.90.337

The results in OV1 (the subregion with the largest reduction in cartilage thickness in each knee) were significantly different between non-exposed healthy and radiographic OA knees (P = 5.5 × 10−14) (Figure 1). The OV1 changes were −137 μm in calculated K/L grade 2, −180 μm in calculated K/L grade 3, and −200 μm in calculated K/L grade 4 knees. The Mann-Whitney U tests revealed that changes in OV1 were significantly greater in both calculated K/L grade 3 and 4 knees than in non-exposed healthy knees, but not significantly greater in calculated K/L grade 2 than in non-exposed control knees (Table 2 and Figure 1). Note that OV1 may refer to different subregions across persons (and K/L grades).

Figure 1.

Box plots showing the rate of change in cartilage thickness for ordered value 1 (in μm) in non-exposed control (NEC) knees and in knees with calculated Kellgren/Lawrence grades (cKLG) 2, 3, and 4.

Exploration of other OVs revealed that calculated K/L grade 4 knees displayed significantly greater cartilage loss than non-exposed healthy knees in OVs 1–13, calculated K/L grade 3 knees in OVs 1–10, and calculated K/L grade 2 knees only in OV11 (Table 2). Results in OV16 (the subregion with the smallest loss or largest increase in cartilage thickness) did not display significant differences between groups (Kruskal-Wallis test P = 0.48). Results obtained with the Welch test were very similar to those reported above for the Mann-Whitney U test.

Cartilage compartments, plates, and subregions (Table 3 and Figure 2) in calculated K/L grade 2 knees showed only small losses in thickness (up to −0.6% in plates and up to −1.0% in subregions). The most negative SRM was −0.22 both at the plate (LT) and at the subregional level (internal LT); these changes were not significantly different from those in the non-exposed healthy sample, except for central LT (Table 3). In calculated K/L grade 3 knees, the largest loss at the plate level was observed in cMF (−1.8%, SRM −0.32) and at the subregional level in central cMF (−2.5%); the most negative SRM (−0.35) was seen in central LT (Table 3), indicating that the most homogeneous change occurred in this subregion. In calculated K/L grade 4 knees, the largest reduction at the plate level (−2.1%) was observed in cMF, and the smallest SRM (−0.51) in LT. At the subregional level, the largest reduction in calculated K/L grade 4 knees was observed in external MT (−3.9%) and the most negative SRM (−0.47) in central LT (Table 3). Calculated K/L grade 4 knees generally displayed the largest rates (and sensitivity to change) compared with all other groups (Table 3). The OV approach was more sensitive in revealing differences in progression between calculated K/L grade and non-exposed healthy knees than the region-based approach.

Figure 2.

Box plots showing the rate of change in cartilage thickness for the medial femorotibial compartment (in μm) in non-exposed control (NEC) knees and in knees with calculated Kellgren/Lawrence grades (cKLG) 2, 3, and 4.

DISCUSSION

In this study, we explored the 1-year rate of (and sensitivity to) change in femorotibial cartilage thickness in a large subset of OAI knees. Systematic comparisons were made across all radiographic disease stages, ranging from non-exposed healthy reference to end-stage radiographic OA. We tested the hypotheses that knees with end-stage radiographic OA (calculated K/L grade 4) have a rate of change similar to those with mild to moderate radiographic OA (calculated K/L grade 2 or 3), and that radiographic OA knees display larger rates of change than non-exposed healthy control knees. Our results show, for the first time, that knees with end-stage radiographic OA display a similar or even higher rate of and sensitivity to change compared with knees with less severe JSN (calculated K/L grade 3) when MRI-based measures of subregional cartilage thickness changes are used. In keeping with another (but smaller) longitudinal study involving radiography and MRI (30), knees with definite osteophytes but without JSN (calculated K/L grade 2) did not show significantly greater rates of change than non-exposed healthy reference knees.

One study reported that an MRI-based measure of cartilage loss was a better predictor of future TKA than radiography (16); however, the clinical relevance of cartilage thickness change still remains to be established. This will occur through a variety of studies qualifying a biomarker such as “MRI-based cartilage thickness change.” Such studies should describe and establish the performance of the marker in patients with various stages and phenotypes of disease (as done in the current study) and then further need to link the biomarker performance with clinical outcome. Finally, clinical trials will have to establish whether treatment effects on the biomarker are reflected in clinical improvement.

A limitation of the study is that radiographic OA disease stages were defined based on the site rather than central readings of fixed flexion radiographs, but central readings were only available for a small part of the cohort examined here. The approach taken here, however, is similar to many clinical trials, where participants are included (excluded) based on a site reading of the baseline radiograph. Nevertheless, future studies may explore to what extent rates of cartilage loss in different radiographic OA stages are affected by the type of reading (i.e., central versus sites, calculated K/L grade versus original K/L grade). Another limitation of the approach taken here is that precision errors reported for MRI-based measures of cartilage thickness (13, 36–38) are relatively large when compared with changes observed over 1 year. Yet, 1-year followup periods are highly preferable from a clinical trial perspective. The symmetric distribution of the OVs in the healthy reference knees (−121 μm for OV1 to +124 μm for OV16) in whom no change in cartilage thickness is expected (and in whom no such change was observed at regional level) can be viewed as an expression of random reading errors at the subregional level. These values are used as a reference here to test whether the changes observed in radiographic OA knees are significantly greater than those occurring from random error.

A strength of the current study is the inclusion of knees from the non-exposed healthy reference cohort without symptoms, radiographic signs, or risk factors of knee OA. This group displayed no relevant change over 1 year, and this provides assurance that the rates of change of cartilage thickness measured in radiographic OA knees in the OAI are real and not due to scanner drift or other systematic biases. The specific strength of the OV approach is the separation of the rate of change from its specific location in an individual knee. It was shown that the location of maximal change varies substantially among knees, depending on knee alignment (23, 25) and the location of meniscal damage (41). Although the OV approach is not suited for testing whether or not a given change is significantly different from zero (specifically when looking at OV1), the approach was shown to be superior to a region-specific comparison in identifying differences in the rate of cartilage thickness changes between knees with and without JSN (39, 40). This observation is confirmed by the current study in that P values for differences in rates of change between calculated K/L grade groups were much smaller for OV1 than for any given femorotibial cartilage compartment, plate, or subregion. This superiority is further enhanced by eliminating the need to adjust for testing multiple regions in parallel, if the location of the largest change is not known a priori. For these reasons, OV1 was defined as the primary outcome. Nevertheless, results in compartments, plates, and subregions point in the same direction, confirming the OV results, but as stated above, these did not attain statistical significance.

Our results show that knees with end-stage radiographic OA (calculated K/L grade 4 and OARSI JSN grade 3) display rates of (and sensitivity to) change that tend to be larger than in calculated K/L grade 3 or 2 knees. Although previous studies reported higher rates of change in knees with JSN compared to those without JSN (29, 30, 39, 40, 42), this has not been shown for end-stage radiographic OA (calculated K/L grade 4 knees). Similar observations were previously made based on semiquantitative readings of cartilage changes (43) using the Whole-Organ MRI scoring system (44). The authors (43) reported that the proportion of knees with an increase in cartilage lesions at followup was similar to or larger for end-stage radiographic OA knees compared with knees with less severe radiographic disease. These findings suggest that, at least from a perspective of sensitivity to change, calculated K/L grade 4 knees need not to be excluded from longitudinal studies, and that these knees can still be followed in terms of “progression” when MRI-based measures of cartilage morphology (i.e., thickness) are used. Whether or not a drug will be able to modify progression of OA at such a late stage of disease and whether differences in subsequent cartilage loss among knees with end-stage radiographic OA are related to differences in clinical outcome, however, will have to be explored in future studies. A potential advantage of a drug effect occurring at this late disease stage is that it may be easier to show a translation of the structural treatment effect into an improvement of an accepted clinical outcome such as the delay of TKA, whereas much longer followup periods would be required for “earlier” disease stages in this context. Even if drug effects at this late stage are deemed unlikely, calculated K/L grade 4 knees need not to be excluded from epidemiologic studies investigating risk factors of OA progression, when MRI is used as an outcome. In contrast, using radiographs, there is little chance to measure further progression in JSW reductions longitudinally in calculated K/L grade 4 knees with a 67% to 100% reduction in JSW at baseline.

The observation of lower rates of change in calculated K/L grade 2 knees (without JSN) than in calculated K/L grade 3 knees (with JSN) has been previously reported using radiographic outcomes (30, 45–47) and MRI-based measures of cartilage thickness (29, 30, 39, 40). It is surprising that the rate of change in calculated K/L grade 2 knees was only marginally larger than (and not significantly different from) that in the non-exposed healthy control knees. However, similar observations had been made in a previous (albeit much smaller) study (30). Another recent study suggested that, although the mean rate of change was not significantly different between calculated K/L grade 2 and healthy knees (30), the distribution of subregional changes was, i.e., some calculated K/L grade 2 knees displayed significant cartilage increase (hypertrophy or swelling), whereas others showed cartilage loss (48). Comparison of OV16 in the current study, however, did not indicate that there is a difference in the rate of cartilage thickening between calculated K/L grade 2 and non-exposed healthy knees in this cohort.

In conclusion, we find that MRI-based cartilage thickness measures display high rates of loss and sensitivity to change in cartilage thickness at end-stage radiographic OA, which are similar to or slightly higher than those in knees with less severe baseline JSN and small rates of change (statistically indistinguishable from non-exposed healthy control knees) in mild radiographic OA (knees with osteophytes, but without JSN at baseline). From the perspective of sensitivity to change, therefore, calculated K/L grade 4 knees need not to be excluded from longitudinal studies that use MRI-based cartilage thickness as an end point, in particular when an OV approach is employed. A potential benefit of studying knees at this late stage of the disease is that the potential translation of structural changes or treatment effects into improvements of clinical outcomes (i.e., delay in TKA) can be tested over relatively short time intervals.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Eckstein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Eckstein, Nevitt, Gimona, Wirth.

Acquisition of data. Nevitt, Hudelmaier, Maschek, Wirth.

Analysis and interpretation of data. Eckstein, Nevitt, Gimona, Picha, Lee, Davies, Dreher, Benichou, Hellio Le Graverand, Hudelmaier, Maschek, Wirth.

ROLE OF THE STUDY SPONSOR

The consortium sponsors as institutions (Pfizer, Inc., Eli Lilly & Co., MerckSerono SA, GlaxoSmithKline, Inc., Wyeth Research, Centocor Research and Development, Inc., Novartis Pharma AG, the coordinating center of the Osteoarthritis Initiative [OAI] at University of California, San Francisco, and Chondrometrics GmbH) were not involved in the study design, data analysis, and writing of the manuscript. The use of the funded data, but not the publication of this article, was contingent on the approval of the consortium sponsors. The private sector sponsors of the OAI (Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline, and Pfizer, Inc.) were not involved in the study design, data analysis, and writing of the manuscript, and submission of the manuscript was not contingent on their approval. However, the manuscript received the approval of the OAI Publications Committee, in which one representative of the above private sponsors is included, based on a review of its scientific content and data interpretation.

Acknowledgements

We would like to thank the following readers, Gudrun Goldmann, Linda Jakobi, Manuela Kunz, Jana Matthes, Sabine Mühlsimer, Annette Thebis, and Dr. Barbara Wehr, for dedicated data segmentation.

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