Glucosamine is one of the most popular food supplements, taken to reduce pain and stiffness associated with osteoarthritis, and to support joint repair in those taking part in active sports. But how does it work, and how effective is it?
Glucosamine is found in the highest concentration within joints, where it is synthesised by cartilage-forming cells (chondrocytes) from glucose and the amino acid, glutamine. Cells use glucosamine as a building block to make larger molecules (such as chondroitin sulphate and hyaluronic acid) that are needed for the production of new cartilage and synovial fluid. Elsewhere, glucosamine contributes to the structure of tendons, ligaments, heart valves, mucous membranes lining your digestive and respiratory tracts, and to healthy skin and nails.
Glucosamine and joint cartilage
Articular cartilage allows bones to slip over one another rather than rubbing together. It has a tough, slippery coating that is an order of magnitude better at resisting friction than Teflon – the smoothest, most durable, industrial coating available to engineers. Tough, flexible fibres of type II collagen provide the basic structure of cartilage, coiling around each other to form triple-stranded ‘ropes’. These ropes cross-link to trap large, proteoglycans complexes known as aggrecan.
Aggrecan consists of chains of chondroitin sulphate attached to a protein core. Up to 100 of these chains come together and bind to a long backbone-like molecule called hyaluronic acid to form a structure that resembles a centipede. Both the chondroitin sulphate and the hyaluronic acid are made within your cartilage cells using glucosamine as a basic building-block. These glucosamine-derived components attract water to form a hydrogel, which is what makes cartilage such a good shock absorber.
During normal activities, such as standing, walking, running and jumping, your articular cartilage is subjected to extraordinary pressures. Jumping down from a tractor cab, for example, subjects your joints to impact forces as high as 12 times your body weight. This compresses the joint cartilage and would lead to joint failure if the cartilage were unable to resist this deformity.
Glucosamine and synovial fluid
Synovial fluid is mostly composed of water and two lubricating glucoproteins – hyaluronic acid (which attracts water) and lubricin (or proteoglycan 4) which also contains glucosamine. Synovial fluid has a slippery consistency, similar to egg white and forms a thin, cushioning layer over articular cartilage. As well as lubricating your joints, it provides cartilage cells with oxygen and nutrients when your joint is resting. Scientists recently discovered that lubricin doesn’t just reduce friction within a joint, but also forms a barrier that repels joint surfaces and prevents their contact.
Glucosamine synthesis declines with age
The amount of glucosamine your chondrocytes produce naturally falls as you get older, as does the quality and size of your aggrecan molecules. In fact, the amount of aggrecan your cartilage cells produce typically halves between the ages of 20 and 45; by the age of 69 you make just 25% of the amount made in your early 20s. This decline in glucosamine production is associated with synovial fluid becoming thinner and less cushioning with age, and with cartilage becoming more brittle and cracking. Glucosamine supplements are widely taken to help replenish falling levels and promote continued repair in ageing joints.
Glucosamine is produced commercially from the chitin shells of crustaceans (lobster, crab and prawns) or synthesised from vegetable sources such as corn.
Two main forms are available: glucosamine sulphate and glucosamine hydrochloride. Glucosamine sulphate is digested by hydrochloric acid in the stomach so that around half dissociates into neutral glucosamine and half into ionised glucosamine. If recovered, most would be in the form of glucosamine hydrochloride which means there is little to choose between these two versions. One advantage of taking glucosamine hydrochloride is that, weight for weight, it supplies 40% more glucosamine than glucosamine sulphate. An advantage of taking glucosamine sulphate is that the sulphur component has an additional anti-inflammatory action which some people find beneficial.
Both forms of glucosamine are readily absorbed from the intestines, with more than 90% of an oral dose becoming deposited in articular cartilage. Because the molecules are small, they penetrate and diffuse through the cartilage matrix to be absorbed by chondrocytes to increase synthesis of proteoglycans such as aggrecan.
Glucosamine is not just a building block
Although glucosamine supplements provide building blocks for making new structural tissues and proteoglycans in joints, the concentrations achieved after taking supplements suggest this is not the main way in which it promotes healing and reduces joint pain and stiffness. It also acts as a biological signal to stimulate the formation of new cartilage and synovial fluid, and to suppress the activity of immune cells involved in the inflammatory breakdown of cartilage. It was also found to increase the level of hyaluronic acid in synovial fluid to make it more cushioning and, within chondrocytes from people with osteoarthritis, triggers a dose-dependent increase in aggrecan core protein levels. However, as with many prescribed drugs such as paracetamol, ibuprofen and codeine, some people inherit genes that mean they do not respond to these biological signals. One study found that chondrocytes obtained from 40% of patients with osteoarthritis did not show a significant response. The only way to know if you are within the 60% who will benefit is to try it for three months to assess improvements in joint pain and stiffness.
Early positive glucosamine trials
One of the first studies into glucosamine was published in The Lancet in which 212 people with knee osteoarthritis took either 1500mg glucosamine sulphate daily, or inactive placebo, for three years. As expected, those randomised to inactive placebo developed progressive narrowing of their knee-joint space and a gradual worsening of symptoms over the three-year trial period. Those receiving glucosamine sulphate, however, showed no significant loss of joint space and enjoyed significant improvements in pain and disability.
A later analysis suggested that glucosamine sulphate was most effective in people whose joints still had significant amounts of cartilage present, which makes sense if glucosamine acts through an effect on live chondrocytes. Participants who’d taken 1500mg glucosamine sulphate for up to three years in these studies were then followed for a further 5 years, on average, after their supplements were stopped. Those who had formerly taken glucosamine sulphate underwent fewer surgical knee replacements than those taking placebo, and also needed fewer painkillers and anti-inflammatory drugs to control their symptoms.
A large meta-analysis that pooled data from 20 randomised controlled trials looked at the effects of taking glucosamine in 2570 adults with knee and hip osteoarthritis with an average age of 61 years. Most studies used an oral dose of 1500mg glucosamine sulphate daily and, overall the results showed that glucosamine was more effective than placebo, with a significant reduction in pain of 28% and a 21% improvement in joint mobility, when measured using a scoring system known as the Lequesne Index. In four studies comparing glucosamine sulphate with non-steroidal anti-inflammatory drugs (NSAIDs, mostly ibuprofen), glucosamine was superior in two and equivalent in two. Adverse events and drop-out rates were much higher in the NSAID treatment groups than in the glucosamine sulphate groups suggesting that glucosamine was better tolerated.
So around ten years ago, everything looked rosy for glucosamine and many doctors prescribed it or recommended it to their patients.
Later negative glucosamine trials
Following this promising start, the GAIT (Glucosamine/chondroitin Arthritis Intervention Trial) study was set up to assess short-term effectiveness (24 weeks) on pain and joint function and long-term (a further 18 months) effects on progression of knee OA in patients using glucosamine and/or chondroitin compared with the prescribed NSAID drug, celecoxib. Over 1500 adults, aged 40 and over, with a history of at least six months’ knee pain and X-ray evidence of knee OA, were randomly assigned to receive either glucosamine hydrochloride or chondroitin, both supplements, celecoxib or inactive placebo.
The results showed no overall benefit from either glucosamine or chondroitin, whether taken together or alone, after the first six month period. Benefit for the combination of glucosamine hydrochloride and chondroitin sulphate was found in a subgroup of patients with moderate-to-severe knee pain, however. About 79% had a 20% or greater reduction in pain versus about 54% taking placebo. At the end of the longer, two-year period, which was designed to assess X-ray outcomes in 572 of the participants with knee osteoarthritis, no statistically significant difference in loss of joint space width on knee X-ray was seen in any treatment group. BUT what was not widely reported was that the placebo response in this study was unusually high at 60.1%. This made it difficult for any interventions to produce significant results in comparison and, in fact, the prescribed analgesic, celecoxib did not show a significant response in participants with moderate to severe knee pain, while glucosamine plus chondroitin did show a significant improvement.
Then came a negative meta-analysis of 10 trials published in the BMJ in 2010. This concluded that, compared with placebo, glucosamine, chondroitin and their combination did not reduce joint pain or have an impact on narrowing of joint space. Surprising? Not when you discover that one of these trials lasted just 4 weeks, and that in all of the studies included, some patients only took the supplements for only one week. And, for reasons that were not explained, the authors only included information from twelve (covering ten trials) out 58 eligible reports available.
The researchers did agree that glucosamine and chondroitin were safe, and stated that people should continue with these supplements as long as they continue to see a benefit. However, the authors used their publication to discourage the NHS prescription of glucosamine. As a result, doctors who might otherwise agree to prescribe these supplements are now firmly advised not to. If the trial had shown benefit, of course, doctors might have felt ethically obliged to prescribe them at a potentially huge cost to the national health service.
It is generally accepted that longer-term trials of at least 2 years (chondroitin) and 3 years (glucosamine) are needed to show significant reductions in joint space narrowing versus placebo. In the same year as the BMJ meta-analysis was published, other researchers published their assessment of the effects of taking glucosamine sulphate for at least three years, in six randomised controlled trials involving 1,502 people. This showed a small to moderate protective effect on minimum joint space narrowing, and a protective effect on severe joint space narrowing. The authors concluded that glucosamine sulphate (1,500mg/day for three years or more) may delay the natural progression of osteoarthritis of the knee.
Possible reasons for the conflicting results seen in various trials include differences in study design, short length of trial, and different strengths and quality of the supplements used. It’s important to only select supplements made to a pharmaceutical standard known as GMP (Good Manufacturing Practice) to ensure tablets contain the correct ingredients, in a consistent dose. The genetic make-up of the trial population is also important as some people will not respond to the standard dose. Another factor is that some trials allowed participants to take paracetamol which neutralises the sulphur component of glucosamine sulphate and may reduce its effectiveness.
Effects of glucosamine on Longevity
Researchers from the University of Washington and the Fred Hutchinson Cancer Research Centre, found that, out of 77,719 people aged 50 to 76, those who were taking glucosamine on at least four days a week, for at least three years, were 17% less likely to die from any cause than non-users over the following five years. When followed for an average of eight years use of glucosamine (with or without chondroitin) was associated an 18% lower risk of mortality compared with never-users. Overall, current use of glucosamine was associated with a significant 13% decreased risk of death from cancer and a 41% reduced risk of death from respiratory disease. This is covered more fully here.
The most widely recommended dose for glucosamine is 1500 mg a day, however up to 3g daily may be taken for additional benefits although some people develop digestive side effects at high doses.
Glucosamine salts are generally well-tolerated, and the incident of side effects is similar to that of inactive placebo. Benefits are often seen within one month but at least 12 weeks is needed to assess whether or not it will help you as an individual. If, after 2 months, your symptoms are not sufficiently improved, you may wish to add in, or switch to, a chondroitin sulphate supplement to see if that suits you better.
A Cochrane Review of 20 randomised controlled trials, involving almost 5000 patients, concluded that ‘Glucosamine was as safe as placebo in terms of the number of subjects reporting adverse reactions.’
If you have diabetes, always monitor blood glucose levels when making any dietary changes or starting a new supplement. Reassuringly, a study from 2011 found that glucosamine itself has no effect on fasting blood glucose levels in individuals with diabetes, or those with impaired glucose tolerance.
Do you take glucosamine?
I take glucosamine and notice a benefit. My knees, which were creaky and painful from running now feel as if they’re cushioned by soft cotton-wool, presumably due to better synovial oil production. Have you tried glucosamine supplements? Did you find them helpful? If you have any comments or questions, please use the form below and I’ll get back to you as soon as I can.
Image credits: frauke_feind/pixabay; pat_guiney/flickr