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Glucosamine: The Unsinkable Rubber Duck

Glucosamine is widely used for osteoarthritis pain. It is not as impossible as homeopathy, but its rationale is improbable. As I explained in a previous post,

Wallace Sampson, one of the other authors of this blog, has pointed out that the amount of glucosamine in the typical supplement dose is on the order of 1/1000th to 1/10,000th of the available glucosamine in the body, most of which is produced by the body itself. He says, “Glucosamine is not an essential nutrient like a vitamin or an essential amino acid, for which small amounts make a large difference. How much difference could that small additional amount make? If glucosamine or chondroitin worked, this would be a medical first and worthy of a Nobel. It probably cannot work.”

Nevertheless, glucosamine (alone or with chondroitin) is widely used, and there are some supporting studies. But they are trumped by a number of well-designed studies that show it works no better than placebo, as well as a study showing that patients who had allegedly responded to glucosamine couldn’t tell the difference when their pills were replaced with placebos. The GAIT trial was a large, well-designed, multicenter study published in The New England Journal of Medicine that showed no effect in knee osteoarthritis. A subsequent study of hip osteoarthritis also showed it worked no better than placebo.

A new study shows that glucosamine works no better than placebo for osteoarthritis pain in the low back. It was published in the JAMA: Effect of Glucosamine on Pain-Related Disability in Patients with Chronic Low Back Pain and Degenerative Lumbar Osteoarthritis: A Randomized Controlled Trial, by Wilkens et al.

It is well-designed, randomized and double blind, with 250 subjects, a low drop-out rate, a 6 month duration with a one year follow-up, appropriate clinical criteria for improvement (disability, pain, quality of life, use of rescue medications), intention-to-treat analysis, and even an “exit poll” to insure that blinding had been effective, that patients couldn’t guess which group they were in. It used the doses of glucosamine sulfate that had been called for by critics of previous studies. It was done in Norway, where glucosamine is a prescription drug (in the US it is marketed as a diet supplement under DSHEA regulations so there is a greater possibility of dosage variations and impurities); it was independently funded, with no involvement of industry.

Although no one study can be definitive, this one is pretty convincing when viewed in the context of all the other published data. The authors rightly conclude that glucosamine doesn’t work any better than placebo, but they go on to say some rather strange things. They say it should not be recommended for “all” patients with osteoarthritic low back pain, implying that it might still be recommended for “some” patients. But if so, which patients and according to what criteria? They seem strangely defensive. They stress that glucosamine caused no side effects and could be used safely. They suggest that glucosamine might work for a subset of patients or for joints other than the spine. For instance, the knee. But another new study has confirmed that it is ineffective for the knee.

I don’t understand this. If they had found that a new antibiotic worked no better than a placebo for pneumococcal pneumonia, would they say it should not be recommended for “all” patients with pneumococcal pneumonia or would they simply say it should not be used for pneumococcal pneumonia? Would they speculate that it might work for a small subset of pneumonia patients or for infections in other parts of the body? Probably not. They thought glucosamine worked; they tested it; it didn’t. Why not just say so? Are they letting a prior belief in glucosamine influence their thinking? Unbiased science-based researchers are not usually so hesitant to give up on a treatment that repeatedly fails to pass tests.

I must be psychic, because I had predicted this in a post I wrote two and a half years ago (about the study showing that glucosamine didn’t work for hip pain). I said:

They can always complain that maybe it works for knees but not for hips, or that a different dosage might have worked better, or that it works for some small sub-set of patients. There will always be “one more study” to do.

This new study confirms my opinion that we shouldn’t spend any more research dollars doing “one more study” on glucosamine.

Posted in: Clinical Trials, Herbs & Supplements

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40 thoughts on “Glucosamine: The Unsinkable Rubber Duck

  1. David Driscoll says:

    Not a great premise to start the article with(the Wallace quote). Creatine would be the gold standard of ergogenic supplement research, is found in the body in reasonable quantities (not as high as glucosamine though), can be manufactured in the body by it’s constituent amino acids and can be obtained directly from the diet and yet supplementation provides a considerable ergogenic benefit after a week of use! Nobel prize coming??

  2. Dax says:

    @David Driscoll: trying to muddy the water a bit? This post refers to glucosamine for which the evidence is neutral at best, but mostly negative. This thus has got nothing to do with creatine. Arguing in favour of one, is not evidence for the other. Second of all, creatine only shows modest effects, mostly in studies involving athletes at a high exercise intensity, and mostly only for men. The results are moderate, to say the least, not considerable. Also, the metabolic mechanisms are different.

    Anyway, enough about that, back to topic. As a runner I often hear stories about glucosamine supplementation. They’re all along the lines of “I started taking these pills and the problems with my knee [or insert other joint] just disappeared”. I always cringe when I hear that but nowadays no longer jump on it by pointing out that there’s no basis for the claim. People “know” it works and that’s that. Unfortunately, trying to educate people about confirmation bias and placebo effects only angers them. *sigh*

  3. Smed says:

    A co-worker of mine uses Glucosamine for her knees and thinks that she couldn’t live without it. Personally, I’d like to know if I were taking a placebo, but I’m not so sure this person feels the same way.

    From an ethical perspective, what’s the best coarse of action? Do you share the knowledge with your peers and potentially ruin the placebo effect that they seem to be enjoying, or do you let them live out their delusions in peace?

  4. qetzal says:

    David Driscoll,

    According to this review, total creatine in a human is on the order of 120/g. A typical creatine supplementation regimen is described as a loading phase of 20g/day x 5 days, followed by a maintenance phase of ~ 3g/day. This typically results in a modest but reproducible increase in intramuscular creatine (17 to 20+%).

    It’s interesting that this modest increase apparently has reproducible clinical effects, but I don’t agree that it’s particularly relevant to glucosamine supplementation at only 0.01 – 0.1% of normal levels. Dr. Sampson’s point is valid. It’s highly improbable that you could have a clinically relevant effect at such miniscule relative doses.

  5. Jeff says:

    Unlike homeopathy there is a plausible explanation how supplemental glucosamine could be effective. The body makes glucosamine for the synthesis of joint cartilage. My understanding was that osteoarthritis occurs when glucosamine production is deficient. There are studies showing glucosamine sulfate actually works.

    The GAIT trial can be dismissed since glucosamine hydrochloride was used – a form which has never demonstrated effectiveness.

  6. Watcher says:

    @Jeff:

    You’re making Harriet’s point; there’s always one more study to do. When is enough a enough?

  7. Josie says:

    even if it is plausible that glucosamine could have an effect –it’s marketed as an oral otc drug here in the states. Does it really survive the digestive tract? would it not be better as a shot?

    My vet prescribed glucosamine for my 16yo cat as an alternative to a more aggressive drug for her (assumed) joint pain. I was a little annoyed that all i have available to ease my cat’s discomfort is an unproven “drug” or a full on knock-her-paws-off pain medication. No aspirin or NSAIDS for kitties.

    I went through the box of glucosamine but did not see any improvement. I know that alone is just an n=1…but I won’t be spending any more money on it.

  8. WilliamLawrenceUtridge says:

    From my vague recollection of when I was in undergraduate studies, creatine mimics the biochemical effects of a specific type of exercise – high intensity resistance training. Both boost the amount of creatine phosphate in the muscle – one artificially, the other through the deplete-replete cycle the body goes through when challenged. The end result is the same – enough creatine phosphate to replete the ATP in the muscle to allow for high-intensity contractions of the large fast-twitch muscle fibers, allowing an extra rep or two to be pushed out, with concomittant effects on actin-myosin contractile filaments. In other words, it delays fatigue and contractile failure (due to insufficient energy) at extremely forceful contractions . I tried creatine for a couple months and didn’t notice a difference, and one effect my profs cautioned about was possible kidney damage, since it’s basically like consuming five pounds worth of steak in one spoonful.

    You could get it by training towards that goal anyway, it just takes patience and effort. Meh.

  9. trrll says:

    Jeff, why would you expect that the counter-ion (Sulfate vs. Chloride) would make a difference? After all, the glucosamine is not going to hang onto its counter-ion for long once it is in the body. Are you trying to suggest that it is actually sulfate, not glucosamine, that is good for the knees?

    Josie, I’ve noticed in the past that veterinarians seem to believe in the effectiveness of glucosamine for cats and dogs. Does anybody know why? Are there animal studies supporting this?

  10. khan says:

    I took it for a while.
    I do see why people desperately try stuff that might help with arthritis.
    Observing yourself deteriorating is no fun and you want to believe something/anything can help.

  11. keleton says:

    @Josie

    Re: Veterinary use of glucosamine/chondroitin

    My favorite dog, RIP, had arthiritis in her knee that was painful and causing her to limp. The vet recommended OTC glucosamine/chondroitin supplements and we saw a marked improvement within about a month. We continued the supplements for several months. They seemed to be helping so much.

    Within the year she was diagnosed with Addison’s disease and had to be on steroid replacement therapy for the duration of her life. Given that steroids reduce inflammation in the body, I wonder if her lack of steroids caused the inflammation in her joint? Still doesn’t explain the perceived improvement with the supplements. But after she was treated for her Addison’s, this 8 year old dog was a puppy again and it was so joyful to see how happy she was until her final days when she died suddenly from liver failure.

    Anyway, it seemed to work, but I don’t know why or if something else was causing the improvement.

  12. urodovic says:

    “They thought glucosamine worked; they tested it; it didn’t. Why not just say so? Are they letting a prior belief in glucosamine influence their thinking?”

    Either they don’t have the guts to just say so or they have the “meme” of glucosamine beneficial effects rooted some place in their brains. In this, they may just be behaving like many CAM proponent who as stated on Skepdic:

    http://www.skepdic.com/placebo.html

    “CAM practitioners, don’t even want to know whether a treatment is a placebo or not. Their attitude is that as long as the treatment is effective, who cares if it a placebo?”

    But the cost is “an open door to quackery”

  13. ecisler says:

    This blogger posits that glucosamine works not by providing raw material for connective tissue reconstruction, but rather by binding to errant/free tissue transglutaminase and stemming inflammatory signaling throughout the body.

    http://coolinginflammation.blogspot.com/2008/09/glucosamine-paininflammation-relief.html

    This seems to confirm that “deregulation of [tTG] enzyme activity [is] generally associated with major disruptions in cellular homoeostatic mechanisms.” Maybe arthritis is one of those major disruptions?

    http://www.ncbi.nlm.nih.gov/pubmed/12366374

  14. Scott says:

    Bloggers may posit whatever mechanisms they like. For that matter, papers may be written positing whatever mechanisms they like. So long as the evidence points towards a lack of effect, it’s not something with practical application.

  15. ecisler says:

    Well, it does something for atherosclerotic lesions (in rabbits). http://ajpheart.physiology.org/cgi/content/short/297/1/H268

    “In a combined rabbit model of chronic arthritis and atherosclerosis, orally administered GS reduced the markers of inflammation in peripheral blood, as well as the femoral and synovial membrane lesions. GS also prevented the development of inflammation-associated aortic lesions. These results suggest an atheroprotective effect of GS.”

  16. WilliamLawrenceUtridge says:

    …except testing in humans revealed no effect in multiple well-designed trials. So, glucosamine may help rabbits and suggest other veterinary applications. But for humans, we should be looking elsewhere.

    Also, this post isn’t about glucosamine for atherosclerosis. It’s about glucosamine for arthritis, which the rabbit study doesn’t seem to say much about arthritis – merely the synovial lesions. In addition to these being markers of atherosclerosis, and the prophylactic use of glucosamine against induced atherosclerosis and arthritis.

    If animal studies are promising, you test it in humans. If it passes the test in humans, it becomes part of the medical arsenal. If it doesn’t, it still gets promoted by CAM practitioners as a miracle cure.

  17. Jeff says:

    trrll: Are you trying to suggest that it is actually sulfate, not glucosamine, that is good for the knees?

    At least one researcher has suggested precisely that. Perhaps this is why other sulfur-containing supplements, like S-Adenosyl methionine (SAMe) have shown effectiveness in the treatment of osteoarthritis.

  18. patienz says:

    I think there’s good evidence that glucosamine might be useful with osteoarthritis–if it is introduced by intra-articular injection.

    This seems unlikely to be developed, since no company can patent glucosamine and a use patent seems unlikely. It happens that the molecule exits the joint very quickly–but there is still an effect. OTOH, repeated intra-articular injections may not welcomed by patients . . .

    There are several pertinent animals studies. Here’s one example:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1755188/?tool=pubmed

  19. qetzal says:

    I have a bizarre idea. I’ve seen several recent discussions about the roles of gut bacteria, and how there appear to be complex interactions between them and their host. Among other things, gut bacteria can apparently have significant effects on various cytokine levels. Here is one reference that explores this phenomenon in mice.

    Now, I don’t know how firmly established such findings really are, but something occurred to me. What if a supplement (such as glucosamine) had direct effects on gut bacteria, which in turn affected the levels of inflammatory cytokines in the host, which in turn affected inflammation-mediated diseases like OA? In that case, it might not matter if the dose was too small to affect total glucosamine in the host’s blood or tissues. What would matter is whether the dose changes glucosamine levels in the gut, sufficiently to affect the relevant gut bacteria.

    Extremely speculative, of course, but seemed intriguing enough to share. I know that some people are indeed looking at gut bacteria as an underappreciated target for treating human disease, but the stuff I’ve seen is mostly about trying to treat gastrointestinal disorders. I have no idea if anyone is looking at gut bacteria as possible routes for treating distal/systemic problems.

  20. research says:

    There is a Cochrane Review published in 2009: Glucosamine Therapy for Treating OA (78 pages for those that can access Cochrane Database of Systematic Reviews). The free summary is here: http://www2.cochrane.org/reviews/en/ab002946.html

  21. antipodean says:

    The Sydney-based LEGS study is listed as ongoing but closed to recruitment. So it’s findings should be out within 2-3 years I would imagine? It’s testing participants allocated to glucosamine sulphate and/or chondroitin in a double-blind placebo controlled trial.

    http://clinicaltrials.gov/ct2/show/NCT00513422

  22. “I was a little annoyed that all i have available to ease my cat’s discomfort is an unproven “drug” or a full on knock-her-paws-off pain medication. No aspirin or NSAIDS for kitties.”

    Yes, it seems fever reducing and anti-inflammatories are difficult for cats. Our kitten was very sick with a temp of 107 F. Apparently there are no fever reducing medicines safe for cats. All they could do is put her on IV fluids, antibiotics and line her crate with ice-packs.

    The first time I heard about Glucosamine was from my cousin. He said that he was trying it for his knees because he thought it worked wonders for his horses.

    I would be curious to hear from Vets on staff at SBM regarding Glucosamine results for various animals.

  23. wertys says:

    @patienz

    I absolutely agree. Why has nobody given it by intra-articular injection ? That would rapidly prove one way or another whether it regenerates cartilage as claimed. My suspicion is that IAI’s may not be as readily available as bottled capsules, and Big Vita have no interest in it.

    My interpretation of the current evidence is in line with the UK NICE osteoarthritis guidelines which disregard the mechanism but argue against glucosamine purely on cost-effectiveness grounds.
    http://www.nice.org.uk/nicemedia/pdf/CG59NICEguideline.pdf

    look for section1.3.6

  24. cdw860 says:

    You really must be psychic! My partners father was espousing the virtues of this to her today and she detected the whiff of bullshit and when the first place I looked it up (SBM) showed it as the very first most recent entry… well, that’s just too freaky to be coincidence…

  25. Oh, fascinating. I thought that one reason vets were so keen on it is that when you buy glucosamine at the pet store it’s often combined with MSM. When I looked up MSM a few years ago, when I was giving it to my dog, it was described as a veterinary painkiller commonly prescribed to horses. I wanted to link to it here to suggest a bait-and-switch: include painkillers in your supplement, and of course the supplement appears to reduce pain.

    But looking up MSM now tells me about a cure-all dietary supplement with little supporting evidence. Not a conventional painkiller. So that theory is out the window.

  26. BillyJoe says:

    keleton,

    “My favorite dog, RIP, had arthiritis in her knee that was painful and causing her to limp.”

    That’s not bad for a dog who has died. :D

    ——————-

    smed asked: “CAM practitioners, don’t even want to know whether a treatment is a placebo or not. Their attitude is that as long as the treatment is effective, who cares if it a placebo?”

    urodovic answered: “But the cost is “an open door to quackery””

    My view exactly.
    And with that open door to quackery eventually comes harm.

    —————-

    qetzal,

    “What if a supplement (such as glucosamine) had direct effects on gut bacteria, which in turn affected the levels of inflammatory cytokines in the host, which in turn affected inflammation-mediated diseases like OA?”

    As someone once said, before you try to explain something make sure there is something to explain.
    There is not.

  27. art malernee dvm says:

    If anyone has a positive animal study that shows glucosamine works that has been repeated by a second independent study please post it. Every positive animal study that I have found can only be repeated by those selling glucosamine. Does anyone know why rabbits seemed to be used a lot to study glucosamine? Since rabbits must eat their own poop to avoid vitamin deficiency I wonder how the glucosamine rabbit studies control the amount and effect of this part of their diet in the study. Maybe the glucosamine gets the rabbit to eat more or less poop which may have an effect. Right now I believe glucosamine works best for ducks with long legs and stethoscopes around their necks but would be willing to change my mind since selling the glucosamine in my office would be very profitable for me. At least the MDs do no sell it out of their office like most veterinarians do right now.

    art malernee dvm
    fla lic 1820

  28. qetzal says:

    BillyJoe,

    I don’t actually think that glucosamine (or most suppplements, for that matter) is doing much of anything significant. I was just using it to illustrate a more general idea that may have some relevance.

    We generally assume that any drug or supplement taken orally has to be absorbed into the body before it can have any pharmacological effect. However, there is apparently a growing body of research suggesting that intestinal flora can interact with the host and have systemic effects. Thus, it’s at least plausible that one could indirectly affect systemic host physiology by directly targeting gut bacteria.

    Part of the point is that we tend to think of ourselves as single organisms. But I keep seeing articles that remind me we’re really not; we’re actually walking communities of commensal species, comprising ~ 10^13 human cells and perhaps 10 times as many microbial cells representing at least 100′s of different species. Yet we tend to assume those microbes are irrelevant beyond their local niches (GI tract, skin, mouth). When we treat a human with a drug, unless it’s an antibiotic we tend not to even consider the possibility that it may also affect our commensals, and that that could have indirect effects on “us.” Maybe that’s usually a non-issue, but recent research suggests we shouldn’t be too sure.

    I don’t know if anyone is seriously trying to target non-GI disorders via gut bacteria. It just struck me as an interesting idea. (One I’m sure other had long before me.) If it were reallly possible, it might open up some pretty novel therapeutic approaches.

  29. manixter says:

    It’s a protein, people! You eat it, and your body breaks it down into its component amino acids and absorbs it in that form. It would make just as much sense to eat cartilage itself.
    The theories of how cartilage breaks down to create osteoarthritis (remember, cartilage on cartilage has 1/7 the friction of ice on ice) are incomplete. Abnormal forces (obesity, poor muscle tone around the joint, joint misalignment such as valgus deformities, removal and/or damage of the meniscus &c) and abnormal cartilage (desication that happens with aging &c) certainly contribute.

  30. qeztal – “I don’t know if anyone is seriously trying to target non-GI disorders via gut bacteria. It just struck me as an interesting idea. (One I’m sure other had long before me.) If it were reallly possible, it might open up some pretty novel therapeutic approaches.”

    I think this train of thought is fascinating. Seems I’ve heard of a someone studying a possible link between intestinal flora and/or parasites and allergies/asthma…

  31. Wolfy says:

    Dr Hall: Love the title :)

  32. BillyJoe says:

    qetzal,

    “I don’t actually think that glucosamine (or most suppplements, for that matter) is doing much of anything significant. I was just using it to illustrate a more general idea that may have some relevance.”

    Oh, okay…and I agree, interesting idea. :)

  33. jt512 says:

    Dr. Hall rather arbitrarily dismisses discrepant studies as having been “trumped”; however, the fact is that there have been well-controlled trials, such as the recent GUIDE trial, that showed benefits for glucosamine sulfate for OA of the knee, as reflected in the Chochrane systematic review mentioned by another commenter. Furthermore, in contrast to what the quote by Wally Sampson was apparently supposed to imply, studies have shown that glucosamine sulfate supplementation increases plasma and synovial fluid concentrations of both glucosamine and sulfate. And, since glycosaminoglycans in joint cartilage are sulfated molecules, it is certainly plausible that the glucosamine anion is important.

    So, yes, Dr. Hall, the best evidence to date suggests that both site of OA and the glucosamine anion matter.

    What is unfortunate is that all the good studies that have shown a benefit for glucosamine sulfate have been sponsored by the glucosamine manufacturer, Rotta Pharmaceuticals. If there is another study that is needed, it is one which replicates the methodology of the Rotta studies, but which is independently funded.

  34. Bear says:

    Thanks for the post. A family member was recommended glucosamine recently by his general practitioner, and although I was fairly certain of its placebo status, you’ve provided a great resource here for educators. I’ll be passing this around.

  35. cloudskimmer says:

    Drat. Another possibility gone. Some friends have been taking glucosamine/chondroitin supplements and think they help, but my own take on the evidence is that they are ineffective, and also suffer from the problem that, thanks to DSHEA, no one can know if the pill they are taking actually contains the substance, or how much. It always seemed equivalent to eating cartilage, and probably as (in)effective.

    As someone who’s had torn cartilage problems, whatever happened to the possibility of growing your own replacement cartilage? Did that turn out to be just another chimera? I’m swimming now to try and keep my knees going as long as possible, but am concerned about the lack of impact causing bone atrophy as I grow older. It looks like there are no good answers to age-related joint problems, whether in knees, hips, or spine, so I guess we’ll all be taking varying amounts of over-the-counter pain medications. And an equally severe problem is chronic back pain due to degeneration. Are we all condemned to increasing pain as we get older, and no medical solution in sight? It’s no wonder that so many people, in desperation, turn to quackery.

  36. tmac57 says:

    Just received my Sept. issue of Consumer Reports, and in a report on “Dangerous Supplements” of which they named 12, they also included “Eleven Supplements to Consider” one of which was Glucosamine Sulfate :”Likely effective treatment for reducing symptoms of osteoarthritis of the knee. Might also help slow progression of osteoarthritis,”
    I generally trust CR , but I have no opinion on this. Just reporting what I read.

  37. Prometheus says:

    Glucosamine has followed the same trajectory as many other “alternative” treatments:

    First, it was found to be a wonder-drug, curing arthritis in all people (and animals) who took it.

    Next, it was found to be modestly effective in certain cases.

    Then, early (legitimate) studies showed that its effects were difficult to distinguish from placebo. The “true believers” explained this away as “not the right preparation”, “not the right dose” or “not the right patients”.

    As more studies showed less and less effect, the “true believers” branched out, claiming that glucosamine works through “immune modulation” or by interacting with gut bacteria or by providing needed sulfate….. all without explaining how any of these hypotheses account for glucosamine’s lack of effect.

    The next phase – if glucosamine follows other failed “alternative” treatments – will be to claim that it does work, but “Big Pharma” is suppressing the data. Or maybe we’re already there….

    The bigger and better studies are showing glucosamine to be no better than placebo (and much more expensive than placebo), so it doesn’t matter how glucosamine might work because it apparently doesn’t work.

    Quite simply, the bulk of the data suggest that glucosamine is indistinguishable from placebo in its effects. That suggests that the likely mechanism of action for glucosamine is the same as that of placebo.

    Prometheus

  38. spencerjones says:

    The Consumer Reports article this story is based on is highly biased. It is thoroughly refuted at:

    http://colloidalsilversecrets.blogspot.com/2010/08/consumer-reports-lists-colloidal-silver.html

  39. Scott says:

    Spencer,

    You really ought to actually READ posts before you comment on them. If you had, you’d know that this post has no relation to either a Consumer Reports article nor collodial silver.

  40. Prometheus says:

    The idea that an essay on a website named “colloidalsilversecrets” could refute a Consumer Reports artcle – let alone Dr. Hall’s article above – is laughable. The fact is that glucosamine’s effects have – like those of many other “alternative” treatments before and after it – evaporated under rigorous study.

    If the “alt-med” types would study their “treatments” before putting them on the market, they would have fewer of these embarassing moments.

    Prometheus

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