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Objectives: To assess the associations of biomarkers in serum [highsensitivity C-reactive protein (hs-CRP), serum cartilage oligomeric protein (sCOMP), serum propeptide of type I procollagen (sPINP) and serum osteocalcin (sOC)] and urine [urinary type II collagen telopeptide (uCTX-2)] with the extent and progression of nocturnal pain, pain while walking, and fatigue in participants with hip and/or knee pain suspected to be early stage osteoarthritis (OA). Methods: hs-CRP, uCTX-2, sCOMP, sPINP and sOC were measured at baseline in 1,002 participants of the Cohort Hip and Cohort Knee (CHECK). Nocturnal pain, pain while walking and fatigue were assessed by self-reported questionnaires at baseline and 2-year follow-up. Associations between these biomarkers and symptoms were examined using logistic and linear regression analyses. Results: hs-CRP was significantly associated with mild nocturnal pain (OR 1.18 95% CI 1.01–1.37), with mild and moderate pain while walking (OR 1.17 95% CI 1.01–1.35 and OR 1.56 95% CI 1.29–1.90, respectively) and with progression of nocturnal pain (OR 1.25 95% CI 1.07–1.46). uCTX-2 was associated with mild nocturnal pain (OR 1.40 95% CI 1.05–1.85) and with mild and severe-extreme pain while walking (OR 1.35 95% CI 1.04–1.75 and OR 2.55 95% CI 1.03–6.34, respectively). sPINP was associated with severe-extreme nocturnal pain (OR 0.45 95% CI 0.25–0.82). No significant associations were found for sCOMP and sOC, nor for any of the biomarkers and fatigue. Conclusion: This study of biomarkers in a large cohort of participants with hip and/or knee pain suspected to reflect early stage hip and/or knee OA suggests that inflammation and cartilage matrix degeneration play a role in pain, but not in fatigue.

Summary Objective To provide an insightful summary of studies on biochemical markers for osteoarthritis (OA). Design Two investigators systematically searched the electronic PubMed database for clinical studies into soluble biochemical markers for OA in humans that were published between 01-03-2018 and 01-03-2019. Data from selected publications were systematically extracted and tabulated and were summarized in a narrative review. Results Out of 1,279 publications, 124 fulfilled all selection criteria and were selected for data extraction. The majority were around knee OA, cross-sectional in design, relatively small, and/or focused on one or a few biochemical markers. Among the intervention studies, relatively many were on non-pharmacological interventions, used clinical outcomes and/or were rather short. Some leads that were provided by this year's studies pertained to less conventional inflammatory mediators, oxidative stress, acidosis, angiogenesis and/or autoantibody formation. Conclusions This year's biochemical marker studies did provide potential leads for therapeutic targets or other biochemical marker applications that require robust and strategic follow-up research to be validated.

Summary Objective To describe the radiographic and symptomatic course in subjects with hip or knee complaints suspected of early osteoarthritis (OA). Design CHECK (Cohort Hip and Cohort Knee) is a multicenter, prospective observational cohort study of 1,002 subjects with first complaints in knee(s) and/or hip(s) (age 56 ± 5 years; 79% female; body mass index (BMI) 26 ± 4 kg/m2). Visits took place at baseline and at 2, 5, 8, and 10 year follow-up. At each visit, questionnaires were administered, physical examination performed, and X-ray images obtained. Clinical OA was defined according to the clinical American College of Rheumatism (ACR) criteria. Radiographic OA (ROA) was defined as Kellgren and Lawrence score (K&L) ≥2. Results 83% of the subjects reported knee pain, 59% hip pain, and 42% reported both hip and knee pain at baseline. 85% of the subjects completed 10-year follow-up. Pain scores remained rather stable over time, although individual scores fluctuated. A total of 138 subjects never fulfilled the clinical American College of Rheumatology (ACR) criteria. 60% (n = 601) had ROA in one or both knees, and 51% (n = 513) had ROA in one or both hips at 10 years. Only 13.5% of the subjects did not develop ROA after 10 years. Most joint replacements (n = 52 (57%)) took place in subjects with multiple affected joints. Conclusions The symptomatic course in subjects with hip or knee complaints suspected of OA remained fairly stable on population level, though individual scores fluctuated. The radiological course was progressive, with joint replacements particularly in subjects with both hip and knee OA.

Background The concept of osteoarthritis (OA) heterogeneity is evolving and gaining renewed interest. According to this concept, distinct subtypes of OA need to be defined that will likely require recognition in research design and different approaches to clinical management. Although seemingly plausible, a wide range of views exist on how best to operationalize this concept. The current project aimed to provide consensus-based definitions and recommendations that together create a framework for conducting and reporting OA phenotype research. Methods A panel of 25 members with expertise in OA phenotype research was composed. First, panel members participated in an online Delphi exercise to provide a number of basic definitions and statements relating to OA phenotypes and OA phenotype research. Second, panel members provided input on a set of recommendations for reporting on OA phenotype studies. Results Four Delphi rounds were required to achieve sufficient agreement on 11 definitions and statements. OA phenotypes were defined as subtypes of OA that share distinct underlying pathobiological and pain mechanisms and their structural and functional consequences. Reporting recommendations pertaining to the study characteristics, study population, data collection, statistical analysis, and appraisal of OA phenotype studies were provided. Conclusions This study provides a number of consensus-based definitions and recommendations relating to OA phenotypes. The resulting framework is intended to facilitate research on OA phenotypes and increase combined efforts to develop effective OA phenotype classification. Success in this endeavor will hopefully translate into more effective, differentiated OA management that will benefit a multitude of OA patients.

BACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons.METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses.RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms.CONCLUSIONS: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.

Summary Purpose The aim of this "Year in Review" article is to summarize and discuss the implications of biochemical marker related articles published between the Osteoarthritis Research Society International (OARSI) 2015 Congress in Seattle and the OARSI 2016 Congress in Amsterdam. Methods The PubMed/MEDLINE bibliographic database was searched using the combined keywords: ‘biomarker' and ‘osteoarthritis'. The PubMed/MEDLINE literature search was conducted using the Advanced Search Builder function (http://www.ncbi.nlm.nih.gov/pubmed/advanced). Results Over two hundred new biomarker-related papers were published during the literature search period. Some papers identified new biomarkers whereas others explored the biological properties and clinical utility of existing markers. There were specific references to several adipocytokines including leptin and adiponectin. ADAM Metallopeptidase with Thrombospondin Type 1 motif 4 (ADAMTS-4) and aggrecan ARGS neo-epitope fragment (ARGS) in synovial fluid (SF) and plasma chemokine (CeC motif) ligand 3 (CCL3) were reported as potential new knee biomarkers. New and refined proteomic technologies and novel assays including a fluoro-microbead guiding chip (FMGC) for measuring C-telopeptide of type II collagen (CTX-II) in serum and urine and a novel magnetic nanoparticle-based technology (termed magnetic capture) for collecting and concentrating CTX-II, were described this past year. Conclusion There has been steady progress in osteoarthritis (OA) biomarker research in 2016. Several novel biomarkers were identified and new technologies have been developed for measuring existing biomarkers. However, there has been no "quantum leap" this past year and identification of novel early OA biomarkers remains challenging. During the past year, OARSI published a set of recommendations for the use of soluble biomarkers in clinical trials, which is a major step forward in the clinical use of OA biomarkers and bodes well for future OA biomarker development.

Purpose: Exercise therapy with a focus on muscle strengthening has proven to be effective for the management of knee osteoarthritis (OA). Yet it is not known whether high-intensity resistance training (RT) is more effective in improving upper leg muscle strength and physical performance than low-intensity RT. Still, there is some controversy regarding the effectiveness of high-intensity RT and whether or not it is harmful, for instance by accelerating cartilage degeneration, osteophyte formation, or increasing synovitis. Any catabolic or anabolic response of musculoskeletal tissue to RT might first be visible on a biochemical level before changes in clinical symptoms are measurable. Serum biomarkers can objectively measure early biochemical changes and assess whether RT leads to a more anabolic or catabolic response. The aim of this study is to assess (i) whether high-intensity RT elicits a different response (e.g. catabolic) on systemic inflammation and musculoskeletal tissues in and surrounding the joint, including bone, cartilage, muscle, and synovial tissue compared to low-intensity RT; and (ii) whether there is an association between changes in serum levels of inflammatory and musculoskeletal tissue-derived biomarkers and improvements in clinical outcomes (performance-based tests and self-reported outcomes on pain and activity limitations).Methods: In a randomized controlled trial, 177 participants with knee OA conducted a high-intensity (70%-80% of the Repetition Maximum (1RM)) or low-intensity (40%-50% 1RM) RT program 3 times a week for 12 weeks. Measures of clinical outcomes and serum samples were collected at the start of RT (pre-intervention), after 3 months at the end of RT (post-intervention), and 6 months after RT (follow-up). As a reflection of systemic inflammation (CRP), synovitis (CRPM, C3M), bone turnover (OC, CTX-I), cartilage turnover (PRO-C2, C2M, huARGS), muscle turnover (PRO-C3, PRO-C6), and cell behaviour (col10neo) a total of eleven serum biomarkers were analysed. With the exception of CRP, which was determined with an immunoturbidimetric assay, ELISA assays were used to quantify serum levels of the other 10 serum biomarkers. The primary outcome measures are the changes in serum biomarker levels. Other outcome measures include upper leg muscle strength, performance-based tests, and self-reported outcomes on pain and activity limitations.Results: High-intensity RT resulted in greater improvements in muscle strength compared to low-intensity RT when measured by the estimated 1RM. No significant differences between groups were found for upper leg muscle strength (Nm/kg) when measured with an isokinetic dynamometer. Both groups showed similar improvements in pain and physical functioning. Although there is no difference between groups in clinical outcomes, except for the estimated 1RM, we expect that participants in the high-intensity RT group are more likely to have enhanced serum levels of catabolic biomarkers than participants in the low-intensity RT group. Since both the high-intensity RT group and low-intensity RT group improved over time, we expect that changes in serum biomarker levels are associated with overall improvements in clinical outcomes. Almost all participants had normal CRP values (Conclusions: The work to date on CRP serum levels suggests that RT did not influence CRP levels. This result may be explained by the high percentage of participants with normal CRP levels (

Objective To design an automated workflow for hip radiographs focused on joint shape and tests its prognostic value for future hip osteoarthritis.Design We used baseline and eight-year follow-up data from 1002 participants of the CHECK-study. The primary outcome was definite radiographic hip osteoarthritis (rHOA) (Kellgren-Lawrence grade ≥2 or joint replacement) at eight-year follow-up. We designed a method to automatically segment the hip joint from radiographs. Subsequently, we applied machine learning algorithms (elastic net with automated parameter optimization) to provide the Shape-Score, a single value describing the risk for future rHOA based solely on joint shape. We built and internally validated prediction models using baseline demographics, physical examination, and radiologists scores and tested the added prognostic value of the Shape-Score using Area-Under-the-Curve (AUC). Missing data was imputed by multiple imputation by chained equations. Only hips with pain in the corresponding leg were included.Results 84% were female, mean age was 56 (±5.1) years, mean BMI 26.3 (±4.2). Of 1044 hips with pain at baseline and complete follow-up, 143 showed radiographic osteoarthritis and 42 were replaced. 91.5% of the hips had follow-up data available. The Shape-Score was a significant predictor of rHOA (odds ratio per decimal increase 5.21, 95%- CI (3.74 – 7.24)). The prediction model using demographics, physical examination, and radiologists scores demonstrated an AUC of 0.795, 95%-CI (0.757 – 0.834). After addition of the Shape-Score the AUC rose to 0.864, 95%-CI (0.833 – 0.895).Conclusions Our Shape-Score, automatically derived from radiographs using a novel machine learning workflow, may strongly improve risk prediction in hip osteoarthritis.

The blood metabolome incorporates cues from the environment as well as the host’s genetic background, potentially offering a holistic view of an individual’s health status. We have compiled a vast resource of 1H-NMR metabolomics and phenotypic data encompassing over 25,000 samples derived from 26 community and hospital-based cohorts. Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual’s biological age. Exploration in independent cohorts demonstrates that being judged older by one’s metabolome, as compared to one’s chronological age, confers an increased risk on future cardiovascular disease, mortality and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data. In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardio-metabolic health.

Background Assessment of disease activity is a critical component of tight-control, treat-to-target treatment strategies of rheumatoid arthritis (RA). Recently, the HandScan has been validated as a novel method for objectively assessing RA disease activity in only 1.5 min, using optical spectral transmission (OST) in hands and wrists. We describe the protocol of a randomized controlled clinical trial (RCT) to investigate whether HandScan-guided treatment aimed at ‘HandScan remission’ (HandScan arm) is at least as effective as and more cost-effective than clinically guided treatment aimed at ACR/EULAR 2011 Boolean remission (DAS arm). Methods/design The study is a multi-center, double-blind, non-inferiority RCT of 18 months duration. Patients ≥ 18 years with newly diagnosed, disease-modifying antirheumatic drug (DMARD)-naïve RA according to the ACR 2010 classification criteria, will be randomized to the DAS arm or the HandScan arm. The efficacy of the arms will be compared by evaluating Health Assessment Questionnaire (HAQ) scores (primary outcome) after 18 months of DMARD therapy, aimed at remission. The equivalence margin in HAQ scores between study arms is 0.2. Secondary outcomes are differences in cost-effectiveness and radiographic joint damage between treatment arms. The non-inferiority sample size calculation to obtain a power of 80% at a one-sided p value of 0.05, with 10% dropouts, resulted in 61 patients per arm. In both arms, DMARD strategy will be intensified monthly according to predefined steps until remission is achieved; in both arms DMARDs and treatment steps are identical. If sustained remission, defined as remission that persists consistently over three consecutive months, is achieved, DMARD therapy will be tapered. Discussion The study protocol and the specifically designed decision-making software application allow for implementation of this RCT. To test a novel method of assessing disease activity and comparing (cost-)effectiveness with the contemporary method in treat-to-target DMARD strategies in early RA patients. Trial registration Dutch Trial Register, NTR6388. Registered on 6 April 2017 (NL50026.041.14). Protocol version 3.0, 19-01-2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3285-8) contains supplementary material, which is available to authorized users.

ObjectiveTo determine whether optical spectral transmission (OST) can be used to assess synovitis in hand and wrist joints of patients with hand osteoarthritis (OA).DesignHand and wrist joints of 47 primary hand OA patients with at least one clinically inflamed hand or wrist joint were assessed for synovitis by OST and ultrasound (US). Associations between standardized OST and US synovitis were studied in linear mixed effects models, across all joint types together and individually for wrist, proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints, and were adjusted for OA features that showed associations with US synovitis. Diagnostic performance was determined using receiver operator characteristic (ROC) curves analysis, with US as reference standard.ResultsAltogether, 6.7% of joints showed US synovitis. Statistically significant associations between OST scores and US synovitis were found for all joints combined (Δ0.37SD, pConclusionsOST scores and US synovitis are statistically significantly associated, independent of osteophytes and dorsal vascularity. At this stage, OST performs fair in the assessment of synovitis in PIP joints of hand OA patients.

Objectives: There is sparse evidence for a relationship between cardiovascular disease (CVD) and osteoarthritis (OA). We investigated the association between incidence of arterial calcifications and incidence of radiographic knee and/or hip OA. Design: We used baseline and 8-year follow-up data of Cohort Hip and Cohort Knee (CHECK). Knees and hips were either Kellgren-Lawrence (KL) grade 0 or 1 at baseline. Arterial calcifications were scored on hip and knee radiographs using a four-grade scale. Scores were summed for patient-level analyses. To investigate incidence, participants with arterial calcifications at baseline or missing follow-up were excluded. Incident OA was defined per joint as KL ≥ 2 or prosthesis at year eight. The association between incidenct of arterial calcifications and incident OA was studied using mixed-effects logistic regression. Results: Of 763 participants included, 623 (82%) were women. Mean (sd) age was 56 (5.1) years, mean (sd) body mass index (BMI) 26.2 (4.1) kg/m2. Arterial calcifications developed in 174 participants (283 joints). OA developed in 456 participants (778 joints). Sex modified the association between arterial calcification and OA. In women, incident arterial calcification around a joint was positively associated with incident OA in that joint (adjusted OR 2.51 (95% CI 1.57-4.03)). In men, no association was observed on joint-level, but at patient-level the arterial calcification sum score was negatively associated with incident OA (adjusted OR per point increase 0.70 (95% CI 0.54-0.90)) indicating a systemic effect. Conclusions: We observed sex-dependent associations between incident arterial calcification and incident radiographic knee and/or hip OA, which differs between joint- and patient-level.

Objective: To assess the ability of radiography-based bone texture variables in proximal femur and acetabulum to predict incident radiographic hip osteoarthritis (rHOA) over a 10 years period. Design: Pelvic radiographs from CHECK at baseline (987 hips) were analyzed for bone texture using fractal signature analysis (FSA) in proximal femur and acetabulum. Elastic net (machine learning) was used to predict the incidence of rHOA (including Kellgren–Lawrence grade (KL) ≥ 2 or total hip replacement (THR)), joint space narrowing score (JSN, range 0–3), and osteophyte score (OST, range 0–3) after 10 years. Performance of prediction models was assessed using the area under the receiver operating characteristic curve (ROC AUC). Results: Of the 987 hips without rHOA at baseline, 435 (44%) had rHOA at 10-year follow-up. Of the 667 hips with JSN grade 0 at baseline, 471 (71%) had JSN grade ≥ 1 at 10-year follow-up. Of the 613 hips with OST grade 0 at baseline, 526 (86%) had OST grade ≥ 1 at 10-year follow-up. AUCs for the models including age, gender, and body mass index (BMI) to predict incident rHOA, JSN, and OST were 0.59, 0.54, and 0.51, respectively. The inclusion of bone texture variables in the models improved the prediction of incident rHOA (ROC AUC 0.68 and 0.71 when baseline KL was also included in the model) and JSN (ROC AUC 0.62), but not incident OST (ROC AUC 0.52). Conclusion: Bone texture analysis provides additional information for predicting incident rHOA or THR over 10 years.

Background Osteoarthritis (OA) is one of the leading causes of chronic pain worldwide. Yet, relatively little is known about the trajectories of pain in early knee and hip OA. Objectives To determine subgroups of patients with homogenous patterns of pain over 10 years follow-up, among patients with early hip and/or knee complaints in primary care. Methods Data from the CHECK cohort (Cohort Hip and Cohort Knee) were used. For this cohort, 1002 patients between 45 and 65 years at or within 6 months from their first consultation at a general practitioner for symptoms of their hips and/or knees, were included and followed for 10 years. A numeric rating scale (NRS) for perceived pain was obtained at baseline and after 2, 5, 8 and 10 years, or until total joint replacement. Using these longitudinal data, subgroups of patients with comparable trajectories over time were identified using Latent Class Growth Analysis (LCGA). Models with 3 to 6 classes when using linear, cubic and quadratic trajectories were evaluated using Mplus software. Results At baseline, the 998 subjects (79% women) with ≥2 NRS data points available had a mean age of 55.9±5.2 years and a mean BMI of 26.2±4.0 kg/m2. In total, 410 patients reported knee pain only (41%), 173 hip pain only (17%), and 415 reported both knee and hip pain (42%) at baseline. On a joint level, 156 knees and 160 hips had KL-grade ≥2 at baseline. The by LCGA derived models of 3 groups with a linear trajectory and of 6 groups with a cubic trajectory resulted in comparable goodness of fit indicators (Bayesian Information Criteria 17 991 vs. 17927, Akaike Information Criteria 17 927 vs. 17761, and entropy 0.694 vs. 0.683 for the 3 and 6 group models, respectively). Both models and the corresponding trajectories are presented in the figure 1. In the 3 group model, the ‘high pain trajectory’ (group 2, blue line, n=206) contained most patients with knee and hip complaints (53%), females (84%), TJR (21%), and the highest mean BMI (27.6±4.6). The ‘low pain trajectory’ (group 3, green line, n=441) contained most patients with only hip (19%) and only knee (48%) complaints, and the lowest mean BMI (25.3±3.6). In the 6 group model, the ‘always high pain trajectory’ (group 1, red line, n=176) contained most females (86%) and TJR (24%), and the highest mean BMI (27.7±4.7). The ‘always low pain trajectory’ (group 5, brown line, n=289) contained most patients with only knee complaints (51%) and the lowest mean BMI (25.0±3.4). The ‘decreasing pain trajectory’ (group 2, blue line, n=37) contained most patients with only hip complaints (22%). The ‘fluctuating high pain trajectories’ (groups 3 (n=88) and 4 (n=142), green and pink lines) contained most females (3:83% and 4:86%), and patients with knee and hip complaints (3:61% and 4:44%). Conclusions The 6 group model identified more extreme groups with lower minimal and higher maximal prevalence of the presented clinical characteristics. In the end, the conclusion drawn from the two models appear similar; Patients presenting with both knee and hip complaints had less favourable pain trajectories over the following 10 years and the number of total joint replacements was the highest in the groups always reporting high pain scores. Disclosure of Interest None declared

Background Osteoarthritis (OA) is the most prevalent joint disease and one of the leading causes of chronic pain and disability worldwide. Yet, relatively little is known about the early course of OA. Objectives To describe the clinical and radiological early course of hip and/or knee OA. Methods CHECK (Cohort Hip and Cohort Knee) is a multicenter, prospective observational cohort study of 1002 participants. Inclusion criteria were: 1) age 45–65 years at the time of inclusion, 2) pain in knee(s) and/or hip(s), 3) never or not longer than 6 months ago for the first time consulted a physician for these symptoms. Participants were included through general practitioners and advertisements. Visits took place at baseline, and at 2, 5, 8, and 10 year follow-up (T0, T2, T5, T8 and T10). At each visit, questionnaires, including joint pain presence (Numeric rating score, NRS), morning stiffness, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), were inquired, and physical examination, and x-ray imaging were performed. Clinical OA was defined by the clinical American College of Rheumatism (ACR) criteria. Radiographic OA (ROA) was defined as Kellgren and Lawrence score (K and L) of ≥2. Results 1002 participants (age 56±5 years (mean ±sd); 79% female; BMI 26±4 kg/m2) were included. 83% reported knee pain at baseline, 59% reported hip pain, and 42% reported both. 10 year follow-up data were complete for 85% of the participants. The total WOMAC score showed a median of 21 (range 0–80) at baseline and remained rather constant over time (T2=20 (0–83); T5=20 (0–86); T8=19 (0–88); T10=19 (0–81)). The same was observed for pain (NRS). At baseline, 520 participants fulfilled the clinical ACR criteria for knee and/or hip OA. Of these, only 91 (17.5%) participants subsequently fulfilled the ACR criteria at every follow-up visit. 138 participants did never fulfil the clinical ACR criteria for hip or knee OA. At baseline, 157 participants showed ROA in on or both knees and 161 participants showed ROA in on or both hips. After 10 years follow-up, 601 (60%) participants had ROA in one or both knees and 513 (51%) participants had hip ROA in one or both hips. Of those with hip OA in at least one hip, 256 (50%) had bilateral knee ROA at T10. Of the participants with knee OA in at least one knee, 256 (43%) had bilateral hip ROA at T10. Most joint replacements took place between 2 and 8 years follow-up (11 knees, 29 hips), predominantly in participants with multiple affected joints. Only 115 (13.5%) participants did not develop ROA of knee or hip. Conclusions Although mean pain scores remain fairly stable over time, individual scores tend to fluctuate over time. Therefore, only few participants constantly fulfil the clinical criteria for OA. More than half of the participants had ROA after 10 year follow-up and a large overlap of knee and hip ROA was observed. Numbers of joint replacements were highest in participants developing both hip and knee OA. Disclosure of Interest None declared

Objective: On a population level, the incidence of knee prostheses (KPs) has increased, but excess health care costs per patient, compared to matched controls without a KP, in the years surrounding these procedures and their determinants are largely unknown. We therefore aimed to provide estimates of age-and sex-specific incidence of KPs, revision KPs, and prosthesis complications in patients with knee osteoarthritis (OA) and to determine excess health care costs in the years surrounding surgery compared with matched controls. Methods: All KPs in OA patients in the Achmea Health Database were identified as well as up to four controls. Incidence rates of KPs, revisions, and complications from 2006 to 2013 were determined. Annual health care cost and excess costs (over matched controls) preceding, during, and after surgery were calculated and their determinants were evaluated. Results: The increased incidence of KPs, revisions, and complications was strongest in younger age categories and men. The average costs per patient were relatively stable between 2006 and 2012. KP patient's annual health care costs increased towards the year of surgery. After surgery, costs decreased, but remained higher as compared to costs prior to surgery. High post-surgery costs were mainly associated with subsequent revisions or additional KPs, but costs were also higher in females, lower age categories, and lower social economic status. Conclusion: These results underscore the increasing burden and medical need associated with end-stage OA, especially in younger age categories. Improvement of guidelines tailored to individual patient groups aimed at avoiding complications and revisions is required to counteract this increasing burden. (C) 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Background Among the currently available biochemical markers for osteoarthritis (OA), urinary collagen type II C-telopeptide (uCTX-II) is one of the most frequently investigated markers1. Much research has been performed into the performance of uCTX-II, but most of it in relatively small cohort studies1. Therefore, we performed a meta-analysis to summarize uCTX-II studies in a quantitative way. Objectives To perform a meta-analysis of the performance of uCTX-II as a biomarker for diagnosing knee osteoarthritis (KOA) and its association with radiographic KOA severity. Furthermore, to look for patient and study characteristics that determine uCTX-II performance. Methods Medline and Embase databases were searched for studies into uCTX-II levels in adult subjects with radiographic KOA according to the Kellgren and Lawrence (K&L) classification system. uCTX-II levels were compared between subjects with KOA K&L ≥2 versus healthy control subjects and between subjects with KOA K&L 2 versus K&L 3–4 (i.e. moderate vs severe KOA). Controls were either selected based on lack of knee symptoms, based on K&L score, or were randomly selected from the general population. Differences between KOA subgroups were expressed as standardized mean differences (SMD). Subgroup analyses were performed to compare uCTX-performance between genders, ethnicities, and large and small studies. Differences between subgroups were considered relevant when SMDs differed >25% between groups. Results 2035 Studies were screened for eligibility, of which ten studies were included. A moderate pooled SMD of 0.52 (confidence interval (CI): 0.40–0.65, P Conclusions This is the first meta-analysis of uCTX-II performance in subjects with radiographic KOA. It appeared that uCTX-II levels can distinguish with moderate strength between radiographic KOA subjects and controls. Moreover, uCTX-II levels are consistently increased in severe versus moderate radiographic KOA. Female gender and Caucasian ethnicity were found to enhance uCTX-II performance in distinguishing radiographic KOA from controls. Yet, the number of studies was relatively small and criteria for KOA and control subjects differed between studies. References Van Spil WE, DeGroot J, Lems WF, Oostveen JCM, Lafeber FPJG. Serum and urinary biochemical markers for knee and hip-osteoarthritis: A systematic review applying the consensus BIPED criteria. Osteoarthr Cartil 2010;18(5):605–12. Doi: 10.1016/j.joca.2010.01.012. Disclosure of Interest None declared

Background It is hypothesized that patients with knee osteoarthritis (OA) can be classified into different phenotypes. Knowledge of these phenotypes may contribute to developing effective targeted treatment strategies. Objectives To identify different longitudinal phenotypes of knee OA using biochemical markers and to compare these phenotypes with regard to radiographic joint space loss (JSL) and/or pain progression. Methods Baseline, 1-year, and 2-year biochemical marker data from the FNIH OA Biomarker Consortium were used. This consortium is a nested case-control study of 600 subjects with one symptomatic index knee showing radiographic OA changes of Kellgren and Lawrence grade 1 to 3 1 . Subjects were classified as either JSL progressors, pain progressors, JSL+pain progressors, or non-progressors according to predefined criteria (pain progression=persistent increase in WOMAC pain≥9 points (0–100 scale) from baseline to 2, 3 or 4 years, JSL progression=decrease in JSW≥0.7mm from baseline to 2, 3 or 4 years). Biochemical markers included in the current analysis were sCTX-I, uαCTX-I, uβCTX-I, sNTX-I, uCTX-II, sCPII, sC2C, sC1,2C, sColl2–1 NO2, sCOMP, sHA, and sMMP (u=urinary, s=serum). First, using principal component analysis (PCA), the individual markers were reduced into a number of clusters of markers (components) that may represent common underlying domains. Second, a hierarchical cluster analysis (HCA) was performed to differentiate between longitudinal courses (phenotypes) of these marker clusters. The optimum number was determined from the additive value of each newly identified phenotype as compared to already identified phenotypes. Third, these longitudinal phenotypes were compared with regard to percentages of patients in each of the JSL and/or pain progression categories. Results PCA showed an optimal solution of three components. Looking at the markers that loaded maximally onto each of the components, they were interpreted as cluster of bone (sCTX-I, uαCTX-I, uβCTX-I, sNTX-I, uCTX-II), cartilage (sCPII, sC2C, sC1,2C, sColl2–1 NO2), and synovial (sCOMP, sHA, and sMMP) metabolism, respectively. HCA revealed an optimum of seven longitudinal phenotypes. Based on the relative predominance of the component(s) throughout follow-up, phenotypes were named “high bone”, “high cartilage”, “high synovium”, “low cartilage”, “low synovium”, “low bone, cartilage and synovium” and “low bone and high synovium” phenotype, respectively (Figure 1, dendrogram and heatmap). Phenotypes differed with regard to percentages of patients in JSL and/or pain progression categories (Figure 1, pie charts) as well as other demographic, clinical, and radiographic parameters (data not shown). Conclusions Seven longitudinal phenotypes of knee OA could be identified based on biochemical markers representing bone, cartilage and synovial metabolism. These phenotypes showed relevant differences in other characteristics, such as JSL and/or pain progression. References Kraus VB, Collins JE, Hargrove D, et al. Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers Consortium. Ann Rheum Dis. 2016. Disclosure of Interest None declared

Background Opening-wedge high tibial osteotomy (HTO) is primarily indicated in treating varus gonarthrosis. The rationale behind HTO treatment of knee osteoarthritis (OA) is to unload the affected compartment, this is accomplished by correcting the angular deformity towards the unaffected compartment, i.e. shifting the hip-knee-ankle angle (HKA; mechanical axis) towards varus for a medial lesion. Knee joint distraction (KJD) is an alternative joint-sparing treatment for knee OA and has been demonstrated to decrease pain, improve function, and increase joint space width (JSW)1. Objectives To investigate the importance of axial alignment (and correction) in these two effective (joint-sparing) treatments of medial knee OA. Methods Patients with medial knee OA, a HKA less than 12° varus, normal knee stability, younger than 65 years, and a BMI less than 35 kg/m2 were randomized to HTO (n=46) or KJD (n=23). WOMAC and VAS pain were collected at baseline and after twelve months. To assess structural outcome, JSW was measured on knee radiographs, before and after both treatments. HTO patients had full leg standing anteroposterior radiographs taken before and after surgery, KJD patients only had these taken before surgery. Therefore, the femur-tibia angle (FTA; anatomical axis), acquired using Knee Image Data Analysis (KIDA), was investigated as an alternative for assessing axial alignment. Agreement between axial alignment as defined by HKA and by FTA appeared to be fair (ICC=-0.414). WOMAC and VAS Pain were then related to (changes in) axial alignment, Kellgren & Lawrence (K&L) grade, BMI, gender, pre-operative range of motion (ROM), and age as independent variables in linear regression models. Results Patient baseline characteristics were not statistically significantly different between patients treated with KJD or HTO (see table 1). WOMAC increased statistically significantly one year after either treatment (KJD:Δ21.05±19.93; HTO:Δ27.80±15.32; both p Conclusions Both KJD and HTO lead to a statistically significant clinical and structural benefit after one year. Nevertheless, the change in FTA was associated with WOMAC change after one year in the HTO group, but not in the KJD group. This indicates that axial alignment correction may not per se be necessary for clinical benefit. References van der Woude et al. Five-Year Follow-up of Knee Joint Distraction. 2016 Cartilage. Disclosure of Interest None declared

Background Knee osteoarthritis (OA) is a progressive joint disease generally associated with increasing pain. In severe symptomatic knee OA, knee prosthesis (KP) can improve health-related quality of life. In the Netherlands, the incidence of KPs and KP revisions has increased, but health care costs related to these procedures over time and their determinants are unknown. 1 Objectives To provide estimates of age and sex-specific incidence of KPs, revision KPs, and prosthesis complications in patients with knee OA. To determine average annual health care costs of patients undergoing KP compared with matched controls in the Netherlands, and to understand drivers of costs. Methods All KPs in knee OA patients in the Achmea Health Database were identified and matched by age, sex, and region to a maximum of four controls. Incidence rates of KPs, KP revisions, and their complications (/1000 persons) from 2006–2013 were determined. Annual health care cost and excess costs compared to matched controls, preceding, during and after surgery were calculated and associated factors evaluated using longitudinal regression analysis. Results The incidence of KPs, KP revisions, and complications increased between 2006 and 2013. This increase was strongest in younger age categories and in men (Table 1). Annual health care costs slightly increased up to the year of surgery, with highest costs in the year of surgery. Post-surgery costs remained slightly higher than pre-surgery costs. High post-surgery costs were mainly associated with subsequent KPs. Other factors associated with high excess costs were younger age, female gender, and complications. Conclusions These results underscore the increasing burden associated with severe knee OA, especially in younger age categories. Improved guidelines aimed at avoiding complications and revisions are required to counteract this trend. References Dutch Arthroplasty Register (LROI). Arthroplasty in the Picture, Annual Report of the Dutch Arthroplasty Register. 2014. Disclosure of Interest None declared

Summary 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.

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the ‘omics’ (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.

Background Knee joint distraction (KJD) is a surgical joint-preserving treatment in which the knee joint is temporarily distracted by an external frame. It is associated with joint tissue repair and clinical improvement. Initially, patients were submitted to an eight-week distraction period, and currently patients are submitted to a six-week distraction period. This study evaluates whether a shorter distraction period influences the outcome. Methods Both groups consisted of 20 patients. Clinical outcome was assessed by WOMAC questionnaires and VAS-pain. Cartilaginous tissue repair was assessed by radiographic joint space width (JSW) and MRI-observed cartilage thickness. Results Baseline data between both groups were comparable. Both groups showed an increase in total WOMAC score; 24 ± 4 in the six-week group and 32 ± 5 in the eight-week group (both p

Context: Molecules that are released into biological fluids during matrix metabolism of articular cartilage, subchondral bone, and synovial tissue could serve as biochemical markers of the process of osteoarthritis (OA). Unfortunately, actual breakthroughs in the biochemical OA marker field are limited so far. Objective: By reviewing the status of commercially available biochemical OA markers according to the "Burden of disease, Investigative, Prognostic, Efficacy of intervention, and Diagnostic" ("BIPED") classification, future use of this "BIPED" classification is encouraged and more efficient biochemical OA marker research stimulated. Data sources: Three electronic databases [PubMed, Scopus, EMBASE (1997-May 2009)] were searched for publications on blood and urinary biochemical markers in human primary knee and hip-OA. Study selection: Stepwise selection of original English publications describing human studies on blood or urinary biochemical markers in primary knee or hip-OA was performed. Selected articles were fully read to determine whether biochemical markers were investigated on performance within any of the "BIPED" categories. Eighty-four relevant publications were identified. Data extraction: Data from relevant publications were tabulated according to the "BIPED" classification. Individual analyses within a publication were summarized in general "BIPED" scores. Data synthesis: An uneven distribution of scores on biochemical marker performance and heterogeneity among the publications complicated direct comparison of individual biochemical markers. Comparison of categories of biochemical markers was therefore performed instead. In general, biochemical markers of cartilage degradation were investigated most extensively and performed well in comparison with other categories of biochemical markers. Biochemical markers of bone metabolism performed less adequately. Biochemical markers of synovial tissue metabolism were not investigated extensively, but performed quite well. Conclusions: Specific biochemical markers and categories of biochemical markers as well as their nature, origin and metabolism, need further investigation. International standardization of future investigations should be pursued to obtain more high-quality, homogenous data on the full spectrum of biochemical OA markers. © 2010 Osteoarthritis Research Society International.

Objective: First, to study how markers of matrix metabolism, inflammation markers, and adipokines relate to (superior) cam deformity and (possible) cam impingement of the hip. Second, to investigate whether they can identify subjects with cam deformity that are at risk of future hip osteoarthritis (OA). Method: In a cohort of 1002 subjects (CHECK), (superior) cam deformity was defined by an alpha angle > 60 degrees on anteroposterior pelvic radiographs and (possible) cam impingement by a cam deformity together with internal hip rotation = 2 or total hip replacement. Results: Subjects with (superior) cam deformity and (possible) cam impingement showed lower levels of bone turnover markers (uCTX-I, uNTX-I, sPINP, sOC) than those without. Cam deformity was positively associated with future hip OA, but associations were weaker at high levels of bone turnover. sCOMP and sHA levels were higher in subjects with cam deformity, while other cartilage and synovium markers were not. Some markers of inflammation (pLeptin, pAdiponectin, and erythrocyte sedimentation rate) were lower in presence of cam deformity and cam impingement, but high-sensitivity C-reactive protein was not. Most associations depended largely on gender differences. Conclusion: Bone metabolism may be relevant in the pathogenesis of (superior) cam deformity and in the development of (superior) cam deformity into hip OA. Subjects with cam deformity and cam impingement surprisingly showed lower levels of inflammation markers and adipokines. Associations of cartilage turnover markers with cam deformity and cam impingement were less obvious. 2015 Osteoarthritis Research Society International. (C) Published by Elsevier Ltd. All rights reserved.

Objective: To relate systemic biochemical markers of joint metabolism to presence, incidence, and progression of early-stage radiographic knee and/or hip osteoarthritis (OA). Method: The cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, and synovial markers sHA and sPIIINP were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of CHECK (Cohort Hip and Cohort Knee), a cohort study of early-stage symptomatic knee and/or hip OA. Knee and hip radiographs were obtained at baseline and 5-year follow-up. Presence of OA at baseline was defined as Kellgren and Lawrence (K&L) = 1 (maximum observed). Incidence of OA was defined as K&L = 0 at baseline and K&L = 1 at 5-year follow-up. Progression of OA was defined as K&L = 1 at baseline and K&L >= 2 at 5-year follow-up. Results: Data were available for 801 subjects at baseline and for 723 subjects at both baseline and 5-year follow-up. Multiple cartilage and synovial markers showed positive associations with presence and progression of knee and hip OA and with incidence of hip OA, except for negative associations of uCTX-II and sCOMP with incidence of knee OA. uCTX-II and sCOMP showed multiple interactions with other biomarkers in their associations with knee and hip OA. Bone markers were positively associated with presence of radiographic knee OA, but negatively associated with progression of radiographic hip OA. Conclusion: Especially metabolism in cartilage and synovial matrix appear to be of relevance in knee and hip OA. The role of bone metabolism appears to differ between knee and hip OA. (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

The urinary level of the carboxy-terminal telopeptide of collagen type II (uCTX-II) currently is one of the most frequently used biochemical markers for assessing collagenolysis in articular cartilage during osteoarthritis. However, we published data suggesting release of CTX-II epitope from bone in Cohort Hip and Cohort Knee (CHECK), a large cohort of subjects with very early stage knee and/or hip osteoarthritis. As was observed for markers of bone metabolism, uCTX-II showed an abrupt increase in women aged 48–53 years that appeared to be attributable to menopause.1 Moreover, earlier work had already shown that uCTX-II has specifically strong associations with marker of bone metabolism as compared …

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the ‘omics’ (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

Objective: Soluble mediators in synovial fluid (SF) are acknowledged as key players in the pathophysiology of osteoarthritis (OA). However, a wide-spectrum screening of such mediators in SF is currently lacking. In this study, the levels of 47 mediators in the SF of control donors and osteoarthritic (OA) patients were compared. Materials & Methods: SF was collected from control donors (n=16) and end-stage knee OA patients (n=18) and analysed for 47 cytokines, chemokines and growth factors using several multiplex enzyme-linked immunosorbent assays (ELISAs). A Mann-Whitney U test was used to determine differences between OA and control controls. A principal component analysis (PCA) was performed to cluster the 47 mediators. Results: The majority of the mediators could be detected in both control and OA SF. Interleukin (IL)-6, interferon inducible protein (IP)-10, macrophage derived chemokine (MDC), platelet derived growth factor (PDGF)-AA and regulated on activation normal T cell expressed and secreted (RANTES) levels were found to be higher in OA compared to control SF (P

SummaryIn 2010, in Osteoarthritis and Cartilage, we published a comprehensive systematic review applying the consensus BIPED criteria (Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic) criteria on serum and urinary biochemical markers for knee and hip osteoarthritis (OA) using publications that were available at that time. It appeared that none of the biochemical markers at that time were sufficiently discriminating to allow diagnosis and prognosis of OA in individual or limited numbers of patients, nor performed so consistently that they could function as primary outcome parameters in clinical trials. Also at present, almost 3 years later, this ultimate goal has not been reached (yet). Frankly, it might be questioned whether we are making the most adequate steps ahead and maybe we have to take a step back to reconsider our approaches.Some reflections are made and discussed: A critical review of molecular metabolism in OA and validation of currently investigated marker molecules in this may be vital and may lead to new and better markers. Creating cohorts in which synovial fluid (SF) is obtained in a systematic way, together with serum and urine, may also bring the field a further step ahead. Thirdly, better understanding of different phenotypes (subtypes) of OA may facilitate identification and validation of biochemical markers. Finally, the systems biology approach as discussed in the last years OA in review on biomarkers, although very complex, might provide steps forward.Looking ahead, we are optimistic but realistic in our expectations, we believe that the field can be brought forward by critically and cautiously reconsidering our approaches, and making changes forward, one step at a time.

Summary Objective To investigate cross-sectional and predictive associations of plasma adipokines with biochemical markers of systemic joint metabolism and radiographic signs of early-stage knee osteoarthritis (OA). Design The adipokines pLeptin, pAdiponectin, and pResistin, the cartilage markers C-terminal telopeptide of type II collagen (uCTX-II), N-terminal propeptide of type IIA procollagen (sPIIANP), chondroitin sulfate 846 (sCS846), and cartilage oligomeric matrix protein (sCOMP), and the synovial markers hyaluronic acid (sHA) and N-terminal propeptide of type III procollagen (sPIIINP) were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of Cohort Hip and Cohort Knee (CHECK), a cohort of 1002 subjects with early-stage symptomatic knee and/or hip OA. Knee radiographs were obtained at baseline and after 2 and 5 years and scored according to Kellgren & Lawrence. Results pLeptin showed positive associations with uCTX-II, sCOMP, sPIIANP, sHA, and sPIIINP, and with presence and progression of radiographic knee OA. Associations expectedly disappeared after adjustment for body mass index. pResistin showed positive associations with sPIIINP and present and incident radiographic knee OA that were largely independent of BMI. pAdiponectin showed positive associations with uCTX-II and sCOMP. Furthermore, pAdiponectin did not show associations with radiographic knee OA on itself, but associations of pResistin with present radiographic knee OA were stronger in higher pAdiponectin tertiles ( P = 0.024 for interaction between pAdiponectin and pResistin). Although statistically significant, all associations were weak. Conclusions Adipokines may have aggravating, although may be minor, structural effects in early-stage knee OA.

SummaryObjectiveAdipose tissue is an endocrine tissue releasing adipokines suggested to be involved in the pathogenesis of osteoarthritis (OA). Nevertheless, their relative contribution and exact mechanisms are still ambiguous. The aim of this study is to compare serum adipokine levels between end-stage knee OA patients and controls and to relate these serum levels to local parameters of cartilage damage and synovial inflammation.MethodsSerum was collected from 172 severe knee OA patients, shortly before total knee replacement (TKR) surgery and from 132 controls without radiographic knee OA [Kellgren & Lawrence (K&L) = 0]. Serum adiponectin, leptin, and resistin levels were measured by enzyme-linked immunosorbent assay (ELISA). Cartilage and synovial tissue were collected at TKR surgery and assessed for cartilage degeneration and synovial inflammation by histochemistry and biochemical analyses.ResultsThe adipokine levels were all distinctly higher in OA patients as compared to controls. Especially adiponectin and leptin were associated with female gender (stand beta = 0.239 and 0.467, respectively, P