Can gait patterns be explained by joint structure in people with and without radiographic knee osteoarthritis? Data from the IMI-APPROACH cohort.

OBJECTIVE: To determine the association between joint structure and gait in patients with knee osteoarthritis (OA). METHODS: IMI-APPROACH recruited 297 clinical knee OA patients. Gait data was collected (GaitSmart®) and OA-related joint measures determined from knee radiographs (KIDA) and MRIs (qMRI/MOAKS). Patients were divided into those with/without radiographic OA (ROA). Principal component analyses (PCA) were performed on gait parameters; linear regression models were used to evaluate whether image-based structural and demographic parameters were associated with gait principal components. RESULTS: Two hundred seventy-one patients (age median 68.0, BMI 27.0, 77% female) could be analyzed; 149 (55%) had ROA. PCA identified two components: upper leg (primarily walking speed, stride duration, hip range of motion [ROM], thigh ROM) and lower leg (calf ROM, knee ROM in swing and stance phases). Increased age, BMI, and radiographic subchondral bone density (sclerosis), decreased radiographic varus angle deviation, and female sex were statistically significantly associated with worse lower leg gait (i.e. reduced ROM) in patients without ROA (R2 = 0.24); in ROA patients, increased BMI, radiographic osteophytes, MRI meniscal extrusion and female sex showed significantly worse lower leg gait (R2 = 0.18). Higher BMI was significantly associated with reduced upper leg function for non-ROA patients (R2 = 0.05); ROA patients with male sex, higher BMI and less MRI synovitis showed significantly worse upper leg gait (R2 = 0.12). CONCLUSION: Structural OA pathology was significantly associated with gait in patients with clinical knee OA, though BMI may be more important. While associations were not strong, these results provide a significant association between OA symptoms (gait) and joint structure.

Which risk factors determine cartilage thickness and composition change in radiographically normal knees? - Data from the Osteoarthritis Initiative.

Objective: Therapy for osteoarthritis ideally aims at preserving structure before radiographic change occurs. This study tests: a) whether longitudinal deterioration in cartilage thickness and composition (transverse relaxation-time T2) are greater in radiographically normal knees "at risk" of incident osteoarthritis than in those without risk factors; and b) which risk factors may be associated with these deteriorations. Design: 755 knees from the Osteoarthritis Initiative were studied; all were bilaterally Kellgren Lawrence grade [KLG] 0 initially, and had magnetic resonance images available at 12- and 48-month follow-up. 678 knees were "at risk", whereas 77 were not (i.e., non-exposed reference). Cartilage thickness and composition change was determined in 16 femorotibial subregions, with deep and superficial T2 being analyzed in a subset (n â€‹= â€‹59/52). Subregion values were used to compute location-independent change scores. Results: In KLG0 knees "at risk", the femorotibial cartilage thinning score (-634 â€‹± â€‹516 â€‹µm) over 3 years exceeded the thickening score by approximately 20%, and was 27% greater (p â€‹< â€‹0.01; Cohen D -0.27) than the thinning score in "non-exposed" knees (-501 â€‹± â€‹319 â€‹µm). Superficial and deep cartilage T2 change, however, did not differ significantly between both groups (p â€‹≥ â€‹0.38). Age, sex, body mass index, knee trauma/surgery history, family history of joint replacement, presence of Heberden's nodes, repetitive knee bending were not significantly associated with cartilage thinning (r2<1%), with only knee pain reaching statistical significance. Conclusions: Knees "at risk" of incident knee OA displayed greater cartilage thinning scores than those "non-exposed". Except for knee pain, the greater cartilage loss was not significantly associated with demographic or clinical risk factors.

Evaluation of S201086/GLPG1972, an ADAMTS-5 inhibitor, for the treatment of knee osteoarthritis in ROCCELLA: a phase 2 randomized clinical trial.

OBJECTIVE: To evaluate the efficacy and safety of the anti-catabolic ADAMTS-5 inhibitor S201086/GLPG1972 for the treatment of symptomatic knee osteoarthritis. DESIGN: ROCCELLA (NCT03595618) was a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 trial in adults (aged 40-75 years) with knee osteoarthritis. Participants had moderate-to-severe pain in the target knee, Kellgren-Lawrence grade 2 or 3 and Osteoarthritis Research Society International joint space narrowing (grade 1 or 2). Participants were randomized 1:1:1:1 to once-daily oral S201086/GLPG1972 75, 150 or 300 mg, or placebo for 52 weeks. The primary endpoint was change from baseline to week 52 in central medial femorotibial compartment (cMFTC) cartilage thickness assessed quantitatively by magnetic resonance imaging. Secondary endpoints included change from baseline to week 52 in radiographic joint space width, Western Ontario and McMaster Universities Osteoarthritis Index total and subscores, and pain (visual analogue scale). Treatment-emergent adverse events (TEAEs) were also recorded. RESULTS: Overall, 932 participants were enrolled. No significant differences in cMFTC cartilage loss were observed between placebo and S201086/GLPG1972 therapeutic groups: placebo vs 75 mg, P = 0.165; vs 150 mg, P = 0.939; vs 300 mg, P = 0.682. No significant differences in any of the secondary endpoints were observed between placebo and treatment groups. Similar proportions of participants across treatment groups experienced TEAEs. CONCLUSIONS: Despite enrolment of participants who experienced substantial cartilage loss over 52 weeks, during the same time period, S201086/GLPG1972 did not significantly reduce rates of cartilage loss or modify symptoms in adults with symptomatic knee osteoarthritis.

Test-retest precision and longitudinal cartilage thickness loss in the IMI-APPROACH cohort.

OBJECTIVE: To investigate the test-retest precision and to report the longitudinal change in cartilage thickness, the percentage of knees with progression and the predictive value of the machine-learning-estimated structural progression score (s-score) for cartilage thickness loss in the IMI-APPROACH cohort - an exploratory, 5-center, 2-year prospective follow-up cohort. DESIGN: Quantitative cartilage morphology at baseline and at least one follow-up visit was available for 270 of the 297 IMI-APPROACH participants (78% females, age: 66.4 ± 7.1 years, body mass index (BMI): 28.1 ± 5.3 kg/m2, 55% with radiographic knee osteoarthritis (OA)) from 1.5T or 3T MRI. Test-retest precision (root mean square coefficient of variation) was assessed from 34 participants. To define progressor knees, smallest detectable change (SDC) thresholds were computed from 11 participants with longitudinal test-retest scans. Binary logistic regression was used to evaluate the odds of progression in femorotibial cartilage thickness (threshold: -211 µm) for the quartile with the highest vs the quartile with the lowest s-scores. RESULTS: The test-retest precision was 69 µm for the entire femorotibial joint. Over 24 months, mean cartilage thickness loss in the entire femorotibial joint reached -174 µm (95% CI: [-207, -141] µm, 32.7% with progression). The s-score was not associated with 24-month progression rates by MRI (OR: 1.30, 95% CI: [0.52, 3.28]). CONCLUSION: IMI-APPROACH successfully enrolled participants with substantial cartilage thickness loss, although the machine-learning-estimated s-score was not observed to be predictive of cartilage thickness loss. IMI-APPROACH data will be used in subsequent analyses to evaluate the impact of clinical, imaging, biomechanical and biochemical biomarkers on cartilage thickness loss and to refine the machine-learning-based s-score. GOV IDENTIFICATION: NCT03883568.

Association between osteoarthritis-related serum biochemical markers over 11 years and knee MRI-based imaging biomarkers in middle-aged adults.

OBJECTIVE: To describe the associations between osteoarthritis (OA)-related biochemical markers (COMP, MMP-3, HA) and MRI-based imaging biomarkers in middle-aged adults over 10-13 years. METHODS: Blood serum samples collected during the Childhood Determinants of Adult Health (CDAH)-1 study (year:2004-06; n = 156) and 10-13 year follow-up at CDAH-3 (n = 167) were analysed for COMP, MMP-3, and HA using non-isotopic ELISA. Knee MRI scans obtained during the CDAH-knee study (year:2008-10; n = 313) were assessed for cartilage volume and thickness, subchondral bone area, cartilage defects, and BML. RESULTS: In a multivariable linear regression model describing the association of baseline biochemical markers with MRI-markers (assessed after 4-years), we found a significant negative association of standardised COMP with medial femorotibial compartment cartilage thickness (ß:-0.070; 95%CI:-0.138,-0.001), and standardised MMP-3 with patellar cartilage volume (ß:-141.548; 95%CI:-254.917,-28.179) and total bone area (ß:-0.729; 95%CI:-1.340,-0.118). In multivariable Tobit regression model, there was a significant association of MRI-markers with biochemical markers (assessed after 6-9 years); a significant negative association of patellar cartilage volume (ß:-0.001; 95%CI:-0.002,-0.00004), and total bone area (ß:-0.158; 95%CI-0.307,-0.010) with MMP-3, and total cartilage volume (ß:-0.001; 95%CI:-0.001,-0.0001) and total bone area (ß:-0.373; 95%CI:-0.636,-0.111) with COMP. No significant associations were observed between MRI-based imaging biomarkers and HA. CONCLUSION: COMP and MMP-3 levels were negatively associated with knee cartilage thickness and volume assessed 4-years later, respectively. Knee cartilage volume and bone area were negatively associated with COMP and MMP-3 levels assessed 6-9 years later. These results suggest that OA-related biochemical markers and MRI-markers are interrelated in early OA.

Correction to: Patient-Specific Mandibular Reconstruction Plates Increase Accuracy and Long-Term Stability in Immediate Alloplastic Reconstruction of Segmental Mandibular Defects.

[This corrects the article DOI: 10.1007/s12663-019-01323-9.].

Endogenous anandamide and self-reported pain are significantly reduced after a 2-week multimodal treatment with and without radon therapy in patients with knee osteoarthritis: a pilot study.

Multimodal therapies comprising spa applications are widely used as non-pharmaceutical treatment options for musculoskeletal diseases. The purpose of this randomized, controlled, open pilot study was to elucidate the involvement of the endocannabinoid system in a multimodal therapy approach. Twenty-five elderly patients with knee osteoarthritis (OA) received a 2-week spa therapy with or without combination of low-dose radon therapy in the Bad Gastein radon gallery. A 10-point numerical rating scale (pain in motion and at rest), WOMAC questionnaire, and the EuroQol-5D (EQ-5D) questionnaire were recorded at baseline, and during treatment period at weeks one and two, and at 3-month and 6-month follow-ups. Plasma levels of the endocannabinoid anandamide (AEA) were determined at baseline and at 2 weeks, and serum levels of several cartilage metabolism markers at all five time-points. A significant and sustained reduction of self-reported knee pain was observed in the study population, but no further significant effect of the additional radon therapy up and above base therapy. This pain reduction was accompanied by a significant reduction of AEA plasma levels during treatment in both groups. No significant differences were seen in serum marker concentrations between the groups treated with or without radon, but a small reduction of serum cartilage degradation markers was observed during treatment in both groups. This is the first study investigating AEA levels in the context of a non-pharmacological OA treatment. Since the endocannabinoid system represents a potential target for the development of new therapeutics, further studies will have to elucidate its involvement in OA pain.

Early anterior cruciate ligament reconstruction does not affect 5 year change in knee cartilage thickness: secondary analysis of a randomized clinical trial.

OBJECTIVE: To compare 5-year change in femorotibial cartilage thickness in 121 young, active adults with an acute anterior cruciate ligament (ACL) tear randomized to a strategy of structured rehabilitation plus early ACL reconstruction (ACLR) or structured rehabilitation plus optional delayed ACLR. DESIGN: 62 patients were randomized to early ACLR, 59 to optional delayed ACLR. Magnetic resonance imaging (MRI) was acquired within 4 weeks of injury, at two- and 5-years follow-up. Main outcome was 5-year change in overall femorotibial cartilage thickness. Secondary outcomes included the location-independent cartilage ChangeScore, summarizing thinning and thickening in 16 femorotibial subregions. An exploratory as-treated comparison was performed additionally. RESULTS: Baseline and at least one follow-up MRI were available for 117 patients. Over 5 years, a comparable increase in overall femorotibial cartilage thickness was observed for patients randomized to early ACLR (n = 59) and patients randomized to optional delayed ACLR (n = 58, adjusted mean difference: -5 µm, 95% CI: [-118, 108]µm). However, the location-independent cartilage ChangeScore was greater in those treated with early ACLR than in patients treated with optional delayed ACLR (adjusted mean difference: 403 µm [119, 687]µm). As-treated analysis showed no between-group differences for the main outcome, while the location-independent cartilage ChangeScore was greater for patients treated with early (adjusted mean difference: 632 µm [268, 996]µm) or delayed ACLR (adjusted mean difference: 449 µm [108, 791]µm) than for patients treated with rehabilitation alone. CONCLUSIONS: In young active adults with acute ACL-injury, choice of treatment strategy for the injured ACL did not modify the magnitude of 5-year change in overall femorotibial cartilage thickness. TRIAL REGISTRATION: ISRCTN84752559.

Osteoarthritis year in review 2020: imaging.

This narrative "Year in Review" highlights a selection of articles published between January 2019 and April 2020, to be presented at the OARSI World Congress 2020 within the field of osteoarthritis (OA) imaging. Articles were obtained from a PubMed search covering the above period, utilizing a variety of relevant search terms. We then selected original and review studies on OA-related imaging in humans, particularly those with direct clinical relevance, with a focus on the knee. Topics selected encompassed clinically relevant models of early OA, particularly imaging applications on cruciate ligament rupture, as these are of direct clinical interest and provide potential opportunity to evaluate preventive therapy. Further, imaging applications on structural modification of articular tissues in patients with established OA, by non-pharmacological, pharmacological and surgical interventions are summarized. Finally, novel deep learning approaches to imaging are reviewed, as these facilitate implementation and scaling of quantitative imaging application in clinical trials and clinical practice. Methodological or observational studies outside these key focus areas were not included. Studies focused on biology, biomechanics, biomarkers, genetics and epigenetics, and clinical studies that did not contain an imaging component are covered in other articles within the OARSI "Year in Review" series. In conclusion, exciting progress has been made in clinically validating human models of early OA, and the field of automated articular tissue segmentation. Most importantly though, it has been shown that structure modification of articular cartilage is possible, and future research should focus on the translation of these structural findings to clinical benefit.

Patient-Specific Mandibular Reconstruction Plates Increase Accuracy and Long-Term Stability in Immediate Alloplastic Reconstruction of Segmental Mandibular Defects.

OBJECTIVES: The aim of the current study was to evaluate potential differences in the accuracy of mandibular reconstruction and long-term stability, with respect to different reconstructive procedures. METHODS: In total, 42 patients who had undergone primary segmental mandibular resection with immediate alloplastic reconstruction, with either manually pre-bent or patient-specific mandibular reconstruction plates (PSMRP), were included in this study. Mandibular dimensions, in terms of six clinically relevant distances (capitulum [most lateral points], capitulum [most medial points], incisura [most caudal points], mandibular foramina, coronoid process [most cranial points], dorsal tip of the mandible closest to the gonion point) determined from tomographic images, were compared prior to, and after surgery. RESULTS: Dimensional alterations were significantly more often found when conventionally bent titanium reconstruction plates were used. These occurred in the area of the coronoid process (p = 0.014). Plate fractures were significantly (p = 0.022) more often found within the manually pre-bent group than within the PSMRP group (17%/0%). CONCLUSION: The results suggest that the use of PSMRP may prevent rotation of the proximal mandibular segment, thus avoiding functional impairment. In addition, the use of PSMRP may potentially enhance the long-term stability of alloplastic reconstructions.

Automated MRI assessment confirms cartilage thickness modification in patients with knee osteoarthritis: post-hoc analysis from a phase II sprifermin study.

BACKGROUND: Sprifermin is under investigation as a potential disease-modifying osteoarthritis drug. Previously, 2-year results from the FORWARD study showed significant dose-dependent modification of cartilage thickness in the total femorotibial joint (TFTJ), medial and lateral femorotibial compartments (MFTC, LFTC), and central medial and lateral TFTJ subregions, by quantitative magnetic resonance imaging (qMRI) using manual segmentation. OBJECTIVE: To determine whether qMRI findings from FORWARD could be reproduced by an independent method of automated segmentation using an identical dataset and similar anatomical regions in a post-hoc analysis. METHOD: Cartilage thickness was assessed at baseline and 6, 12, 18 and 24 months, using automated cartilage segmentation with active appearance models, a supervised machine learning method. Images were blinded for treatment and timepoint. Treatment effect was assessed by observed and adjusted changes using a linear mixed model for repeated measures. RESULTS: Based on automated segmentation, statistically significant, dose-dependent structural modification of cartilage thickness was observed over 2 years with sprifermin vs placebo for TFTJ (overall treatment effect and dose response, both P < 0.001), MFTC (P = 0.004 and P = 0.044), and LFTC (both P < 0.001) regions. For highest dose, in the central medial tibial (P = 0.008), central lateral tibial (P < 0.001) and central lateral femoral (P < 0.001) regions. CONCLUSIONS: Cartilage thickness assessed by automated segmentation provided a consistent dose response in structural modification compared with manual segmentation. This is the first time that two independent quantification methods of image analysis have reached the same conclusions in an interventional trial, strengthening the conclusions that sprifermin modifies structural progression in knee osteoarthritis.

Association of infra-patellar fat pad size with age and body weight in children and adolescents.

BACKGROUND: The infra-patellar fat pad (IPFP) represents a potential mediator between obesity, low grade inflammation, and knee osteoarthritis via endocrine pathways. Yet, not only in adults, but also in childhood obesity negatively impacts knee structures. OBJECTIVE: The current study therefore investigated the sex-specific growth of the IPFP with age and body weight in healthy children and adolescents. MATERIALS AND METHODS: Thirty young healthy subjects (60% girls; age 4-17 years, body weight 14-90 kg in girls and 29-105 kg in boys; BMI 12.2-32.4 kg/m2) without magnetic resonance imaging (MRI) knee pathology were studied. The IPFP volume was determined from sagittal T-1 weighted and proton-density spectral attenuated inversion recovery MRIs. The primary analysis focused on the sex-specific IPFP volume/body weight ratio as dependent, and age as independent variable, using linear regression models. A secondary analytic focus was the slope of the age-dependence of IPFP volume, without normalization to body weight. RESULTS: There was no statistically significant association of the IPFP volume/body weight ratio with age in girls (p = 0.57) or boys (p = 0.31), the R2 of ranging from -0.32 to 0.14. The ratio was greater in boys (0.54 ±â€¯0.10 cm3/kg) than in girls (0.45 ±â€¯0.07 cm3/kg) (p < 0.01). The IPFP volume increased by approx. 2 cm3 per annum in both girls and boys, without any indication of a non-linear relationship. CONCLUSION: Our findings reveal that the ratio of the IPFP volume and body weight remains constant between age 4 and 17 in both normal weight girls and boys, and that the IPFP volume increases linearly with age throughout this period.

Predicting knee replacement in participants eligible for disease-modifying osteoarthritis drug treatment with structural endpoints.

OBJECTIVE: Evaluate associations between 2-year change in radiographic or quantitative magnetic resonance imaging (qMRI) structural measures, and knee replacement (KR), within a subsequent 7-year follow-up period. METHOD: Participants from the Osteoarthritis Initiative were selected based on potential eligibility criteria for a disease-modifying osteoarthritis (OA) drug trial: Kellgren-Lawrence grade 2 or 3; medial minimum joint space width (mJSW) ≥2.5 mm; knee pain at worst 4-9 in the past 30 days on an 11-point scale, or 0-3 if medication was taken for joint pain; and availability of structural measures over 2 years. Mean 2-year change in structural measures was estimated and compared with two-sample independent t-tests for KR and no KR. Area under the receiver operating characteristic curve (AUC) was estimated using 2-year change in structural measures for prediction of future KR outcomes. RESULTS: Among 627 participants, 107 knees underwent KR during a median follow-up of 6.7 years after the 2-year imaging period. Knees that received KR during follow-up had a greater mean loss of cartilage thickness in the total femorotibial joint and medial femorotibial compartment on qMRI, as well as decline in medial fixed joint space width on radiographs, compared with knees that did not receive KR. These imaging measures had similar, although modest discrimination for future KR (AUC 0.62, 0.60, and 0.61, respectively). CONCLUSIONS: 2-year changes in qMRI femorotibial cartilage thickness and radiographic JSW measures had similar ability to discriminate future KR in participants with knee OA, suggesting that these measures are comparable biomarkers/surrogate endpoints of structural progression.

Association of baseline and change in tibial and femoral cartilage thickness and development of widespread full-thickness cartilage loss in knee osteoarthritis - data from the Osteoarthritis Initiative.

OBJECTIVE: To investigate whether baseline cartilage thickness and its longitudinal change are associated with incident widespread full-thickness cartilage loss (wsFTCL) in knee osteoarthritis, and whether there are optimal cut-off values for predicting wsFTCL. METHODS: Central medial tibial (cMT) and femoral (cMF) cartilage were assessed using quantitative magnetic resonance imaging data from the Osteoarthritis Initiative cohort (N = 600 knees). Cartilage thickness was measured at baseline and 12 months. wsFTCL was defined semi-quantitatively (scores 2 and 3 from the MRI Osteoarthritis Knee Score) and its incidence at 24 months recorded. Logistic regression was used to determine the odds of developing wsFTCL for baseline and for each 0.1 mm decrease in cartilage thickness. Cut-off values were investigated using the minimal-p method and area under the Receiver Operating Characteristic curves (AUC). RESULTS: Incident wsFTCL was observed in 66 (12%) and 73 (14%) knees in cMT and cMF, respectively. Lower baseline cMT and cMF cartilage thickness values were associated with wsFTCL (OR = 1.20; 95% CI: 1.11, 1.28 and OR = 1.15; 95% CI: 1.06 to 1.24, respectively). Optimal cut-off AUCs for the tibia and femur were 0.64 (0.57-0.70) and 0.63 (0.57-0.69), respectively. Longitudinal decrease in femoral, but not tibial, cartilage thickness was associated with incident wsFTCL (OR = 1.77; 95% CI: 1.30 to 2.40); optimal cut-off AUC 0.65 (95% CI: 0.58-0.72). CONCLUSION: Lower baseline cMT and baseline/change (decrease) over 12 months in cMF cartilage thickness were associated with incident, location-specific, wsFTCL at 24 months. Optimal cut-off values were relatively low and of uncertain utility for predicting incident wsFTCL.

The effect of weight loss on the progression of meniscal extrusion and size in knee osteoarthritis: a post-hoc analysis of the Intensive Diet and Exercise for Arthritis (IDEA) trial.

OBJECTIVE: Weight loss has beneficial effects on clinical outcomes in knee osteoarthritis (OA), but the mechanism is still unclear. Since meniscus extrusion is associated with knee pain, this study assessed whether weight loss by diet and/or exercise is associated with less progression in meniscus extrusion measures over time. DESIGN: The Intensive Diet and Exercise for Arthritis trial (IDEA) was a prospective, single-blind, randomized-controlled trial including overweight and obese older adults with knee pain and radiographic OA. Participants were randomized to 18-month interventions: exercise only, diet only or diet + exercise. In a random subsample of 105 participants, MRIs were obtained at baseline and follow-up. The medial and lateral menisci were segmented and quantitative position and size measures were obtained, along with semiquantitative extrusion measures. Linear and log-binomial regression were used to examine the association between change in weight and change in meniscus measures. Between-group differences were analyzed using an analysis of covariance. RESULTS: Weight loss was associated with less progression over time of medial meniscus extrusion as measured by the maximum (ß: -24.59 µm, 95%CI: -41.86, -7.33) and mean (ß: -19.08 µm, 95%CI: -36.47, -1.70) extrusion distances. No relationships with weight loss were observed for lateral meniscus position, medial or lateral meniscus size or semiquantitative measures. Change in meniscus position and size did not differ significantly between groups. CONCLUSIONS: Weight loss was associated with beneficial modifications of medial meniscus extrusion over 18 months. This may be one of the mechanisms by which weight loss translates into a clinical benefit. CLINICAL TRIAL REGISTRATION: NCT00381290.

Radiographically normal knees with contralateral joint space narrowing display greater change in cartilage transverse relaxation time than those with normal contralateral knees: a model of early OA? - data from the Osteoarthritis Initiative (OAI).

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.

Cartilage loss in radiographically normal knees depends on radiographic status of the contralateral knee - data from the Osteoarthritis Initiative.

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.

Trajectories of femorotibial cartilage thickness among persons with or at risk of knee osteoarthritis: development of a prediction model to identify progressors.

OBJECTIVE: There is significant variability in the trajectory of structural progression across people with knee osteoarthritis (OA). We aimed to identify distinct trajectories of femorotibial cartilage thickness over 2 years and develop a prediction model to identify individuals experiencing progressive cartilage loss. METHODS: We analysed data from the Osteoarthritis Initiative (OAI) (n = 1,014). Latent class growth analysis (LCGA) was used to identify trajectories of medial femorotibial cartilage thickness assessed on magnetic resonance imaging (MRI) at baseline, 1 and 2 years. Baseline characteristics were compared between trajectory-based subgroups and a prediction model was developed including those with frequent knee symptoms at baseline (n = 686). To examine clinical relevance of the trajectories, we assessed their association with concurrent changes in knee pain and incidence of total knee replacement (TKR) over 4 years. RESULTS: The optimal model identified three distinct trajectories: (1) stable (87.7% of the population, mean change -0.08 mm, SD 0.19); (2) moderate cartilage loss (10.0%, -0.75 mm, SD 0.16) and (3) substantial cartilage loss (2.2%, -1.38 mm, SD 0.23). Higher Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) pain scores, family history of TKR, obesity, radiographic medial joint space narrowing (JSN) ≥1 and pain duration ≤1 year were predictive of belonging to either the moderate or substantial cartilage loss trajectory [area under the curve (AUC) 0.79, 95% confidence interval (CI) 0.74, 0.84]. The two progression trajectories combined were associated with pain progression (OR 1.99, 95% CI 1.34, 2.97) and incidence of TKR (OR 4.34, 1.62, 11.62). CONCLUSIONS: A minority of individuals follow a progressive cartilage loss trajectory which was strongly associated with poorer clinical outcomes. If externally validated, the prediction model may help to select individuals who may benefit from cartilage-targeted therapies.

The role of thigh muscle and adipose tissue in knee osteoarthritis progression in women: data from the Osteoarthritis Initiative.

OBJECTIVE: To determine whether loss in thigh muscle strength in women concurrent with knee osteoarthritis progression is associated with reductions of muscle anatomical cross-sectional area (ACSA) or specific-strength (i.e., isometric force÷ACSA), and to explore relationships with local adiposity. DESIGN: Female participants from the Osteoarthritis Initiative with Kellgren-Lawrence grade ≤3, thigh isometric strength measurements, and thigh magnetic resonance images at year-two (Y2) and year-four (Y4) (n = 739, age 62 ± 9 years; body mass index measurements (BMI) 28.8 ± 5.9 kg/m2) were grouped into: (1) those with vs without symptomatic progression (≥9 increase in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-pain [scale: 0-100]); and (2) those with vs without radiographic progression (≥0.7 mm reduction in minimum joint space width). The change in knee extensor and flexor ACSA and specific-strength, and subcutaneous and intermuscular fat (IMF) ACSAs were compared between progressors and non-progressors using analysis of covariance. RESULTS: Symptomatic progression was associated with a significantly greater loss (p < 0.001) of knee extensor ACSA (-2.0%, 95%CI -2.5, -1.5) compared to those without progression (-0.7%, 95%CI -1.0, -0.4), and greater loss (p = 0.020) of knee flexor specific-strength (-7.6%, 95%CI -11.5, -3.7; vs -2.4%, 95%CI -4.8, 0.0). Radiographic progression was associated with a significantly greater increase (p = 0.023) in IMF (+1.7%, 95%CI -0.1, +3.6) compared to those without progression (-0.6%, 95%CI -1.6, +0.3). CONCLUSION: The significant reduction in thigh muscle strength concurrent with symptomatic progression in women appears to be associated with loss of extensor muscle ACSA and flexor specific-strength. In contrast, radiographic progression appears to be unrelated to muscle properties, but to be associated with local (intermuscular) adiposity gains.

Is local or central adiposity more strongly associated with incident knee osteoarthritis than the body mass index in men or women?

OBJECTIVE: To determine whether central (abdominal) or peripheral (thigh) adiposity measures are associated with incident radiographic knee osteoarthritis (RKOA) independent of body mass index (BMI) and whether their relation to RKOA was stronger than that of BMI. DESIGN: 161 Osteoarthritis Initiative (OAI) participants (62% female) with incident RKOA (Kellgren/Lawrence grade 0/1 at baseline, developing an osteophyte and joint space narrowing (JSN) grade ≥1 by year-4) were matched to 186 controls (58% female) without incident RKOA. Baseline waist-height-ratio (WHtR), and anatomical cross-sectional areas of thigh subcutaneous (SCF) and intermuscular fat (IMF) were measured, the latter using axial magnetic resonance images. Logistic regression assessed the relationship between each adiposity measure and incident RKOA before and after adjustment for BMI, and area under receiver operating characteristic curves (AUC) for each adiposity measure was compared to that of BMI using chi-squared tests. RESULTS: BMI, WHtR, subcutaneous fat (SCF) and IMF were all significantly associated with incident RKOA when analysed separately, with similar effect sizes (odds ratio range 1.30-1.53). After adjusting for BMI, odds ratios (ORs) for WHtR, SCF and IMF were attenuated and no longer statistically significant. No measure of central or peripheral adiposity was significantly more strongly associated with incident RKOA than BMI. Results were similar for men and women. CONCLUSIONS: Although both central (WHtR) and peripheral (SCF and IMF) adiposity were significantly associated with incident RKOA, neither was more strongly associated with incident RKOA than BMI. The simple measure of BMI appears sufficient to capture the elevated risk of RKOA associated with greater amounts of localised adiposity.