The Pharmaceutical Journal Vol 265 No 7123 p759-763
November 18, 2000 Original papers

Is glucosamine an effective treatment for osteoarthritis? A meta-analysis

By S. B. Kayne, PhD, FRPharmS, K. Wadeson, BSc, MRPharmS, and A. MacAdam, PhD, MRPharmS

AIM o To investigate the evidence to support the use of glucosamine in osteoarthritis.

METHOD o Two meta-analyses using different techniques. One involved 10 studies; the other, six studies.

RESULTS o Several trials failed on quality of methodology, and it is therefore difficult to assess the overall effectiveness of glucosamine, although the results were generally positive.

CONCLUSION o Glucosamine should be used judiciously for limited periods of time. There is no evidence that glucosamine provides a long-term cure for osteoarthritis and no evidence that it is safe to take over extended periods.

Osteoarthritis is the most common rheumatic disease known to man with symptoms visible in all cultural groups. It affects about 15 per cent of the world's population, with individuals aged 64 years and above suffering to the greatest extent.1-3 There is some doubt as to whether the disease should be called osteoarthritis, a description given more than 100 years ago and implying the involvement of inflammation,4 or whether it should be called osteoarthrosis, suggesting degeneration. The condition has also been called degenerative joint disease.5 However, the way in which the disease develops suggests that the term osteoarthritis is likely to be more appropriate.
For many patients, management of the condition relies on optimising the use of pharmacotherapy, together with appropriate exercise, lifestyle adjustment and physiotherapy.6 Unfortunately, a cure is unlikely without the surgical replacement of joints.
Non-steroid anti-inflammatory drugs (NSAIDs) are a common choice, but may be associated with adverse reactions or be contraindicated in some patients. As many as 12,000 hospitalisations7 and about 200 deaths8 may be attributed to NSAID use in the United Kingdom. Although NSAIDs may suppress pain in the short term, some have been shown to inhibit the synthesis of articular cartilage in the longer term, and are therefore contraindicated.9 Furthermore, patients taking these drugs are said to have a three- to five-fold risk increase of gastrointestinal complications compared with non-users.10 This results in the necessity for further interventions increasing treatment costs by up to 45 per cent.11 Care should therefore be exercised by patients prescribed these drugs for extended periods on an "as required" basis. Of all the commonly prescribed NSAIDs, ibuprofen is usually claimed to have the lowest incidence of GI effects and to be the safest.12
It has been suggested that the administration of glucosamine could be beneficial in promoting the regeneration of damaged cartilage without the disadvantages of NSAIDs. In patients suffering from osteoarthritis, glucosamine levels may be depleted.13 Glucosamine occurs naturally in the body and is important in the synthesis of articular cartilage. It is advertised widely in popular newspapers and in sports magazines to promote recovery from injury.

Aetiology of osteoarthritis Osteoarthritis is a slow, progressive, degenerative joint disease characterised by loss of cartilage, cartilage damage and eventual loss of collagenous matrix to expose underlying bone.5 It results from both mechanical and biological events that destabilise the normal coupling of degradation and synthesis of articular cartilage, chondrocytes and extracellular matrix, and subchondral bone. These changes are initiated by many factors, including genetic, developmental and metabolic factors, and they frequently occur in sport as a result of traumatic stimuli.
Obesity has been accepted as a definite contributory factor, because excessive weight imposes a mechanical burden on the joints.14 Evidence has shown that a decrease in body weight significantly reduces osteoarthritis in women, particularly in the knee joint.15 Women appear to be more susceptible to osteoarthritis and this may be due to the depletion of bone, particularly in older women, a fact that should be borne in mind by postmenopausal athletes.
The role of exercise in preventing osteoarthritis has become controversial. In 1993, Lane et al performed a trial to investigate the risk of osteoarthritis with running and ageing.16 It was a five-year trial and each participant had healthy joints at the start. At the end the runners were compared with non-running controls and the runners showed no significant risk of clinical or radiographic osteoarthritis of the knees or lower spine. However, two years later, Lane looked at higher intensity exercise (including long distance running, basketball and football) and found that at competitive levels the possibility of developing arthritis was, in fact, increased.17 But if the disease is incurred through exercise at an early stage of life, there appears to be a better chance of recovery and delay in the onset of osteoarthritis.18

Pathogenesis of osteoarthritis Cartilaginous tissues consist of three primary components - chondrocytes, extracellular water and an abundant extracellular matrix - which, together with collagen and other precursors, all assemble into cartilage. In mature cartilage, chondrocytes contribute about 5 per cent of the total tissue volume whereas the aqueous matrix, mainly proteoglycans (of which glucosaminoglycans are a major component) makes up the rest. The proteoglycans consist of protein bound with either glucosamine or galactosamine in repeating disaccharide units, and they are actively synthesised by the chondrocytes to compensate for the degradation and normal metabolic turnover of the extracellular matrix. Failure to replenish lost matrix leads to cartilage degradation and functional impairment. Osteoarthritis may be characterised as:

• Tissue failure generated by mechanical wear


• Failure of the chondrocyte cells in the joints to synthesise and repair cartilage
• An inflammatory condition.

Glucosamine in cartilage structure Glucosamine is an aminomonosaccharide, synthesised in the body by the union of glutamic acid and glucose.19 As stated above, it is found in high concentration in cartilage, being an important substrate in the biosynthesis of glucosaminoglycans, which are a constituent of cartilage tissue matrix.
An example of a glucosaminoglycan is chondroitin sulphate synthesised by the chondrocytes, a process that is controlled by DNA and RNA and is catalysed by various different enzyme pathways.20
Hyaluronic acid is another example of a glucosaminoglycan and is present in synovial fluid.14

Symptoms of osteoarthritis In middle age, early osteoarthritic changes develop slowly.21 The bony surfaces of the joints change shape as a result of wear and tear and articular cartilage may degenerate on weight bearing surfaces. Intra-articular fibrocartilage may also suffer from wear, owing to repetitive pulling on the capsules or ligaments. These changes mean that the joint surfaces lose congruity, there is more play between them and they are more easily displaced by outside forces.
Similar changes can also occur in younger athletes whose joints are subjected to excessive mechanical forces. For example, professional football players who sustain repeated and inadequately treated ligament sprains can develop osteoarthritis in much earlier life.
The general symptoms of osteoarthritis include pain, stiffness, swelling, limitation of movement and variable degrees of local inflammation. It is the localised pain that prompts most patients to seek a consultation.22 The condition may involve the joint (when it is termed articular) or the bursae, tendons or ligaments (when it is termed periarticular). The pain becomes worse with activity and improves with rest. Common signs are inflammation, mild joint enlargement, tenderness and joint instability. There may also be loss of appetite, general malaise and depression.

Glucosamine in the treatment of osteoarthritis Biochemical data collected by Mankin et al during in vitro experiments in 1981 have shown that there is a significant decrease in the glucosamine content of osteoarthritic cartilage, which in turn leads to a fall in the amount of chondroitin sulphate.13 Furthermore, the joint capsule becomes thickened and the synovial fluid has a reduced concentration of lactate and glucose, inhibiting the synthesis of hyaluronic acid.
As glucosamine takes part in the synthesis of both chondroitin sulphate and hyaluronic acid, and because these two compounds are depleted in osteoarthritis, it has been suggested that replacing glucosamine could be of benefit to patients suffering from the condition.23
Over the past 40 years many in vitro studies have shown that the addition of exogenous glucosamine to cultures of cartilage substantially enhances the secretion of mucopolysaccharides and collagen.24 Glucosamine itself is not an intermediate in the standard biochemical pathways, but its derivatives are.
Studies using exogenous glucosamine sulphate in cultured chick embryo vertebral cartilage revealed that the sulphate group was split off and the glucosamine incorporated into mucopolysaccharides.25 The most likely explanation for this is that the exogenous glucosamine is a good substrate for an enzyme that catalyses the transfer of phosphate groups. Thus the exogenous glucosamine would be converted to glucosamine-6-phosphate before further incorporation into the biochemical processes.
Bassleer et al working with human articular chondrocyte cultures showed that not only does exogenous glucosamine become incorporated into mucopolysaccharides, but it also appears to activate core protein synthesis in human chondrocytes.26 Both investigations, though positive, suffer from the limitations of applying in vitro results to humans.
Setnikar et al, working with animal models, observed an interesting phenomenon.27 They found that orally administered glucosamine sulphate protected rats from arthritic inflammation induced by kaolin or mycobacterial adjuvant and from inflammation or oedema induced by an injection of croton oil, carageenan, dextran or formalin. However, the glucosamine sulphate had no effect on the inflammatory response produced by an injection of inflammatory mediators. The compound would appear to inhibit inflammation caused by certain foreign agents, but does not seem able to produce generalised anti-inflammatory action. The authors suggested that the basis of this antireactive effect might be an enhanced production of protective proteoglycans that in turn play a role in the clinical activity of glucosamine sulphate.
It would, therefore, appear that there are three mechanisms by which glucosamine sulphate could work:

• Inhibition of cartilage breakdown
• Promotion of cartilage repair
• An anti-inflammatory effect resulting from certain foreign agents

Availability of glucosamine There are three basic forms of glucosamine available commercially:

N-Acetyl glucosamine N-Acetyl glucosamine is metabolised differently from other forms. It is selectively taken up by the liver and other tissues and is involved in the generation of proteins, so there is less available to repair cartilage.

Glucosamine sulphate Since pure glucosamine breaks down in the presence of air and water, sodium or potassium chloride is often used as a stabiliser and accounts for about one third of the total weight of the compound. In addition, the sulphate grouping accounts for a further 20 per cent, so some of the products available may only contain half their weight of glucosamine.

Glucosamine hydrochloride Glucosamine hydrochloride is also available and claimed to contain 83 per cent active principle, to be more stable than the sulphate and to be sodium free.

The suggested dose varies with body weight, and the dose is to be taken two to four times daily with food. Amounts quoted include 1,000mg (up to 120lb body weight), 1,500mg (up to 200lb body weight) and 2,000mg (over 200lb body weight).

Early evidence McCarty24 attributes the introduction of glucosamine sulphate as a therapeutic agent for treating osteoarthritis to German physicians who first administered it in 1969. They used an injectable presentation providing 400mg of glucosamine sulphate administered intramuscularly, intravenously or intra-articularly once daily.
The physicians reported substantial reduction in pain together with increased mobility in many patients. Unfortunately, the study suffered from the absence of a control group. Furthermore, the measurement of pain by questionnaire as an outcome indicator is subject to individual patient perception.
Several other studies have been done since, and we have conducted a meta-analysis to find out whether the use of
glucosamine in osteoarthritis could be supported.

METHOD

In order to assess further the evidence for glucosamine, 10 clinical studies that gave enough details for inclusion in a meta-analysis were extracted from the literature using Medline. Studies were included if they tested for glucosamine alone.
The widely cited method adopted by Kleijnen et al in their investigation of over a hundred homoeopathic trials was applied in this assessment.28 The scheme awards a total of 100 points to each methodology in the following categories:

• Adequate description of patient characteristics (maximum score 10 points)
• Size of patient groupings (25-49, 10 points; 50-99, 20 points; 100+, 30 points)
• Details of randomisation (20 points)
• Adequate description of intervention (5 points)
• Double blinding (20 points)
• Relevant measurement of effect (10 points)
• Appropriate representation of results (5 points)

To obtain some assessment of the efficacy of glucosamine, a further meta-analysis was carried out on the six trials. This technique, accredited to Mantel and Haenzsel, involved a number of statistical calculations based on expected and observed outcomes.29 The odds ratio estimated the odds of achieving a successful treatment using glucosamine sulphate, against the odds of achieving a successful outcome using placebo. The higher the odds ratio the better the treatment. A value greater than 1 for the 95 per cent confidence intervals of the odds ratio indicated that glucosamine had a significant effect. An expected value for the number of patients likely to experience positive outcomes from the administration of glucosamine was calculated for each trial using a formula that involved figures derived from the intervention and control groups. It was then compared with the results obtained by observation and a variance calculated. This figure was added (or subtracted) from the observed value to give a true range for the expected value. The higher the variance the more effective the glucosamine.

RESULTS

The results of the first meta-analysis are summarised in Table 1.

Only half the studies passed Kleijnen et al's arbitrary pass mark of 55 points for satisfactory quality of methodology. However, the scores for seven of the 10 studies were clustered around 50 points, giving little to choose between the quality of their methodology. The results of the second meta-analysis are summarised in Table 2.

DISCUSSION

A meta-analysis gives an indication of the weight that can be attributed to each of the authors' methodologies and thus a measure of the likely value of the outcome. McAlindon et al40 evaluated the benefit of glucosamine and chondroitin preparations for osteoarthritis symptoms using a meta-analysis combined with systematic quality assessment of clinical trials of these preparations in knee and/or hip osteoarthritis. Reviewers performed data extraction and scored each trial using a quality assessment instrument. Of the 15 trials analysed, only six concerned glucosamine; the remaining nine, almost all of which were sponsored by manufacturers, were judged to be of inadequate quality by the authors. Nevertheless, they concluded that trials of glucosamine and chondroitin preparations for osteoarthritis symptoms did show moderate to large beneficial effects, but acknowledged that quality issues and likely publication bias might have exaggerated these benefits. Three of the studies included in McAlindon et al's study were also included in our analysis.
The major downfall in most of the trials in our meta-analysis was a lack of participants. Four trials scored zero on Kleijnen's scale indicating that fewer than 50 participants were included. Another problem was a lack of detail about the randomisation process; only two of the trials - Muller-Fassbender et al37 and Noack et al38 - explained the randomisation process in sufficient detail to allow replication of their work. The latter trial scored highest for quality in our analysis and was also the highest rated "adequate" in McAlindon's analysis. A more complete explanation by the other authors would have improved scores significantly. As osteoarthritis is a chronic disease, longer trials would have been more appropriate. All the trials failed to monitor patients after the trial period had finished. Thus no assessment of ongoing benefit could be made.
Unfortunately, of the 10 clinical trials, only six compared glucosamine sulphate with placebo. Of the remaining four trials, two compared glucosamine with ibuprofen and the other two used glucosamine sulphate alone. Three of these trials - those by Muller-Fassbender et al,37 Noack et al38 and Reichelt et al,39 all carried out in 1994 - appeared to be the best in both analyses and were likely to have produced the most reliable results. However, the Muller-Fassbender trial compared glucosamine with ibuprofen and had to be excluded.
The next best trial was that of Drovanti et al.31 This was a double-blind trial involving 80 inpatients with established arthritis who were split into two groups randomly. The first group received two 250mg capsules of glucosamine sulphate and the second group an undistinguishable placebo. Each dose was given three times daily for 30 days. Articular pain, joint tenderness and restriction of movement were scored on a scale of 1-4 at one week intervals. Any adverse reactions were similarly scored. Safety was monitored by haematology; urine analysis and occult faecal blood were recorded before and after treatment. Samples of articular cartilage from two patients of each group and from one healthy subject were submitted to scanning electron microscopy after the end of treatment. Patients treated with glucosamine sulphate experienced a reduction in overall symptoms that was almost twice as great and twice as fast as those who had placebo. The results were supported by the findings of electron microscopy.
Noack et al38 carried out a double-blind trial using 252 outpatients who had suffered arthritis in the knee to a measurable amount for at least six months. The trial randomly allocated the patients to two groups, one receiving 250mg tablets of glucosamine sulphate and the other placebo, three times daily. The trial extended over four weeks with assessment at enrolment and weekly thereafter. It was concluded that glucosamine sulphate might be a safe and effective symptomatic treatment for osteoarthritis.
Reichelt et al39 also carried out a double-blind trial, involving 155 outpatients with osteoarthritis of the knee. Inclusion criteria included a requirement to have been suffering from symptoms for at least six months. The two groups, consisting of 79 and 76 patients, received 400mg glucosamine sulphate and placebo, respectively, administered as intramuscular injection twice weekly. Assessment was done at enrolment, at two-weekly intervals during the trial and once after the trial had been concluded. At the end of the trial the patients were assessed by the investigator and classified as good, moderate, unchanged or worse. Safety was monitored by a number of biochemical tests. A significant improvement in symptoms was noted compared with placebo.
There are various limitations of the meta-analysis. In the application of the meta-analysis technique the choice of inclusion criteria is always going to be a source of possible bias. The award of points in some cases may also be reflective of the analyst's personal perception of importance. Another factor is the awareness of clinical heterogeneity. This refers to considerable differences in each trial with respect to patient selection and baseline disease severity. It is important that these differences do not introduce incompatibilities. Another disadvantage of the Kleijnan scale is that it does not take into account the time-scale of the trial. In this case the length of trial varied between three weeks (Crolle and D'Este30) and eight weeks (Vaz35). Routes of administration may introduce variables. In the trials chosen the oral, intramuscular and intra-articular routes were used.
Dietary supplementation with tissue-derived extracts, such as beef or shark cartilage, has been studied over the past 20 years and has been claimed to slow the rate of osteoarthritic debilitation. These observations have led to a number of products being marketed with the aim of helping patients to alleviate the symptoms of osteoarthritis.41 Cartilage extracts digest slowly providing glucosamine over a longer period. Since the early 1990s, glucosamine has been used along with cartilage to increase its therapeutic efficacy. One orally administered formulation of glucosamine, which is particularly successful in the US, is a combination with chondroitin sulphate. Chondroitin is involved in the glucosamine biochemical pathway. Such combinations appear to be increasing in popularity.
A novel, complementary approach has been suggested by Vaz, using glucosamine sulphate along with an anti-inflammatory agent during an initial period of about two weeks to ensure prompt reduction of pain and then to continue treatment for a further six to 10 weeks or longer with only glucosamine.35
The evidence for this suggestion was provided by a double-blind trial in 40 patients with unilateral osteoarthritis of the knee to compare the efficacy and tolerance of oral treatment with 1.5g glucosamine sulphate or 1.2g ibuprofen daily over a period of eight weeks.
Pain scores decreased faster during the first two weeks in the ibuprofen than in the glucosamine treatment group. Although the rate of decrease was slowed, the reduction in pain scores was continued throughout the trial period in patients on glucosamine, and the difference between the two groups turned significantly in favour of the glucosamine at week eight. No significant differences were observed in swelling or any other parameters monitored.

CONCLUSION

All the variations in the studies mentioned above mean that it is difficult to come to a firm conclusion as to the overall effectiveness of using glucosamine for the treatment of osteoarthritis. Randomised clinical trials based on one product and a single route of administration are necessary to enable a true assessment to be made. The amount of evidence for the use of chondroitin appears to be less than for glucosamine; studies are urgently required in this area.
The results of our analysis for glucosamine would seem broadly to back up McAllinden et al's work and were positive, notwithstanding the methodological limitations and possible publication bias.
Osteoarthritis is normally a chronic condition. There is no evidence that taking glucosamine will provide a long-term cure. Most importantly, there is no evidence that it is safe to take the compound for an extended period. As with other so-called supplements, the advice would seem to be that glucosamine should be used judiciously over limited periods, say for no more than three months at a time.

Dr Kayne is a community pharmacist and visiting lecturer at the school of pharmacy, University of Strathclyde, Glasgow. Miss Wadeson is a community pharmacist in Worthing, West Sussex. Dr MacAdam is senior lecturer in pharmacy practice at the school of pharmacy and biomolecular sciences, University of Brighton. Correspondence to Dr Kayne at 20 Main Street, Busby, Glasgow G76 8DU (e-mail SKayne9665@cs.com)

References

1. Scott DL, Shipley M, Dawson A, Edwards S, Symmons DPM, Wolf AD. The clinical management of rheumatoid arthritis and osteoarthritis: strategies for improving clinical effectiveness. Br J Rheumatol 1998;37:546-54.
2. Lawrence JS, Bremmer JM, Bier F. Osteoarthrosis. Prevalence in the population and relationship between symptoms and X-ray changes. Ann Rheum Dis 1966;25: 1-24.
3. Osteoarthritis - time to shift paradigm? BMJ 1999;318: 1299-300.
4. Goldthwaite JE. Treatment of disabled joints resulting from so-called rheumatoid disease. Boston Med Surg J 1897;136: 79-84.
5. Melvin JL. Rheumatic disease in the adult and child (3rd ed). New York: Davis Co; 1989. pp49-55.
6. Bayraktar A, Hudson S, Watson A, Fraser S. Arthritis. Pharm J 2000;264:57-68.
7. NSAID focus. Bandolier 1998;(52):1-7.
8. Henry D, Dobson A, Turner C. Variability in the risk of major gastrointestinal complications from non-aspirin non-steroidal anti-inflammatory drugs. Gastroenterology 1993; 195:1078-88.
9. Howell DS, Pita JC, Muller FJ, Manicourt DH, Altman RD. Treatment of osteoarthritis with tiaprofenic acid: biochemical and histological protection against cartilage breakdown in the Pond-Nuki canine model. J Rheumatol 1991;18(Suppl 27): 138-42.
10. Lange P, Oun H, Fuller S, Turney JH. Eosinophilic colitis due to rifampicin. Chest 1980;77:579.
11. Bloom BS. Cost of treating arthritis and NSAID-related GI side effects. Aliment Pharmacol Ther 1988;2S:131-9.
12. Henry D, Lim LL, Garcia Rodriguez LA, Perez Guttham SP, Carson JL, Griffin M et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaboratorive meta-analysis. BMJ 1996;312:1563-6.
13. Mankin HJ, Johnson ME, Lippiello LE. Biochemic and metabolic abnormalities in articular cartilage from osteoarthritic human hips. J Bone Joint Surg Am 1981;63:131-9.
14. McCarty D. Arthritis and allied conditions. A text book of rheumatology (11th ed). London: Lea and Febiger; 1989. pp1571-641.
15. Felson DT, Zhang Y, Antony J, Naimark A, Anderson JJ. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. Ann Intern Med 1992;116:535-9.
16. Lane NE, Beat M, Bjorkengren A. The risk of osteoarthritis with running and ageing: a five-year longtitudinal study. J Rheumatol 1993;20:461-8.
17. Lane NE. Exercise: a cause for arthritis. J Rheumatol 1995;22;3-6.
18. Oddis CV. New perspectives on osteoarthritis. Am J Med 1996;100:105-55.
19. Briffa J. Glucosamine sulphate in the treatment of osteoarthritis. Int J Altern Comple Med 1997;(October):15-16.
20. Boonyaratavej N. Synovial cytology of osteoarthrosis after intra-articular injection of glucosamine salts. J Med Assoc Thai 1977;60:30-4.
21. Lachman S. Soft tissue injuries in sport. Oxford: Blackwell Scientific Publications; 1988. pp40-41.
22. Creamer P, Hochberg MC. Osteoarthritis. Lancet 1997;349:503-9.
23. Bucci LR. Chondroiprotective agents - glucosamine salts and chondroitin sulphate. Townsend Letter for Doctors 1994;(January):52-4.
24. McCarty MF. The neglect of glucosamine as a treatment for osteoarthritis - a personal perspective. Med Hypotheses 1994;42:323-7.
25. Kimm JJ, Conrad HE. Effects of d-glucosamine concentration on the kinetics of mucopolysaccharide biosynthesis in cultured chick embryo vertebral cartilage. J Biol Chem 1974;249:3091-7.
26. Basleer C, Henrotin Y, Franchimont P. In vitro evaluation of drugs proposed as chondroprotective agents. Int J Tissue React 1992;14:231-41.
27. Setnikar I, Pacini MA, Revel A. Antiarthritic effects of glucosamine sulphate in animal models. Arzneimittelforschung 1993;41:542-5.
28. Kleijnen J, Knipschild P, ter Riet G. Clinical trials of homoeopathy. BMJ 1991;302:316-23.
29. Mantel N, Haenzsel W. Statistical aspects of the analyses of data from retrospective studies of diseases. J Nat Cancer Inst 1959;22:719-48.
30. Crolle G, D'Este E. Glucosamine sulphate for the management of arthrosis: a controlled clinical investigation. Curr Med Res Opin 1980;7:104-9.
31. Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulphate in osteoarthritis: a placebo controlled double blind investigation. Clin Ther 1980;3:260-72.
32. Pujalte JM, Llavore EP, Ylescupidez FR. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthritis. Curr Med Res Opin 1980;7:11-114.
33. D'Ambrosio E, Casa B, Bompani R, Seali G, Scali M. Glucosamine sulphate: a controlled clinical investigation in arthrosis. Pharmather 1981;2:504-8.
34. Tapadinhas MJ, Rivera IC. Oral glucosamine sulphate in the management of arthrtosis: report on multicentre open investigation in Portugal. Pharmather 1982;3:158-68.
35. Vaz AL. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthritis of the knee in outpatients. Curr Med Res Opin 1983;3:145-9.
36. Vajranetra P. Clinical trial of glucosamine compounds for osteoarthritis of knee joints. J Med Assoc Thai 1984;67:409-18.
37. Muller-Fassbender H, Bach G, Haase W, Rovati LC, Setnikar I. Glucosamine sulphate compared with ibuprofen in osteoarthritis of the knee. Osteoarth Cart 1994;2:61-9.
38. Noack W, Fischer M, Forster K, Roivati LC, Setnikar I. Glucosamine in osteoarthritis of the knee. Osteo Cart 1994;2:51-9.
39. Reichelt A, Forster KK, Fischer M, Rovati LC, Setnikar AR. Efficacy and safety of intramuscular glucosamine sulphate in osteoarthritis of the knee. Arzneimittelforschung 1994;44: 75-80.
40. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis. A systematic quality assessment and meta-analysis. JAMA 2000; 283:1469-75.
41. Grant GF, Gracy RW. Therapeutic neutraceutical treatments for osteoarthritis and ischaemia. Exp Opin Ther Patents 2000;10:39-48.