W.E. van Spil

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.

Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage

OBJECTIVE Adipose 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. METHODS Serum 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. RESULTS The 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 < 0.001) and body mass index (BMI) (stand beta = -0.189 and 0.396, respectively, P < 0.001). No associations between serum levels of adipokines and cartilage damage (histochemistry, proteoglycan content) were found whereas weak but positive associations with synovial inflammation were found [adiponectin and interleukin-1β (IL-1β), stand beta = 0.172, P = 0.02; resistin and histology, stand beta = 0.183, P = 0.034, adjusted for demographics]. CONCLUSION This study suggests an important involvement of adipokines in OA patients considering their high serum levels compared to controls. Associations of systemic adipokines with local synovial tissue inflammation were found, although not represented by similar relations with cartilage damage, suggesting that adipokines are of relevance in the inflammatory component of OA.

Associations of CTX-II with biochemical markers of bone turnover raise questions on its tissue origin: data from CHECK, a cohort study of early osteoarthritis

Objective CTX-II (C-terminal telopeptide of type II collagen) has been put forward as a marker of collagen type II degradation being part of osteoarthritis. In this study, the authors describe similarities between CTX-II and bone markers arguing against CTX-II as a marker of (solely) cartilage degradation. Methods uCTX-II, the bone markers uCTX-I, uNTX-I, sPINP, and sOC (C-terminal and N-terminal telopeptides of collagen I, aminoterminal propeptide of type I procollagen, and osteocalcin, respectively), and other (candidate) cartilage markers sCOMP, sCS846, and sPIIANP (cartilage oligomeric matrix protein, chondroitin sulphate 846 and type IIA collagen N-propeptide, respectively) were assessed by ELISA in CHECK (Cohort Hip and Cohort Knee), a cohort of 1002 individuals with early pain and/or stiffness in knee and/or hip. Results uCTX-II was more strongly associated with the bone markers than with the other cartilage markers, while the other cartilage markers were not so strongly associated with the bone markers. Moreover, both uCTX-II and bone markers but not the other cartilage markers showed an abrupt menopausal shift in women aged 48-53 years, also when adjusted for age and BMI. Conclusion The similarities between uCTX-II and bone markers could be attributable to a link between cartilage and bone metabolism through metabolic and biomechanical mechanisms. However, other cartilage markers were hardly associated with uCTX-II and did not show such evident associations with bone markers. uCTX-II has unique relations with bone markers as compared to other cartilage markers and might reflect bone rather than cartilage metabolism. More thorough molecular validation of uCTX-II is required.

Osteoarthritis year 2013 in review: biomarkers; reflecting before moving forward, one step at a time

In 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.

The ability of systemic biochemical markers to reflect presence, incidence, and progression of early-stage radiographic knee and hip osteoarthritis: data from CHECK

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.

Systemic biochemical markers of joint metabolism and inflammation in relation to radiographic parameters and pain of the knee: data from CHECK, a cohort of early-osteoarthritis subjects

OBJECTIVE To investigate associations of biochemical markers of joint metabolism and inflammation with minimum joint space width (JSW) and osteophyte area (OP area) of knees showing no or doubtful radiographic osteoarthritis (OA) and to investigate whether these differed between painful and non-painful knees. DESIGN Serum (s-) and urinary (u-) levels of the cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, synovial markers sPIIINP and sHA, and inflammation markers hsCRP and erythrocyte sedimentation rate (ESR) were assessed in subjects from CHECK (Cohort Hip and Cohort Knee) demonstrating Kellgren and Lawrence grade ≤1 OA on knee radiographs. Minimum JSW and OP area of these knees were quantified in detail using Knee Images Digital Analysis (KIDA). RESULTS uCTX-II levels showed negative associations with minimum JSW and positive associations with OP area. sCOMP and sHA levels showed positive associations with OP area, but not with minimum JSW. uCTX-I and uNTX-I levels showed negative associations with minimum JSW and OP area. Associations of biochemical marker levels with minimum JSW were similar between painful and non-painful knees, associations of uCTX-II, sCOMP, and sHA with OP area were only observed in painful knees. CONCLUSIONS In these subjects with no or doubtful radiographic knee OA, uCTX-II might not only reflect articular cartilage degradation but also endochondral ossification in osteophytes. Furthermore, sCOMP and sHA relate to osteophytes, maybe because synovitis drives osteophyte development. High bone turnover may aggravate articular cartilage loss. Metabolic activity in osteophytes and synovial tissue, but not in articular cartilage may be related to knee pain.

Associations of CTX-II with biochemical markers of bone turnover raise questions about its tissue origin: new insights from CHECK

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 …

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.

Disease burden of knee osteoarthritis patients with a joint replacement compared to matched controls: a population-based analysis of a Dutch medical claims database

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 patients 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.

SAT0536 Axial alignment of the knee – importance in cartilage repair? high tibial osteotomy vs. distraction

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<0.001). Likewise, VAS pain decreased (KJD:Δ-23.89±29.67,p=0.001; HTO:Δ-35.42±24.06,p<0.001). KJD led to a statistically significant increase in mean JSW (Δ0.50±0.88mm,p=0.014), and both treatments led to a statistically significant increase in medial (KJD:Δ0.81±1.16mm,p=0.004; HTO:Δ0.47±0.69mm,p<0.000) as well as minimal JSW (KJD:Δ0.85±0.96mm,p<0.000; HTO:Δ0.35±0.51mm,p<0.000) after one year. The FTA changed significantly in the HTO group after one year (Δ0.73o,p=0.005), while the KJD group showed a trend (Δ0.77o,p=0.105). In the KJD group, changes in clinical outcomes were not associated with pre-operative HKA, changes in FTA, K&L grade, BMI, gender, pre-operative ROM, or age. In contrast, in the HTO group a significant association was demonstrated for a change in WOMAC with a change in FTA (std.β=-0.341) and for a change in VAS Pain with baseline age (std.β=-0.323), as seen in table 2. 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