Is detection of disease-modifying osteoarthritis drug treatment more effective when performing cartilage morphometry without blinding to MR image acquisition order?

OBJECTIVE: We here explore whether observed treatment effects of a putative disease-modifying osteoarthritis drug (DMOAD) are greater when cartilage morphometry is performed with rather than without knowledge of magnetic resonance imaging (MRI) acquisition order (unblinded/blinded to time point). METHODS: In the FORWARD (FGF-18 Osteoarthritis Randomized Controlled Trial with Administration of Repeated Doses) randomized controlled trial, 549 knee osteoarthritis patients were randomized 1:1:1:1:1 to three once-weekly intra-articular injections of placebo, 30 µg sprifermin every 6 or 12 months (M), or 100 µg every 6/12 M. After year 2, cartilage segmentation of BL through 24 M MRIs was performed, with blinding to acquisition order. After year 5, 24 and 60 M MRIs were analyzed together, with unknown relative order, but with segmented BL images as reference (24 M unblinded vs. BL), by the same operators. Total femorotibial joint cartilage thickness (TFTJ_ThC) change was obtained for 352 participants analyzed under both conditions. RESULTS: Twenty-four-month data read unblinded to order revealed a -35 ± 44 µm lower TFTJ_ThC than blinded analysis (all groups: lower/upper bounds -120/+51 µm; correlation r2 = 97%). With unblinded analysis, the placebo group lost -46 ± 57 µm TFTJ_ThC over 24 M, whereas 100 µg/every 6 M lost -2.2 ± 73 µm (difference =44 µm [95% CI: 22, 66]). With blinded analysis, placebo lost -11 ± 53 µm, whereas 100 µg/every 6 M gained 30 ± 62 µm (difference = 40 µm [95% CI: 21, 60]). 100 µg sprifermin injected every 6 M showed statistically significant (p < 0.001) treatment effects on TFTJ_ThC, with Cohen D = -0.66 for unblinded and D = -0.69 for blinded analysis. CONCLUSIONS: These results do not reveal that detection of proposed DMOAD treatment is enhanced with MRIs read unblinded to order; rather, the sensitivity is similar to blinded analysis. Choices on blinded vs. unblinded analysis may thus be based on other criteria.

Association of quantitative measures of medial meniscal extrusion with structural and symptomatic knee osteoarthritis progression - Data from the OAI FNIH biomarker study.

OBJECTIVE: To study the association of quantitative medial meniscal position measures with radiographic and symptomatic knee osteoarthritis (OA) progression over 2-4 years. METHODS: The FNIH OAI Biomarkers study comprised 600 participants in four subgroups: 194 case knees with combined structural (medial minimum joint space width (minJSW) loss ≥0.7 mm) and symptomatic (persistent Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale increase ≥9 [0-100 scale]) progression; 200 knees with neither structural nor symptomatic progression; 103 knees with isolated structural and 103 with isolated symptomatic progression. Coronal double echo at steady state (DESS) MRIs were used for segmenting five central slices of the medial meniscus. Associations with progression were examined using logistic regression (adjusted for demographic and clinical data). RESULTS: Greater baseline medial meniscal extrusion was associated with combined structural/symptomatic progression (OR 1.59; 95%CI: [1.25,2.04]). No relationship was observed for tibial plateau coverage or meniscal overlap distance. The two-year increase in meniscal extrusion (OR 1.48 [1.21, 1.83]), and reduction in tibial plateau coverage (OR 0.70 [0.58,0.86]) and overlap distance (OR 0.73 [0.60,0.89]) were associated with combined progression. Greater baseline extrusion was associated with isolated structural and less extrusion with isolated symptomatic progression. The longitudinal increase in meniscal extrusion, and reduction in tibial plateau coverage and overlap distance were associated with structural, but not with symptomatic progression. CONCLUSION: Baseline measures of medial meniscal extrusion were consistently positively associated with combined radiographic/symptomatic progression and with isolated structural, but not with isolated symptomatic progression. These measures may therefore allow one to assess the risk of structural knee OA progression and to monitor interventions restoring meniscal position and function.

Quantitative measurement of cartilage morphology in osteoarthritis: current knowledge and future directions.

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).

Structural tissue damage and 24-month progression of semi-quantitative MRI biomarkers of knee osteoarthritis in the IMI-APPROACH cohort.

BACKGROUND: The IMI-APPROACH cohort is an exploratory, 5-centre, 2-year prospective follow-up study of knee osteoarthritis (OA). Aim was to describe baseline multi-tissue semiquantitative MRI evaluation of index knees and to describe change for different MRI features based on number of subregion-approaches and change in maximum grades over a 24-month period. METHODS: MRIs were acquired using 1.5 T or 3 T MRI systems and assessed using the semi-quantitative MRI OA Knee Scoring (MOAKS) system. MRIs were read at baseline and 24-months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. In descriptive fashion, the frequencies of MRI features at baseline and change in these imaging biomarkers over time are presented for the entire sample in a subregional and maximum score approach for most features. Differences between knees without and with structural radiographic (R) OA are analyzed in addition. RESULTS: Two hundred eighty-nine participants had readable baseline MRI examinations. Mean age was 66.6 ± 7.1 years and participants had a mean BMI of 28.1 ± 5.3 kg/m2. The majority (55.3%) of included knees had radiographic OA. Any change in total cartilage MOAKS score was observed in 53.1% considering full-grade changes only, and in 73.9% including full-grade and within-grade changes. Any medial cartilage progression was seen in 23.9% and any lateral progression on 22.1%. While for the medial and lateral compartments numbers of subregions with improvement and worsening of BMLs were very similar, for the PFJ more improvement was observed compared to worsening (15.5% vs. 9.0%). Including within grade changes, the number of knees showing BML worsening increased from 42.2% to 55.6%. While for some features 24-months change was rare, frequency of change was much more common in knees with vs. without ROA (e.g. worsening of total MOAKS score cartilage in 68.4% of ROA knees vs. 36.7% of no-ROA knees, and 60.7% vs. 21.8% for an increase in maximum BML score per knee). CONCLUSIONS: A wide range of MRI-detected structural pathologies was present in the IMI-APPROACH cohort. Baseline prevalence and change of features was substantially more common in the ROA subgroup compared to the knees without ROA. TRIAL REGISTRATION: Clinicaltrials.gov identification: NCT03883568.

Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of location in the femorotibial joint: post-hoc analysis of a randomised, placebo-controlled phase II clinical trial.

OBJECTIVES: In 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. METHODS: Patients 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. RESULTS: Thinning 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. CONCLUSIONS: Sprifermin increases cartilage thickness, and substantially reduces cartilage loss, expanding FORWARD primary results. TRIAL REGISTRATION NUMBER: NCT01919164.

Validation of a novel blinding method for measuring postoperative knee articular cartilage using magnetic resonance imaging.

OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Five-minute knee MRI for simultaneous morphometry and T2 relaxometry of cartilage and meniscus and for semiquantitative radiological assessment using double-echo in steady-state at 3T.

BACKGROUND: Biomarkers for assessing osteoarthritis activity necessitate multiple MRI sequences with long acquisition times. PURPOSE: To perform 5-minute simultaneous morphometry (thickness/volume measurements) and T2 relaxometry of both cartilage and meniscus, and semiquantitative MRI Osteoarthritis Knee Scoring (MOAKS). STUDY TYPE: Prospective. SUBJECTS: Fifteen healthy volunteers for morphometry and T2 measurements, and 15 patients (five each Kellgren-Lawrence grades 0/2/3) for MOAKS assessment. FIELD STRENGTH/SEQUENCE: A 5-minute double-echo steady-state (DESS) sequence was evaluated for generating quantitative and semiquantitative osteoarthritis biomarkers at 3T. ASSESSMENT: Flip angle simulations evaluated tissue signals and sensitivity of T2 measurements. Morphometry and T2 reproducibility was compared against morphometry-optimized and relaxometry-optimized sequences. Repeatability was assessed by scanning five volunteers twice. MOAKS reproducibility was compared to MOAKS derived from a clinical knee MRI protocol by two readers. STATISTICAL TESTS: Coefficients of variation (CVs), concordance confidence intervals (CCI), and Wilcoxon signed-rank tests compared morphometry and relaxometry measurements with their reference standards. DESS MOAKS positive percent agreement (PPA), negative percentage agreement (NPA), and interreader agreement was calculated using the clinical protocol as a reference. Biomarker variations between Kellgren-Lawrence groups were evaluated using Wilcoxon rank-sum tests. RESULTS: Cartilage thickness (P = 0.65), cartilage T2 (P = 0.69), and meniscus T2 (P = 0.06) did not significantly differ from their reference standard (with a 20° DESS flip angle). DESS slightly overestimated meniscus volume (P < 0.001). Accuracy and repeatability CVs were <3.3%, except the meniscus T2 accuracy (7.6%). DESS MOAKS had substantial interreader agreement and high PPA/NPA values of 87%/90%. Bone marrow lesions and menisci had slightly lower PPAs. Cartilage and meniscus T2 , and MOAKS (cartilage surface area, osteophytes, cysts, and total score) was higher in Kellgren-Lawrence groups 2 and 3 than group 0 (P < 0.05). DATA CONCLUSION: The 5-minute DESS sequence permits MOAKS assessment for a majority of tissues, along with repeatable and reproducible simultaneous cartilage and meniscus T2 relaxometry and morphometry measurements. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1328-1341.

Worsening of Articular Tissue Damage as Defined by Semi-Quantitative MRI Is Associated With Concurrent Quantitative Cartilage Loss Over 24 Months.

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.

Selection of Knees With Subsequent Cartilage Thickness Loss Based on Magnetic Resonance Imaging Semiquantitative Grading: Data From the Osteoarthritis Initiative Foundation for the National Institutes of Health Biomarker Cohort.

OBJECTIVE: To investigate which magnetic resonance imaging (MRI)-based articular pathologies are predictive of subsequent medial femorotibial compartment quantitative cartilage thickness loss and therefore suitable for enrichment of clinical trials with participants showing a high likelihood for structural progression. METHODS: Semiquantitative MRI Osteoarthritis Knee Score (MOAKS) assessments at baseline and quantitative cartilage thickness measurements at baseline and year-2 follow-up were performed in 599 participants (age 62 years; body mass index 31 kg/m2 ; 59% female) from the Osteoarthritis Initiative-based Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium. Knees were classified as medial femorotibial compartment (MFTC) progressors or nonprogressors based on MFTC cartilage thickness change (smallest detectable change threshold -111 µm). Logistic regression was used to investigate the association between baseline presence and severity of MFTC MOAKS pathologies with subsequent MFTC progression. The standardized response mean (SRM) was computed to estimate the sensitivity to change that can be achieved when selecting knees based on MOAKS pathologies. RESULTS: Presence of MFTC MOAKS cartilage damage (odds ratio [OR] 2.77 [95% confidence interval (95% CI) 1.76, 4.36]), MFTC bone marrow lesions (OR 2.69 [95% CI 1.89, 3.83]), medial meniscus extrusion or damage (OR 2.21 [95% CI 1.37, 3.55]), as well as MOAKS severity subscales for cartilage and meniscus damage were associated with subsequent progression. The SRM was greater in knees with than in knees without the presence of these pathologies and was associated with the severity of those pathologies. CONCLUSION: MRI-based grading of articular pathologies makes it possible to specifically select progressor knees suitable for inclusion in clinical trials but also to identify knees in which treatment is not indicated (e.g., knees without cartilage damage despite presence of radiographic osteoarthritis).

Is Laminar Cartilage Composition as Determined by T2 Relaxometry Associated with Incident and Worsening of Cartilage or Bone Marrow Abnormalities?

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.

Changes in Cartilage Thickness and Denuded Bone Area after Knee Joint Distraction and High Tibial Osteotomy-Post-Hoc Analyses of Two Randomized Controlled Trials.

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'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-Lawrence grade ≥3 showed significant restoration (p < 0.01) after KJD; grade ≤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.

Longitudinal Change in Knee Cartilage Thickness and Function in Subjects with and without MRI-Diagnosed Cartilage Damage.

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.

Frequencies of MRI-detected structural pathology in knees without radiographic OA and worsening over three years: How relevant is contralateral radiographic osteoarthritis?

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.

Longitudinal quantitative MR imaging of cartilage morphology in the presence of gadopentetate dimeglumine (Gd-DTPA).

MRI-based cartilage morphometry can monitor cartilage loss in osteoarthritis. Intravenous Gd-DTPA injection is needed for compositional (proteoglycan) cartilage imaging with delayed gadolinium enhanced MRI (dGEMRIC). However, longitudinal changes of cartilage morphology have not been compared in the presence and absence of Gd-DTPA. Baseline and 2-year follow-up images were acquired in 41 female participants with definite medial radiographic osteoarthritis, both before and 2 h after Gd-DTPA injection, and cartilage thickness was measured. In the absence of Gd-DTPA, a 2.6% reduction in cartilage thickness was observed between baseline and follow-up in the central subregion of the medial femorotibial compartment (standardized response mean [SRM]= -0.33; P<0.05), but only a 0.7% reduction (SRM= -0.10; P=0.51) in the presence of Gd-DTPA. The findings suggest that morphometric cartilage measurement in the presence of Gd-DTPA needs to undergo further validation, before one can recommend longitudinal dGEMRIC and morphological cartilage imaging to be performed in a single session.

Baseline structural tissue pathology is not strongly associated with longitudinal change in transverse relaxation time (T2) in knees without osteoarthritis.

PURPOSE: To evaluate whether baseline MRI-defined structural abnormalities are associated with subsequent change in laminar femorotibial cartilage transverse relaxation time (T2) of participants without radiographic signs, symptoms or risk factors for knee osteoarthritis (OA). METHOD: We studied all right knees with longitudinal MRI data of the refined Osteoarthritis Initiative Healthy Reference cohort. Baseline osteophytes, effusion-synovitis, Hoffa-synovitis, bone marrow lesions, cartilage lesions, and meniscus morphology and - extrusion were scored semiquantitatively from MR images by an expert reader. Deep and superficial layer cartilage T2 was computed in the medial and lateral femorotibial compartment (MFTC/LFTC) at baseline and at 1- and 4-year follow-up from multi-echo spin-echo MR images. Statistical analyses were performed using UNIANOVA. RESULTS: 82 participants (age 54.1 ±â€¯7.2y, BMI 24.2 ±â€¯3.0 kg/m²; 61% women, bilateral Kellgren-Lawrence 0) were studied. Number of baseline MRI pathologies was not significantly associated with longitudinal change in MFTC or LFTC cartilage T2 over 1 or 4 years. Feature-specific analyses suggested that presence of baseline MFTC osteophytes may be associated with prolongation in superficial MFTC cartilage T2 over one (0.8 vs. 0.0 ms, p = 0.02) and four years (2.3 vs. 0.9 ms, p = 0.01), and that MFTC meniscal damage or extrusion may be associated with prolongation in deep layer T2 times over the first year (0.7 vs. 2.1 ms, p = 0.02). CONCLUSIONS: Our study does not provide evidence that, in knees without radiographic OA, baseline structural MRI abnormalities are strongly related to compositional progression during normal aging and/or the potentially earliest phases of the disease as measured by cartilage T2.

Sex- and age-dependence of region- and layer-specific knee cartilage composition (spin-spin-relaxation time) in healthy reference subjects.

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<0.001) cartilage layer (Friedman test). Yet, layer- and region-specific femorotibial T2 did not differ between men and women, or between healthy adults below and above the median age (54 years). In conclusion, this first study to report subregional (layer-specific) compositional variation of femorotibial cartilage T2 in healthy adults identifies significant differences in both superficial and deep cartilage T2 between femorotibial subregions. However, no relevant sex- or age-dependence of cartilage T2 was observed between age 45-78 years. The findings suggest that a common, non-sex-specific set of layer-and region-specific T2 reference values can be used to identify compositional pathology in joint disease for this age group.

Longitudinal change in patellofemoral cartilage thickness, cartilage T2 relaxation times, and subchondral bone plate area in adolescent vs mature athletes.

OBJECTIVE: Patellofemoral cartilage changes have been evaluated in knee trauma and osteoarthritis; however, little is known about changes in patellar and trochlear cartilage thickness, T2 relaxation-time and subchondral bone plate area (tAB) during growth. Our prospective study aimed to explore longitudinal change in patellofemoral cartilage thickness, T2 and tAB in adolescent athletes, and to compare these data with those of mature (i.e., adult) athletes. MATERIALS AND METHODS: 20 adolescent (age 16±1years) and 20 mature (46±5years) volleyball players were studied over 2-years (10 men and 10 women each group). 1.5T MRI 3D-VIBE and multi-echo spin-echo sequences were acquired at baseline and 2-year follow-up. Using manual segmentation and 3D reconstruction, longitudinal changes in patellar and trochlear cartilage thickness, patellar cartilage T2 (mono-exponential decay curve with five echoes [9.7-67.9ms]), and patellar and trochlear tAB were determined. RESULTS: The annual increase in both patellar and trochlear cartilage thickness was 0.8% (95% confidence interval [CI] 0.6, 1.0) and 0.6% (0.3, 0.9), for adolescent males and females respectively; the longitudinal gain in patellar and trochlear tAB was 1.3% (1.1, 1.5) and 0.5% (0.2, 0.8), and 1.6% (1.1, 2.2) and 0.8% (0.3, 0.7) for adolescent males and females, respectively (no significant between-sex differences). Mature athletes showed smaller gains in tAB, and loss of <1% of cartilage thickness annually. While no significant sex-differences existed in adolescent patellar T2 changes, mature males gained significantly greater T2 than mature females (p=0.002-0.013). CONCLUSIONS: Patellar and trochlear cartilage thickness and tAB were observed to increase in young athletes in late adolescence, without significant differences between sexes. Mature athletes displayed patellar cartilage loss (and T2 increases in mature males), potentially reflecting degenerative changes.

Brief report: intraarticular sprifermin not only increases cartilage thickness, but also reduces cartilage loss: location-independent post hoc analysis using magnetic resonance imaging.

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.

Greater Lateral Femorotibial Cartilage Loss in Osteoarthritis Initiative Participants With Incident Total Knee Arthroplasty: A Prospective Cohort Study.

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/m(2)), 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.

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.

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.