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Objective To assess the association of worsening of magnetic resonance imaging (MRI) semi-quantitative (SQ) tissue features with concurrent change in quantitative (Q) cartilage thickness measurements over 24 months within the Foundation for the National Institutes of Health (FNIH) Biomarker Consortium study. Methods In all, 599 participants were included. SQ assessment included cartilage damage, meniscal extrusion and damage, osteophytes, bone marrow lesions (BMLs), and effusion- and Hoffa-synovitis. Change in medial compartment Q cartilage thickness was stratified by concurrent ipsicompartmental SQ changes. Between-group comparisons were performed using analysis of covariance (ANCOVA) with adjustment for age, sex, and body mass index (BMI). Results were presented as adjusted mean difference. Results Knees with any increase in SQ cartilage scores in the medial compartment ( n = 268) showed more Q cartilage loss compared to knees that remained stable (mean adjusted difference [MAD] = -0.16 mm, 95% confidence interval [CI]: [-0.19, -0.13] mm). Knees with any increase in meniscal extrusion in the medial compartment (n = 98) showed more Q cartilage loss than knees without (MAD = -0.18 mm, 95% CI: [-0.22, -0.14] mm. Comparable findings were seen for meniscal damage worsening. Regarding BMLs, an increase by one subregion resulted in a MAD of Q cartilage loss of -0.10 mm, 95% CI: [-0.14, -0.06] mm, while this effect almost tripled for change in two or more subregions. Increase in either effusion- and/or Hoffa-synovitis by one grade resulted in a MAD of -0.07 mm, 95% CI: [-0.10, -0.03] mm. Conclusion Worsening of SQ cartilage damage, meniscal extrusion and damage, number of subregions affected by BML, maximum size of BMLs and worsening of effusion- and/or Hoffa synovitis is associated with increased Q cartilage loss.

Quantitative measures of cartilage morphology (“cartilage morphometry”) extracted from high resolution 3D magnetic resonance imaging (MRI) sequences have been shown to be sensitive to osteoarthritis (OA)-related change and also to treatment interventions. Cartilage morphometry is therefore nowadays widely used as outcome measure for observational studies and randomized interventional clinical trials. The objective of this narrative review is to summarize the current status of cartilage morphometry in OA research, to provide insights into aspects relevant for the design of future studies and clinical trials, and to give an outlook on future developments. It covers the aspects related to the acquisition of MRIs suitable for cartilage morphometry, the analysis techniques needed for deriving quantitative measures from the MRIs, the quality assurance required for providing reliable cartilage measures, and the appropriate participant recruitment criteria for the enrichment of study cohorts with knees likely to show structural progression. Finally, it provides an overview over recent clinical trials that relied on cartilage morphometry as a structural outcome measure for evaluating the efficacy of disease-modifying OA drugs (DMOAD).

Objective To test the hypothesis that superficial cartilage composition (T2) is associated with subsequent incidence or worsening of cartilage damage, and deep T2 with that of bone marrow lesions (BMLs) in knees without radiographic osteoarthritis (ROA). Design A total of 201 knees from the Osteoarthritis Initiative without ROA were included: 78 from the healthy reference cohort, 60 without ROA but with risk factors, and 63 without ROA but with contralateral ROA. Year 1 (Y1) superficial and deep cartilage T2 were derived in the medial and lateral (weightbearing) femur (MF/LF) and tibia (MT/LT), using sagittal multiecho spin echo magnetic resonance images. Cartilage and BMLs were assessed in the medial (MFTJ) and lateral femorotibial joint (LFTJ) at Y1 and 3 years later. Binary logistic regression statistics were applied. Results Incidence or worsening of cartilage damage was more frequent (MFTJ 15%, LFTJ 13%) than incidence or worsening of BMLs (6.0%, 4.5%). In knees with incident or worsening cartilage lesions in the MF and LT, deep layer T2 in the same plate was elevated (MF, 43.6 ± 4.0 vs. 41.3 ± 3.8 ms, P = 0.047; LT, 33.8 ± 2.3 vs. 32.0 ± 2.2 ms, P = 0.008) compared to those without. In knees with incident or worsening of BMLs in the LFTC and LT, superficial layer T2 was elevated (LFTJ, 49.6 ± 4.8 vs. 46.7 ± 3.1 ms; LT, 47.4 ± 4.9 vs. 44.0 ± 3.3 ms, both Ps = 0.04). Conclusions Contrary to our hypothesis, increased deep layer cartilage T2 was associated with subsequent worsening of cartilage damage, whereas superficial layer T2 was related to subsequent BML worsening. Yet, this relationship was observed in some, but not in all cartilage plates.

Summary Objective To develop a model of early osteoarthritis, by examining whether radiographically normal knees with contralateral joint space narrowing (JSN), but without contralateral trauma history, display greater longitudinal cartilage composition change (transverse relaxation time; T2) than subjects with bilaterally normal knees. Methods 120 radiographically normal knees (Kellgren Lawrence grade [KLG] 0) from the Osteoarthritis Initiative were studied. 60 case knees displayed definite contralateral radiographic knee osteoarthritis (KLG ≥ 2) whereas 60 reference subjects were bilaterally KLG0, and were matched 1:1 to cases based on age, sex, and BMI. All had multi-echo spin-echo MRI acquired at year (Y) 1 and 4 follow-up, with cartilage T2 being determined in superficial and deep cartilage layers across 16 femorotibial subregions. T2 across all regions was considered the primary analytic focus. Results Of 60 KLG0 case knees (30 female, age: 65.0 ± 8.8 y, BMI: 27.6 ± 4.4 kg/m2), 21/22/13/4 displayed contralateral JSN 0/1/2/3, respectively. The longitudinal increase in the deep layer cartilage T2 between Y1 and Y4 was significantly greater (P = 0.03; Cohen's D 0.50) in the 39 KLG0 case knees with contralateral JSN (1.2 ms; 95% confidence interval [CI] [0.4, 2.0]) than in matched KLG0 reference knees (0.1 ms; 95% CI [−0.5, 0.7]). No significant differences were identified in superficial T2 change. T2 at Y1 was significantly greater in case than in reference knees, particularly in the superficial layer of the medial compartment. Conclusions Radiographically normal knees with contralateral, non-traumatic JSN represent an applicable model of early osteoarthritis, with deep layer cartilage composition (T2) changing more rapidly than in bilaterally normal knees. Clinicaltrials.gov identification NCT00080171 .

High tibial osteotomy (HTO) and knee joint distraction (KJD) are joint-preserving treatments that unload the more affected compartment (MAC) in knee osteoarthritis. This post-hoc study compares two-year cartilage-thickness changes after treatment with KJD vs. HTO, and identifies factors predicting cartilage restoration. Patients indicated for HTO were randomized to KJD (KJDHTO) or HTO treatment. Patients indicated for total knee arthroplasty received KJD (KJDTKA). Outcomes were the MRI mean MAC cartilage thickness and percentage of denuded bone area (dABp) change two years after treatment, using radiographic joint space width (JSW) as the reference. Cohen&rsquo, s d was used for between-group effect sizes. Post-treatment, KJDHTO patients (n = 18) did not show significant changes. HTO patients (n = 33) displayed a decrease in MAC cartilage thickness and an increase in dABp, but an increase in JSW. KJDTKA (n = 18) showed an increase in MAC cartilage thickness and JSW, and a decrease in dABp. Osteoarthritis severity was the strongest predictor of cartilage restoration. Kellgren&ndash, Lawrence grade &ge, 3 showed significant restoration (p &lt, 0.01) after KJD, grade &le, 2 did not. Effect sizes between severe KJD and HTO patients were large for MAC MRI cartilage thickness (d = 1.09, p = 0.005) and dABp (d = 1.13, p = 0.003), but not radiographic JSW (d = 0.28, p = 0.521). This suggests that in knee osteoarthritis patients with high disease severity, KJD may be more efficient in restoring cartilage thickness.

Objective Cartilage damage diagnosed by magnetic resonance imaging (MRI) is highly prevalent in the population. In this article, we explore whether such cartilage damage is associated with greater longitudinal change in 3D cartilage thickness and knee function in subjects without (risk factors of) knee osteoarthritis. Design Eighty-two knees of Osteoarthritis Initiative healthy reference cohort participants had baseline and 4-year follow-up MRI and knee function data. Baseline presence of semiquantitatively assessed MRI-based cartilage damage (MOAKS [MRI Osteoarthritis Knee Score] ≥ grade 1.0) was recorded by an experienced radiologist. Longitudinal femorotibial cartilage thickness change was determined after segmentation, using location-independent methodology. Knee function was evaluated by patient-reported outcomes and functional performance measures. Statistical comparisons included analysis of covariance adjusting for age, sex, and body mass index. Results Forty-five percent of the participants had cartilage damage in at least one femorotibial subregion; the cartilage thickness change score was 15% greater in participants with than in those without damage (1216 ± 434 vs. 1058 ± 277 µm). This difference reached borderline statistical significance with and without adjustment for age, sex, and body mass index ( P = 0.05). No significant differences in the change of patient-reported outcomes of knee function (PASE [physical activity score of the elderly] and WOMAC [Western Ontario McMaster Osteoarthritis Index]) or chair stand test results were detected. Of those without femorotibial damage, 58% had cartilage damage in at least one femoropatellar subregion; these had a 9% greater femorotibial cartilage change score than those without femoropatellar or femorotibial damage (difference not statistically significant). Conclusions In the absence of osteoarthritis risk factors, semiquantitatively assessed MRI-based cartilage damage appears to be associated with greater longitudinal location-independent femorotibial cartilage thickness changes, but not with greater functional deteriorations.

Purpose To test whether radiographically normal knees with contralateral radiographic knee osteoarthritis (ROA) (i.e. ‘early OA model’) exhibit MRI-defined structural tissue pathology to a greater extent and show higher rates of progression compared to knees with bilateral radiographically normal knees without risk factors (‘healthy reference’). Methods We included 154 knees from the Osteoarthritis Initiative without ROA (Kellgren-Lawrence = 0), but with definite ROA (Kellgren-Lawrence ≥2) in the contralateral knee, and 78 participants from the OAI healthy reference cohort (without any signs of radiographic OA, knee pain or risk factors in either knee). Effusion-synovitis, Hoffa-synovitis, bone marrow lesions (BMLs), cartilage lesions, meniscus morphology and - extrusion and osteophytes were assessed at year 1 (Y1) and year 4 (Y4). Frequencies of features for both groups at Y1 and rates of worsening from Y1 to Y4 were compared using Fisher's exact test. Results 69% (early OA model) vs. 46% (healthy reference) had baseline Hoffa-synovitis, 26% vs. 19% effusion-synovitis, 27% vs. 13% femorotibial (FT) BMLs, 77% vs. 50% FT cartilage lesions, 36% vs. 9% meniscal damage, 51% vs. 24% meniscus extrusion, and 92% vs. 74% FT osteophytes. Apart from effusion-synovitis, all differences were statistically significant. For structural worsening, statistically significant differences were observed for FT cartilage (p = 0.03) and FT osteophytes (p = 0.01). Conclusion MRI structural abnormalities are substantially more frequent and more progressive in radiographically normal knees with contralateral osteoarthritis than in 'healthy reference' controls. Compared with published data, they also are more frequent compared to radiographically normal knees “at risk”, without contralateral knee OA.

ObjectivesIn the phase II FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses (FORWARD) study, sprifermin demonstrated cartilage modification in the total femorotibial joint and in both femorotibial compartments by MRI in patients with knee osteoarthritis. Here, we evaluate whether sprifermin reduces cartilage loss and increases cartilage thickness, independent of location.MethodsPatients were randomised 1:1:1:1:1 to three once-weekly intra-articular injections of 30 µg sprifermin every 6 months (q6mo); 30 µg sprifermin every 12 months (q12mo); 100 µg sprifermin q6mo; 100 µg sprifermin q12mo; or placebo. Post-hoc analysis using thinning/thickening scores and ordered values evaluated femorotibial cartilage thickness change from baseline to 24 months independent of location. Changes were indirectly compared with those of Osteoarthritis Initiative healthy subjects.ResultsThinning scores were significantly lower for sprifermin 100 µg q6mo versus placebo (mean (95% CI) difference: 334 µm (114 to 554)), with a cartilage thinning score similar to healthy subjects. Thickening scores were significantly greater for sprifermin 100 µg q6mo, 100 µg q12mo and 30 µg q6mo versus placebo (mean (95% CI) difference: 425 µm (267 to 584); 450 µm (305 to 594) and 139 µm (19 to 259), respectively) and more than doubled versus healthy subjects.ConclusionsSprifermin increases cartilage thickness, and substantially reduces cartilage loss, expanding FORWARD primary results.Trial registration numberNCT01919164.

Compositional measures of articular cartilage are accessible in vivo by magnetic resonance imaging (MRI) based relaxometry and cartilage spin-spin transverse relaxation time (T2) has been related to tissue hydration, collagen content and orientation, and mechanical (functional) properties of articular cartilage. The objective of the current study was therefore to evaluate subregional variation, and sex- and age-differences, in laminar (deep and superficial) femorotibial cartilage T2 relaxation time in healthy adults. To this end, we studied the right knees of 92 healthy subjects from the Osteoarthritis Initiative reference cohort (55 women, 37 men; age range 45-78 years; BMI 24.4±3.1) without knee pain, radiographic signs, or risk factors of knee osteoarthritis in either knee. T2 of the deep and superficial femorotibial cartilages was determined in 16 femorotibial subregions, using a multi-echo spin-echo (MESE) MRI sequence. Significant subregional variation in femorotibial cartilage T2 was observed for the superficial and for the deep (both p

Background:Both high tibial osteotomy (HTO) and knee joint distraction (KJD) are joint preserving surgical techniques unloading the affected femorotibial compartment in patients with knee osteoarthritis (OA). While HTO permanently unloads the more affected compartment (MAC) by overcorrecting the leg axis, KJD temporarily unloads the whole joint by separating the tibia and femur for 5 mm for 6 weeks. In a previous randomized controlled trial (RCT), comparable clinical benefit and radiographic joint space width (JSW) increase over 2 years follow-up were demonstrated for both treatments1. Yet, comparison of JSW before and after HTO may be unreliable, as pseudo-widening of the unloaded compartment may occur due to the induced leg axis change. Therefore, direct cartilage thickness measurements need to be compared between KJD and HTO, to accurately evaluate the efficacy of both treatment options on cartilage structure.Objectives:To compare two-year cartilage thickness changes after treatment with KJDvsHTO and identify factors predicting cartilage thickness restoration.Methods:Patients indicated for HTO were randomized to KJD (KJDHTO) or HTO treatment. Patients indicated for total knee arthroplasty received KJD (KJDTKA). Standardized semi-flexed weight-bearing radiographs and 3T MRIs with 3D spoiled gradient recalled imaging sequence with fat suppression (SPGR-fs) were acquired before and two years after surgical treatment. Cartilage thickness in the knee was measured using Chondrometrics Works 3.0 software. On the radiographs the mean JSW in the MAC were measured with KIDA software. Readers were blinded to the type of intervention and acquisition order. The primary and secondary outcomes were the mean MAC cartilage thickness (ThCtAB) and percentage of denuded bone area (dABp) change before and two years after treatment (MRI), with radiographic joint space width (JSW) used as a reference.Results:No statistically significant differences in the baseline characteristics were seen between KJDHTO(n=18) and HTO (n=33). The KJDTKAgroup (n=18) had a higher age and Kellgren-Lawrence grade (KLG) than the HTO and KJDHTOgroups.KJDHTOpatients did not show significant changes in MAC cartilage thickness, dABp, or JSW over time (all p>0.10; figure 1). HTO patients displayed a decrease in MAC cartilage thickness and an increase in dABp (both pTKAshowed a significant increase in MAC cartilage thickness and JSW and decrease in dABp (all psevere; KLG ≥3) showed significant restoration (all pmild; KLG ≤2) showed a slight deterioration. KJDsevereshowed a significantly greater cartilage restoration response in the MAC than HTOseverefor cartilage thickness (p=0.005) and dABp (p=0.003), but not JSW change (p=0.521). The changes in all three parameters did not differ significantly between KJDmildand HTOmild(all p>0.08).Conclusion:In patients with severe knee OA, KJD is more efficient in restoring cartilage thickness than HTO is. In these patients, KJD causes significant cartilage restoration while HTO, despite shifting the leg axis and demonstrating radiographic joint space widening, shows loss of cartilage as measured on MRI. In patients with mild knee OA, neither HTO nor KJD treatment results in significant cartilage restoration and both treatments show a slight deterioration that is likely the result of natural OA progression. As such, this research promotes the choice KJD as joint-preserving surgery in case of knee OA patients with more severe structural damage.References:[1]MP Jansenet al, Cartilage 2019.Disclosure of Interests:Mylène Jansen: None declared, Susanne Maschek Shareholder of: Stock/stock options at Condrometrics GmbH, Employee of: Employment at Condrometrics GmbH, Ronald Van Heerwaarden: None declared, Simon Mastbergen: None declared, Wolfgang Wirth Shareholder of: Stock/stock options at Condrometrics GmbH, Consultant of: Consultancy to Galapagos NV, Employee of: Employment at Condrometrics GmbH, Floris Lafeber Shareholder of: Co-founder and shareholder of ArthroSave BV, Felix Eckstein Shareholder of: Stock/stock options at Condrometrics GmbH, Consultant of: Consultancy at Merck KGaA, Samumed, Bioclinica, Galapagos, Servier, Novartis, Employee of: Employment at Condrometrics GmbH, Speakers bureau: Development of educational presentations for Medtronic

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

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

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

Objective To explore whether baseline to 12-month followup change in femorotibial cartilage thickness differs between subjects who received a total knee arthroplasty (TKA) between 24 and 60 months from those without TKA (non-TKA). Methods In this prospective cohort study, 531 right knees from Osteoarthritis Initiative participants with definite radiographic knee osteoarthritis (Kellgren/Lawrence [K/L] grades 2–4) were studied. Segmentation was applied to coronal fast low-angle shot magnetic resonance images, to quantitatively determine cartilage thickness in 16 femorotibial subregions. Unadjusted P values (t-tests) and P values adjusted for age, baseline body mass index (BMI), K/L grade, and sex (generalized estimating equation models) were used to evaluate differences in longitudinal 1-year rates of cartilage thickness between TKAs and non-TKAs, with total knee arthroplasty status as fixed effect. Results Of the 531 participants (mean ± SD ages 63 ± 9 years, BMI 30 ± 4.8 kg/m2), 40 received a femorotibial TKA within 4 years. At baseline, TKAs had thinner medial and lateral femorotibial cartilage (−15%; P < 0.001) than non-TKAs. Longitudinal cartilage thickness change was significantly greater in TKAs than in non-TKAs in the total femorotibial joint (area under the curve [AUC] 0.64), the lateral compartment (AUC 0.66), both tibiae (AUC ≥ 0.61), and the first 9 (of 16) ordered values of subregion change (AUC 0.64–0.69). Discrimination was stronger for TKAs that occurred at 24 and 36 months (n = 18) than for those at 48 and 60 months (n = 22). Conclusion Knees with incident TKA displayed smaller baseline cartilage thickness and greater lateral as well as location-independent ordered value femorotibial cartilage loss than non-TKAs. Discrimination of cartilage loss was greater for TKAs occurring within 2 years after the measurement than for those occurring later.

Summary Objective To explore whether subregional laminar femorotibial cartilage spin–spin relaxation time (T2) is associated with subsequent radiographic progression and cartilage loss and/or whether one-year change in subregional laminar femorotibial cartilage T2 is associated with concurrent progression in knees with established radiographic OA (ROA). Methods In this case-control study, Osteoarthritis Initiative (OAI) knees with medial femorotibial progression were selected based on one-year loss in both quantitative cartilage thickness Magnetic resonance imaging (MRI) and radiographic joint space width (JSW). Non-progressor knees were matched by sex, Body mass index (BMI), baseline Kellgren-Lawrence-grade (2/3), and pain. Baseline and one-year follow-up superficial and deep cartilage T2 was analyzed in 16 femorotibial subregions using multi-echo spin-echo MRI. Results 37 knees showed medial femorotibial progression whereas 37 matched controls had no medial or lateral compartment progression. No statistically significant baseline differences between progressor and non-progressor knees in medial femorotibial cartilage T2 were observed in the superficial (48.9 ± 3.0 ms; 95% CI: [47.9, 49.9] vs 47.8 ± 3.6 ms; 95% CI: [46.6, 49.0], P = 0.07) or deep cartilage layer (40.8 ± 3.6 ms; 95% CI: [39.5, 42.0] vs 40.1 ± 4.7 ms; 95% CI: [38.5, 41.6], P = 0.29). Concurrent T2 change was more pronounced in the deep than the superficial cartilage layer. In the medial femorotibial compartment (MFTC), longitudinal change was greater in the deep layer of progressor than non-progressor knees (1.8 ± 4.5 ms; 95% CI: [0.3, 3.3] vs −0.2 ± 1.9 ms; 95% CI: [−0.8, 0.5], P = 0.02), whereas no difference was observed in the superficial layer. Conclusion Medial compartment cartilage T2 did not appear to be a strong prognostic factor for subsequent structural progression in the same compartment of knees with established ROA, when appropriately controlling for covariates. Yet, deep layer T2 change in the medial compartment occurred concurrent with medial femorotibial progression.

Summary Objective To compare unbiased estimates of short- vs long-term cartilage loss in osteoarthritic knees. Method 441 knees [216 Kellgren Lawrence (KL) grade 2, 225 KL grade 3] from participants of the Osteoarthritis Initiative were studied over a 4-year period. Femorotibial cartilage thickness was determined using 3 T double echo steady state magnetic resonance imaging, the readers being blinded to time points. Because common measurement time points bias correlations, short-term change (year-1 to year-2: Y1 → Y2) was compared with long-term change (baseline to year-4: BL → Y4), and initial (BL → Y1) with subsequent (Y2 → Y4) observation periods. Results The mean femorotibial cartilage thickness change (standardized response mean) was −1.2%/−0.8% (−0.42/−0.28) over 1 (BL → Y1/Y1 → Y2), −2.1%/−2.5% (−0.56/−0.55) over 2 (BL → Y2/Y2 → Y4), −3.3% (−0.63) over 3 (Y1 → Y4), and −4.5% (−0.78) over 4 years. Spearman correlations were 0.33 for Y1 → Y2 vs BL → Y4, and 0.17 for BL → Y1 vs Y2 → Y4 change. Percent agreement between knees showing progression during Y1 → Y2 vs BL → Y4 was 59%, and 64% for BL → Y1 vs Y2 → Y4. The area under the receiver operating characteristic curve was 0.66 for using Y1 → Y2 to predict BL → Y4, and 0.59 for using BL → Y1 to predict Y2 → Y4 change. Conclusion Weak to moderate correlations and agreement were observed between individual short- vs long-term cartilage loss, and between initial and subsequent observation periods. Hence, longer observation periods are recommended to achieve robust results on cartilage loss in individual knees. At cohort and subcohort level (e.g., KLG3 vs KLG2 knees), the mean cartilage loss increased almost linearly with the length of the observation period and was constant throughout the study.

Summary Objective The sensitivity to change of quantitative analysis of cartilage in knee osteoarthritis using magnetic resonance imaging (MRI) is compromised by the spatial heterogeneity of cartilage loss. We explore whether extended (medial–lateral) "ordered values" (OVs) are superior to conventional approaches of analyzing subregional cartilage thickness loss and to radiography, in differentiating rates of progression in knees with and without joint space narrowing (JSN). Methods 607 Osteoarthritis Initiative (OAI) participants (308 without and 299 with baseline JSN at baseline) were studied over 12 months. Subregional femorotibial cartilage loss was determined in all knees, and changes in minimum joint space width (mJSW) in a subset of 290 knees. Subregional thickness changes in medial and lateral tibial and femoral cartilages were sorted in ascending order (OV1-16). A Wilcoxon rank-sum test was used to compare rates of change in knees with and without JSN. Results JSN-knees displayed greater cartilage loss than those without JSN, with minimal P -values of 0.008 for femorotibial subregions, 3.3×10 −4 for medial OV1, and 5.4×10 −7 for extended (medial and lateral) OV1. mJSW measurements ( n =290) did not discriminate between longitudinal rates of change in JSN vs no-JSN knees ( P =0.386), whereas medial OV1 ( P =5.1×10 −4 ) and extended OV1 did ( P =2.1×10 −5 ). Conclusion Extended OVs showed higher sensitivity to detecting differences in longitudinal rates of cartilage loss in knees with and without baseline JSN than anatomical (sub)regions and radiography. The OV technique also circumvents challenges of selecting particular regions "a priori" in clinical trials and may thus provide a powerful tool in studying risk factors or treatment efficacy in osteoarthritis.

Summary Objective To compare femorotibial cartilage thickness changes over a 2- vs a 1-year observation period in knees with radiographic knee osteoarthritis (OA). Methods One knee of 346 Osteoarthritis Initiative (OAI) participants was studied at three time points [baseline (BL), year-1 (Y1), year-2 (Y2) follow-up]: 239 using coronal fast low angle shot (FLASH) and 107 using sagittal double echo at steady state (DESS) MR imaging. Changes in cartilage thickness were assessed in femorotibial cartilage plates and subregions, after manual segmentation with blinding to time-point. Results The standardized response mean (SRM) of total joint cartilage thickness over 2 years was modestly higher than over 1 year (FLASH: −0.44 vs −0.32/−0.28 [first/second year]; DESS: −0.42 vs −0.39/−0.18). For the subregion showing the largest change per knee (OV1), the 2-year SRM was similar or lower (FLASH: −1.20 vs −1.22/−1.61; DESS: −1.38 vs −1.64/−1.51) than the 1-year SRM. The changes in total joint cartilage thickness were not significantly different in the first and second year (FLASH: −0.8% vs −0.7%; DESS: −1.3% vs −0.8%) and were negatively correlated. Analysis of smallest detectable changes (SDCs) revealed that only few participants displayed significant progression in both consecutive periods. The location of the subregion contributing to OV1 in each knee was highly inconsistent between the first and second year observation period. Conclusions The SRM of region-based cartilage thickness change in OA is modestly larger following a 2-year vs a 1-year observation period, while it is relatively similar when an OV-approach is chosen. Structural progression displays strong temporal and spatial heterogeneity at an individual knee level that should be considered when planning clinical trials.

Objective To determine by magnetic resonance imaging (MRI), whether knees with advanced radiographic disease (medial joint space narrowing [mJSN]) encounter greater longitudinal cartilage loss than contralateral knees with earlier disease (no or less mJSN). Methods Participants were selected from 2,678 cases in the Osteoarthritis Initiative, based on exhibition of bilateral pain, body mass index >25 (kg/m2), mJSN in 1 knee, no or less mJSN in the contralateral knee, and no lateral JSN in both knees. Eighty participants (mean ± SD age 60.6 ± 9.1 years) fulfilled these criteria. Medial tibial and femoral cartilage morphology was analyzed from the baseline and the 1-year followup MRI (sagittal double echo at steady state by 3.0T) of both knees by experienced readers blinded to the time point and mJSN status. Results Knees with more radiographic mJSN displayed greater medial cartilage loss (−80 μm) assessed by MRI than contralateral knees with less mJSN (−57 μm). The difference reached statistical significance in participants with an mJSN grade of 2 or 3 (P = 0.005–0.08), but not in participants with an mJSN grade of 1 (P = 0.28–0.98). In knees with more mJSN, cartilage loss increased with higher grades of mJSN (P = 0.003 in the medial femur). Knees with an mJSN grade of 2 or 3 displayed greater cartilage loss in the weight-bearing medial femur than in the posterior femur or in the medial tibia (P = 0.048). Conclusion Knees with advanced mJSN displayed greater cartilage loss than contralateral knees with less mJSN. These data suggest that radiography can be used to stratify fast structural progressors, and that MRI cartilage thickness loss is more pronounced at advanced radiographic disease stage.

Summary Objective The Osteoarthritis Initiative (OAI) is aimed at validating (imaging) biomarkers for monitoring progression of knee OA. Here we analyze regional femorotibial (FT) cartilage thickness changes over 1 year using 3 Tesla MRI. Specifically, we tested whether changes in central subregions exceed those in the total cartilage plates. Methods The right knees of a subsample of the OAI progression subcohort ( n =156, age 60.9±9.9 years) were studied. Fifty-four participants had definite radiographic osteoarthritis (OA) (KLG 2 or 3) and a BMI>30. Mean and minimal cartilage thickness were determined in subregions of the medial/lateral tibia (MT/LT), and of the medial/lateral weight-bearing femoral condyle (cMF/cLF), after paired (baseline, follow up) segmentation of coronal FLASHwe images with blinding to the order of acquisition. Results The central aspect of cMF displayed a 5.8%/2.8% change in mean thickness in the group of 54/156 participants, respectively, with a standardized response mean (SRM) of −0.47/−0.31, whereas cartilage loss in the total cMF was 4.1%/1.9% (SRM −0.49/−0.30). In the central MT, the rate of change was −1.6%/−0.9% and the SRM −0.29/−0.20, whereas for the entire MT the rate was −1.0%/−0.5% and the SRM −0.21/−0.12. Minimal thickness displayed greater rates of change, but lower SRMs than mean thickness. Conclusions This study shows that the rate of cartilage loss is greater in central subregions than in entire FT cartilage plates. The sensitivity to change in central subregions was higher than for the total cartilage plate in the MT and was similar to the total plate in the medial weight-bearing femur.

Objective:The Osteoarthritis Initiative (OAI) is a multicentre study targeted at identifying biomarkers for evaluating the progression and risk factors of symptomatic knee OA. Here cartilage loss using 3 Tesla (3 T) MRI is analysed over 1 year in a subset of the OAI, together with its association with various risk factors.Methods:An age- and gender-stratified subsample of the OAI progression subcohort (79 women and 77 men, mean (SD) age 60.9 (9.9) years, body mass index (BMI) 30.3 (4.7)) with both frequent symptoms and radiographic OA in at least one knee was studied. Coronal FLASHwe (fast low angle shot with water excitation) MRIs of the right knee were acquired at 3 T. Seven readers segmented tibial and femoral cartilages blinded to order of acquisition. Segmentations were quality controlled by one expert.Results:The reduction in mean cartilage thickness (ThC) was greater (p = 0.004) in the medial than in the lateral compartment, greater (p = 0.001) in the medial femur (−1.9%) than in the medial tibia (−0.5%) and greater (p = 0.011) in the lateral tibia (−0.7%) than in the lateral femur (0.1%). Multifactorial analysis of variance did not reveal significant differences in the rate of change in ThC by sex, BMI, symptoms and radiographic knee OA status. Knees with Kellgren–Lawrence grade 2 or 3 and with a BMI >30 tended to display greater changes.Conclusions:In this sample of the OAI progression subcohort, the greatest, but overall very modest, rate of cartilage loss was observed in the weight-bearing medial femoral condyle. Knees with radiographic OA in obese participants showed trends towards higher rates of change than those of other participants, but these trends did not reach statistical significance.

Summary Objective To compare the rate and sensitivity to change of quantitative cartilage thickness change with magnetic resonance imaging (MRI) across specific radiographic strata of knee osteoarthritis (KOA) from central expert readings of the Osteoarthritis Initiative (OAI). Specifically, we explored whether Kellgren Lawrence grade (KLG) 2 knees with radiographic joint space narrowing (JSN) displayed greater cartilage loss than those without JSN, and whether knees with medial JSN grade2 had greater loss than those with grade1. Methods One-year femorotibial cartilage thickness change was obtained for 836 knees, 112 without, and 724 with definite radiographic KOA based on baseline site readings. The maximum subregional cartilage loss, and cartilage thickness change in the total femorotibial joint (FTJ) and medial femorotibial compartment (MFTC) were analyzed across different radiographic strata (central vs site readings). Results The maximum subregional rate of change was significantly greater in central_KLG2 knees with than in those without JSN (172 ± 152 vs 134 ± 100 μm; P = 0.03). In contrast, the rate did not differ significantly between central_KLG1 knees with and without JSN. MFTC cartilage loss in central_medial_grade2 JSN knees was substantially and significantly greater than in grade1 knees (−70 ± 159 vs −31 ± 126 μm; P = 0.02). For comparison, the loss in grade3 knees was −72 ± 122 μm. Conclusions In KLG2 knees, presence of radiographic JSN was associated with significantly and substantially greater rates of subregional cartilage loss. Differentiating knees with mild vs moderate medial JSN, and definite radiographic OA knees with vs without JSN is important in predicting structural progression of KOA, and for planning clinical trials testing the efficacy of disease modifying drugs (DMOADs).

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 (