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Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial
Original TextDr Jean Yves Reginster MD a b , Rita Deroisy PhD a, Lucio C Rovati MD c, Richard L Lee MSc d, Eric Lejeune PhD a, Olivier Bruyere PhD a, Giampaolo Giacovelli PhD c, Yves Henrotin PhD a, Jane E Dacre MD d, Christiane Gossett MD a
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.
We did a randomised, double-blind placebo controlled trial, in which 212 patients with knee steoarthritis 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.
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.
The long-term combined structure-modifying and symptom-modifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in osteoarthritis.
Osteoarthritis is a major cause of disability and is among the most frequent forms of musculoskeletal disorders.The goal of pharmacological treatment is usually to control symptoms of the disease, pain, and limitation of function, which is traditionally accomplished by the use of analgesic agents or non-steroidal anti-inflammatory drugs (NSAIDs).Drugs for the treatment of osteoarthritis have been classified as symptom-modifying drugs and also as structure-modifying drugs if they are able to alter the joint structure favourably and thus actually interfere with the progression of the disease. Although no drug can be included in the second category as yet, compounds are being searched for that may exert more specific effects than those of NSAIDs, directly interfering with some of the possible disease processes. Thus, these compounds might also favourably affect joint structure changes during long-term treatment, contrary to what has been observed with some NSAIDs that could even worsen progression.
Glucosamine sulphate is the sulphate derivative of the natural aminomonosaccharide glucosamine. Glucosamine, a normal constituent of glycosaminoglycans in cartilage matrix and synovial fluid,could have various pharmacological actions in articular cartilage and joint tissues. Several short-term to medium-term clinical trials in osteoarthritis have shown the significant symptom-modifying effect of glucosamine sulphate and its good safety profile. The need for long-term clinical trials with this compound has been emphasised. We did a randomised double-blind placebo-controlled trial to establish whether glucosamine sulphate can affect progression of symptoms and joint structure changes in osteoarthritis.
Study design and selection of patients
We recruited patients from the outpatient clinic of the Bone and Cartilage Metabolism Research Unit of the University Hospital Centre in Liege, Belgium. Inclusion criteria were age over 50 years and primary knee osteoarthritis of the medial femorotibial compartment, diagnosed according to the clinical and radiological criteria of the American College of Rheumatology. Disease severity was graded on the basis of the Kellgren and Lawrence radiographic system. Major exclusion criteria were: history or active presence of other rheumatic diseases that could be responsible for secondary osteoarthritis; severe articular inflammation as confirmed by physical examination (excluded also by erythrocyte sedimentation rate <40 mm/h and serum rheumatoid factor titre < 1:40); traumatic knee lesions; overweight defined as a body mass index >30; substantial abnormalities in haematological, hepatic, renal, or metabolic functions; and intra-articular or systemic corticosteroids in the 3 months preceding enrolment. The study was approved by the ethics commitee of the University of Liege and all patients gave their oral and written informed consent to participate.
Crystalline glucosamine sulphate (Dona, Viartril-S, or Xicil, Rotta Research Group, Monza, Italy) is a defined pure substance that is synthesised from chitin, and in which glucosamine, sulphate, chloride, and sodium ions are present in stoichiometric ratios of 2:1:2:2. The net content of glucosamine sulphate in the dose form (powder for oral solution, with standard inactive excipients) is 1500 mg. This product has been approved at this once daily dosage as a prescription treatment for osteoarthritis in many countries in Europe and elsewhere.
Patients were randomly assigned to receive 1500 mg of glucosamine sulphate or placebo once daily for 3 years. For rescue analgesia, patients were allowed access to paracetamol in 500 mg tablets, or to one of the following NSAIDs (the most used in Belgium at the time of the trial): diclofenac in 50 mg tablets, piroxicam in 20 mg capsules, or proglumetacin in 150 mg tablets. Use of the rescue medications was recorded by the patients in a diary, with appropriate washout—ie, at least five half-lives of the selected medication were allowed before symptom assessment. Compliance with study treatment was established by asking the patients about missed doses and by counting unused sachets. No other co-interventions for osteoarthritis were allowed.
The randomisation list was generated by computer in blocks of four, and patients received their randomization number in chronological order. The principal investigator was provided with individual envelopes, each containing patient codes, thus concealing treatment assignment.
The primary outcome measure for joint structural changes was represented by the mean joint-space width of the medial compartment of the tibiofemoral joint. Weightbearing, anteroposterior, separate radiographs of each knee were taken at baseline, 1, and 3 years by a standardised technique.In brief, patients stood with their knees fully extended and the posterior aspect of the knee in contact with the vertical cassette. The lower limbs were rotated until the patella was centralised over the lower end of the femur. Feet were positioned a small distance apart: foot maps were used for repositioning the patient. The X-ray beam was centred on the joint space and parallel to the tibial plateau. Fluoroscopy was used to correct lower limb positioning and X-ray beam alignment. The focus to film distance was 110 cm.
We digitised the radiographs and did the image analysis automatically by a validated system,14 which located the proximal and distal joint margins excluding outlier points and calculated the mean joint-space width of the medial and lateral compartments of the tibiofemoral joint. We calculated the mean (SD) shortterm and long-term coefficient of variation of this system for reproducing measurements as 1·82% (1·29) and 1·62% (1·31), respectively, for the medial compartment, which is in good agreement with the 1·84% coefficient of variation reported in the original validation of this method. All radiographs obtained in a single radiological unit in Liege were measured in London by a single reader unaware of treatment assignment. A further masked analysis was visual determination of the minimum joint-space width—ie, at the narrowest point—with a 0·1 mm graduated magnifying lens.
We assessed symptoms of osteoarthritis by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, a validated, disease-specific questionnaire addressing severity of joint pain (five questions), stiffness (two questions), and limitation of physical function (17 questions), and referring to the 48 h before assessment. The visual analogue scale version of the index was used—ie, with the patient assessing each question by a 100 mm visual analogue scale, and the total index score being represented by the sum of the 24 component item scores. A higher WOMAC score represents worse symptom severity, with 2400 mm being the worst possible total score.
Secondary outcome measures were use of rescue medications as recorded in a daily diary; withdrawal rates; occurrence of adverse events; and routine safety laboratory tests, including testing for glucose homoeostasis assessed by fasting glucose concentrations at yearly intervals in all patients still receiving the study treatment.
We calculated sample size on the basis of the recommendations available at the time of study planning, of a 0·5 mm target difference in joint-space narrowing between groups after 3 years, given the validation data of the digital image analysis technique adopted as the principal outcome. We calculated that a sample size of at least 60 patients in each group would give a power of 80% in detecting such a difference at the 5% significance level. We increased the sample size to at least 100 patients per group to allow an up to 40% dropout rate.
The primary efficacy outcome measure for structure modification was joint-space narrowing in the signal joint—ie, the change in joint-space width after 3 years in the narrowest medial tibiofemoral joint compartment at enrolment. The medial tibiofemoral joint space is preferred in clinical trials, as opposed to the lateral space, since this is the area that is subjected to the greatest pressure and thus the most osteoarthritis cartilage loss, and for which outcome measures are better validated. The 3-year % change in the total WOMAC score was taken for the primary assessment of symptom modification, with the final changes in the pain, physical function, and stiffness subscales analysed as secondary endpoints. Results were expressed as difference between the final group means and 95% CI, with p values based on analysis of variance. All primary efficacy analyses were done on patients who completed the 3-year observation period, and by intention-to-treat analysis for all randomised patients. Every effort was made to carry out the final examinations after 3 years, regardless of patient's compliance or whether the patient was still on the study treatment. When this was not possible, the intention-to-treat analysis was carried out according to three different approaches. First, we did a worst scenario analysis in which a poor outcome was assigned to patients in whom the final 3-year assessment was not completed, corresponding to the average change recorded in patients in the placebo group who were assessed for 3 years. For consistency we also used the last observation carried forward approach, and to avoid repeatedly assigning the same value to a series of missing values we used the random sampling method. In the random sampling approach, missing endpoint values were replaced with values selected randomly from the distribution of all known endpoint values—ie, glucosamine sulphate and placebo combined. To lower sampling error, 50 such datasets were constructed, analysed independently by analysis of variance and the median of the significance values was taken.
Among secondary analyses, we arbitrarily defined a cutoff point for marked structural damage progression as a joint-space narrowing of more than 0·5 mm, based on previous reports—the proportion of all randomised patients reaching such a progression cutoff was compared between groups by the X2 test. The mean number of days of rescue medication intake was assessed by analysis of variance. We used the Spearman correlation test to assess correlation between structure and symptom outcomes. Adverse event and dropout rates were analysed by X2 or Fisher's exact tests, as appropriate. Baseline characteristics were compared by the X2 test for categorical variables and by analysis of variance for continuous data. All reported p values are two sided with α=0·05.
We have reported here that long-term administration of glucosamine sulphate over 3 years can prevent joint structure changes in patients with osteoarthritis of the knee with a significant improvement in symptoms.
Different validated methods have been proposed for measuring joint-space width from standardised radiographs, such as visual methods (using a caliper, ruler, or a magnifying lens) usually at the narrowest point of the joint, and computed readings of digitised radiographs, suggested to decrease observer-based error. We used a validated method of digital image analysis to calculate mean joint-space width and visual measurement of the narrowest point of the joint by a magnifying lens. Both methods had very similar final results for joint-space narrowing, with the measurement at the narrowest point showing a slightly higher sensitivity to change, as previously suggested. Although the two methods of measurements were similar, as indicated by other studies, our decision to use digital image analysis to determine mean joint-space width as the primary outcome measure proved to be more conservative and allowed sounder conclusions.
Several studies have assessed the natural rate of joint-space narrowing in patients with knee osteoarthritis, but a wide spectrum of possible rates have been reported, ranging between 0·06 and 0·6 mm/year. However, most of these studies had short follow-up periods, or a small number of observations. Other reasons for the differences in rates could include the varied radiographic or measurement procedures, different risk factors, or the population studied. Community-based studies such as the Baltimore Longitudinal Study of Aging and the Framingham Study yielded rates at the lower end of the spectrum—ie, in the 0·1 mm/year range. However, a large long-term study has shown that the yearly rate of progression even in clinic-based populations should be in the 0·1 mm range. The final overall joint-space narrowing we recorded with placebo is in this range. However, the rate of joint-space narrowing we observed was not linear, since the loss in mean space width with placebo after the first year was only of 0·05 mm. When individual joint-space changes were analysed, twice as many patients receiving placebo had a striking joint-space narrowing, than those receiving glucosamine sulphate.
In clinical terms, the baseline values of the WOMAC index correspond to symptoms of mild to moderate severity—patients who completed treatment with glucosamine sulphate had a 20—25% improvement in symptoms, compared with the slight worsening of symptoms in the placebo group. Analysis of the WOMAC index subscales for pain and for physical function, confirmed the symptom improvement with glucosamine sulphate compared with placebo. Intentionto-treat analysis confirmed the beneficial effect of glucosamine sulphate on joint structure and symptoms reported when patients who completed the study treatment were assessed.
The precise mechanism of action of glucosamine sulphate has not been fully elucidated yet. Cartilage-unrelated effects, such as the inhibition of superoxide-radical generation or the inhibition of inducible nitric oxide synthesis have been suggested to explain the fast onset of action on symptoms noted in short-term clinical trials. However, the long-term effects we recorded could be due to the reported effects of the compound on cartilage metabolism, including stimulation of anabolic activities, such as the synthesis of proteoglycans, and the depression of catabolic activities, such as the effects of metalloproteases.
Previous short-term studies have shown glucosamine sulphate is fairly safe and more safe than standard NSAIDs, especially concerning the gastrointestinal tract. We did not report any significant differences from placebo in safety, with no distinct adverse event pattern. Similarly, routine labratory tests did not show any general system modification nor metabolic changes. The latter included no alteration of glycaemic homoeostasis, contrary to what has been suggested by experimental models as a possible untoward target for aminomonosaccharides.12
In this study, glucosamine sulphate was approved as a prescription drug, therefore, our results cannot be generalised to other glucosamine products (or compound mixtures) such as those available in some countries as dietary supplements.
As a possible limitation of our trial, we should acknowledge that although current scientific and regulatory recommendations still advise use of the fully extended, weightbearing radiographic view that we used to assess joint structural changes, more recent reports suggest that other radiographic views could be more efficient. In particular, these views might avoid changes in patient positioning due to symptom changes during the study (eg, better knee extension and consequently lower apparent joint-space narrowing, due to symptom improvement in the glucosamine sulphate group). However, we believe it is unlikely that the symptom change observed in the two groups might have affected the results, given the mild to moderate disease and symptom conditions at baseline and throughout the study. Furthermore, the general correlation between symptom and structure changes was poor, as suggested by other studies.23 Patients receiving glucosamine sulphate but with severe joint-space narrowing did have an improvement in their symptoms, which did not prevent the radiographic structure impairment.
Whether the effect of glucosamine sulphate on the average joint-space narrowing detected in our study and others will be of clinical importance in the longer term cannot be concluded from the present data. Further studies, with longer follow-up and different designs are needed to assess whether these changes are predictive of further clinical progression of osteoarthritis-eg, modifying the indication for possible joint surgery or the time to substantial disability.
J Y Reginster contributed to the design of the study, analysed and interpreted the results, and did the patient assessments. R Deroisy, E Lejeune, and C Gosset coordinated patient clinic visits and assessments. O Bruyère and Y Henrotin were responsible for radiographic assessment of minimum joint-space width and conributed to analysis of the results. L C Rovati and G Giacovelli helped design the study and analyse the data. J E Darce had previously developed the radiograph digital image analaysis system used for the primary analysis of efficacy. J E Darce and R L Lee did all the actual digital image analyses of mean joint-space width.
The study was supported by a research grant from the Rotta Research Group, Monza, Italy.
Glusoamine for osteoarthritis: dawn of a new era?
Osteoarthritis (OA) is a disease with formidable public health impact that has been dogged by negative attitudes among physicians (“wear and tear”) and low expectations of the value of treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonest symptomatic treatment for OA but have major adverse effects and might even worsen the osteoarthritic process. Although inestimable resources have been poured into the development of a panoply of NSAIDs, scarce currency has been given to the notion that progression of OA could be retarded pharmacologically, let alone by a nutritional product. The report of the clinical trial in today's Lancet may radically change this situation.
The 3-year randomised placebo-controlled trial suggests that an oral agent, glucosamine sulphate, retards the progression of symptomatic knee osteoarthritis. The study is a landmark in OA research, not only for its scientific results, but also for highlighting vexing issues in this area.
The quest for disease-modifier in OA is long overdue, and this contender comes from an unexpected quarter. The idea that glucosamine has such effects originates from the notion that consumption of cartilage derivatives could provide substrates for cartilage repair, but doubts about its absorption and metabolic fate have fuelled scepticism about its therapeutic potential. Even if this small aminosugar could be absorbed and distributed intact to articular cartilage, how it would be incorporated in the growth of matrix oligosaccharides is not clear. This dilemma has stimulated several recent studies, which have shown that oral glucosamine sulphate is absorbed and distributed to joint tissues, and that it has antinflammatory and anabolic properties. Despite these observations, glucosamine remains a compound whose potential to influence cartilage destruction awaits a robust mechanistic explanation.
It could be argued that the importance of a good biological explanation is reduced by the demonstration of therapeutic efficacy in a robust clinical trial. Certainly, the study by Jean-Yves Reginster and colleagues shows many hallmarks of a well-conducted trial, including rigorous descriptions of randomisation, blinding, and allocation concealment, as well as use of state-of-the-art approaches to measurement of outcome. Even so, some elements of the methods merit attention. As recommended by expertconsensus, the study used change in width of medial tibiofemoral joint space as its primary measure of the biological effect. Precise measurement of this variable is contingent on standardised radiographic techniques, and could be biased when the presence of pain impairs the ability of participants to extend the knee fully. How much this theoretical limitation translates into real bias is unclear, but there are also fundamental questions about the relevance of width of radiographic joint space as a single measure of biological severity in knee OA. The use of this measure derives from the conceptualisation of OA as a disorder of progressive hyaline-cartilage loss, and the belief that hyaline-cartilage thickness correlates with width of radiographic joint space. In fact, recent magnetic-resonance-imaging studies have highlighted the panarticular nature of knee OA and have shown that mild to moderate joint-space loss reflects meniscal extrusion rather than hyaline-cartilage erosion. Even more troublesome is the common clinical observation that radiographic severity is one of the least important of the predictors of outcomes that matter, such as pain and physical function.
Although much of the hype will relate to radiographic outcome, it is the well-validated WOMAC algofunctional scores that give the strongest indication of the potential of glucosamine to provide long-term benefits for people with knee OA. In fact, the results are impressive; patients assigned to glucosamine experienced significant improvements in pain and disability that were sustained for the 3 years of the study, whereas the scores among the placebo group worsened. Furthermore, adverse-event rates were not higher than those associated with placebo. These findings are consistent with those seen in previous symptom-based studies of glucosamine. Even though the effect sizes are modest, glucosamine sulphate could play an important part in the long-term therapy of OA.
In the face of such results, the medical profession customarily tackles the usual questions about who might benefit and who should pay, but the situation for glucosamine is complicated. It is licensed in parts of Europe as a drug, but is already widely available in the UK and the USA as a nutritional supplement. Since glucosamine is generally self-prescribed, the likely primary beneficiary of this trial will be the nutritional-product industry rather than the pharmaceutical company that sponsored the trial, even though the results may not be generalisable to the highly variable formulations of nutritional products. Although health-care professionals generally expect to be involved in medical decisions of public-health importance, the reality is that they are not regarded as a repository of objective advice about nutritional products and are generally kept out of the loop. This situation must change. It is time for the professsion to accommodate the possibility that many nutritional products may have valuable therapeutic effects and to regain the credibility of the public at large.
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