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Glucosamine Update: A New Study and a New Product

ResearchBlogging.orgWhen I recently wrote about glucosamine, I discussed the evidence up through the New England Journal of Medicine study of 2006, which I thought was a pretty definitive study showing that neither glucosamine, chondroitin or a combination of the two was more effective than placebo.  Subsequent studies have continued to fuel the controversy. One 2007 study showed that glucosamine sulfate was better than placebo for knee osteoarthritis.  Another 2007 study showed that glucosamine HCl and chondroitin, with or without exercise, were no better than placebo for knee osteoarthritis. Sources like the Natural Medicines Comprehensive Database believe the evidence favors glucosamine sulfate but not glucosamine hydrochloride.

A new study was published 19 February 2008 in the prestigious Annals of Internal Medicine.  It is arguably the best study to date, and may shed some light on the controversy. Carried out in the Netherlands in a primary care setting, it studied 222 patients with hip osteoarthritis over a 2 year period. Half the patients took glucosamine sulfate 1500 mg a day; half took a placebo. They concluded that glucosamine sulfate was no better than placebo in reducing symptoms and progression of hip osteoarthritis.

Some of the highlights:

  1. It was done with glucosamine sulfate, the form preferred by advocates.
  2. It was independently funded,  without pharmaceutical company or supplement manufacturer support.
  3. It had adequate numbers of subjects (111 per group).
  4. It had a low dropout rate.
  5. It was carefully double-blinded.
  6. At the end of the study they confirmed that patients had not been able to guess which group they were in.
  7. The study lasted for 2 years, much longer than previous studies.
  8. In addition to subjective (pain) endpoints, they measured an objective endpoint:  joint space narrowing on x-ray.  They tried to improve on the methods used for this measurement in previous studies, which had been questioned. They achieved excellent inter-observer agreement.
  9. They did quality control checks to insure accurate dosage.
  10. They followed the published guidelines for clinical trials in osteoarthritis as formulated by a task force of the Osteoarthritis Research Society over 16 months of deliberations.
  11. It was published in one of the most prestigious peer-reviewed medical journals.

It seems to me that this study should put an end to the controversy.  Previous research can be characterized as inconclusive, with 8 out of 15 trials showing no effect, and with higher quality trials less likely to show an effect.  This study did its level best to avoid the pitfalls of previous studies and provide as definitive an answer as possible.

Of course, it won’t put an end to the controversy, because there are too many people who are invested (emotionally, financially or otherwise)  in the idea that glucosamine works. 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.

Rozendaal, R.M., et al, . (2008). Effect of Glucosamine Sulfate on Hip Osteoarthritis. Annals of Internal Medicine, 148(4), 268-277.

Part 2 – JointFlex Cream.

In another bizarre development, a cream containing glucosamine and chondroitin is now on the market - you simply rub it on wherever the pain is. The trademarked Fusome proprietary delivery system allows it to penetrate into the joint and work its magic. It offers instant relief and a money-back guarantee. I saw an ad for JointFlex in the newspaper and looked into the science behind its claims. There is one published study from Australia that supposedly supports its use.

The study, published in The Journal of Rheumatology in 2003, compared a topical preparation to placebo in 63 patients over an 8-week period. They concluded that it was effective in relieving pain in osteoarthritis of the knee, and improvement was evident within 4 weeks. The test cream  contained glucosamine sulfate, chondroitin sulfate, shark cartilage, camphor and peppermint oil. The rationale for this mixture is not explained, but they claim chondroitin acts as a transfer agent for dermal drugs. The test cream also contained high efficiency emulsifiers, skin emollients, and micro-encapsulation of the active ingredients. The placebo cream used conventional skin emollients, petrolatum and mineral oil, conventional emulsifiers, and stearic acid and glycerol stearate rather than the proprietary technology. It also contained a lesser amount of peppermint oil.  They comment that “there may have been some slight differences in the texture of the placebo and active creams” but they made no effort to ask patients which they thought they were getting, or to verify that the lesser amount of peppermint could not be used to identify the placebo. The endpoints were subjective.  They made no effort to determine whether the active ingredients had actually penetrated into the joint. The study has not been replicated elsewhere.

In the first place, the quality of this research was inferior in almost every way to the study described above in Part 1. In the second place, the study appears to show that glucosamine and chondroitin are effective topically, but the marketer completely disregards that, even while using the study to validate its product!

The real surprise for me was the list of ingredients in JointFlex on the Natural Medicines Comprehensive Database website. Only one active ingredient is listed, and that is camphor 3.1%!! There is a long list of inactive ingredients: Acetylated lanolin, acrylates/C10-30, alkyl acrylate, crosspolymer, Aloe Vera, C12-15 alkyl benzoate, Chondroitin Sulfate, purified water, diazolidnyl urea, dimethicone, dimethiconol stearate, disodium EDTA, dl panthenol, Glucosamine Sulfate, glycerin, Glycerol stearate, glycosaminoglycans, hydroxylated lanolin, hydroxypropylene methylcellulose, lodopropynyl, butylcarbomate, methyl gluceth-20, methyl glucose, sesquistearate, Peppermint oil, polysorbate 20, Potassium carbomer, tocopheryl acetate.

I went back to the JointFlex website and noticed a strange disclaimer: “These nutrients have been added as part of the skin conditioning base. We believe that the healthier and moister the skin, the better we can deliver the active pain relieving ingredients [sic - the NMCD lists only one active ingredient] to the spot where they are needed most making JointFlex® effective at relieving pain. We do not make any other claims at this time regarding these nutrients.”

This is really weird. I don’t know what’s going on here, and I’m not sure I want to know.  I can’t see my way to recommending glucosamine in any form until I see more credible evidence that it works.

Is doing more glucosamine studies a good use of our research dollars, or is it time to turn to more promising avenues of research?

REFERENCE:

Rozendaal, R.M., Koes, B.W., van Osch, G.V., Uitterlinden, E.J., Garling, E.H., Willemsen, S.P., Ginai, A.Z., Verhaar, J.A., Weinans, H., Bierma-Zeinstra, S.M. (2008). Effect of Glucosamine Sulfate on Hip Osteoarthritis. Annals of Internal Medicine, 148(4), 268-277.

Posted in: Clinical Trials, Herbs & Supplements

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20 thoughts on “Glucosamine Update: A New Study and a New Product

  1. Oldfart says:

    This will never go away. Just saw an advert on a local station (Kansas City) for Glucosamine and Chondroitin making all kinds of claims. I guess so long as it doesn’t hurt you, it’s ok for people to be scammed out of their hard-earned cash.

  2. apteryx says:

    There are a lot of RCTs of glucosamine, with or without chondroitin, for knee arthritis. Most show positive results, and as you note, there are a variety of flaws that negative studies could have suffered from, such as inadequate dosage (a point you don’t mention), failure to confirm material quality, or – um – having been published in an insufficiently prestigious journal? Here are PubMed references to studies that had a THREE-year duration, over 100 patients per treatment arm, and found no joint space narrowing in glucosamine users versus statistically significant narrowing in placebo users. (The abstracts do not mention how obsessively they tried to prove that patients were blinded; however, if the placebo effect will in fact build cartilage, you had better start studying “mind-body medicine”.)

    Bruyere et al. 2004, Menopause 11:138-43
    http://www.ncbi.nlm.nih.gov/pubmed/15021442?ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    Pavelka et al. 2002, Arch. Intern. Med. 162:2113-23.
    http://www.ncbi.nlm.nih.gov/pubmed/12374520?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    Reginster et al. 2001, Lancet 357:251-6.
    http://www.ncbi.nlm.nih.gov/pubmed/11214126?ordinalpos=20&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    You grouse that “They” will “complain that maybe it works for knees but not for hips.” Well, maybe that’s true, or maybe this study had a flaw we don’t see, or maybe it was a fine study that just happened to get false negative results. As far as I can tell, this is the only significant RCT for hip osteoarthritis, versus a pile of studies of knee osteoarthritis, some of them larger and including more patients. Why should the results from a hip study be assumed to be valid also for the knee, rather than vice versa? Just because the former are negative?

  3. Dr. Hall notes that, “There will always be “one more study” to do.” (I assume she means that is what supplement proponets will always claim.) For those who like to debate, that offers an excellent opportunity to argure that that is a very good reason why it is necessary to have some form of government approval procedure in place, such as exists for drugs, which requires supplement manufacturers to formulate, standardize and test the products they make claims for and to test them for the condition which they claim they effectively treat.

    Regarding JointFlex, is it FDA approved or does the site and label contain a little disclaimer in small print somewhere? Creams and topical treatments don’t come under DSHEA. Which means a few shoddy studies just ain’t gonna get it legally onto the shelf of a store near you folks. So sorry about the Big, Bad Government interferring with your right to buy and SELL any garbage or poison you want.

    Also, did I miss something? How is the cream supposed to penetrate the skin and get to the joint? Magic maybe?

  4. captbluebear says:

    I can explain the confusion with the joint cream. It has to do with whether a product is classified by the FDA as a drug, supplement, or cosmetic. If you eat it, it is a drug or supplement, but if you rub it on your skin it is a drug or a cosmetic. The different classes of products allow different types of claims in advertising. A product that contains an approved drug AND moisturizes your skin can be both a drug and a cosmetic, which this product is.
    Now, if a product is a cosmetic, you can only claim it physically affects the outside of the body (i.e. makes it moist, makes it soft, makes it beautiful, makes it shimmery). You cannot claim a cosmetic affects the inside of the body (for instance you can’t say a cosmetic will treat arthritis.)
    If it is a supplement, you can make a claim that it affects a structure or function of the body, but you can’t claim that it cures, treats, or prevents a disease. BUT, a cream cannot be a supplement because it isn’t orally ingested.
    If it is a drug, it is the most tightly regulated–ie all drugs must be approved by FDA. Camphor topical cream to reduce pain is an existing approved drug, so they are selling the product as a drug–that way they can state that it reduces pain. The glucosamine and chondroitin may in actuality have an internal effect of reducing pain, but the company is NOT ALLOWED TO SAY SO because they are considered COSMETIC ingredients. They are banking on the reputation of glucosamine and chondroitin to induce people to buy it. So the strange disclaimer is only there due to the strict regulatory environment imposed by the FDA.

  5. daedalus2u says:

    The placebo effect most certainly will build cartilage, reduce inflammation and reduce osteoporosis. These effects are all mediated through nitric oxide, and the placebo effect is mediated by raising nitric oxide levels.

    The reason they list camphor as the only “active ingredient” is because the FDA has defined a number of over the counter drugs as being “safe and effective”, so long as they contain the appropriate “active ingredient” that has been shown/assumed/grandfathered in via being deemed GRAS.

    Camphor is an ingredient considered to be an “Analgesic, anesthetic, and antipruritic active ingredients.” (along with juniper tar and menthol). (21 CFR 346.16)

    Any claim of another “active ingredient” is a medical claim, which makes the “active ingredient” a “new drug” which requires a New Drug Application.

    The “trial” of the cream containing glucosamine for topical application also contained camphor (which the placebo cream did not). Camphor is known to be effective at reducing pain when applied to joints (hence its authorization as an OTC drug by the FDA). The “trial” thus compared a cream containing a known active ingredient with a placebo which did not.

    http://www.jrheum.com/subscribers/04/04/correspondence.html

  6. apteryx says:

    Daedalus2u – Thanks for the link to the letter regarding the JointFlex trial. I am not surprised to learn that the methodology was poor. Chondroitin is a pretty large molecule and if that could be efficiently absorbed through the skin I would think we would leak like sieves.

    I admit to not having carefully followed your nitric oxide hypothesis, but your definition of “placebo effect” seems to be rather broader than most people’s. The usual meaning is of pain relief mediated by the brain’s endogenous opioid system in response to culturally meaningful but biochemically inert stimuli. It can be completely shut off by opioid antagonists. You seem to be talking rather about a biochemical pathway that, while it might be important biologically, has not much to do with that. I’m not sure whether you argue that endogenous opioids in turn raise nitric oxide levels, or vice versa – but either way, if a treatment had the range of effects you suggest, even if it was “touch healing,” then it wouldn’t be a placebo in the traditional sense but an active treatment.

  7. Harriet Hall says:

    apteryx,

    Two of the 3 articles you cite were discussed in the introduction to the new hip study. They also cited 3 other articles that had expressed concern about the radiography protocol used in those two trials, and they commented that “further study is needed to clarify these findings.” In designing the hip study, they went out of their way to develop a radiography protocol that would not be subject to similar criticisms. I’m not an expert in that area, and I can’t say whether they succeeded, but at least they were aware of the problem of accurately measuring tiny differences in x-rays that appear different with tiny changes in patient positioning, and they tried their best.

    The 3rd study you cite, by Bruyere, is co-authored by the two lead authors of the other two studies, Pavelka and Reginster, and was published in the journal Menopause rather than in a mainstream journal. When all the joint space narrowing research comes from one “inbred” group, it seems wise to withhold judgment until an independent research group can replicate their findings.

    I think it is still very much open to question whether any study has convincingly shown that glucosamine slows the progression of osteoarthritis.

    In my first glucosamine article, I raised the question Wally Sampson asked about prior plausibility. If Wally is right, it is highly unlikely that glucosamine “could” perform as claimed. In all the comments so far, no one has commented on that. I wish someone who understands the basic science better than I do would chime in and educate us.

  8. daedalus2u says:

    I have quite a specific idea of what I consider the placebo effect to be which I discuss in my blog on it. I see it only in terms of physiology.

    http://daedalus2u.blogspot.com/2007/04/placebo-and-nocebo-effects.html

    I see the placebo effect as the physiology behind how the body prepares itself for stress, the “fight or flight” state where resources are mobilized for immediate consumption via voluntary pathways as in “running from a bear”, and then how the body “stands down” from that stressful state, where resources are reallocated to non-immediate needs via involuntary pathways such as for healing.

    Everything the body does takes resources, usually in the form of ATP. When you are “running from a bear”, to be caught is certain death. Any injury short of death that allows survival is infinitely better than being caught. Serious injury is acceptable if it prevents death. As the state of stress increases, resources are diverted from long time constant pathways (such as healing) to immediate consumption. Your body will let you run yourself to death. That is a “feature”, which balances death from exhaustion with survival from outrunning the bear chasing you. This turning off of involuntary pathways is also known as ischemic preconditioning.

    I have another blog where I discuss what happens in the end stages of stress induced resource diversion. That is, what your body does just short of when it is going to die from exhaustion. That is the Euphoric Near Death State (or ENDS for short). When you are running from a bear, if you felt tired you would want to stop and rest which would be fatal because the bear would catch you. Under that extreme metabolic stress your body produces the delusion that you are not tired, also known as the “runner’s high”. This is a delusional state. Does some sort of emergency source of energy come on line after all other sources are exhausted? Of course not. That would be a terrible waste of that energy source to only use it a few times in a lifetime. Your body doesn’t generate more energy in that state, what it does is use less. The involuntary pathways get turned off and the ATP they would have consumed can now be used to take a few more steps running from the bear. Those involuntary pathways are the ones involved in healing and cellular repair. Things that are completely unnecessary if you are caught by the bear.

    http://daedalus2u.blogspot.com/2007/08/low-nitric-oxide-acute-psychosis.html

    Much of this blog is written in the context of postpartum psychosis induced infanticide, which I see as a mechanism for a lactating mammal to shed metabolic load when lactation cannot be sustained.

    Since ENDS must be euphoric, there must be an aversive state between the “normal” at rest state and the euphoric near death state (otherwise organisms would enter that state and risk death uselessly). I think that is what depression is. The normal aversive state characterized by insufficient metabolic resources. In modern times I see it more as a response to low NO which causes low ATP and low mitochondria. I think in the past it was more due to malnutrition and starvation as well as acute stress, but the pathways are pretty much the same.

    I think that the euphoria induced by stimulants of abuse, autoerotic asphyxiation, hypoxia, drowning, and solvent huffing, are similar in that they are characterized by ATP depletion and invoke ENDS. I think that is why all of these things cause symptoms characteristic of degenerative diseases. Healing and repair are turned off to save ATP, so organs degenerate. Which ones degenerate first is an idiosyncratic detail which depends on that individual’s physiology.

    It makes a lot of sense to me that low NO would be the signal that triggers ENDS. The whole body needs to in sync, all the cells need to get into the same state so that glucose consumption by the immune systems stops to free up glucose for muscles.

    NO does trigger endogenous opiates and endogenous opiates trigger NO. I consider “touch healing” to be a placebo in that the NO release is neurogenic by the person being touched. A mother’s “kiss it and make it better” is the archetypal placebo. Once you produce “enough” NO by any mechanism to switch physiology from the fight or flight state, more NO won’t have any physiological effects. I think the bacteria I am working with can do that, and once they do, placebos can’t do anything.

  9. apteryx says:

    Harriet- For Bruyere, I see, I might have done better to cite:

    Bruyere et al. 2003 Osteoarthritis Cartilage 11:1-5
    http://www.ncbi.nlm.nih.gov/pubmed/12505481?ordinalpos=23&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    which I surmise was the original source of some of the data mentioned in the analysis of women-only data in Menopause. I am surprised by your definition of Menopause as non-mainstream. Do you mean to tell us that it is devoted to the sort of stuff you folks around here like to call “woo” and “quackery,” or do you just mean that it is specialist rather than generalist and lacks a super-high impact factor? Not every one of the thousands of studies completed each month can be published in JAMA or NEJM, after all — in fact, if they are on CAM and have favorable results, there is basically zero percent chance that they will be. Those studies have to go somewhere, and specialist journals is where they go.

    Indeed, the researchers you mention have collaborated on publications, along with a considerable number of other colleagues. But they are not the only people who have done clinical trials or other research on glucosamine, as a PubMed search will show. Describing these overlapping research groups as “inbred” is a handy way of instructing your audience that their data are untrustworthy (by implication, faked?) and therefore can be overruled by a smaller amount of data from another single research group whose results you prefer. I think when the tactic is pointed out, your readers will want more evidence for that than your say-so.

    Sampson’s general argument about prior plausibility is something I have not cared to touch, not being a mathematician, but other readers have already made the connection that only treatments he approves of will be assigned a high enough “prior plausibility” to make any amount of positive clinical trial results informative in his eyes. There is nothing inherently implausible about treating arthritis with orally delivered isolated molecules; Big Pharma makes fortunes doing just that. I have seen Sampson assert that because the body naturally contains glucosamine, adding a little more cannot improve health. The same logic would support arguments that iron or calcium supplements cannot improve anyone’s health, that raising blood sugar from 120 to 130 shouldn’t make any difference, and that global warming can’t be real because the pollution we generate annually is very small in comparison to the CO2 already in the atmosphere. (After reading Sampson’s pro-war article, I wouldn’t be altogether surprised to see him make that case.)

  10. Harriet Hall says:

    The new Bruyere citation doesn’t add anything because it is from the same inbred group. Yes, there have been other groups researching various other aspects of glucosamine, but all the positive research involving measuring joint spaces seems to come from this one group. It needs to be replicated elsewhere before we can place much confidence in it.

    I meant no disrespect to the journal Menopause. I only meant to point out that it was a journal with lesser impact than the journals where the other articles were published. It is common for researchers to do a study and then divide their data into subgroups for publication in specialty journals to pad their CV. It helps their careers, but doesn’t necessarily advance science.

    Your ad hominem comments about Dr. Sampson are offensive and have no place in this discussion.

    What Dr. Sampson found implausible was that the amount of glucosamine in the typical supplement dose is on the order of 1/1000th or 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.”

    Even if glucosamine reached the site of cartilage synthesis, is there any reason to think a .001% increase in concentration would have a measurable effect? And the real increase would be expected to be much, much less, because only a small fraction of the oral dose is going to reach the joint. In your analogy with glucose, a .001% increase in blood glucose would not even register, because it would be within the error range of the measurement. This is very different from supplying a small amount of an essential nutrient like a vitamin.

  11. daedalus2u says:

    Here is an article that touches on glucosamine physiology.

    http://ard.bmj.com/cgi/content/full/65/2/222

    Just about all of it is synthesized from glucose by cells and not incorporated as glucosamine from diet. The levels that are absorbed in vivo are much smaller than what was used in the in vitro testing. What was measured in this study was plasma levels. The levels actually reaching the target tissues are likely lower (because some glucosamine would be absorbed before the plasma got to those peripheral tissues).

    From this article I would put the prior probability of oral glucosamine at doing something positive for arthritis as pretty small.

    The difference between implausibility for glucosamine and plausibility for iron is that iron is not synthesized by the body from abundant precursors. Glucosamine is. Glucose flux through the body is a couple hundred grams per day, about 100 times the ingested glucosamine. If glucosamine is doing “something”, it is likely through a pharmacological effect and not through a nutritive effect.

  12. apteryx says:

    You have once again termed the three lead researchers we are discussing, and all of their various collaborators who worked on just one of the three studies, “inbred” simply because the lead researchers have worked on more than one study of the same subject. Speaking of ad hominems… Generally, when people do a study and get interesting results, they are inclined to pursue opportunities to do more research on the same subject. There is nothing suspicious about that fact; if you published exciting results then hurried to abandon the field, that would be fishy. Two of these researchers also worked on a study which found that baseline joint space narrowing was not significantly correlated with WOMAC pain and function scales, and argued that although joint space deterioration over time was significantly correlated with clinical progression, the clinical relevance of the fact might be limited. Here’s the abstract.

    http://www.ncbi.nlm.nih.gov/pubmed/11922194?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    Thus, while these authors are using joint space narrowing as an “objective” measure – perhaps to answer critics who will interpret all improvements in pain and function as “placebo effects” even in placebo-controlled trials — they do not themselves appear to believe that that measure is the ne plus ultra of arthritis evaluation. Their studies, like studies done by other groups with no members in common, also demonstrate symptomatic improvement, which is what counts for the consumer.

    I don’t know how much glucosamine is in the body normally, but apparently neither do you. You suggest that the supplement dose is 1/1000 or 1/10,000 of the existing quantity, then speak of a 0.001% increase in concentration, which, of course, would be equivalent to 1/100,000. So you feel sure that the amount is very large, but admit uncertainty within two orders of magnitude. Let us for the moment discount the apparent possibility that chondroitin increases the activity of these supplements, and avoid any question of whether the glucosamine sulfate is more active for any reason than the form of glucosamine already in the body. A dose of 1500 mg once per day is pretty common; let’s guesstimate that that equals 1000 mg of glucosamine (since I am too lazy to look up the actual MWs). If that were indeed 1/1000 of the existing amount in the body, the body would contain 1 kilo, or 2.2 pounds. Yikes. We probably do not need to consider the possibility that the specified dose is 1/100,000 of the amount in the body.

    Here is the abstract of a 2007 study of plasma glucosamine levels in 12 arthritic patients before and after supplementation with 1500 mg/day.

    http://www.ncbi.nlm.nih.gov/pubmed/17353133?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    To sum up for the audience: before supplementation, patients’ plasma levels were 41-121 ng/ml and synovial fluid levels (inside the joint space) were <10-67 ng/ml. (There is a lot of variation among individuals.) After supplementation, plasma levels were 600-4061 ng/ml and synovial fluid levels were 577-2248 ng/ml. Average values for both were over twenty TIMES greater after supplementation.

    In short, Dr. Sampson is simply wrong. Wrong, and apparently not following the literature on the subject, so I cannot in future regard him as a reliable source unless he is backed up by recent citations from, as you would put it, mainstream journals.

    Daedalus – The link you attached requires subscription or purchase of the article. I looked up the PubMed abstract (Biggee et al, 2006), and find that this group looked at plasma concentrations only within the first three hours after a single dose. They found too little to detect (with their methods) before the dose, and the equivalent of 340-2000 ng/ml within 1.5-3 hours afterward. Despite the weaker methods used, these results are similar to those of the study mentioned above. They show that free glucosamine concentrations are dramatically increased by the usual supplement dose. Biggee et al simply argue that because these levels are lower than have been shown to cause certain effects in in vitro studies, they are too low to provide activity in vivo. Well, we all know that it is dangerous to extrapolate from in vitro studies to complex organisms. Some molecules are certainly active in vivo at much lower concentrations. The question of whether this concentration is high enough to be doing something (like, say, being slowly absorbed into joint tissue over months of regular consumption) is one best answered by experiment, which is how the active dose of other clinically tested substances is determined.

  13. pmoran says:

    Apteryx: ” You grouse that “They” will “complain that maybe it works for knees but not for hips.” Well, maybe that’s true, or maybe this study had a flaw we don’t see, or maybe it was a fine study that just happened to get false negative results. As far as I can tell, this is the only significant RCT for hip osteoarthritis, versus a pile of studies of knee osteoarthritis, some of them larger and including more patients. Why should the results from a hip study be assumed to be valid also for the knee, rather than vice versa? Just because the former are negative?”

    Well, maybe, to some extent, yes.

    Are you assuming that positive and negative studies have opposing but symmetrical scientific significance? That seems to be a common viewpoint, but I don’t see it that way. It is much easier, in general, to understand how studies may be falsely positive than it is to explain why a purportedly effective treatment should fail to produce any noticeable effect at all in an apparently well-performed study using similar methodology to the positive ones.

    Surely this study should swing the balance of probabilities strongly towards glucosamine having little or no effect on osteoarthritis?

  14. Harriet Hall says:

    apteryx,

    There are other articles that appear to disagree with the one you cited. For instance,

    http://findarticles.com/p/articles/mi_qa4100/is_200406/ai_n9453798/pg_1

    and

    http://www.ncbi.nlm.nih.gov/pubmed/15641100?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    This one says, “Clinically relevant dosing of glucosamine HCl in this large monogastric animal model results in serum and synovial fluid concentrations that are at least 500-fold lower than those reported to modify chondrocyte anabolic and catabolic activities in tissue and cell culture experiments.”

    I don’t want to get into a citation feud. I think I’ve made it clear that I don’t “know”and don’t have the knowledge to sort out what these conflicting studies really mean. I’ll simply repeat that it is not clear that orally administered glucosamine retards progression of joint space narrowing, and showing that it results in measurable changes in biochemistry might support a hypothetical mechanism of action but would not prove that a clinicallly significant effect had occurred.

    I must agree with Dr. Sampson that it would be surprising to find a clinically important effect from adding more of something the body already has plenty of precursors for and can readily produce for itself.

    I think you missed my point about “inbred.” I was most certainly not criticizing them for doing multiple studies! Every good scientist knows that when all the positive research comes out of one lab or one group of researchers, it is wise to withhold judgment until the research can be replicated elsewhere. Now we have the first good study from another source attempting to find x-ray evidence, and it failed to find any. The methods of the first group were criticized, and the second group tried to improve its methods to avoid those ciriticisms. I think that is significant.

  15. wertys says:

    For the life of me I have not been able to understand why there has never been a trial of intra-articular injections of glucosamine/chondroitin, as this seems to be the only logical way to administer it. The hypothesis under trial is that the state of arthritic cartilage can be improved in some way by glucosamine/chondroitin but oral administration is fraught with uncertainty. If it was injected IA there could be no grousing about bioavailability issues, and we would get a definitive answer.

    Personally I thought the radiology protocols in the knee trials were so flawed as to constitute a bigger logical fallacy than the original hypothesis, ie that the correlation between the height of joint space on plain films is directly indicative of the symptomaticity of the joint.

    Having read the Annals article I think I will leave it out of my practice now.

  16. daedalus2u says:

    Injected glucosamine is clearly a “drug” and so requires a “new drug application”. I can’t imagine that glucosamine would be patentable, so there is no way that who ever files a new drug application will ever be able to recover their costs in doing so. If it works, generic glucosamine will be just as effective and much cheaper.

  17. Harriet Hall says:

    daedalus2u

    I think a drug manufacturer could easily develop a patentable product based on injectable glucosamine. They are very ingenious at developing proprietary delivery systems and tweaking molecules.

    Isn’t it possible they’re not studying it because they perceive low prior plausibility?

  18. apteryx says:

    It is also possible that they know injectable glucosamine would never take off because consumers would figure out they can use oral products to increase synovial fluid glucosamine levels over 2000% without having to pay for frequent doctor’s visits and prescription drug costs in order to – yowch – have needles repeatedly jammed into their knee joints.

    The argument that the post-supplementation concentration is still low and therefore not bioactive carries a very strong implication that glucosamine as naturally present in the body (at less than 5% the concentration) is also not bioactive, or at least not in any way that has any relevance to cartilage maintenance or joint function. Are you asserting that glucosamine has no such role in the body? I had thought that its relevance was uncontroversial. The concentration of glucosamine required in vivo in order for the body to utilize it in some fashion over the long term may be much less than the concentration required to produce immediate and obvious effects in a petri-dish assay. If glucosamine indeed has any function or bioactivity in joint tissues, then increasing its concentration 20-fold could plausibly increase the efficiency of that process over time. The body might “be able to produce glucosamine for itself,” but clearly it does NOT produce it in those concentrations. There are quite a few drugs that duplicate natural molecules produced by the body, if the body is not producing enough for ideal health (or just if someone thinks that more would be better).

  19. wertys says:

    It is interesting how the glucosamine argument refuses to lie down and die. In the latest NICE guidelines published in the BMJ this week the authors clearly and specifically state that glucosamine/chondoitin is not recommended on the basis of the consensus of clinical trials combined with cost effectiveness. They also KO electroacupuncture, IA hyaluronate and rubefacients on the same grounds. Interestingly they decline to dismiss non-electroacupuncture out of hand due to lack of enough high-quality evidence !

    In a supplementary article, two different professors of rheumatology list areas of controversy in regard to the guidelines, and they make the stunning comment that they have been

    ‘impressed by the willingness of elderly patients to pay for this agent in a jurisdiction (New Zealand) where patients will traditionally pay only for medications that are symptomatically effective. ‘

    As a candidate for logical fallacy of the week this is not bad. I am not aware that the placebo effect has been found to be less common in New Zealand than elsewhere. Naturally as an Australian I am delighted to find my prejudice about humourless and dour Kiwis so clearly affirmed. Special pleading anyone ? A dose of argumentum ad populum to follow ?

  20. dochollis says:

    I am a member of a wine tasting group. Gout is a wine judge’s routine problem. Unaware of this, one of our members successfully treated his later-confirmed case of gout with glucosamine and condroitin, thinking it was arthritis in his knees. Slim and active, he had no sign of arthritis on the scans that were done. It may be very likely that these products do give relief to mild cases of gout, but at an exorbitant price to the liver and kidneys and the pocketbook. Another instance where a little knowledge is a dangerous thing.
    Self-treating is so tempting; advertisers and hucksters have free reign to exploit this impulse, thanks to the disempowerment of the FDA. GOP or Dem or whatever, vote in doctors so we can get some common sense into Congress again. Any candidates?

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