Glucosamine for better knees

KarlGuass-as the resident endocrinologist on the SDMB, and in no way am I looking for medical diagnosis from you, but only informed opinion: I contend that glucosamine supplementation over the “long term” can lead to insulin resistance: type II diabetes.

I’ve got a bad knee, meaning osteoarthritis and chonrdomalacia, due to atheletic injury years ago. I asked my surgeon about glucosamine and he bailed out by saying he’s only the mechanic. Talk to a pharmacist.

Not good enough for me. But so many people have testified to improvement, and so I have to listen.

I’ve done PubMed searches on glucosamine and cartilage and the gist is that it’s good for the knee, but it may cause type II diabetes.

What do you think is going to happen down the road with glucosamine supplementation? If I start taking it, will I have increased chance of type II diabetes?

Just an informal informed opinion as a guy in the field, please. I just want to weigh benifits vs costs, and whatever I read here is off the record. But informed info is appreciated.

Any treatment would by my doctor’s and my consent alone.

From http://www.berkeleywellness.com

A recent article in The Lancet points out that glucosamine, even in very low doses, can have adverse effects on blood sugar levels, possibly increasing insulin resistance. Many people with osteoarthritis are older and overweight, and have diabetes or are at risk for it. It’s not known that the supplements actually harm diabetics or bring on diabetes, but they might.

I just read a couple recent meta-analyses on glucosamine supplementation. I’ll leave it up to the endocrinologist to discuss DM, but if glucosamine is good for the knee, I want to see much better evidence.

A recent analyses of all glucosamine studies appeared in JAMA near the end of last year and also in CMAJ about a month ago.

Conclusion: the studies are crap. All of them were heavily funded by drug companies with strong vested interests. This is common in trials, but not usually to the extend of having everyone in the study a paid consultant, not revealing the sources of funding and having the drug company representatives write the actual papers.

Many of the studies involve fewer than 80 people, the largest has some 300. Osteoarthritis is a common condition and it would be very easy to do a study of adequate power with thousands of people.

These are large molecules. How do they get from the stomach to the knee? Doesn’t matter if they are the constituents of cartilage if they can’t get there.

Many of the studies are so shoddy they don’t bother to report standard deviations. They generally fail to report people who dropped out of the study. They don’t mention doses of glucosamine, nor recommend one. They don’t distinguish between PO, IM and IV administration. Clinical improvement is monitored by many different subjective scales, even so the ones used most commonly such as WOMAC and Likert are only used sporadically.

In short, none of the seven orthopedic surgeons I’;ve worked with this week would recommend this to their patients onthe basis of the evidence. Most, however, would not actively stop their patients from taking it on their own. The consensus you speak of is artificial and highly dependent on drug company marketing. No such consensus exists. In short, positive results have been reported in studies of remarkable laxity and uncommonly heavy-handed influence. The data thus far is useless.

Hm. I wonder if that’s the same medicine/supplement my father is taking…? It’s apparently working rather well for him. Heck, my dog’s taking the veterinary equivalent and she’s acting 3 or 4 years younger.

I probably should have put KarlGauss in the header to get his attention.

Dr_Paprika–Thanks, you summed up what I suspected, the search for review articles gave me abstracts that basically said the trials to date were “poorly designed”. I haven’t read any yet, but if they don’t report standard errors of treatment means–WTF? Who the hell reviewed that?

I just got off the phone with a pharmacist who advocates glucosamine. While I’d rather take glucosamine than the heavy prescription shit over the long term if I have to (and osteoarthritis is degenerative and I’m fairly young and in shape), this guy was confused when I was skeptical. I mentioned an anecdote about a guy selling homeopathic dihydrogen monoxide (H2O–water) treatments and the pharmacists said: “What’s that?” WTF again? This guy has an advance degree in pharmocology and he can’t interpet dihydrogen monoxide in his head?

He told me to go to the Web site of the company that sells glucosamine for info. Not the most reliable source of information in my opinion.

Jesus, fuck a grad school education, maybe I should sell snake oil and dress it up in “jargon” and spend my time making dollars instead of real research data.

I shake my head and hope some of the Teeming Millions can give me better sources.

I was recommended by a doctor to take glusamine for my knees, which were aching after long hikes, probably due to lack of cartilage in them. I was also recommended by an herbalist-in-training to take a combination of glucasamine and chondroitin, which act synergistically to build up joints. I took 2500 grams of the glucosamine daily for 4-5 months and the problem went away. I’m sold unless I hear otherwise…

Just because studies are sponsored by makers of glucosamine is not a good reason to discount the studies if they are otherwise well controlled. Small studies are not as good as larger studies, but still evidence.

Four clinical trials conducted in Europe showed that it helps relieve the pain and increases the mobility of osteoarthritis. One study had electron microscopic evidence of cartilage repair and regeneration. So it appears that the glucosamine does find its way to the cartilage. None of the trials lasted over eight weeks, but at least in the short term no harmful side effects were noted. Thus this has the advantage over anti-inflammatories in that it helps repair cartilage and does not injure the stomach, kidneys, bone marrow, or any other body tissue.

In February, 1999, one of the first US studies of glucosamine and chondroitin sulfate was presented at the American Academy of Orthopedic Surgeons. The study involved giving 93 patients either a placebo or a combination of 2,000 mg of glucosamine and 1,600 mg of chondroitin sulfate per day. At the end of six months, 52% of the patients taking the supplements experienced a significant lessening of the pain of their arthritis compared with only 28% of the patients taking a placebo. (Harvard Health Letter, July 1999)

Running Times, April 1999, reported the results of several longer lasting studies. In one study, conducted at St. John’s Hospital in Oporto, Portugal, doctors divided a group of 68 patients, giving half a daily dose of 1.5 grams of glucosamine sulfate, the other 1.2 grams of ibuprofen (Motrin). The study was double-blind. After six months, the glucosamine group had significantly less pain than the ibuprofen group. Another double-blind study divided 30 chronic arthritis patients into two groups. One group received 500 mg of glucosamine sulfate per day for 14 days, the other got a placebo. Pain, swelling, tenderness and loss of function we lessened in 71% in the glucosamine group but were little changed in the placebo group. In a 3d study, 51 male and 17 female young athletes with cartilage damage of the knee were given 1500 mg of glucosamine sulfate daily for 40 days and then 750 mg for 90 to 100 days. Of the 68 athletes, 52 had complete disappearance of symptoms and resumed full training. A follow-up 12 months later showed no signs of cartilage damage in any of them.

A team of Boston researchers scoured three decades of medical literature to find studies that tested either chondroitin or glucosamine for treating osteoarthritis. Fifteen studies met specific criteria that qualified them to be included in the analysis. The result: glucosamine moderately improved both pain and function, while chondroitin had a large effect on those measures.

As with any other non-controlled substance, the ingredients in any supplement may not be what is said on the label. Nearly one-third of 25 major brands of supplements containing glucosamine and/or chondroitin did not contain all the labeled ingredients. (The New England Journal of Medicine, Health News, May 2000)

Doctors from Boston U. School of Medicine conducted a meta-analysis of research studies on glucosamine and chondroitin. Only the highest quality placebo-controlled, double-blind, and randomized studies were included in the analysis. They concluded that glucosamine and chondroitin are quite effective in treating the symptoms of osteoarthritis, but raised two points: no regulation of the supplements and the studies that show no effect may be less likely to be published and therefore skew the analysis. (Running & FitNews, June 2000)

True. But it is customary to report sources of funding. Of the 15 studies included inthe Boston meta-analysis, all did, only 6 reported it. Usually, drug companies do not write the paper and play a limited role when writing the paper. Evidence needs statistical significance; also if the study has no power, the chance of a type II error is high. It is also likely studies showing no benefit from glucosamine sponsored by drug companies are not published.

I am now rotating through orthopedics. None of the seven orthopedic surgeons I work with believe it gets to the cartilage. All of them feel this study was poorly done. There is evidence that the pain is subjectively lessened, true, but there are big inconsistencies in how much.

Not quite true, but nothing serious and not much greater than placebo. The fact that none of the trials lasted over eight weeks is very significant when discussing taking life long medication for a chronic condition that gets worse at variable speeds.

Except anti-inflammatories control pain much better. Cartilage is not a vascular structure and therefore cannot easily be repaired by the body. In circumstances where cartilage is reformed or implanted, the cartilage is of far inferior quality to the original and does not provide very good shock absorption.

Ninety-three patients is a very small study. To avoid the ethical complications of permitting pain, the inclusion criteria for this study allowed the use of aspirin and DMARDs which squirrel the interpretation. Nevertheless, it is true many patients do seem toget some relief from glucosamine/chondroitin. No one disagrees with this, but the studies are not well designed. That doesn’t mean an effect doesn’t exist.

Known as a high quality professional peer-reviewed journal

Oh please. This is statistical manipulation at its best. Fourteen days of treatment is meaningless in a chronic condition, it would be very easy to do larger studies, female young athletes dont have significant meniscal damage and even the best studies do not show a complete disappearance of symptoms.

This is the meta-analysis I referred to above. All of the studies were sponsored by drug companies who revealed there involvement in only 6 papers. Only 2 of them had an intention-to-treat approach. Four studies included in the paper did not report standard deviations and these were invented. The study did not report doses and the 15 also included one IM and one IV administration. The effect of chondroitin was, in fact, moderate. The study said very frankly that all of the studies were poorly conducted; none had a “quality” score higher than 45%. Even so, the results were good enough that a properly controlled trial is begging to be done.

This is a major problem, and presumably why dose was not included in the Boston study.

But these were still piss-poor with very low quality scores. The fact a study satisfies all these conditions does not make it good, significant or useful. The studies that did not report standard deviations on mean values presumably did so for a reason and should have been thrown out, as should the parenteral studies. Doses were not reported, and 4 weeks was the minimum. Intention-to-treat was in 2 of the 15 included (out of 37 found).

Being familiar with the study, they had several other concerns including failure to disclose who funded the research and poor quality scores with regard to 14 features found in well-conducted trials.

I did find one good study recently published in The Lancet which showed minimal progression of joint space loss in patients who take 1500mg glucosamine on X-ray findings. This study did have sufficient power and is one of the best out there.

Most rheumatologists and orthopods will tell you it is not harmful and works for a few people. The anecdotal reports of this are good but not compelling - this is still Class D evidence. I have studied the recent literature on this specific topic in some depth and good studies need to be done. Most professionals do not believe it gets to the cartilage, nor is there any plausible mechanism for this. Some believe it helps the pain in some people, but so does gold, penacillamine, methotrexate and quinines.

In summary, the meta-analyses you speak of showed moderate effect in studies highly biased by drug companies and of staggeringly poor quality. This does not mean an effect doesn’t exist, but it needs to be verified despite what you find on MedLine. Arthritis is common, here in the small Canadian town I work it would be easy to conduct a trial with 3000 people with standardized doses. I know pharmacists who swear by these drugs. But the evidence they make new cartilage is very poor and hard to believe mechanistically. They do seem to improve pain and function in some people and this is why better studies need to be done. I have had specific training in medical epidemiology and have read many of the actual papers. My mom has arthritis, I tell her what I’m telling you.

Well, I share your concern that glucosamine may lead to insulin resistance or even type II diabetes. Still, AFAIK, there is no good data to suggest that this is the case. In the folowing letter from the LANCET, November 6, 1999, the authors marshall evidence to essentially refute the speculation that glucosamine, as used for arthritis treatment, will lead to insulin resistance. (This letter, which I’ve edited so as not to infringe, I hope, on copyright, was in response to an article by Mark Adams who raised the insulin resistance concern. Adams died two weeks ago.):

There is a recent review of glucosamine here. You’ll see that the evidence is pretty convincing that it works for osteoarthritis, and apparently with few side effects. This article is from Bandolier, an absolutely superb and free evidence based medicine site. Anyone interested in objective contemporary reviews on medical issues should check it out.

This free article from the Lancet, cited in the Bandolier article, and found here, lends strong support to the idea that glucosamine is effective.

The Towheed article is the same as the Boston meta-analysis listed above. Despite showing moderate effect sizes, I have read the article in some detail. It has all of the flaws above. I do not mind the use of funnel plots, but despite a lot of studies the ovwerwhelming pattern is that few have been conducted well.

Karlgauss also mentions the recent Lancet study by McClintock, this is the study I refer to above as:

This is a good study (perhaps one of the few), as I said, but raises some interesting questions, sheds no light on mechanism. It does lend some support to the idea glucosamine is effective at SLOWING joint space loss as measured by weight-bearing X-rays (there are some minor problems with this technique) in 106 people randomized to 1500mg glucosamine. The study also reports some lowering of pain as measured using the WOMAC scoring developed by a research adviser of mine. However, one study is not conclusive and there are good reasons to be critical of the vast majority of studies out there. If KarlGauss had actually read them in full and taken the time to talk to orthopods and rheumatologists, as I have done, he wouild realize why family practioners might be hesitant to recommend these expensive and drugs to their patients especially given their cost and variable dose. If he has read these studies, I would be interested in hearing refutations of my points above.

Dr_Pap, B.Eng (honours biomechanical engineering), M.D.

Well, perhaps I should just stick to diabetes. And in that regard, I stand by my impression - there is no evidence to prove that glucosamine as used to treat arthritis causes glucose intolerance or insulin resistance.

With respect to the putative effects of glucosamine on arthritis, no, I am not an expert, and no I have not “taken the time to talk to orthopods and rheumatologists” as you have done. Indeed, opinion is a type of evidence. And, when there is no better evidence, opinion is all one has. Meta-analysis is another form of evidence. Hopefully, but not definitely, it is of better quality than opinion-based “evidence”. One uses it advisedly.

Randomized clinical trials (RCT’s) are the gold standard in Medicine. Thankfully, there is now an RCT on the subject. We both cited it. Only one of us, though, seems to believe that one good RCT is worth a dozen meta-analyses, or the collective clinical wisdom of practising “experts”.

I agree expert opinion is not good evidence. And I don’t like meta-analyses despite your snarky insinuations, so wonder why you quoted one (as I did) as evidence. But there are dozens of RCTs on the subject, and few of them are well conducted although many do show a modest improvement. The McClintock article in Lancet is an exception, it is sufficiently long testing period, and is as you say good evidence. I don’t disagree, but it must be weighed accordingly. I happened to read the article in Lancet over lunch (after spoending half an hour discussing it with an orthopedic surgeon who is an expert in the area, and in fact gave me the article and his views on it) and it certainly shows more good studies are needed. Glucosamine may be very good, and this needs to be shown by more RCTs and not non-expert opinion, nor expert opinion on the basis of an abstract or two.

My apologies to KarlGauss. That was a little more pointed than I intended.

The take-home message is that the best blinded RCT shows glucosamine may slow down the rate of joint space loss seen in osteoarthritis. According to this actual article, in the opinion of the researchers who conducted it joint space loss has not been well correlated with improvements in cartilage, pain control, stiffness or mobility even though modest gains are suggested. Evidence of new cartilage is not present. Still, the research is tantalizing and gains have been shown by other studies with significant biases. Experts I know of who I know to be aware of all these current articles would neither recommend nor dissuade someone from taking these drugs; some feel they act in a way similar to NSAIDs and DMARDs.

Well, for one thing, pharmacists do not have advanced degrees in pharmacology. They have degrees in pharmacy, which is a wholly different (but related) field than pharmacology. As the 2 M.D.'s have already pointed out, studies on glucosamine’s efficacy are sparse and usually unreliable, so you can’t assume that he’s a doofus just because he isn’t able to answer your question. The data just is not there yet. I would have gotten the dihydrogen monoxide reference, but hey, come on. I bet a whole lot of chemistry majors would miss it as well if caught off guard. Give the guy a break - he’s only trying to help you out.

In the Reginster article in Lancet 2001;357:251-26 (the same one cited previously, I believe), the researchers saw a 20-25% improvement in patients on glucosamine sulfate vs. a 9% worsening in patients on placebo on the WOMAC index. This has nothing to do with measurement of joint space loss. A new large scale study http://jama.ama-assn.org/issues/v285n3/ffull/jha00014-2.html involving 1600 patients and funded by the National Institute of Arthritis and Musculoskeletal Disease is underway and may shed more light on the role this substance plays in cartilage repair and efficacy compared to NSAIDs.

Anyway, as an answer to the OP, whenever consulted regarding glucosamine, I neither advocate or advise against its use. I do tell my diabetic patients who want to use this drug to make sure they monitor their blood sugar rigorously though.

Informative debate so far. Sorry if it got people testy. This is the article that got me wondering: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve=PubMed=10806197=Abstract Phosphorylation of Human Glutamine: Fructose-6-phosphate Amidotransferase by cAMP-dependent Protein Kinase at Serine 205 blocks the Enzyme Activity. JBC 275; 29; pp21981-87.

Glutamine: Fructose-6-phosphate Amidotransferase (GFAT) metabolizes Fructose-6-phosphate to glucosamine and this enzyme is regulated by PKA phosphorylation. Fructose-6-phosphate is a substrate that can enter a number of metabolic pathways: glycolysis, gluconeogenesis, and glucosamine synthesis; its fate depends on the nutritional state of the organism. Levels of insulin, glucagon, leptin, and epinephrine (and other hormones, I’m sure) will determine its fate. Activities of enzymes and transcription factors involved in glucose homeostasis depend on their phosphorylation and glycosylation states. Glucosamine is obviously involved with glycosylation. (I know most of the posters have this background).

The paper states in the discussion: “There is accumulating evidence that the flux of glucose into the hexamine pathway may be involved in the pathogenesis of diabetes. It has been suggested that the toxicity of glucose to pancreatic beta cells may involve this pathway, and there is evidence that glucose-stimulated gene expression that could lead to diabetes complications involves the metabolism of glucose to glucosamine.”

These are the papers referenced:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve=PubMed=10717000=Abstract
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve=PubMed=9756093=Abstract
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve=PubMed=9917327=Abstract
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve=PubMed=8663078=Abstract
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve=PubMed=9641678=Abstract

I’m not asking anybody to plow through these papers; I thought I’d give some evidence of my concerns, though. But it seems to me if levels of glucosamine are involved glucose regulation and regulation of enzymes and transcription factors involved in the various metabolic pathways of the fate of glucose, mucking them up by taking endogenous glucosamine can’t be totally risk free.

When I’m told that taking glucosamine for a bad knee has no ill side-effects, I think: “Well, none that have come to light yet. How about ten years from now?”

As I said, I’m a fairly young guy and my osteoarthritis isn’t going away. I’m wondering what’s going to happen if I take glucosamine for the next 10+ years. Still, it seems a better alternative at present than the prescription shit that will involve liver testing every six months. But that brings back the question of whether it really helps; if it does, I may decide benefits outweigh the unknown risks; if it doesn’t help, I’m just fucking with my glucose metabolism needlessly.

I know one paper, even in JBC, has to evaluated to one’s own satisfaction. The Resistin paper in Science (IIRC) recently comes to mind. They might have described a novel hormone, but the evidence was pretty iffy (the Northern looked like a joke) and they used different and probably inappropriate statistical tests to get significant differences with identically set up assays. And how long did it take to get accepted?

Still, the implications of taking glucosamine give me concerns.

kspharm?I didn?t mean to disparage pharmacists and you?re right about the pharmacology degree. I was annoyed that this guy, who was referred to me as having background in the glucosamine debate, seemed dismissive of my concerns. ?There is NO evidence of glucosamine being detrimental? is what he told me. My above post links to evidence that it might be.

The fact that, besides the H2O blunder, he treated me like some nitwit taking up his time, made me a little sour. He said he couldn?t be expected to keep up with every journal article. That is true, the volume of literature is overwhelming. But to tell me there is NO evidence AT ALL with regard to possible side effects of glucosamine in the literature, when there are papers in Proc Natl Acad of Sci, Nature, and J Bio Chem. (see above) that have asked this question recently, makes me dismissive of how with it he is. Hopefully, my local guy is less presumptive.

I don?t know. You?re a pharmacist, what do you guys read? The above-mentioned journals are pretty universal in biology. It takes some decent research to get published (usually) there, as opposed to Running World. I would imagine these journals have some influence on pharmacy.

But then again, researchers don?t see the effects of medication with regard to Joe Smo who gets his prescription at the local pharmacy in day-to-day life.

Even though you don?t recommend glucosamine, what do YOU think about it?

Shameless bump, but I should have said exogenous glucosamine instead of endogenous.

And, I’ve been told that the chondroitin sulfate that is sold on the market is undigestable (and therefore a ripoff) but it ranks up there with substances that the average schmo will spend good money on.

What should a young guy do–with osteoarthritis?

A young guy with OA should not get a knee replacement; if you are not all that active, you can only get 10 or so years from it.

High tibial osteotomies and opening wedge osteotomies are good operations, but again depend on the location and severity of your arthritis. If you were in your 40s and 50s, this may be a good solution.

There is good research currently being done on cartilage transplants. It isn’t there yet, and is probably ten years away. About 50% of patients seem to benefit from arthroscopic general cleaning.

NSAIDs help a lot of people. Celebrex and Vioxx have much fewer side effects and are nearly or as effective. Topical NSAIDs with no GI side effects can occasionaly be used too. Some patients also recieve benefit from steroid injection. But its a tricky problem, OA in a young person. If you weren’t in the infantry, why do you have it so bad? What sort of work do you do?

Anyone up for this same conversation, only about SAM-e? Isn’t it reputed to have similar effects on joints, but with fewer interactions or negative effects? Damned expensive though–buck a dose.

Dr_Paprika–I’m not even thinking about joint replacement now, although I fear it might be in my future down the road.

I work in a cell biology lab, so I don’t need to be physically active for my job; it’s the brain and skill that counts. But, I’ve always been physically active (I was getting recruited in 2 Div I sports when I blew my knee out in High school). I had surgery then and now it’s catching up with me. 75% of my cartilage has been scoped out. I had all kinds of problems before I had ACL reconstruction and now I begin to sense the return of dysfunction.

I saw my weight bearing X-rays and without any radiology interpetation training at all, I could tell they looked bad (the gap between the femur and tibia of my bad knee is MUCH smaller than my good knee and even I could regognize the roughness of the articular surfaces–it was that obvious there was a BIG difference between the good and bad knee).

This really sucks. I still want to be able to play hoops, lacrosse, and ski…etc. (I’ve always been physically active in my life); but right now I know it will really fuck my knee up if I push it. I’m just over 30 and I’m already detecting deposition of body fat due to the lack of physical activity and I hate not being able to just do my normal physical activity. And, I know it just gets worse.

I guess in my OP, I’m wondering how bad glucosamine is and what it’s benefits are. I don’t like taking any drugs such as any NSAIDs long term and am wondering about glucosamine.

But I’m under the impression that (diabetic effects that I think we’re going to hear about down the road in a few years aside) it’s better than prescription drugs for the long term. Which I have to face.

My knee is really damaged. Otherwise I wouldn’t be even thinking this. Glucosamine may be the lesser of the evils if it works. And we don’t know yet if it really does; but a lot of people swear it improves their function.

Look at Darrell Green of the Redskins–high levels of physical activity are maintainable into your 40’s. I know I’m nowhere near his level; but I don’t want to be unable to do robust physical activity at my younger age. Which is where I’m at right now, for fear of further damage.

I’m weighing the risks of trying glucosamine long term. You (Dr._P.) say it’s BS and I can see why. KarlGuass can’t say about diabetic effects (nobody can’t tell yet). I might make myself a guinea pig for this. I’m worried less about my glucose levels than my ability to use my legs how I want to.

Stay tuned.

Oh yeah, I was told that the chondroitin sulfate supplements that are sold are completely indigestable. Seems like another ripoff. Chondroitin sulfate PLUS glucosamine seems to do a better job at relieving pain, but those studies used injections, IIRC. So if you’re paying for oral chondroitin sulfate–buyer beware.