A randomised, double-blind, controlled trial comparing two intra-articular hyaluronic acid preparations differing by their molecular weight in symptomatic knee osteoarthritis

Objectives: To compare the effects of an intermediate molecular weight (MW) intra-articular hyaluronic acid (HA) with a low MW product on knee osteoarthritis (OA) symptoms. Methods: Patients with symptomatic knee OA were enrolled inarandomised, controlled, double-blind, parallel-group, non-inferiority trial with the possibility to shift to superiority. Patients were randomised to GO-ON(MW 800–1500 kD, 25 mg/2.5 ml) or Hyalgan(MW 500–730 kD, 20 mg/2 ml) injected at 3-weekly intervals. The primary outcome was 6-month change in the WOMAC pain subscale (0–100 mm). Sample size was calculated on a non-inferiority margin of 9 mm, lower than the minimum perceptible clinical improvement. Secondary endpoints included OARSI-OMERACT responder rates Results: The intention-to-treat (ITT) and per-protocol (PP) populations consisted of 217 and 209 patients and 171 and 172 patients in the GO-ON and Hyalgan groups, respectively. ITT WOMAC pain of 47.5±1.0(SE) and 48.8±1.0 mm decreased by 22.9±1.4 mm with GO-ON and 18.4±1.5 mm with Hyalgan after 6 months. The primary analysis was conducted in the PP population followed by the ITT population.Mean (95% CI) differences in WOMAC pain change were 5.2 (0.9 to 9.6)mm and 4.5 (0.5 to 8.5)mm, respectively,favouring GO-ON, satisfying the claim for non-inferiority (lower limit>−9 mm) and for statistical superiority (95% CI all>0, p=0.021). Ahigher proportion of OARSI/OMERACT responders was observed with GO-ONthan with Hyalgan (73.3% vs58.4%, p=0.001). Both preparations were well tolerated. Conclusions: Treatment with 3-weekly injections of intermediate MW HA may be superior to low MW HA on knee OA symptoms over 6 months, with similar safety

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

Model for replication potential

This report is a deliverable for the REMOURBAN (REgeneration MOdel for accelerating the smart URBAN transformation) project which is a HORIZON 2020 programme project. Deliverable 5.2 was aimed at the development of a model for replication potential

OARSI/OMERACT Initiative to Define States of Severity and Indication for Joint Replacement in Hip and Knee Osteoarthritis. An OMERACT 10 Special Interest Group

To define pain and physical function cutpoints that would, coupled with structural severity, define a surrogate measure of “need for joint replacement surgery,” for use as an outcome measure for potential structure-modifying interventions for osteoarthritis (OA)

Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man

Objective: Pharmacokinetic data on glucosamine are scant, limiting the understanding of glucosamine sulfate mechanism of action in support of its treatment effects in osteoarthritis. This study investigated the oral pharmacokinetics and dose-proportionality of glucosamine after administration of the patented crystalline glucosamine sulfate in man. Methods: Twelve healthy volunteers received three consecutive once-daily oral administrations of glucosamine sulfate soluble powder at the doses of 750, 1500, and 3000 mg, in an open, randomised, cross-over fashion. Glucosamine was determined in plasma collected up to 48 h after the last dose by a validated Liquid Chromatography method with Mass Spectrometry detection. Pharmacokinetic parameters were calculated at steady state. Results: Endogenous plasma levels of glucosamine were detected (10.4-204 ng/ml, with low intra-subject variability). Glucosamine was rapidly absorbed after oral administration and its pharmacokinetics were linear in the dose range 750-1500 mg, but not at 3000 mg, where the plasma concentration-time profiles were less than expected based on dose-proportionality. Plasma levels increased over 30-folds from baseline and peaked at about 10 mu M with the standard 1500 mg once-daily dosage. Glucosamine distributed to extravascular compartments and its plasma concentrations were still above baseline up to the last collection time. Glucosamine elimination half-life was only tentatively estimated to average 15 h. Conclusions: Glucosamine is bioavailable after oral administration of crystalline glucosamine sulfate, persists in circulation, and its pharmacokinetics support once-daily dosage. Steady state peak concentrations at the therapeutic dose of 1500 mg were in line with those found to be effective in selected in vitro mechanistic studies. This is the only glucosamine formulation for which pharmacokinetic, efficacy and safety data are now available. (c) 2005 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved

Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man

SummaryObjectivePharmacokinetic data on glucosamine are scant, limiting the understanding of glucosamine sulfate mechanism of action in support of its treatment effects in osteoarthritis. This study investigated the oral pharmacokinetics and dose-proportionality of glucosamine after administration of the patented crystalline glucosamine sulfate in man.MethodsTwelve healthy volunteers received three consecutive once-daily oral administrations of glucosamine sulfate soluble powder at the doses of 750, 1500, and 3000mg, in an open, randomised, cross-over fashion. Glucosamine was determined in plasma collected up to 48h after the last dose by a validated Liquid Chromatography method with Mass Spectrometry detection. Pharmacokinetic parameters were calculated at steady state.ResultsEndogenous plasma levels of glucosamine were detected (10.4–204ng/ml, with low intra-subject variability). Glucosamine was rapidly absorbed after oral administration and its pharmacokinetics were linear in the dose range 750–1500mg, but not at 3000mg, where the plasma concentration–time profiles were less than expected based on dose-proportionality. Plasma levels increased over 30-folds from baseline and peaked at about 10μM with the standard 1500mg once-daily dosage. Glucosamine distributed to extravascular compartments and its plasma concentrations were still above baseline up to the last collection time. Glucosamine elimination half-life was only tentatively estimated to average 15h.ConclusionsGlucosamine is bioavailable after oral administration of crystalline glucosamine sulfate, persists in circulation, and its pharmacokinetics support once-daily dosage. Steady state peak concentrations at the therapeutic dose of 1500mg were in line with those found to be effective in selected in vitro mechanistic studies. This is the only glucosamine formulation for which pharmacokinetic, efficacy and safety data are now available

Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial

BACKGROUND: Treatment of osteoarthritis is usually limited to short-term symptom control. We assessed the effects of the specific drug glucosamine sulphate on the long-term progression of osteoarthritis joint structure changes and symptoms. METHODS: We did a randomised, double-blind placebo controlled trial, in which 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extension were taken at enrolment and after 1 and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width--ie, at the narrowest point--was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. FINDINGS: The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of -0.31 mm (95% CI -0.48 to -0.13). There was no significant joint-space loss in the 106 patients on glucosamine sulphate: -0.06 mm (-0.22 to 0.09). Similar results were reported with minimum joint-space narrowing. As assessed by WOMAC scores, symptoms worsened slightly in patients on placebo compared with the improvement observed after treatment with glucosamine sulphate. There were no differences in safety or reasons for early withdrawal between the treatment and placebo groups. INTERPRETATION: The long-term combined structure-modifying and symptom-modifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in osteoarthritis