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Objective: Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy than is currently available; this could accelerate and facilitate OA drug discovery and development programs. The goal of this document is to provide a summary and guide to the application of in vitro (biochemical and other soluble) biomarkers in the development of drugs for OA and to outline and stimulate a research agenda that will further this goal. Methods: The Biomarkers Working Group representing experts in the field of OA biomarker research from both academia and industry developed this consensus document between 2007 and 2009 at the behest of the Osteoarthritis Research Society International Federal Drug Administration initiative (OARSI FDA initiative). Results: This document summarizes definitions and classification systems for biomarkers, the current outcome measures used in OA clinical trials, applications and potential utility of biomarkers for development of OA therapeutics, the current state of qualification of OA-related biomarkers, pathways for biomarker qualification, critical needs to advance the use of biomarkers for drug development, recommendations regarding practices and clinical trials, and a research agenda to advance the science of OA-related biomarkers. Conclusions: Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. The biomarkers that are likely to have the earliest beneficial impact on clinical trials fall into two general categories, those that will allow targeting of subjects most likely to either respond and/or progress (prognostic value) within a reasonable and manageable time frame for a clinical study (for instance within 1-2 years for an OA trial), and those that provide early feedback for preclinical decision-making and for trial organizers that a drug is having the desired biochemical

Introduction: At present, no disease-modifying osteoarthritis drugs (DMOADS) are approved by the FDA (US Food and Drug Administration); possibly partly due to inadequate trial design since efficacy demonstration requires disease progression in the placebo group. We investigated whether combinations of biochemical and magnetic resonance imaging (MRI)-based markers provided effective diagnostic and prognostic tools for identifying subjects with high risk of progression. Specifically, we investigated aggregate cartilage longevity markers combining markers of breakdown, quantity, and quality. Methods: The study included healthy individuals and subjects with radiographic osteoarthritis. In total, 159 subjects (48% female, age 56.0 ± 15.9 years, body mass index 26.1 ± 4.2 kg/m2) were recruited. At baseline and after 21 months, biochemical (urinary collagen type II C-telopeptide fragment, CTX-II) and MRI-based markers were quantified. MRI markers included cartilage volume, thickness, area, roughness, homogeneity, and curvature in the medial tibio-femoral compartment. Joint space width was measured from radiographs and at 21 months to assess progression of joint damage. Results: Cartilage roughness had the highest diagnostic accuracy quantified as the area under the receiver-operator characteristics curve (AUC) of 0.80 (95% confidence interval: 0.69 to 0.91) among the individual markers (higher than all others, P < 0.05) to distinguish subjects with radiographic osteoarthritis from healthy controls. Diagnostically, cartilage longevity scored AUC 0.84 (0.77 to 0.92, higher than roughness: P = 0.03). For prediction of longitudinal radiographic progression based on baseline marker values, the individual prognostic marker with highest AUC was homogeneity at 0.71 (0.56 to 0.81). Prognostically, cartilage longevity scored AUC 0.77 (0.62 to 0.90, borderline higher than homogeneity: P = 0.12). When comparing patients in the highest quartile for the longevity score to lowest quartil, Mediamatics, Electrical Engineering, Mathematics and Computer Science

Introduction: At present, no disease-modifying osteoarthritis drugs (DMOADS) are approved by the FDA (US Food and Drug Administration); possibly partly due to inadequate trial design since efficacy demonstration requires disease progression in the placebo group. We investigated whether combinations of biochemical and magnetic resonance imaging (MRI)-based markers provided effective diagnostic and prognostic tools for identifying subjects with high risk of progression. Specifically, we investigated aggregate cartilage longevity markers combining markers of breakdown, quantity, and quality. Methods: The study included healthy individuals and subjects with radiographic osteoarthritis. In total, 159 subjects (48% female, age 56.0 ± 15.9 years, body mass index 26.1 ± 4.2 kg/m2) were recruited. At baseline and after 21 months, biochemical (urinary collagen type II C-telopeptide fragment, CTX-II) and MRI-based markers were quantified. MRI markers included cartilage volume, thickness, area, roughness, homogeneity, and curvature in the medial tibio-femoral compartment. Joint space width was measured from radiographs and at 21 months to assess progression of joint damage. Results: Cartilage roughness had the highest diagnostic accuracy quantified as the area under the receiver-operator characteristics curve (AUC) of 0.80 (95% confidence interval: 0.69 to 0.91) among the individual markers (higher than all others, P < 0.05) to distinguish subjects with radiographic osteoarthritis from healthy controls. Diagnostically, cartilage longevity scored AUC 0.84 (0.77 to 0.92, higher than roughness: P = 0.03). For prediction of longitudinal radiographic progression based on baseline marker values, the individual prognostic marker with highest AUC was homogeneity at 0.71 (0.56 to 0.81). Prognostically, cartilage longevity scored AUC 0.77 (0.62 to 0.90, borderline higher than homogeneity: P = 0.12). When comparing patients in the highest quartile for the longevity score to lowest quartil, Mediamatics, Electrical Engineering, Mathematics and Computer Science

OBJECTIVE: At OMERACT 8 a framework for levels of evidence was proposed for the validation of biomarkers as surrogate outcome measures. We aimed to adapt this scheme in order to apply it in the setting of soluble biomarkers proposed to replace the measurement of damage endpoints in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We also aimed to generate consensus on minimum standards for the design of longitudinal studies aimed at validating biomarkers. METHODS: Before the meeting, the Soluble Biomarker Working Group prepared a preliminary framework and discussed various models for association and prediction related to the statistical strength domain. In addition, 3 Delphi exercises addressing longitudinal study design for RA, PsA, and AS were conducted within the working group and members of the Assessments in SpondyloArthritis International Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). This formed the basis for discussions among OMERACT 9 participants. RESULTS: The proposed framework was accepted by consensus. In the study design domain a requirement for both prospective observational studies and randomized controlled trials (RCT) in different drug classes was noted. A template for determining the level of statistical strength was proposed. The addition of a new domain on biomarker assay performance was considered essential, and participants suggested that for any biomarker this domain should be addressed first, i.e., before starting clinical validation studies. Participants agreed on most elements of a longitudinal study design template. Where consensus was lacking the working group has drafted solutions that constitute a basis for prospective validation studies. CONCLUSION: The OMERACT 9 Soluble Biomarker Group has successfully formulated a levels of evidence scheme and a study design template that will provide guidance to conduct validation studies in the setting o

OBJECTIVE: At OMERACT 8 a framework for levels of evidence was proposed for the validation of biomarkers as surrogate outcome measures. We aimed to adapt this scheme in order to apply it in the setting of soluble biomarkers proposed to replace the measurement of damage endpoints in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We also aimed to generate consensus on minimum standards for the design of longitudinal studies aimed at validating biomarkers. METHODS: Before the meeting, the Soluble Biomarker Working Group prepared a preliminary framework and discussed various models for association and prediction related to the statistical strength domain. In addition, 3 Delphi exercises addressing longitudinal study design for RA, PsA, and AS were conducted within the working group and members of the Assessments in SpondyloArthritis International Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). This formed the basis for discussions among OMERACT 9 participants. RESULTS: The proposed framework was accepted by consensus. In the study design domain a requirement for both prospective observational studies and randomized controlled trials (RCT) in different drug classes was noted. A template for determining the level of statistical strength was proposed. The addition of a new domain on biomarker assay performance was considered essential, and participants suggested that for any biomarker this domain should be addressed first, i.e., before starting clinical validation studies. Participants agreed on most elements of a longitudinal study design template. Where consensus was lacking the working group has drafted solutions that constitute a basis for prospective validation studies. CONCLUSION: The OMERACT 9 Soluble Biomarker Group has successfully formulated a levels of evidence scheme and a study design template that will provide guidance to conduct validation studies in the setting o

SUMMARY: In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. BMD increased significantly. Bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges. INTRODUCTION: After completion of the core study, two consecutive, 2-year, open-label extensions investigated the efficacy and safety of zoledronic acid 4 mg over 5 years in postmenopausal osteoporosis. METHODS: In the core study, patients received 1 to 4 mg zoledronic acid or placebo. In the first extension, most patients received 4 mg per year and then patients entered the second extension and received 4 mg per year or calcium only. Patients were divided into three subgroups according to years of active treatment received (2, 3 or 5 years). Changes in BMD and bone turnover markers (bone ALP and CTX-I) were assessed. RESULTS: All subgroups showed substantial increases in BMD and decreases in bone markers. By the end of the core study, 37.5% of patients revealed a suboptimal reduction (< 30%) of bone ALP levels. After subsequent study drug administration during the extensions, there was no evidence of progressive reduction of bone turnover markers. Furthermore, increased marker levels after treatment discontinuation demonstrates preservation of bone remodelling capacity. CONCLUSIONS: This study showed that zoledronic acid 4 mg once-yearly was well tolerated and effective in reducing biomarkers over 5 years. Detailed analysis of bone marker changes, however, suggests that this drug regimen causes insufficient reduction of remodelling activity in one third of patients.

Objective: To assess the relationship of biochemical markers and radiographic signs of osteoarthritis (ROA) in the subjects with symptomatic osteoarthritis (OA) at multiple sites of the Genetics osteoARthritis and Progression (GARP) study. Methods: We have measured eight biochemical markers, representing tissue turnover of cartilage, bone, synovium, and inflammation. ROA was assessed in the knees, hips, hands, vertebral facet joints and spinal disc degeneration (DD) by using the Kellgren score. A proportionate score was subsequently made for each joint location based on the number of joints with ROA. Principal component and linear mixed model analyses were applied to analyze the data. Results: Three different clusters of markers were identified that may reflect different pathophysiological processes of OA. The first component appeared to be reflected by structural markers of cartilage and bone turnover and associated especially in subjects with hip ROA. The second component was reflected by a marker of inflammation and was associated with knee ROA, high Western Ontario and McMaster Universities (WOMAC) scores and body mass index (BMI). The third component included markers of cartilage turnover and was associated with ROA at hands, spine as well as age. High familial aggregation was observed for serum cartilage oligomeric matrix protein (S-COMP) (70%) and serum N-propeptide of collagen type IIA (S-PIIANP) (62%). Conclusion: Using a large well-characterized study and eight biochemical markers, we were able to observe three components that may reflect different molecular mechanisms (bone, cartilage, synovium turnover and inflammation). Our data suggested that these components contribute differently to ROA at different joint sites. © 2006 Osteoarthritis Research Society International.

Measurement of microstructural parameters of trabecular bone noninvasively in vivo is possible with high-resolution magnetic resonance (MR) imaging. These measurements may prove useful in the determination of bone strength and fracture risk, but must be related to other measures of bone properties. In this study in vivo MR imaging was used to derive trabecular bone structure measures and combined with micro-finite element analysis (microFE) to determine the effects of trabecular bone microarchitecture on bone mechanical properties in the distal radius. The subjects were studied in two groups: (I) postmenopausal women with normal bone mineral density (BMD) (n = 22, mean age 58 +/- 7 years) and (II) postmenopausal women with spine or femur BMD -1 SD to -2.5 SD below young normal (n = 37, mean age 62 +/- 11 years). MR images of the distal radius were obtained at 1.5 T, and measures such as apparent trabecular bone volume fraction (App BV/TV), spacing, number and thickness (App TbSp, TbN, TbTh) were derived in regions of interest extending from the joint line to the radial shaft. The high-resolution images were also used in a micro-finite element model to derive the directional Young's moduli (E1, E2 and E3), shear moduli (G12, G23 and G13) and anisotropy ratios such as E1/E3. BMD at the distal radius, lumbar spine and hip were assessed using dual-energy X-ray absorptiometry (DXA). Bone formation was assessed by serum osteocalcin and bone resorption by serum type I collagen C-terminal telopeptide breakdown products (serum CTX) and urinary CTX biochemical markers. The trabecular architecture displayed considerable anisotropy. Measures of BMD such as the ultradistal radial BMD were lower in the osteopenic group (p

Measurement of microstructural parameters of trabecular bone noninvasively in vivo is possible with high-resolution magnetic resonance (MR) imaging. These measurements may prove useful in the determination of bone strength and fracture risk, but must be related to other measures of bone properties. In this study in vivo MR imaging was used to derive trabecular bone structure measures and combined with micro-finite element analysis (microFE) to determine the effects of trabecular bone microarchitecture on bone mechanical properties in the distal radius. The subjects were studied in two groups: (I) postmenopausal women with normal bone mineral density (BMD) (n = 22, mean age 58 +/- 7 years) and (II) postmenopausal women with spine or femur BMD -1 SD to -2.5 SD below young normal (n = 37, mean age 62 +/- 11 years). MR images of the distal radius were obtained at 1.5 T, and measures such as apparent trabecular bone volume fraction (App BV/TV), spacing, number and thickness (App TbSp, TbN, TbTh) were derived in regions of interest extending from the joint line to the radial shaft. The high-resolution images were also used in a micro-finite element model to derive the directional Young's moduli (E1, E2 and E3), shear moduli (G12, G23 and G13) and anisotropy ratios such as E1/E3. BMD at the distal radius, lumbar spine and hip were assessed using dual-energy X-ray absorptiometry (DXA). Bone formation was assessed by serum osteocalcin and bone resorption by serum type I collagen C-terminal telopeptide breakdown products (serum CTX) and urinary CTX biochemical markers. The trabecular architecture displayed considerable anisotropy. Measures of BMD such as the ultradistal radial BMD were lower in the osteopenic group (p