François Abram

To examine whether metformin use was associated with knee cartilage volume loss over 4 years and risk of total knee replacement over 6 years in obese individuals with knee osteoarthritis. This study analysed the Osteoarthritis Initiative participants with radiographic knee osteoarthritis (Kellgren-Lawrence grade ≥ 2) who were obese (body mass index [BMI] ≥ 30 kg/m2). Participants were classified as metformin users if they self-reported regular metformin use at baseline, 1-year and 2-year follow-up (n = 56). Non-users of metformin were defined as participants who did not report the use of metformin at any visit from baseline to 4-year follow-up (n = 762). Medial and lateral cartilage volume (femoral condyle and tibial plateau) were assessed using magnetic resonance imaging at baseline and 4 years. Total knee replacement over 6 years was assessed. General linear model and binary logistic regression were used for statistical analyses. The rate of medial cartilage volume loss was lower in metformin users compared with non-users (0.71% vs. 1.57% per annum), with a difference of − 0.86% per annum (95% CI − 1.58% to − 0.15%, p = 0.02), after adjustment for age, gender, BMI, pain score, Kellgren-Lawrence grade, self-reported diabetes, and weight change over 4 years. Metformin use was associated with a trend towards a significant reduction in risk of total knee replacement over 6 years (odds ratio 0.30, 95% CI 0.07–1.30, p = 0.11), after adjustment for age, gender, BMI, Kellgren-Lawrence grade, pain score, and self-reported diabetes. These data suggest that metformin use may have a beneficial effect on long-term knee joint outcomes in those with knee osteoarthritis and obesity. Randomised controlled trials are needed to confirm these findings and determine whether metformin would be a potential disease-modifying drug for knee osteoarthritis with the obese phenotype.

There is evidence that knee pain not only is a consequence of structural deterioration in osteoarthritis (OA) but also contributes to structural progression. Clarifying this is important because targeting the factors related to knee pain may offer a clinical approach for slowing the progression of knee OA. The aim of this study was to examine whether knee pain over 1 year predicted cartilage volume loss, incidence and progression of radiographic osteoarthritis (ROA) over 4 years. Osteoarthritis Initiative participants with no ROA (Kellgren-Lawrence grade ≤ 1) (n = 2120) and with ROA (Kellgren-Lawrence grade > 2) (n = 2249) were examined. Knee pain was assessed at baseline and 1 year using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Knee pain patterns were categorised as no pain (WOMAC pain < 5 at baseline and 1 year), fluctuating pain (WOMAC pain > 5 at either time point) and persistent pain (WOMAC pain > 5 at both time points). Cartilage volume, incidence and progression of ROA were assessed using magnetic resonance imaging and x-rays at baseline and 4-years. In both non-ROA and ROA, greater baseline WOMAC knee pain score was associated with increased medial and lateral cartilage volume loss (p ≤ 0.001), incidence (OR 1.07, 95% CI 1.01–1.13) and progression (OR 1.07, 95% CI 1.03–1.10) of ROA. Non-ROA and ROA participants with fluctuating and persistent knee pain had increased cartilage volume loss compared with those with no pain (p for trend ≤ 0.01). Non-ROA participants with fluctuating knee pain had increased risk of incident ROA (OR 1.62, 95% CI 1.04–2.54), corresponding to a number needed to harm of 19.5. In ROA the risk of progressive ROA increased in participants with persistent knee pain (OR 1.82, 95% CI 1.28–2.60), corresponding to a number needed to harm of 9.6. Knee pain over 1 year predicted accelerated cartilage volume loss and increased risk of incident and progressive ROA. Early management of knee pain and controlling knee pain over time by targeting the underlying mechanisms may be important for preserving knee structure and reducing the burden of knee OA.

The weight of recommendation for intra-articular therapies such as hyaluronic acid injections varies from one set of guidelines to another, and they have not yet reached unanimity with respect to the usefulness of intra-articular hyaluronic acid (IAHA) injections for the symptomatic treatment of knee osteoarthritis (OA). Among the reasons for the controversy is that the current literature provides inconsistent results and conclusions about such treatment. This study aimed at identifying determinants associated with a better response to IAHA treatment in knee OA. Subjects were selected from the Osteoarthritis Initiative database. Participants were subjects who had radiographic OA, received one IAHA treatment, and had data on demographics and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at visits before (T0) and after (T1; within 6 months) treatment. Pain was analyzed for demographic, clinical, and imaging characteristics at T0 and change over time (T0 to T1). Subjects with WOMAC pain > 0 at T0 were subdivided into Low, Moderate, and High pain groups based on tertile analysis. Further analyses were done with the High pain group (score ≥ 8), which was divided into responders (improvement in pain ≥ 20%) and nonresponders (unchanged or worsening of pain). Participants (n = 310) received a total of 404 treatments (one per knee). In the Low and Moderate pain groups vs the High pain group, participants had significantly lower score at T0 (p < 0.001), and the Low vs High pain group had significantly lower BMI (p = 0.002), greater joint space width (JSW) (p = 0.010) and knee cartilage volume (p ≤ 0.009), and smaller synovial effusion (p = 0.033). In the High pain group, responders vs nonresponders were usually younger (p = 0.014), with greater cartilage volume in the medial compartment (p = 0.046), a trend toward greater JSW, and a significant improvement in all WOMAC scores (p < 0.001), while nonresponders showed worsening of symptoms. This study identified reliable predictive determinants that can distinguish patients who could best benefit from IAHA treatment: high levels of knee pain, younger, and less severe structural damage. These could be implemented in clinical practice as a useful guide for physicians.

There is an obvious need to identify biomarkers that could predict patient response to an osteoarthritis (OA) treatment. This post hoc study explored in a 2-year randomized controlled trial in patients with knee OA, the likelihood of some serum biomarkers to be associated with a better response to chondroitin sulfate in reducing cartilage volume loss. Eight biomarkers were studied: hyaluronic acid (HA), C reactive protein (CRP), adipsin, leptin, N-terminal propeptide of collagen IIα (PIIANP), C-terminal crosslinked telopeptide of type I collagen (CTX-1), matrix metalloproteinase-1 (MMP-1), and MMP-3. Patients were treated with chondroitin sulfate (1200 mg/day; n = 57) or celecoxib (200 mg/day; n = 62). Serum biomarkers were measured at baseline. The cartilage volume at baseline and its loss at 2 years were assessed by quantitative magnetic resonance imaging (MRI). Statistical analysis included analysis of covariance. As data from the original MOSAIC trial showed no differences in cartilage volume and loss in the lateral compartment of the knee joint between the two treatment groups in any comparison, only the medial compartment and its subregions were studied. Stratification according to the median biomarker levels was used to discriminate treatment effect. In patients with levels of biomarkers of inflammation (HA, leptin and adipsin) lower than the median, those treated with chondroitin sulfate demonstrated less cartilage volume loss in the medial compartment, condyle, and plateau (p ≤ 0.047). In contrast, patients treated with chondroitin sulfate with higher levels of MMP-1 and MMP-3, biomarkers of cartilage catabolism, had less cartilage volume loss in the medial compartment, condyle, and plateau (p ≤ 0.050). Patients with higher levels of PIIANP and CTX-1, biomarkers related to collagen anabolism and bone catabolism, respectively, had reduced cartilage volume loss in the medial condyle (p ≤ 0.026) in the chondroitin sulfate group. This study is suggestive of a potentially greater response to chondroitin sulfate treatment on cartilage volume loss in patients with knee OA with low level of inflammation and/or greater level of cartilage catabolism. This is a post hoc study. Original trial registration: ClinicalTrials.gov, NCT01354145 . Registered on 13 May 2011.

In osteoarthritis (OA) treatment, although chondroitin sulfate (CS) was found in a number of studies using radiography to have a structure-modifying effect, to date CS use is still under debate. A clinical study using quantitative magnetic resonance imaging (qMRI) is therefore of the utmost importance. Here we report data from a 24-month, randomised, double-blind, double-dummy, controlled, comparative exploratory study of knee OA. The primary endpoint was to determine the effect of CS 1200 mg/day versus celecoxib 200 mg/day on cartilage volume loss (CVL) in the lateral compartment over time as measured by qMRI. Secondary endpoints included assessment of the OA structural changes and signs and symptoms of OA. qMRI was performed at baseline and at 12 and 24 months. CVL, bone marrow lesion size, and synovial thickness were evaluated using qMRI. The primary statistical analysis was carried out on the modified intention-to-treat (mITT) population (n = 138) using chi-squared, Fisher’s exact, Wilcoxon Mann–Whitney, and Student’s t tests and analysis of covariance. Analyses were also conducted on the according-to-protocol (ATP; n = 120) population. In the adjusted mITT analysis, compared with celecoxib treatment, patients treated with CS had a significant reduced CVL at 24 months in the medial compartment (celecoxib –8.1 % ± 4.2, CS –6.3 % ± 3.2; p = 0.018) and medial condyle (–7.7 % ± 4.7, –5.5 % ± 3.9; p = 0.008); no significant effect was seen in the lateral compartment. In the ATP population, CS reduced CVL in the medial compartment at 12 months (celecoxib –5.6 % ± 3.0, CS –4.5 % ± 2.6; p = 0.049) and 24 months (celecoxib –8.4 % ± 4.2, CS –6.6 % ± 3.3; p = 0.021), and in the medial condyle at 24 months (celocoxib –8.1 % ± 4.7, CS –5.7 % ± 4.0; p = 0.010). A trend towards a statistically reduced synovial thickness (celecoxib +17.96 ± 33.73 mm, CS –0.66 ± 22.72 mm; p = 0.076) in the medial suprapatellar bursa was observed in CS patients. Both groups experienced a marked reduction in the incidence of patients with joint swelling/effusion and in symptoms over time. Data showed similar good safety profiles including cardiovascular adverse events for both drugs. This study demonstrated, for the first time in a 2-year randomised controlled trial using qMRI, the superiority of CS over celecoxib at reducing CVL in knee OA patients. ClinicalTrials.gov NCT01354145 . Registered 13 May 2011.

Change in knee cartilage volume is frequently used as a proxy for change in knee joint space width over time, but longitudinal data on these associations is limited. We aimed to determine whether change in knee cartilage volume, new or worsening meniscal extrusion (ME), meniscal tears and cartilage defects over 2.4 years correlated with change in joint space width (JSW) over 5 years in older community dwelling adults. Participants (n = 153) had their right knee imaged using MR imaging and x-ray at baseline, and after 2.4 years (MRI) and 5 years (x-ray). Cartilage volume, cartilage defects, meniscal extrusions and meniscal tears were assessed on sagittal T1-weighted fat-suppressed MRI. JSW was assessed using standard fixed semi-flexed view radiographs, and scored on those with adequate alignment. Participants were 51–79 (mean 62) years old; 48 % were female. Cartilage volume reduced over time (medial −134 ± 202 μL/year, lateral −106 ± 165 μL/year, p < 0.001), as did JSW (medial −0.05 ± 0.16 mm/year, lateral −0.12 ± 0.24 mm/year, p < 0.001). In multivariable analysis, the only consistent predictor of change in JSW was new or worsening ME (medial tibia R2 3.1 %, p = 0.031; medial femur R2 3.2 %, p = 0.024); change in cartilage volume correlated with change in JSW laterally (R2 4.8 %, p = 0.007) and was borderline medially (R2 2.2 %, p = 0.064); there was no association for meniscal tears or cartilage defects. The magnitude of these associations were similar albeit somewhat greater for ME in participants with radiographic OA (R2 6.2 %, p = 0.017). Change in ME and cartilage volume weakly predict change in JSW, but the vast majority of the variation remains unexplained. Since MRI examines cartilage directly while radiographs examine it indirectly, these results cast doubt on the validity of using JSW as a proxy measure of cartilage loss.