Glucosamine and chondroitin: new evidence of joint protection

Published in Health News and Evidence

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Practice points | The glucosamine story so far | Positive findings from the LEGS trial | MRI study supports increased effect in early disease | Specialist Q&A: glucosamine and chondroitin for osteoarthritis | Information for patients | References

Summary

The mixed results from trials of glucosamine and chondroitin in osteoarthritis have presented a confusing picture. Despite earlier enthusiasm, recent meta-analyses and reviews have tended to be equivocal or negative; concluding that neither agent, nor a combination, has a significant effect on pain or disease progression.

However, two recent studies of glucosamine and chondroitin have shown the combination has a protective effect against structural disease progression in osteoarthritis of the knee.

The authors of both new studies commented that using the supplement combination early on in disease could give the greatest chance of an effect. This could in part explain why some trials in people with more advanced disease have not shown a benefit.

Practice points

  • Glucosamine sulfate and chondroitin may be more effective in combination than either taken alone.1
  • People with early osteoarthritis of the knee may be more likely to benefit from glucosamine/chondroitin than those with more severe disease.1,2
  • Glucosamine and chondroitin are available as single oral supplements, or in combination with each other, or with other ingredients. The sulfate form of both oral supplements was used in a recent positive trial, at doses of glucosamine 1500 mg/day and chondroitin 800 mg/day.1
  • Most glucosamine products are derived from shellfish and are not suitable for people with seafood allergy.3
  • Concerns have been raised about the effect of glucosamine on glycaemic control, and on bleeding time in people on warfarin.3 Authors of a recent trial advised patients with diabetes to be vigilant in monitoring blood glucose levels, and patients taking warfarin were advised to be vigilant about INR monitoring.1
  • Weight loss (if overweight) and exercise are important for improving pain and function.3 Paracetamol is first-line therapy for osteoarthritis symptoms.3

The glucosamine story so far

Many Australians have already decided it is worthwhile taking glucosamine, with more than one in five adults over 45 reporting they take it.4 However, forming a conclusion about its efficacy in osteoarthritis based on scientific evidence has not been easy, given the mixed results from trials.

Several recent reviews have been equivocal or negative.5-8 But hopes have been raised again by new evidence. These include findings from a much-anticipated Australian double-blind randomised placebo-controlled trial (the LEGS trial).1

The recent positive findings might be due to researchers getting closer to identifying who is most likely to benefit from these supplements in osteoarthritis—and how the supplements need to be taken to have the greatest effect.

Some say there may be an effect

A Cochrane review published in 2005 reported some benefit from the combination of glucosamine and chondroitin on pain and function, but noted an effect was seen only in trials that used one type of glucosamine (crystalline glucosamine sulfate, DONA).5 The Cochrane review was positive about safety, concluding that glucosamine is as safe as placebo.

A meta-analysis published in 2010 concluded that glucosamine sulfate (DONA only) or chondroitin sulfate given alone may delay radiological progression of osteoarthritis of the knee.6 Many of the positive trials with DONA glucosamine used a powdered form.9-11

Others say no effect on pain or disease progression

Authors of another meta-analysis of trials with glucosamine, chondroitin, or the combination, were clear in their conclusion that the supplements did not reduce joint pain or affect progression of osteoarthritis, as shown by joint space narrowing.8 They went so far as to say it was “unlikely that future trials will show a clinically relevant benefit” of glucosamine or chondroitin.

They also commented that health authorities and insurers should not cover the costs for glucosamine or chondroitin, given their lack of effect, and new prescriptions for patients should be discouraged.

Anticipation for the Australian LEGS results

Despite their negative conclusions, authors of the meta-analysis conceded that the lack of observed effect may have been due to the inclusion of participants with disease that was either too advanced, or not advanced enough.8

They commented that if another trial were to address these concerns, and overcome factors that have undermined the validity of previous research, it would have to meet rigorous criteria. These include independence from industry, inclusion only of patients with moderate disease, use of concealment methods that ensure blinding, and enough participants to ensure adequate power.

Writing in 2010, the authors said the ongoing Australian-based randomised Long Term Evaluation of Glucosamine Sulfate Study (LEGS) would probably satisfy most of these criteria.8

Positive findings from the LEGS trial

The LEGS results were published in 2014. They showed that the combination of glucosamine sulfate and chondroitin sulfate significantly reduced the amount of joint space narrowing over a two-year period, compared with placebo.1

The participants were aged between 45 and 75 years, and about half had only mild radiographic osteoarthritis of the knee. The 605 participants were randomised to one of four once-daily treatments:

  • glucosamine sulfate, 1500 mg
  • chondroitin sulfate, 800 mg
  • both supplements
  • matching placebos.

Knee X-rays were taken 3 times a year, for 2 years. At the end of the study, X-ray sets for 303 participants met the preset inclusion criteria. Results were adjusted for potential confounders such as BMI and baseline joint space width.

No significant differences were found in the amount of joint space narrowing in people taking glucosamine or chondroitin alone, compared with placebo.

However, people taking the combination of glucosamine and chondroitin had about half the amount of joint space narrowing compared with those taking placebo (a difference of 0.10 mm, p=0.046).

The researchers claimed that if this rate of reduction in joint space narrowing were to be sustained over 10–15 years “it would be very meaningful indeed”, and further noted that the clinical significance of the finding is highlighted by the increased likelihood of knee replacement surgery with more joint space narrowing.

Knee pain, as assessed by pain scores recorded in participant diaries, reduced in all groups over the 2 years, but this was not significantly different from placebo in any of the treatment groups.

Why did GAIT disagree?

These positive findings contrasted with those of the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), another large randomised controlled trial of glucosamine and chondroitin that measured joint space width over 2 years.12 Participants took either glucosamine hydrochloride, chondroitin sulfate, the combination of the two, celecoxib, or placebo. None of the groups showed a significant difference, compared with placebo.

The LEGS authors suggested several reasons1 for the difference in the study outcomes:

  • GAIT included people with more severe osteoarthritis
  • LEGS used more rigorous criteria for inclusion of X-rays, to reduce measurement error
  • The once-daily dosage used in LEGS may have increased adherence and improved the pharmacokinetics of glucosamine and chondroitin.
  • GAIT also used the hydrochloride form of glucosamine, which has given largely negative results in other trials,7 rather than the sulfate form.

MRI study supports increased effect in early disease

MRI data from the US National Institutes of Health Osteoarthritis Initiative cohort study also give some support for a disease-modifying effect of a combination of glucosamine and chondroitin.2 Joint space width measured by X-ray showed no significant differences between the groups. The authors commented that MRI may be a better tool for assessing a disease-modifying effect of osteoarthritis medicines in early disease.

The study examined the effect of commonly-used medicines on structural knee changes in 600 people. Results were analysed separately for those who also took analgesics/NSAIDs (who had more severe disease), and those who did not. After 2 years, among those who took glucosamine and chondroitin, a significant reduction in loss of cartilage volume was seen in:

  • the central tibial plateau of the medial compartment (7.5% vs 8.6%, p=0.007), in the no analgesics/NSAIDs group
  • the central tibial plateau of both compartments (5.6% vs 6.8%, p=0.05) in the analgesic/NSAIDs group.

No significant changes were seen at other subregions at 2 years.

A subanalysis showed that those with the most severe damage at baseline gained no protection from treatment with glucosamine/chondroitin. The authors suggested that glucosamine/chondroitin may not be able to protect cartilage that is already severely damaged.

Specialist Q&A: glucosamine and chondroitin for osteoarthritis

Professor Ric Day

Prof Ric Day

Professor Ric Day, rheumatologist, Director of Clinical Pharmacology and Toxicology, St Vincent’s Hospital, Sydney, and co-author of LEGS

What do you tell your patients about glucosamine and chondroitin?

My approach is to say we are not entirely sure how good the effect is, and mention the positive and negative studies. I say the combination may protect the cartilage, so it is not unreasonable to use it. Although patients with more severe disease may not have a lot of cartilage left, so the protection against joint space narrowing might be less for them.

I also talk about the cost.

Where do you see glucosamine and chondroitin fitting in?

I spend most of my time talking about non-drug strategies as the most effective way to manage osteoarthritis. We could reduce the toll of osteoarthritis hugely with weight loss, improving muscle strength, exercise, and attention to alignment of the legs with proper footwear and orthotics if necessary. Avoiding knee injuries from sport by preventative exercises and techniques would also help.

For symptoms, I emphasise paracetamol in full dose. I de-emphasise continuous NSAIDs as much as possible because of the risk of side effects. If they have to be used, low dose and short term is preferable.

Then I would talk about complementary medicines, including glucosamine with chondroitin. I also mention that it is plausible that fish oil could be helpful in OA as well as RA.

How could it work—isn’t it just broken down before it is absorbed?

The mechanism of glucosamine and chondroitin is a bit of a mystery. It has to somehow get to the cartilage, which is a big call. It is surprising it has an effect, but the fact of the matter is it seems to. Only the sulfate form of glucosamine seems to work, and again we don’t know why.

Why do you think the past results have been so mixed?

You clearly need a large study to be able to damp out extraneous effects. You also need a sound experimental design and a couple of years follow up as a minimum. A very rigorous protocol for X-ray is important, as this is subject to error otherwise.

Are you excited about the US MRI data?

Any protection of bony cartilage that we can believe because of a good study design is pretty exciting, in the sense that we haven’t had any other medicines that slow progression.

It’s an incredibly difficult area of drug development because the condition goes on for so long, and serious side effects are not acceptable. So if we can actually show something happening of a structural nature, it’s a pretty good start.

Information for patients

References
  1. Fransen M, Agaliotis M, Nairn L, et al. Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens. Ann Rheum Dis 2014; Jan 6 doi:10.1136/annrheumdis-2013-203954. [Epub ahead of print] [PubMed]
  2. Martel-Pelletier J, Roubille C, Abram F, et al. First-line analysis of the effects of treatment on progression of structural changes in knee osteoarthritis over 24 months: data from the osteoarthritis initiative progression cohort. Ann Rheum Dis 2013; Dec 13 doi:10.1136/annrheumdis-2013-203906. [Epub ahead of print] [PubMed]
  3. eTG complete [Internet]. Melbourne, Australia: Therapeutic Guidelines Limited, 2014.
  4. Sibbritt D, Adams J, Lui CW, et al. Who uses glucosamine and why? A study of 266,848 Australians aged 45 years and older. PLoS One 2012;7:e41540. [PubMed]
  5. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005;CD002946. [PubMed]
  6. Lee YH, Woo JH, Choi SJ, et al. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis. Rheumatol Int 2010;30:357–63. [PubMed]
  7. Burdett N, McNeil JD. Difficulties with assessing the benefit of glucosamine sulphate as a treatment for osteoarthritis. Int J Evid Based Healthc 2012;10:222–6. [PubMed]
  8. Wandel S, Juni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ 2010;341:c4675. [PubMed]
  9. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357:251–56. [PubMed]
  10. Herrero-Beaumont G, Ivorra JA, Del Carmen Trabado M, et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis Rheum 2007;56:555–67. [PubMed]
  11. Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113–23. [PubMed]
  12. Sawitzke AD, Shi H, Finco MF, et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum 2008;58:3183–91. [PubMed]