Glucosamine and chondroitin are widely taken to help relieve knee pain from osteoarthritis but do they work?
Since 2000 forty-eight percent of new joint health supplements in the US contained glucosamine and twenty-four percent chondroitin (Mintel Global New Products Database). This makes glucosamine the biggest selling US dietary supplement. Plus demand is on the increase. Since the prescription drug Vioxx was taken off the shelves more people have been turning to ‘natural’ dietary supplements - such as glucosamine - for their arthritis relief. Prices have also rocketed in recent years, in part due to the Asian tsunami interrupting supplies of shrimp and crab shells, the main raw material in the production of glucosamine. No one can question that glucosamine and chondroitin sulphate supplements are big business - but do they work?
To try to answer this question $12.5 million of US tax payers money was invested by the National Institutes of Health (NIH) into a study to look at whether glucosamine and chondroitin sulphate are effective in providing relief in the management of knee pain from osteoarthritis. The study was named ‘The Glucosamine/Chondroitin Arthritis Intervention Trial’ - or ‘GAIT’.Recruitment for the study began in May 2002. On November 14, 2005, at the Annual Meeting of the American College of Rheumatology in San Diego, California, Dr Daniel O Clegg, Professor of Medicine and Chief of Rheumatology, Division of Rheumatology, University of Utah School of Medicine, presented the long awaited findings of this multicentric trial in which 1,583 people participated. The results of the study were eagerly anticipated - but at the end of the day they were shrouded in controversy and left medical practitioners hard-pressed to decide whether or not to continue recommending or prescribing these substances for their patients.
The GAIT Study
GAIT was designed to test the short-term (6 months) effectiveness of glucosamine and chondroitin sulphate, either alone or in combination, in reducing pain in knee osteoarthritis. The two drugs were evaluated under an Investigational New Drug application that was filed with the US Food and Drug Administration (FDA).
The study, like most good medical studies, was done ‘double blind’, that is neither the patients nor the people administering to them knew which treatment the patient was on.
Patients were randomly assigned to different treatment subgroups -
* chondroitin sulphate alone (400 mg 3x a day)
* glucosamine hydrochloride alone (500 mg 3x a day)
* combined glucosamine hydrochloride/chondroitin sulphate (same doses but combined)
* celecoxib (Celebrex®) (200 mg per day)
* placebo (inactive dummy tablet)
The dosages for glucosamine and chondroitin were selected at 1500mg a day and 1200mg a day respectively as although the optimal daily dosage hasn’t been determined as yet these levels are the commonly suggested daily amounts. The celecoxib group was included as a positive control for the GAIT study. Celecoxib was used as it has been FDA approved for the management of osteoarthritis pain and investigators therefore expected participants in this group to experience pain relief and that this predictable response would help to validate the GAIT results.
The GAIT Findings
The patients were divided into two groups based on pain levels assessed by a validated index score (WOMAC) -
* mild pain (1,229 patients)
* moderate to severe pain (354 patients)
The effectiveness of the drugs was initially evaluated on all the patients grouped together. Then the two groups were evaluated separately. The results of the overall group of 1583 patients in the GAIT study showed that neither glucosamine nor chondroitin sulphate either on their own or in combination were effective in reducing pain.
But when results of the group of patients with moderate to severe pain was analysed the investigators found that the combination of glucosamine and chondroitin sulphate WAS significantly effective for pain relief!
Also, although the glucosamine and chondroitin sulphate subgroup showed significant improvements in WOMAC score in the moderate to severe pain patients, the celecoxib group showed no significant improvements in pain in the same moderate to severe pain patients. Why is this important? Well, the whole reason a celecoxib group was included was because there was an expectation, based on prior studies, that it would have a significant effect on pain i.e. act as a positive control group. It has therefore been suggested that perhaps the results from all the groups in GAIT are ‘understated’.
At first glance there appears to be a substantial number of patients participating in this study – 1583 in total. However, once the moderate to severe group was split into the treatment subgroups there were only 72 patients taking glucosamine and chondroitin and 70 taking a placebo. In terms of clinical trials these are relatively small patient numbers and this has implications for the recommendations from the GAIT study.
With 744 patients taking either glucosamine or chondroitin or both there were sufficient numbers for some reassurance that side effects from taking these supplements are minor. However, it must be borne in mind that the GAIT study used pharmaceutical grade products that underwent strict quality control.
The GAIT team are continuing their work by looking at whether glucosamine and chondroitin can actually alter the progression of osteoarthritis i.e. disease-modification. The results of this study can be expected in a couple of years time.
The GUIDE study
At the same that the GAIT study released their results a European group also presented results from a similar study at the 2005 Annual Meeting of the American College of Rheumatology. The Glucosamine Unnum-A-Die (Once a Day) Efficacy trial - commonly known as the GUIDE study - compared levels of pain and mobility in 318 osteoarthritis sufferers between the ages of 45 and 75 at 13 European hospitals. The patients were randomly allocated to one of the following groups.
* glucosamine sulphate in soluble powder form 1500mg daily
* acetaminophen (e.g. Tylenol® and paracetamol) 3000mg daily
All groups were allowed to take ibuprofen (Brufen®) as needed as a ‘rescue’ for pain relief.
The GUIDE findings
Both glucosamine sulphate and acetaminophen were more effective in reducing pain than placebo. Patients taking glucosamine sulphate exhibited more relief than patients on acetaminophen.
It was concluded that once-daily 1500 mg oral doses of glucosamine sulphate may be the preferred treatment for knee osteoarthritis.
It must be noted that unlike the GAIT study that was publicly funded the GUIDE study was sponsored by the manufacturers of the glucosamine compound that was used in the trial.
A 2005 article in the Journal of the American Pharmacists Association found that “NO commercially available chondroitin product was deemed appropriate for use in GAIT.”
Because the potency of the product varied too much PLUS contaminants were found in several tests. This is why for the GAIT study the supplements were subjected to pharmaceutical regulation to ensure quality. In many European countries you can only get glucosamine and chondroitin on prescription from a doctor but in the USA and UK you can purchase glucosamine and chondroitin ‘over the counter’ without a prescription. This is because glucosamine and chondroitin are classed as ‘dietary supplements’ and not medications. On the plus side the classification as a dietary supplement means these products are easily accessible to everyone but on the negative side it means the contents are not as strictly regulated and the quality and purity of the products are therefore not assured. So both these studies suggest that, at least in the case of moderate pain, the combination of glucosamine and chondroitin sulphate in adequate dosage are helpful for your joint cartilage. But there is another big issue to talk about and that is - Are you getting what you think you’re paying for?
Product quality is a serious problem with these supplements. One independent product testing company, ConsumerLab.com, found that several combination products of glucosamine and chondroitin were low in chondroitin sulphate (the more expensive ingredient) including one product that only had 90mg when it should have been 500mg! A study published in the Journal of Rheumatology in 2002 analysed 14 commercially available glucosamine sulphate products and found that the amount of glucosamine varied from 59% to 138% of the label amount and a Consumer Report in 2002 found a considerable variation in glucosamine and chondroitin sulphate content for a number of products. So there is a big problem relating results of studies such as GAIT - that have used standardised, regulated glucosamine and chondroitin sulphate preparations - to anyone considering using over-the-counter glucosamine and chondroitin sulphate products that are classed as dietary supplements. In the published results of GAIT the investigators actually state that products identical to the ones used in GAIT may not be commercially available. If you can’t buy the products used in the study how relevant are the results of GAIT to the person on the street with knee pain from osteoarthritis?
What type, how much and when?
Glucosamine is available in several different chemical formats. The GUIDE study, in line with several previous studies, used glucosamine sulphate whereas the GAIT study used glucosamine hydrochloride (HCL). Does this make a difference? Well there is considerable disagreement as to whether one form of glucosamine works better than the other. Glucosamine sulphate is made by chemically modifying glucosamine HCL. Some experts say they perform equally well whereas other experts based on animal studies suggest that glucosamine HCL is an ‘inactive’ form and that glucosamine sulphate works better. In the GAIT study the supplements were taken three times a day whereas in GUIDE they were taken just once a day. There are suggestions that once a day gives better dosing but this hasn’t been backed up scientifically to date.
Assuming you find a reliable manufacturer, what is the best way to get the glucosamine and chondroitin sulphate to your knee cartilage? Glucosamine and chondroitin sulphate supplements come in a variety of pills, capsules, powders and liquid formats. Some people find the large tablets difficult to swallow and prefer to take the supplements in a beverage form. There are an increasing number of commercial companies ‘jumping on the joint health bandwagon’ and marketing ‘super joint care’ drinks. Some medics are recommending glucosamine in a liquid format on the basis that significantly more of the glucosamine actually gets into the blood stream compared with pills. In addition some medics are not recommending glucosamine and chondroitin sulphate combinations to patients as the chondroitin sulphate is so poorly absorbed into the blood stream.
In both the GAIT and GUIDE studies 1500mg of glucosamine daily was used and in the GAIT study 1200mg of chondroitin daily was used. However, some manufacturers suggest that glucosamine and chondroitin sulphate supplements should be taken in two phases, for example -
* A loading phase of a month of increased levels of glucosamine (up to 2250mg) and 1200mg of chondroitin sulphate.
* A maintenance phase of 1500mg of glucosamine and 800mg of chondroitin sulphate.
Other suggestions are that glucosamine and chondroitin sulphate doses should be calculated based on a person’s body weight. One recommendation is 20mg of glucosamine for every 1kg of body weight, whilst another suggestion is as follows:
* If body weight is less than 54.5kg take 1,000mg glucosamine and 800mg chondroitin sulphate.
* If body weight is between 54.5 and 91kg take 1,500mg glucosamine and 1,200 mg chondroitin sulphate.
* If body weight is more than 91kg take 2,000mg glucosamine and 1,600mg chondroitin sulphate.
Are these ploys by supplement companies to sell more of their product or is there a scientific basis for these recommendations? Well, at present the evidence for doses and schedules is fairly sparse and that is one of the reasons why daily doses of 1500mg of glucosamine and 1200mg of chondroitin sulphate are common recommendations.
What about the source of these products?
Chondroitin sulphate is usually produced from cow (bovine) cartilage but can be produced from pig (porcine), chicken and even shark cartilage. Glucosamine on the other hand is derived from shellfish, usually shrimp, lobster or crab shells. There are forms that are available for vegetarians, Kosher diets and those people with shellfish allergies as chondroitin sulphate can be produced from algae or fungus and glucosamine can be produced from corn, but these products tend to be considerably more expensive than their animal counterparts. Also bear in mind that if you are taking supplements in capsule form the capsule itself is often made from bovine gelatin so check the ingredients of the capsule as well as the contents.
One of the concerns that has been raised over the ingestion of bovine chondroitin sulphate is the risk of acquiring Bovine Spongiform Encephalitis (BSE) commonly known as ‘Mad Cow Disease’. BSE is associated with neural tissue and the fact that the cartilage that is used to produce chondroitin sulphate is generally taken from the cow’s windpipe (trachea) and has very limited neural tissue (spinal cord, brain, nerve) would tend to indicate a very low risk of acquiring BSE from chondroitin sulphate supplements. However, the way that the chondroitin sulphate is extracted and processed doesn’t guarantee the destruction of BSE if any is present. So although there are no known direct links of BSE to chondroitin sulphate supplementation if you are concerned about the risk you should look for non-bovine sources of chondroitin sulphate. Similarly, although as far as the author is aware there have been no known cases of anyone contracting Asian bird flu from glucosamine supplements, if this concerns you then look for a non-chicken source of glucosamine.
Chondroitin sulphate production in the body can be hindered if there is a deficiency of some key vitamins and minerals, in particular manganese, vitamin C and vitamin A. As participants in the GAIT study didn’t appear to undergo a dietary analysis prior to the start of the trial it is possible that some individuals may have had deficiencies in these key substances.
There was also another notable omission in the GAIT study design in that participants, according to the published report in NEJM, weren’t asked if they were currently taking or had been recently taking glucosamine or chondroitin sulphate before they started the trial. It is known that glucosamine and chondroitin supplementation takes 6 to 12 weeks to reach peak effect and therefore a long wash out period is needed to avoid a carry over effect of prior use. With such widespread use of these supplements nowadays it is not unreasonable to suggest that a number of the participants were either taking or had recently taken glucosamine and/or chondroitin supplements.
Are there any risks?
The good news is that side effects of taking glucosamine and chondroitin sulphate tend to be mild and not very common. In the GAIT study a number of patients did experience mild side effects such as upset stomachs and nausea but the incidence was at the same level for all the groups including the patients who took the fake pills. There are no long-term studies looking at adverse effects of on-going glucosamine and chondroitin supplementation and there have been no reported incidences of overdose.
There has been some suggestion that glucosamine may worsen insulin resistance and although this hasn’t been proven as yet the general advice is for diabetics to carefully monitor their blood sugar levels when using glucosamine supplementation and not to start taking these supplements without consulting their doctor. Chondroitin has a similar format to blood-thinning drugs so anyone taking such medications, e.g. warfarin, should seek medical advice before taking these supplements.
Medical associations recommend that anyone who is taking any medications, has a health condition, is pregnant or is a child should speak to their doctor before starting to use glucosamine and chondroitin supplements.
What does this mean for YOU?
Glucosamine and chondroitin are extremely popular supplements that have received considerable press coverage over the last few years and there are lots of anecdotal comments flying around. Some people will swear by glucosamine and chondroitin sulphate and others have found it didn’t help their knee pain and will tell you it was a waste of money. So what do the latest study results mean for you?
Well, the best that can be said at present, off the back of the results of the GAIT study, is that glucosamine and chondroitin supplementation may provide some pain relief for knee osteoarthritis sufferers especially those people with moderate to severe pain. At what cost does this pain relief come? Well, even though the side effects are relatively minor these supplements don’t work for everyone and they can be expensive ($1-2 per day). If you start to take glucosamine and chondroitin sulphate and are not finding any effect on your pain after 3 months the advice at present is to stop taking them. So on one hand the risks of side effects are low but on the other hand it is difficult to assure the quality of the products as they are not produced to pharmaceutical grade in the US and UK. So if you are looking at it from a risk to benefits point of view any risk is more likely more to your wallet than to your health.
Putting things into perspective - supplements are just that. They are meant to supplement NOT replace your usual knee management strategies. Yes they may give you some additional pain relief, which is fantastic, but there are currently no studies that provide evidence that glucosamine and chondroitin sulphate actually slow down the progression of the osteoarthritis. There are other management strategies that you can adopt that are likely to offer an equal, if not greater level, of pain relief than glucosamine and chondroitin supplementation. That isn’t to say that you shouldn’t consider supplementation but you should view supplementation as part of your overall management plan not THE management plan.
Herrero-Beaumont, G. et al. (2005). Effects of Glucosamine Sulfate on 6-Month Control of Knee Osteoarthritis Symptoms vs Placebo and Acetaminophen: Results from the Glucosamine Unum in Die Efficacy (GUIDE) Trial. Paper presented at American College of Rheumatology Annual Scientific Meeting, San Diego, USA