Saturday, December 7, 2013

The Final Word on Glucosamine and Knee Pain

That, at least, was what one reader sought in a recent question to the New York Times’s Gretchen Reynolds, for her Ask Well column. He was understandably confused.

While his orthopedic surgeon scoffs, “Don’t waste your money,” a physician’s assistant swears that “I couldn’t get in the car and drive to work in the morning if I didn’t take glucosamine for joint pain.”

I’ve written a few times about glucosamine: here, here, here and most recently here, for starters. Today I thought I’d take a deeper dive on the subject, on a molecular biology level, because that’s where things truly get interesting.

I first became skeptical of glucosamine’s efficacy when it did nothing for me when I had constant knee pain. I took the supplement daily for months. No perceivable benefit. None. At. All.

I didn’t research glucosamine intensely though until I was well into writing Saving My Knees, which was my ambitious quest to rectify what I thought was a lot of wrong-headed information about treating chronic knee pain -- including the pernicious notion that bad joints could never heal. That just wasn’t true, and I was living proof.

At some point, I became aware of a massive, well-run trial, the results of which were published in the New England Journal of Medicine in 2006, that found glucosamine and chondroitin sulfate don’t work. Well, the study did show a benefit for those with moderate-to-severe pain who took both supplements. However, a doctor specializing in biostatistics quoted by the New York Times at the time said, “This is a spurious subset result if I’ve ever seen one.” He turned out to be correct -- the “advantage” for this subgroup washed out on further examination.

So glucosamine is a dud, right? Case closed?

It sure seemed that way to me. Didn’t help me. Didn’t help subjects in a large, well-conducted clinical trial. Sure, some people claim they can’t function without it. But some people would probably report less knee pain if you gave them “magic Ritz crackers” that they really believed were magic. Plus, why is it that glucosamine advocates claim to get relatively fast relief from a supplement that’s supposed to be restoring their cartilage, which is a long-term, months-long process?

But I’m a curious guy. I wanted to know exactly where the glucosamine story broke down. And where the story broke down, it turned out, was where glucosamine itself broke down.

To wit (and now I’m going to start quoting, so you can follow my journey of discovery better):
Orally ingested glucosamine “appears to undergo a significant first-pass effect in the liver, which metabolizes a significant portion of the dose to CO2, water and urea.” (Source: “Arterial Smooth Muscle Cell Proteoglycans Synthesized in the Presence of Glucosamine Demonstrate Reduced Binding to LDL” in Journal of Lipid Research)
Uh oh. That doesn’t sound good. But what does that mean in practice?

Fortunately, there's a clinical study that shows us: 18 subjects, all with osteoarthritis, took 1,500 milligrams of glucosamine sulfate. Then their blood was drawn at periodic intervals. The concentration of glucosamine peaked from 90 minutes to three hours after the supplement was taken, with the amounts ranging from 1.9 to 11.5 micromoles.

From an article summarizing the results:
At best, some patients had about 11 micromoles of glucosamine circulating in their blood several hours after taking the pills. Yet previous studies suggest that it may take glucosamine concentrations of about 10 times that amount to rebuild cartilage. Even at the highest concentration, the typical supplement would contribute only a small percent of the glucosamine needed to build stronger joints.

Taking higher doses of these supplements might increase glucosamine levels to the point needed to fight arthritis, but ... getting too much of this sugar may raise the risk of diabetes.
One of the study’s researchers, Timothy McAlindon, said patients were probably safe using small amounts of glucosamine, while tartly concluding, “The main injury is primarily to the wallet.”

That’s a damning comment, certainly. But there’s more. In 2009, Jeremiah E. Silbert wrote “Dietary Glucosamine Under Question” in the journal Glycobiology. Up front, he makes clear his credentials, “Our laboratory has focused its work on glycosaminoglycan metabolism for many years.”

Warning: His article is technical and dense -- about what you’d expect from someone who speaks chondroitin sulfate cellular biosynthesis as a second language. I struggled with a number of paragraphs, but even so, it was clear that he wasn’t impressed by the idea of popping glucosamine pills.

For one, the glucosamine is diluted hugely:
We found that the radioactive glucosamine [externally introduced] was diluted many fold by glucosamine formed from glucose [naturally occurring] ... dilution by glucosamine derived from glucose was 160- to 635-fold.
At the low levels that glucosamine is found in the bloodstream, it appears to be useless, unfortunately:
We have concluded that insignificant trace amounts of glucosamine enter human serum after ingestion of a standard oral dose of glucosamine sulfate or glucosamine chloride (1500 mg), far below any amount that might contribute directly to chondroitin synthesis. Moreover, this level is limited to a few hours after ingestion, with no establishment of any substantial lasting concentration. It is far below most of the concentrations used for in vitro cell or tissue culture incubations by others, usually for days or weeks, in proposing mechanisms to protect chondrocytes, inhibit chondroitin degradation, diminish inflammation, or provide imunosuppression in articular cartilage mechanisms ... Until consistent actions on cartilage can be demonstrated at the low concentration and limiting time periods that we found, claims of a meaningful direct effect on cartilage or chondrocytes are questionable.
And, at the conclusion, he sounds a warning note that the supplement may not even be as harmless as portrayed:
There were statistically significant glucose elevations with glucosamine ingestion by three subjects who were found by the glucose tolerance test to have previously undiagnosed diabetes. This is the first time that results of this sort have been found with diabetics that were not under treatment and warrant further investigation.
So there you have it. Way more than you ever wanted to know about glucosamine, on a microscopic cellular level.

What then should be the final word on glucosamine? You’re probably expecting me, like the orthopedic surgeon earlier, to scoff and say, “Don’t waste your money! It flat-out doesn’t work!”

I think that a wiser final word comes from the Ask Well column when a doctor observes that at recommended doses, glucosamine is generally safe and some people do say they benefit, so he tells patients “it’s up to them” if they want to buy the supplements.

But he also advises people to keep their expectations low. “In my experience, most people do not benefit.”

Sounds like a good final word to me.


  1. Thanks for this thorough analysis, Richard.

    I guess I am interested because in theory 10x dosage could help, obvi like you said the there is a sugar-intake risk ...but I was raised on cola and processed foods!

    I know Adequan, which is a polysulfated glycosamagin (or however you spell it...) is injected intra-muscularly or intra-articularly (forget...) in animals with success. I wonder if the equivalent for humans will arise.

    I even read on some bodybuilding sites of people using it with success. I'm not that desperate ...yet.

    Thanks for the post. :)

  2. Richard, here's another perspective on glucosamine. Dr. Ayers says it works via the gut, not the bloodstream. Could that explain why it works anecdotally in spite of the studies cited above?

    1. Interesting. I don't know enough about the biochemistry involved to comment; he quickly gets in deep. It would be interesting to run this theory past some of the researchers mentioned above. Frankly, his views seem a bit novel -- I've done a lot of reading on this subject and never encountered this twist on the efficacy of glucosamine before.

      It would explain why there's fast relief from glucosamine. But it still leaves as a mystery why the supplement has no effect on some of us -- like me. My money is still on the placebo effect, but as always, I'm keeping an open mind.

  3. Glucosamine, Chondroitin, MSM, did nothing for me.... money down the drain, for months and months. However, my brother in law swears by it -- his joints stiffen and he can do no sports without it. We are both in our 50s and are both lifelong exercisers. Sample size of 2, no conclusion possible.

    Since the supplements are almost totally broken down... and yet, some people credibly insist that they help anyway... I offer an alternative hypothesis. Perhaps the benefit happens in SOME people because the broken-down products are used as raw material the body to ***make its own glucosamine***. Simply put, it's digested, then reassembled. Perhaps some individuals don't get enough of the raw materials in their regular diet, or perhaps with age they don't synthesize it as efficiently -- and THESE are the "odd" ones that insist that glucosamine really did help. If so, perhaps supplementing with the raw materials would be as effective or more so.

    Worth a study, if anyone's got funding.

    1. Interesting thought, and I've wondered that myself, if a small subset of the population benefits because of the unique circumstances of their physiology. They would have to be a rather small subset though, because otherwise I think they'd be showing up in glucosamine studies that randomly select people.

      Or, then again, it may just be the placebo effect at work: It can be very powerful.