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Abstract and Introduction
Abstract
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.
Introduction
Osteoarthritis manifests as alteration of the whole joint structure, including progressive degradation of cartilage, menisci and ligaments, synovial inflammation and changes to the subchondral bone. The diagnosis of osteoarthritis is currently based on radiographic criteria (eg, joint space width) and clinical symptoms (eg, pain and loss of function). The evaluation of new disease-modifying osteoarthritis drugs (DMOADs) is performed on the same basis, since the regulatory bodies currently require evidence for an impact on radiographic joint space narrowing (JSN) and an impact on symptoms. However, the limitations of radiography (eg, technical issues, precision and sensitivity) have led to research into alternative parameters for monitoring osteoarthritis that could serve as biomarkers in drug development. The National Institutes of Health (NIH) defines a biomarker as 'a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.'
Imaging markers, from magnetic resonance and ultrasound, may be useful biomarkers in the evaluation of osteoarthritis and in drug development in the field. A promising outcome is the use of quantitative MRI to assess changes in cartilage volume or thickness. However, widespread use of MRI is limited by cost, availability and the absence of a validated international score. These imaging markers are beyond the scope of this review and the use of MRI is covered in a separate European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).
Another attractive alternative is the measurement of biochemical markers in blood, urine or synovial fluid samples, which could reflect dynamic and quantitative changes in joint remodelling and therefore disease progression. In the setting of osteoarthritis, a biochemical marker could be either an effector molecule (ie, an operator of joint damage), the result of joint damage, or both, as in the case of cartilage extracellular matrix fragments, such an hyaluronan, that serve as both biomarkers and stimuli of the innate immune chronic wound healing response in the osteoarthritic joint. Such biomarkers may be useful in early phase evaluation of the efficacy and safety of DMOADs and may also find applications in the diagnosis of disease, the assessment of severity and the risk of progression and the monitoring of health status in the general population. Insofar as current diagnostic methods in osteoarthritis combine radiographic and clinical signs, the disease is definitively diagnosed only when destruction of joint tissue is irreversible. Hence, an important characteristic of a new biochemical marker should also be that it can detect early osteoarthritis. Candidate biomarkers in osteoarthritis should also have proven validity, reproducibility and predictive value, and there should be ample information on how they relate to processes in the joint and clinical endpoints (such as structural damage, pain or dysfunction and/or joint replacement). Despite much active research into biomarkers in osteoarthritis, no single biomarker stands out as the gold standard or is sufficiently well validated and recognised for systematic use in drug development. In the light of this situation, the ESCEO convened a working meeting in October 2012 with a group of experts in the field to discuss the value of biomarkers in drug development in osteoarthritis, with a focus on the potential avenues for future research. This article is a summary of these discussions, and the manuscript was revised by the participants of the meeting, as well as additional invited authors, who provided further substantial input.
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