Yves Henrotin

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.

OARSI guidelines for the non-surgical management of knee osteoarthritis

OBJECTIVE To develop concise, up-to-date, patient-focused, evidence-based, expert consensus guidelines for the management of knee osteoarthritis (OA), intended to inform patients, physicians, and allied healthcare professionals worldwide. METHOD Thirteen experts from relevant medical disciplines (primary care, rheumatology, orthopedics, physical therapy, physical medicine and rehabilitation, and evidence-based medicine), three continents and ten countries (USA, UK, France, Netherlands, Belgium, Sweden, Denmark, Australia, Japan, and Canada) and a patient representative comprised the Osteoarthritis Guidelines Development Group (OAGDG). Based on previous OA guidelines and a systematic review of the OA literature, 29 treatment modalities were considered for recommendation. Evidence published subsequent to the 2010 OARSI guidelines was based on a systematic review conducted by the OA Research Society International (OARSI) evidence team at Tufts Medical Center, Boston, USA. Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials were initially searched in first quarter 2012 and last searched in March 2013. Included evidence was assessed for quality using Assessment of Multiple Systematic Reviews (AMSTAR) criteria, and published criticism of included evidence was also considered. To provide recommendations for individuals with a range of health profiles and OA burden, treatment recommendations were stratified into four clinical sub-phenotypes. Consensus recommendations were produced using the RAND/UCLA Appropriateness Method and Delphi voting process. Treatments were recommended as Appropriate, Uncertain, or Not Appropriate, for each of four clinical sub-phenotypes and accompanied by 1-10 risk and benefit scores. RESULTS Appropriate treatment modalities for all individuals with knee OA included biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management. Treatments appropriate for specific clinical sub-phenotypes included acetaminophen (paracetamol), balneotherapy, capsaicin, cane (walking stick), duloxetine, oral non-steroidal anti-inflammatory drugs (NSAIDs; COX-2 selective and non-selective), and topical NSAIDs. Treatments of uncertain appropriateness for specific clinical sub-phenotypes included acupuncture, avocado soybean unsaponfiables, chondroitin, crutches, diacerein, glucosamine, intra-articular hyaluronic acid, opioids (oral and transdermal), rosehip, transcutaneous electrical nerve stimulation, and ultrasound. Treatments voted not appropriate included risedronate and electrotherapy (neuromuscular electrical stimulation). CONCLUSION These evidence-based consensus recommendations provide guidance to patients and practitioners on treatments applicable to all individuals with knee OA, as well as therapies that can be considered according to individualized patient needs and preferences.

The role of reactive oxygen species in homeostasis and degradation of cartilage

OBJECTIVES The metabolism of cells in articular joint tissues in normal and pathological conditions is subject to a complex environmental control. In addition to soluble mediators such as cytokines and growth factors, as well as mechanical stimuli, reactive oxygen species (ROS) emerge as major factors in this regulation. ROS production has been found to increase in joint diseases, such as osteoarthritis and rheumatoid arthritis, but their role in joint diseases initiation and progression remains questionable. METHOD This review is focused on the role of ROS, mainly nitric oxide, peroxynitrite and superoxide anion radicals, in the signaling mechanisms implied in the main cellular functions, including synthesis and degradation of matrix components. The direct effects of ROS on cartilage matrix components as well as their inflammatory and immunomodulatory effects are also considered. RESULTS Some intracellular signaling pathways are redox sensitive and ROS are involved in the regulation of the production of some biochemical factors involved in cartilage degradation and joint inflammation. Further, ROS may cause damage to all matrix components, either by a direct attack or indirectly by reducing matrix components synthesis, by inducing apoptosis or by activating latent metalloproteinases. Finally, we have highlighted the uncoupling effect of ROS on tissue remodeling and synovium inflammation, suggesting that antioxidant therapy could be helpful to treat structural changes but not to relieve symptoms. CONCLUSIONS This review of the literature supports the concept that ROS are not only deleterious agents involved in cartilage degradation, but that they also act as integral factors of intracellular signaling mechanisms. Further investigation is required to support the concept of antioxidant therapy in the management of joint diseases.

Chapter 2. European guidelines for prevention in low back pain : November 2004.

Summary of the concepts of prevention in low back pain (LBP): • The general nature and course of commonly experienced LBP means that there is limited scope for preventing its incidence (first-time onset). Prevention, in the context of this guideline, is focused primarily on reduction of the impact and consequences of LBP. • Primary causative mechanisms remain largely undetermined: risk factor modification will not necessarily achieve prevention. • There is considerable scope, in principle, for prevention of the consequences of LBP – e.g. episodes (recurrence), care seeking, disability, and workloss. • Different interventions and outcomes will be appropriate for different target populations (general population, workers, and children) yet inevitably there is overlap. • Interventions that are essentially treatments in the clinical environment, focused on management of current symptoms, are not considered as ‘prevention’ for the purposes of this guideline: they are covered in the accompanying clinical guidelines

Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis

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 effect. As in vitro biomarkers are increasingly investigated in the context of specific drug treatments, advances in the field can be expected that will lead to rapid expansion of the list of available biomarkers with increasing understanding of the molecular processes that they represent.

Information and low back pain management: a systematic review.

Study Design. A systematic search of three electronic databases was done to identify randomized controlled trials on the effect of written or audiovisual information in low back pain. Objectives. To determine whether information is an effective preventive action and/or therapy for low back pain and which type of information is most effective. Summary of Background Data. Information is commonly used in the primary care of low back pain and mostly delivered by booklets. Methods. A systematic computer-aided search of the Medline, PsyclInfo, and Embase database. A rating system was used to assess the strength of the evidence, based on the methodologic quality of the randomized controlled trials, the relevance of the outcome measures, and the consistency of the results. Results. Eleven randomized controlled trials were selected, including seven trials of high methodologic quality, as well as one parallel group controlled survey and one longitudinal study. Only three of the seven high-quality studies showed favorable results for information. There is strong evidence that a booklet increases knowledge and moderate evidence that physician-related cues increase the confidence in a booklet and adherence to exercises. There is limited evidence that a biopsychosocial booklet is more efficient than a biomedical booklet to shift patients beliefs about physical activity, pain, and consequences of low back trouble. There is strong evidence that booklets are not efficient on absenteeism and conflicting evidence that they are efficient on healthcare use. There is no evidence that e-mail discussion or video programs alone are effective to reduce low back pain, disability, and healthcare costs. Conclusions. Information based on a biopsychosocial model is recommended in primary care to shift patient beliefs on low back pain. Nevertheless, information delivery alone is not sufficient to prevent absenteeism and reduce healthcare costs.

Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone.

OBJECTIVE To determine the phenotype of osteoblasts from the sclerotic zones of human osteoarthritic (OA) subchondral bone. METHODS Human osteoblasts were isolated from sclerotic or nonsclerotic areas of subchondral bone and cultured for 14 days in monolayer. The expression of 14 genes was investigated by real-time reverse transcription-polymerase chain reaction. The activities of alkaline phosphatase (AP) and transglutaminases (TGases) were quantified by enzymatic assays. C-terminal type I procollagen propeptide (CPI), interleukin-1beta (IL-1beta), IL-6, IL-8, transforming growth factor beta1 (TGFbeta1), osteocalcin (OC), and osteopontin (OPN) were assayed in the culture medium by immunoassay. RESULTS Gene expression levels of matrix metalloproteinase 13, COL1A1 and COL1A2, OPN, tissue-nonspecific AP, OC, vascular endothelial growth factor, ANKH, TGase 2, factor XIIIA, and dentin matrix protein 1 were significantly up-regulated in sclerotic osteoblasts compared with nonsclerotic osteoblasts. In contrast, parathyroid hormone receptor gene expression was depressed in sclerotic osteoblasts, but bone sialoprotein levels were unchanged. The activities of AP and TGases were increased in sclerotic osteoblasts, while matrix mineralization, revealed by alizarin red staining, was decreased. In parallel, protein synthesis of CPI, OC, OPN, IL-6, IL-8, and TGFbeta1 was significantly higher in sclerotic osteoblasts than in nonsclerotic osteoblasts, while IL-1beta production was similar in both groups. CONCLUSION These findings contribute to a better understanding of the mechanisms involved in subchondral bone sclerosis and identify osteoblasts with an altered phenotype as a potential target for future OA therapies.

Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study.

OBJECTIVES We compare the symptomatic effects of 300 or 600mg daily of ASU in patients with knee osteoarthritis. METHODS A multicenter, double blind, study comparing a daily intake of 300mg or 600mg of ASU and placebo. The study lasted 3 months and involved patients of both genders, aged 45 to 80 years and presenting with femoro-tibial knee osteoarthritis. The primary endpoint was NSAIDs and analgesics intake between D30 and D90. RESULTS All efficacy parameters were significantly improved (p<0.01), in the two ASU groups compared to the placebo group. At D90, NSAIDs and analgesics intake decreased by more than 50% in 71% of the patients receiving ASU 300mg or 600mg, compared to 36% of the patients receiving placebo. From DO to D90 Lequesnes index dropped by 3.9 and 2.9 points in ASU 300mg and 600mg groups, respectively, against 1.6 in those receiving placebo. CONCLUSION The efficacy of ASU at a dosage of 300mg/day and 600mg/day was consistently superior to that of placebo at all endpoints, with no differences observed between the two doses.Objectives: We compare the symptomatic effects of 300 or 600 mg daily of ASU in patients with knee osteoarthritis. Methods: A multicenter, double blind, study comparing a daily intake of 300 mg or 600 mg of ASU and placebo. The study lasted 3 months and involved patients of both genders, aged 45 to 80 years and presenting with femoro-tibial knee osteoarthritis. The primary endpoint was NSAIDs and analgesics intake between D30 and D90. Results: All efficacy parameters were significantly improved (p< 0.01), in the two ASU groups compared to the placebo group. At D90, NSAIDs and analgesics intake decreased by more than 50% in 71% of the patients receiving ASU 300 mg or 600 mg, compared to 36% of the patients receiving placebo. From D0 to D90 Lequesnes index dropped by 3.9 and 2.9 points in ASU 300 mg and 600 mg groups, respectively, against 1.6 in those receiving placebo. Conclusion: The efficacy of ASU at a dosage of 300 mg/day and 600 mg/day was consistently superior to that of placebo at all endpoints, with no differences observed between the two doses.

Nutraceuticals: do they represent a new era in the management of osteoarthritis? - a narrative review from the lessons taken with five products.

OBJECTIVES The aim of this first global systematic review on selected nutraceuticals was to synthesize and evaluate scientific relevant data available in the literature. Evidences that can support health, physiological or functional benefit on osteoarthritis (OA) were gathered and the level of evidence relative to each of these ingredients was highlighted. METHODOLOGY Relevant scientific data (positive or not) regarding OA were searched for five groups of compounds (avocado/soybean unsaponifiables (ASU), n-3 polyunsaturated fatty acids, collagen hydrosylates (CHs), vitamin D, polyphenols) within preclinical (in vitro and in vivo), epidemiological, and clinical studies. The following criteria were evaluated to assess the methodology quality of each study: (1) study question; (2) study population; (3) primary endpoint; (4) study design (randomization, control, blinding, duration of follow up); (5) data analysis and interpretation. A scientific consensus was determined for all studied nutraceuticals to evaluate their efficacy in OA. RESULTS The studied compounds demonstrated different potencies in preclinical studies. Most of them have demonstrated anti-catabolic and anti-inflammatory effects by various inhibitory activities on different mediators. Vitamin D showed a pro-catabolic effect in vitro and the polyphenol, Genistein, had only anti-inflammatory potency. The evaluation of the clinical data showed that ASU was the only one of the studied ingredients to present a good evidence of efficacy, but the efficient formulation was considered as a drug in some countries. Pycnogenol showed moderate evidence of efficacy, and vitamin D and collagen hydrolysate demonstrated a suggestive evidence of efficacy, whereas curcumin, epigallocatechin-3-gallate (EGCG) and resveratrol had only preclinical evidence of efficacy due to the lack of clinical data. The literature gathered for n-3 PUFA, nobiletin and genistein was insufficient to conclude for their efficacy in OA. CONCLUSION Additional data are needed for most of the studied nutraceuticals. Studies of good quality are needed to draw solid conclusions regarding their efficacy but nutraceuticals could represent good alternates for OA management. Their use should be driven by any recommendations.

Strontium Ranelate Increases Cartilage Matrix Formation

Based on previous studies showing that strontium ranelate (S12911) modulates bone loss in osteoporosis, it could be hypothesized that this drug also is effective on cartilage degradation in osteoarthritis (OA). This was investigated in vitro on normal and OA human chondrocytes treated or not treated with interleukin‐1β (IL‐1β). This model mimics, in vitro, the imbalance between chondroformation and chondroresorption processes observed in vivo in OA cartilage. Chondrocytes were isolated from cartilage by enzymatic digestion and cultured for 24–72 h with 10−4−10−3 M strontium ranelate, 10−3 M calcium ranelate, or 2 · 10−3 M SrCl2 with or without IL‐1β or insulin‐like growth factor I (IGF‐I). Stromelysin activity and stromelysin quantitation were assayed by spectrofluorometry and enzyme amplified sensitivity immunoassay (EASIA), respectively. Proteoglycans (PG) were quantified using a radioimmunoassay. Newly synthesized glycosaminoglycans (GAGs) were quantified by labeled sulfate (Na235SO4) incorporation. This method allowed the PG size after exclusion chromatography to be determined. Strontium ranelate, calcium ranelate, and SrCl2 did not modify stromelysin synthesis even in the presence of IL‐1β. Calcium ranelate induced stromelysin activation whereas strontium compounds were ineffective. Strontium ranelate and SrCl2 both strongly stimulated PG production suggesting an ionic effect of strontium independent of the organic moiety. Moreover, 10−3 M strontium ranelate increased the stimulatory effect of IGF‐I (10−9 M) on PG synthesis but did not reverse the inhibitory effect of IL‐1β. Strontium ranelate strongly stimulates human cartilage matrix formation in vitro by a direct ionic effect without stimulating the chondroresorption processes. This finding provides a preclinical basis for in vivo testing of strontium ranelate in OA.