Value of biomarkers in osteoarthritis: Current status and perspectives

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

Associations of markers of matrix metabolism, inflammation markers, and adipokines with superior cam deformity of the hip and their relation with future hip osteoarthritis

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° on anteroposterior pelvic radiographs and (possible) cam impingement by a cam deformity together with internal hip rotation ≤20°. Hip OA at 5-year follow-up was defined by Kellgren and Lawrence grade ≥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

Osteoarthritis Year in Review 2016 : biomarkers (biochemical markers)

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

Osteoarthritis Year in Review 2016 : biomarkers (biochemical markers)

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

A sex-specific association between incident radiographic osteoarthritis of hip or knee and incident peripheral arterial calcifications : 8-year prospective data from Cohort Hip and Cohort Knee (CHECK)

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

A sex-specific association between incident radiographic osteoarthritis of hip or knee and incident peripheral arterial calcifications : 8-year prospective data from Cohort Hip and Cohort Knee (CHECK)

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

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