Nutraceuticals

Methods of administration

Glucosamine has been used to treat osteoarthritis for more than 20 years. In a double-blind study in an Italian hospital in 1980, its effects were compared with placebo.³ Eighty patients were given two capsules of glucosamine 250mg or placebo three times daily. Intensity of symptoms such as pain, joint tenderness and swelling were recorded each week for a month. At the end of the treatment, significantly more of the glucosamine patients were pain-free and some were totally symptom-free, almost double the speed and extent as compared with placebo. More recent trials using oral glucosamine are described below.
Another early trial was carried out in arthritis patients in Thailand, where, because of their usual sitting position, arthritis of the knee (gonarthrosis) is a major problem, and prevents many people from working and functioning normally.⁴ The double-blind study using 54 patients compared intra-articular glucosamine with placebo. Each patient received a weekly injection for five weeks, and results were noted a month after the end of the treatment period. Exercise, a reduced-calorie diet and avoidance of acute flexion, extension and loading of the knee were recommended for the duration of the study. Both treatments significantly decreased pain, and increased the ability to climb five steps, but the glucosamine resulted in more pain-free patients. The improvement with glucosamine, however, also lasted for at least the following month. There was partial articular function return and effective relief of pain.
A larger study was carried out to determine the effects of intramuscular (IM) glucosamine.⁵ One hundred and fifty-five patients with chronic gonarthrosis symptoms were recruited for the study from 10 outpatient clinics. They were randomly divided to receive twice-weekly IM injections of either 400mg glucosamine sulphate or placebo (saline) for six weeks. Results showed a significant improvement of symptoms in the glucosamine group compared with placebo. This improvement increased as the trial progressed. Tolerability of glucosamine was no different from that of placebo with around a 5 per cent incidence of minor side effects (nausea, headache, skin reactions and local reactions).

Comparison with NSAIDs

The most widely used drugs for osteoarthrisis are the non-steroidal anti-inflammatory drugs (NSAIDs). Even though generally thought of to be safe, NSAIDs have side effects, such as gastrointestinal ulcers, which are often not detected until the symptoms have progressed to a serious level. NSAIDs have also been shown to cause analgesic arthropathy, which is a rapid deterioration of the joints, thought to be due to the direct action of the drug on the joint.²
A study comparing glucosamine with ibuprofen was carried out in 1982⁶ using 40 patients who received either glucosamine 500mg three times daily with meals or ibuprofen 200mg for eight weeks. Although pain decreased in both groups, in the ibuprofen group there was a sharp decrease for two weeks which levelled off, whereas in the glucosamine group pain decreased much more slowly but continued for the entire trial period, reaching a lower score after eight weeks. The authors, therefore, suggested a possible treatment using a combination of ibuprofen and glucosamine for an initial two weeks, followed by continuation with glucosamine alone.
This trial has been criticised as only half the maximum dose of 400mg ibuprofen was used and as such a proper comparison cannot be made.⁷
More recently, another study showed that 500mg glucosamine compared favourably with 400mg ibuprofen when both were given orally three times a day for four weeks.⁸ Two hundred patients with chronic gonarthrosis were entered into the study, which was run as a double-blind, parallel-group design in two different clinics. There were far more side effects noted in the ibuprofen group, most being gastrointestinal. Again the full effect of the glucosamine was seen after two weeks of treatment.
Animal studies have been done to compare indomethacin, another widely used NSAID, with glucosamine.⁹ In models of subacute inflammation in rats, glucosamine was found to be 10 to 30 times safer than indomethacin, which caused serious damage of the gastrointestinal tract, and therefore more suitable in long-term therapy.
These studies have been criticised for being too short.⁷ The recommendations from a task force of the Osteoarthritis Research Society¹⁰ state that where the effect is seen several weeks after the start of therapy (as in the case of glucosamine) "trials will vary from three to¹² months in length. . . . Longer trials (up to two years) may be required to exclude toxicity or establish long-term benefit."
Most studies described in the literature were much shorter than this time and therefore the results are less conclusive. Medical Letter consultants¹¹ also found the published trials "unconvincing".

How does it work?

It has been shown that N-acetylglucosamine inhibits the enzyme elastase in a dose-dependent way.¹² Elastase plays an important role in the breakdown of the articular cartilage, ligaments, tendons and bones in RA. Also, D-glucosamine, the active principle of glucosamine sulphate, is a small molecule that readily diffuses through all biological membranes. It has a high affinity for cartilaginous tissue, and is incorporated into proteoglycan molecules. As stated above it is a preferred building block for the synthesis of GAGs, and these offer protection against the damaging effects of NSAIDs and steroids.² Thus, glucosamine acts against joint degeneration as well as offering joint protection.
Endogenous glucosamine is also a product of the hexosamine pathway, which is involved in insulin responses. Experiments have shown that glucosamine can induce insulin resistance via this pathway, without the presence of high glucose concentration, and fat-induced insulin resistance is likewise affected by the presence of glucosamine.¹³ Thus glucosamine can cause "glucose toxicity", which worsens the diabetic state and makes regulation more difficult, and can lead to the defects in insulin secretion seen in non insulin dependent diabetes mellitus (NIDDM).¹⁴ In the normal state, blood concentrations of glucosamine are negligible but when the body is exposed to non physiological concentrations of glucosamine this hexosamine pathway appears to be activated, leading to changes in the glucose utilisation. As osteoarthritis patients are often elderly and obese and high risk for NIDDM, this effect is possibly of great significance and requires very large-scale trials.

Side effects and contraindications

A large study was carried out in Portugal in which 252 doctors reported on 1,506 arthrosis outpatients, of whom 1,208 completed the study.¹⁵ Each patient received two capsules of glucosamine sulphate 250mg three times a day for six to eight weeks. The results were classed as "good" for 58.7 per cent, "sufficient" for 36 per cent and "insufficient" for 5.3 per cent of patients. Of the last group, a third had not responded to previous treatments either. As might be expected in any large group of patients, many suffered from other diseases and were taking medication for various complaints. The most common complaint was cardiovascular disease (24.7 per cent), followed by gastro-duodenal (8.6 per cent), diabetes (7.6 per cent), hepatic (4.9 per cent) and obesity (2.2 per cent). Medication being used included antihypertensives, antacids and antiulcer drugs, oral hypoglycaemics and diuretics. A different statistical distribution was noted in these patients compared with those without other illnesses in the cases of obesity and gastroduodenal problems. This may be explained by the fact that obese patients may need a dose adjustment and patients suffering from gastroduodenal disorders are less likely to take the full oral dose all the time. Diuretics also had an effect on the treatment and, again, a dose change may be required. However, the presence of other illnesses or treatments did not influence the efficacy or tolerability of the glucosamine except in these few cases and it was concluded that glucosamine was completely compatible with the disease states and medication used in arthrosis patients.
In another paper,¹⁶ an American doctor who has treated over 300 patients with glucosamine reports only one minor side effect, namely, nausea. He also describes how, as a consequence of the positive result that his patients felt, many started giving glucosamine to their dogs with such good effects that veterinary surgeons have adopted glucosamine as a standard treatment for osteoarthritic pets.
Other citations quote side effects in the region of 5 to 6 per cent, most of which were gastrointestinal and could be reduced by taking glucosamine with food.¹⁷

Conclusion

From the literature searched, it appears that glucosamine is a safe, effective and well-tolerated alternative to NSAIDs in the treatment of degenerative joint disease. However, caution is required, as long-term studies have not been carried out and overweight patients as well as those with diabetes should be warned before starting treatment.
In the United States and Europe, glucosamine use is widespread and British pharmacists should certainly be informed about this nutritional supplement as its popularity increases in this country.

The authors are from the School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL. Lisa Rapport is also a practising community pharmacist. Correspondence to Dr Lockwood

References