Arthritis fighters: do glucosamine & chondroitin work?

"Study shows supplements relieve osteoarthritis pain"

--Council for Responsible Nutrition (a supplement trade organization)

"Supplements Fail to Stop Arthritis Pain, Study Says"

--New York Times

Last winter, researchers announced the results of the Glucosamine/ Chondroitin Arthritis Intervention Trial (GAIT). The $12.5 million study, launched by the National Institutes of Health in 2000, was supposed to end a controversy.

In some earlier studies, the two supplements had eased the pain and other symptoms of osteoarthritis, while in other studies they were ineffective. GAIT was to be the biggest, best-designed look at whether glucosamine and chondroitin work.

But when the GAIT study was published last February, its findings led not to clarity, but to more confusion.

An estimated 21 million Americans suffer from osteoarthritis. Their joints become stiff and painful because the cartilage that cushions the ends of their bones begins to fray and wear away (see "Joint Venture"). By 2030, one out of every four U.S. adults will have doctor-diagnosed arthritis.

Current treatments--like exercise and surgery--are no magic bullets. And while anti-inflammatory drugs like Celebrex, ibuprofen, and aspirin can curb the pain, they may increase the risk of gastrointestinal bleeding and heart attacks.

That's why glucosamine and chondroitin have sparked so much enthusiasm. The body makes both glucosamine (a key component of cartilage) and chondroitin (which gives cartilage elasticity by helping it retain water).

The two appeared to relieve arthritis symptoms in some earlier studies, and both are relatively inexpensive and seem to be safer than prescription and over-the-counter pain relievers.

But researchers worried that the earlier studies had flaws that made glucosamine and chondroitin look more effective than they really were. That's why the NIH launched GAIT.

Unsteady GAIT

To carry out GAIT, 16 rheumatology research centers across the United States assigned more than 1,500 women and men with osteoarthritis of the knees to take a daily dose of glucosamine (1,500 mg), chondroitin (1,200 mg), both, Celebrex (200 mg), or a placebo. (1)

After six months, only Celebrex was significantly better at relieving pain than the placebo. But a statistically significant difference doesn't always mean a big difference.

While 70 percent of those taking Celebrex reported a decrease in pain, so did 60 percent of those taking the placebo (as well as 64 percent of those taking glucosamine, 65 percent of those taking chondroitin, and 67 percent of those taking glucosamine plus chondroitin).

That's why some leading osteoarthritis authorities have given up on the supplements. "Glucosamine and chondroitin need to be put to bed now," says David Felson, an arthritis researcher at the Boston University School of Medicine and spokesperson for the Arthritis Foundation. "They don't do anything."

But to others, the glass is half full.

Subgroup Therapy

"This rigorous, large-scale study showed that the combination of glucosamine and chondroitin sulfate appeared to help people with moderate to severe pain from knee osteoarthritis, but not those with mild pain," says Stephen Straus, director of the National Center for Complementary and Alternative Medicine at the National Institutes of Health in Bethesda, Maryland. (NCCAM helped organize and fund the GAIT trial.)

How did he reach that conclusion? A quarter of the GAIT participants started the study with moderate to severe pain in their knees, pain that "generally worsens a person's quality of life," explains the study leader, Daniel Clegg of the University of Utah School of Medicine in Salt Lake City.

When the GAIT researchers looked only at those 354 people, they found that 79 percent reported at least some relief with the glucosamine-chondroitin combination, more than those taking Celebrex (69 percent) or the placebo (54 percent).

"I think the finding in those with moderate to severe pain is important," says Clegg. "But it should be interpreted cautiously."

Others aren't so cautious. "People who experience moderate to severe joint discomfort are the ones most in need of treatment," Jason Theodosakis told Business Week magazine in February.

Theodosakis, who was a member of GAIT's oversight committee, is the author of The Arthritis Cure, a 1997 bestseller that introduced the public to glucosamine and chondroitin.

"For this group, the combination of glucosamine and chondroitin resulted in significant pain and function improvement," he says.

Boston University's David Felson is buying none of it.

"If you mess around with data long enough, you'll find something," he says. But that doesn't mean the results are valid. "If you do 100 studies of a treatment that show no effect, in 90 of them you can find some subgroup where the treatment had an effect just by chance," he explains.

To keep from being swayed by those chance (but tempting) findings, researchers try to look only at what the study was designed to look at. And the GAIT study wasn't designed to look separately at people with moderate to severe pain.

"There's no data from previous studies that suggests that this particular subgroup would be more or less likely to respond to glucosamine or chondroitin," notes Felson.

"The GAIT researchers pre-defined a primary outcome and seven secondary outcomes they would measure to see if the two supplements worked," he explains.

Glucosamine and chondroitin had no impact on the primary outcome (at least a 20 percent decrease in pain) or any of the secondary outcomes (like reduced stiffness).

"None of the outcomes targeted the subgroup of subjects suffering moderate to severe pain," he adds.

Tempting Sulfate?

Why did the GAIT study contradict some earlier studies? One possibility is that the glucosamine hydrochloride used in GAIT doesn't work as well as the glucosamine sulfate used in most earlier studies (and found in most supplements).

GAIT's lead investigator explains why the study used glucosamine hydrochloride.

"The National Institutes of Health required us to test glucosamine like a drug," says Daniel Clegg. "At the time, only glucosamine hydrochloride was manufactured to pharmaceutical specifications."

But the GAIT researchers concluded that people could absorb glucosamine hydrochloride as well as they could absorb glucosamine sulfate. "We did solubility trials that indicated that glucosamine was readily available in either form," says Clegg.

If the GAIT planners had thought the form would matter, they could have had glucosamine sulfate made just for the trial. That's what they did for chondroitin, because "there were no commercial chondroitin products available that were manufactured to drug standards," explains Clegg.

Boston University's David Felson has another explanation for why glucosamine and chondroitin seemed to work in some earlier studies but flopped in the GAIT trial.

"Meta-analyses have shown that industry sponsorship of drug trials produces biased results," he says. Indeed, most of the earlier trials were underwritten by supplement manufacturers. In contrast, "all of the four publicly funded studies have found no effect."

It's not necessarily that industry-funded researchers are fabricating results, but that publicly funded trials are larger and more careful to ensure that when something works, it's not due to chance.

Where does that leave arthritis sufferers? "Because of the small size of the GAIT's moderate-to-severe-pain subgroup," says Clegg, the findings "need to be confirmed in a study designed for that purpose."

While Felson doesn't advise his patients to stop taking the supplements, he thinks that further studies would be a waste.

"If my patients think glucosamine and chondroitin are helping them, who am I to tell them to stop?" he asks. "It doesn't cause any harm and it's not that expensive. But I think there's convincing evidence now that this is not an effective therapy for osteoarthritis and that no further research needs to be done.

"We have many other investments we need to make in arthritis research, especially treatment, since there are few effective treatments."

The Bottom Line

* Glucosamine alone and chondroitin alone don't relieve pain from osteoarthritis of the knees any better than a placebo.

* The combination of glucosamine and chondroitin doesn't help people with mild arthritis pain.

* Glucosamine plus chondroitin seems to help people with moderate to severe arthritis pain, but those results may have been due to chance.

* There's no evidence that taking glucosamine and/or chondroitin is harmful.

Beyond Glucosamine & Chondroitin

Anyone can sell a mix of glucosamine and chondroitin. But if you want customers to pick your brand, you need extra ingredients to make it stand out in the crowd.

Methylsulfonylmethane (MSM). It "plays a critical role in the elasticity and flexibility of the connective tissues of your joints," say the packages of Nature Made Triple Flex, which adds 750 mg of MSM to 1,500 mg of glucosamine and 800 mg of chondroitin.

We couldn't find a single study in humans, animals, or test tubes to back up that claim. Only two published studies have tested MSM on people with arthritis. Both were funded by MSM manufacturers.

* Twenty-one men and women with osteoarthritis of the knees who took 6,000 mg of MSM every day for three months reported slightly less pain than 19 similar people who took a placebo. (1)

The researchers, from the Southwest College of Naturopathic Medicine and Health Sciences in Tempe, Arizona, described that impact as "modest," and cautioned that the importance of MSM for treating osteoarthritis "remains uncertain."

* In India, 30 volunteers with osteoarthritis of the knees who took 1,500 mg a day of MSM for three months reported less pain and swelling in their knees than 30 volunteers who took a placebo. (2) Thirty others who took MSM plus 1,500 mg of glucosamine reported even more relief.

But the researchers pointed out that their study was small and short term.

What's more, most supplements have less MSM than either study used. A daily dose of Nature Made's Triple Flex, for example, has 750 mg.

(1) Osteoarthritis Cartilage 14: 286, 2006.

(2) Clinical Drug Investigation 24: 353, 2004.

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Uniflex and hyaluronic acid. "2x More Effective Than Triple Strength Glucosamine & Chondroitin Alone," says the label on Schiff Move Free Advanced, which mixes glucosamine (1,500 mg) and chondroitin (200 mg) with Uniflex (a proprietary blend of Chinese Scullcap root and Black Catechu bark) and (3.3 mg).

What's Schiff's evidence? An unpublished study that the company calls "preliminary" and won't make public. It was completed two years ago by a private Miami research firm hired by Schiff.

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Isoflavones. Isoflavones "influence the development of cartilage in the joints," says Amerifit Nutrition of Bloomfield, Connecticut. That's why it adds 25 mg of isoflavones derived from soy and the herb kudzu to the glucosamine (1,500 mg) and chondroitin (1,200 mg) in its Estroven Joint & Bone.

We found only one study that tested isoflavones on cartilage in either humans or animals. It came up empty. The company couldn't point us to any others.

Amerifit's isoflavone boast sounds like what the Food and Drug Administration calls a "structure-or-function" claim. They typically use words like "influences the development of," "maintains," or "supports."

Translation: no evidence needed.

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(1) N. Engl. J. Med. 354: 795, 2006.