A Tale of Two Studies


Two new studies presented at this year’s meeting of the American College of Rheumatology (Atlanta) have raised hope that dietary supplements can play a greater role in helping people with osteoarthritis (OA) manage their pain. The studies, both of which were six-month, double-blind, placebo-controlled trials, examined the effects of the supplement ingredients glucosamine and chondroitin. The results, while not conclusive, were promising enough to prompt both research teams to recommend that physicians discuss the supplements with their patients.


Two new studies presented at this year’s meeting of the American College of Rheumatology (Atlanta) have raised hope that dietary supplements can play a greater role in helping people with osteoarthritis (OA) manage their pain. The studies, both of which were six-month, double-blind, placebo-controlled trials, examined the effects of the supplement ingredients glucosamine and chondroitin. The results, while not conclusive, were promising enough to prompt both research teams to recommend that physicians discuss the supplements with their patients.

One study, the Glucosamine Unum in Die Efficacy (GUIDE) trial, compared the effects of glucosamine sulfate to acetaminophen (Tylenol) in 318 patients with knee OA. The researchers found that glucosamine actually worked better than acetaminophen. Another study, the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), compared the effects of glucosamine hydrochloride and chondroitin sulfate with celecoxib (Celebrex). In the GAIT study, results were mixed: the supplements had no effect overall, but they did work better than celecoxib on patients with moderate to severe knee pain.

The two studies may represent another milestone in research on bone and joint health. Many scientists and research organizations eagerly have been awaiting the results of the GAIT trial, which was funded by the National Institutes of Health (NIH; Bethesda, MD), before commencing their own studies on the biological mechanisms of the two ingredients. The GUIDE and GAIT trials, as well as other recent studies, should help accelerate new research efforts.

On the other hand, it’s important to point out some caveats. The GUIDE study used a specific form of glucosamine that isn’t always used in the United States. Moreover, the GAIT study found that the supplements did not work on all people with OA. In addition, both trials only studied the effects of the supplements for six months, which isn’t enough time to gauge their long-term benefits. Still the trials are another step forward, if not a giant leap, in the field of nutraceutical research.


About 12% of Americans age 25–74 have OA, which is marked by progressive damage to joint cartilage. Many studies have examined the effects of supplements on OA, but the trials that have compared supplements with medications have tended to be short-term studies. The six-month GUIDE trial, which was conducted by researchers in Spain and Portugal, compared the effects of glucosamine sulfate with acetaminophen and a placebo. The researchers chose acetaminophen because it is usually the first medication recommended for treating OA pain. The GUIDE researchers recruited 318 patients with knee OA and divided them into three groups. One group took 1500 mg of glucosamine sulfate per day, one group took 1000 mg of acetaminophen three times per day, and one group took a placebo. The patients were also allowed to take 400 mg of ibuprofen as a rescue treatment as needed. At the beginning and end of the study, the patients rated their pain using the Lequesne and WOMAC indexes.

After six months, the researchers found that glucosamine sulfate and acetaminophen both worked better than the placebo at reducing joint pain. But the patients who received glucosamine sulfate appeared to experience more relief than those who received acetaminophen. Specifically, the mean Lequesne score dropped from 11.0 to –3.1 for those on glucosamine sulfate, compared with a drop from 11.1 to –2.7 for those on acetaminophen. Similarly, the mean WOMAC score for the glucosamine group shrank from 38.3 to –12.9, while the mean WOMAC score for the acetaminophen group dropped from 40.4 to –12.3.

“Once-daily 1500-mg oral doses of glucosamine sulfate might be the preferred treatment for symptoms of knee OA,” Gabriel Herrero-Beaumont, MD, director of the rheumatology department at the Jiménez Dîaz Foundation (Madrid), said at the American College of Rheumatology’s meeting in November in San Diego. “Based on these results, physicians who typically recommend acetaminophen may well find their patients gain more comfort taking glucosamine sulfate.”


Another study discussed at the American College of Rheumatology Meeting, the $14 million GAIT trial, was one of the largest supplement studies conducted under the auspices of NIH. NIH’s National Center for Complementary and Alternative Medicine, which coordinates research on natural therapies, has declined to comment on the GAIT study until it has been published in a peer-reviewed journal.

While the GUIDE trial compared the effects of supplements with a nonprescription drug, the GAIT trial compared supplements to celecoxib, a prescription medication that targets COX-2 enzymes. Like the GUIDE trial, the six-month GAIT study also had a placebo group in addition to two treatment groups.

For the GAIT study, researchers recruited 1583 volunteers with knee OA from 16 academic rheumatology centers across the United States. The patients received either a placebo, 500 mg of glucosamine hydrochloride three times per day, 400 mg of chondroitin sulfate three times per day, a combination of glucosamine and chondroitin, or 200 mg of celecoxib once per day. The patients were also allowed to use up to 4000 mg of acetaminophen per day as a rescue treatment. At the beginning of the study, the patients rated their pain using the WOMAC index. Bioibérica’s (Barcelona) CSb Bio-Active chondroitin sulfate was used in the study. An additional 18-month substudy will track the effects of the supplements on the progression of knee OA.

UNC Researchers Identify Possible Link Between Selenium and Arthritis



Selenium deficiency may contribute to the risk of developing osteoarthritis (OA) of the knee, according to researchers at the University of North Carolina (UNC; Chapel Hill, NC).

Using data collected from 940 volunteers, the UNC researchers found that for every tenth of a part per million of selenium in the body, there is a 15–20% decrease in the risk of knee OA. Those with the highest selenium levels had a 40% lower risk than those with the lowest levels. In addition, those with the highest levels had only about half the chance of developing severe OA or disease in both knees. Most people can get enough selenium from their diets if their diets are varied, the researchers said.

“We are very excited about these findings, because no one had ever measured body selenium in this way in relationship to arthritis,” says Joanne Jordan, MD, associate professor of medicine and orthopedics at UNC’s school of medicine. “Our results suggest that we might be able to prevent or delay OA of the knees and possibly other joints in some people if they are not getting enough selenium. That’s important, because the condition, which makes walking painful, is the leading cause of activity limitation among adults in developed countries.”


The results of the GAIT study, unlike the results of the GUIDE trial, were not so clear-cut. Compared with the placebo group, the groups receiving the supplements failed to experience much additional relief. The group receiving celecoxib, however, had a much higher response rate than the other groups. But in a small subgroup of patients with moderate to severe knee pain, the combination of glucosamine hydrochloride and chondroitin sulfate seemed to work better than the prescription drug.

In other words, for all patients, 60.1% responded to the placebo, 64% responded to glucosamine hydrochloride, 65.4% responded to chondroitin sulfate, 66.6% responded to the glucosamine hydrochloride and chondroitin sulfate combination, and 70.1% responded to celecoxib. But for patients with moderate to severe pain, 54.3% responded to the placebo, 65.7% responded to glucosamine hydrochloride, 61.4% responded to chondroitin sulfate, 79.2% responded to the glucosamine and chondroitin combination, and only 69.4% responded to celecoxib. “As expected, celecoxib improved knee pain in patients with OA,” explained Daniel Clegg, MD, chief of the division of rheumatology at the University of Utah (Salt Lake City), at the American College of Rheumatology meeting. “For the study as a whole, the supplements were not shown to be effective. However, an exploratory analysis suggested that the combination of glucosamine and chondroitin sulfate might be effective in OA patients who had moderate to severe knee pain.” Clegg added that adverse events were mild and evenly distributed for all three groups.

According to Patricia Estepa, product manager at Bioibérica, CSb Bio-Active, the chondroitin sulfate used in the trial, is manufactured under strict pharmaceutical good manufacturing practices. “NIH and FDA came to our factory and did an audit to check that we are working under a higher level of manufacturing standards,” Estepa said. ”Our product is also used as a reference standard for USP.“ Estepa adds that CSb Bio-Active was also the source material used for several other clinical trials, including studies published in the Journal of Rheumatology, Arthritis and Rheumatism, and Drugs Under Experimental and Clinical Research.


A small debate between journalists and the supplement industry has erupted over the meaning of the GAIT study results. While the media generally has interpreted the study to mean that the supplements were mostly ineffective, the industry has taken an opposite reading.

For instance, a November 16, 2005, article in the Baltimore Sun titled “No Benefit Found for Arthritis” said the clinical trial found no evidence that the supplements are better than placebos at easing arthritic knee pain. But press releases from several companies that market bone and joint supplements maintained that the study results supported the effectiveness of glucosamine and chondroitin. One recent press release touting a joint health product claimed the study “validates that glucosamine is better than a common painkiller for knee arthritis.”

Branded Approaches to Joint Care



While glucosamine and chondroitin have taken the lion’s share of attention this month, several branded ingredients address joint health issues as well.

BioAsteri: Bioriginal’s (Saskatoon, SK, Canada) BioAsteri borage oil, which contains high amounts of joint-friendly gamma linolenic acid, recently achieved self-affirmed status as a generally recognized as safe (GRAS) ingredient. “This is a significant addition to Bioriginal’s innovative essential fatty acids solutions portfolio,” said Rakesh Kapoor, Bioriginal’s director of science and technology. “It offers food manufacturers the opportunity to enter the growing nutritional foods markets with options to formulate foods with antiinflammatory and health-maintaining properties.”

Cal-Mor: ADM (Decatur, IL) recently introduced Cal-Mor calcium citrate, a highly bioavailable and directly compressible calcium source. According to Darryl Barbee, assistant product manager for ADM’s specialty food ingredients division, Cal-Mor can be used in a wide variety of applications, including baked goods, snacks, desserts, beverages, supplements, and yogurt.

Celadrin: Pacific Rainbow International (City of Industry, CA) distributes Celadrin, a natural joint health ingredient composed of esterified fatty acid carbons and other synergistic compounds. Celadrin can be taken orally in powders and softgels or applied topically in creams. In November, Solgar (Leonia, NJ) announced that it was preparing to launch Celadrin in the UK.

Cynatine FLX: Keratec’s (Christchurch, New Zealand) Cynatine FLX, a digestible wool extract, activates two antioxidant enzymes that are important for joint health: glutathione peroxidase and superoxide dismutase. According to Keratec, the amino acids in Cynatine FLX also stimulate the body’s proteoglycan synthesis to prevent joints from breaking down and build joint polymers.

Kolla2: AIDP (City of Industry, CA) supplies Kolla2, a joint health supplement manufactured using a patented process (U.S. Pat. 6,838,440) that produces denatured and hydrolyzed collagen type II, the primary collagen in cartilage. In addition, Kolla2 contains important glycosaminoglycans, including chondroitin sulfate and hyaluronic acid.

LitoZin: EuroMed (Green Bay, WI) has acquired the North American rights to distribute LitoZin, an herbal extract derived from rose hip (Rosa canina). Results from a new study on LitoZin were presented in December at the Osteoarthritis Research Society International World Congress in Boston. According to EuroMed, the study found that the supplement caused an 82% reduction in joint discomfort after three weeks of use.

MicroLactin: Humanetics Corp. (Eden Prairie, MN) supplies MicroLactin, which is composed of nutrients found naturally in cow’s milk. MicroLactin is thought to inhibit inflammation by decreasing the emigration of neutrophils. According to Humanetics, 16 clinical trials have studied the ingredient’s effects, and a double-blind, placebo-controlled trial also found that MicroLactin compared favorably with glucosamine sulfate.

Nexrutine: Next Pharmaceuticals (Carlsbad, CA) says Nexrutine, a patent-pending plant extract that comes from the phellodendron tree (Phellodendron amurense), was tested in a 50-person open trial and found to help relieve general aches and pains caused by physical activity. In addition, a 30-person double-blind, placebo-controlled trial on osteoarthritis patients in 2004 also tested the extract’s beneficial effects.

OptiMSM: Cardinal Nutrition’s (Vancouver, WA) branded methylsulfonylmethane (MSM) ingredient, OptiMSM, is now available in larger lot sizes. According to David Lakey, president of Cardinal Nutrition, the company decided to offer larger lots to keep pace with rising analytical costs caused by the implementation of good manufacturing practices for dietary supplements. “In preparation for the proposed regulation, we implemented continuous distillation and larger lot size to improve our customers’ efficiencies,” Lakey says.

Regenasure: Cargill’s (Minneapolis) vegetarian glucosamine Regenasure is a featured ingredient in Vegeflex, a new joint health supplement from Windmill Health Products (West Caldwell, NJ). Regenasure, which is manufactured from a vegetable source using fermentation, is the only chondroitin hydrochloride ingredient not derived from shellfish.

SierraSil: Sierra Mountain Minerals (Vancouver, BC, Canada) announced in November that new research on its SierraSil mineral complex was published in the Journal of Inflammation, an open-access, online publication. The double-blind, placebo-controlled study involved more than 100 volunteers. “SierraSil may offer exciting new approaches to limiting the joint destruction and lack of mobility associated with arthritis,” said study supervisor Mark Miller, PhD, a professor of cardiovascular sciences and pediatrics at Albany Medical College.

UC-II: InterHealth Nutraceuticals’ (Benicia, CA) UC-II type II collagen was shown in March 2005 to help reduce lameness and pain associated with arthritis in a four-month animal study conducted at Murray State University Medical College (Hopkinsville, KY). The results were discussed at the 44th annual meeting of the Society of Toxicology (Reston, VA) in New Orleans.


Other companies praised the study without drawing specific conclusions. Luke Bucci, PhD, vice president of research at Schiff Nutrition International (Salt Lake City), said in a November 14, 2005, press release that the company was thrilled with the results of the study because they add to existing evidence. “The findings further support the growing scientific literature demonstrating the benefits of natural supplements such as glucosamine and chondroitin in promoting joint health-and that’s great news for those who suffer from OA.”


While it’s tempting to read too much into the study results, moderation is probably the wisest course when communicating the findings of the GAIT and GUIDE researchers. In the case of the GAIT study, the positive findings only applied to a subset of the OA patients, and in the case of the GUIDE trial, the researchers pointed out that many supplements in the United States use a different form of glucosamine. Also, both trials only lasted for six months. On the other hand, the enthusiasm generated from both studies should go a long way toward creating future studies that address unanswered questions. The next phase of the GAIT trial, for instance, should address the long-term effects of the supplements.

Andrew Shao, PhD, vice president of scientific and regulatory affairs for the Council for Responsible Nutrition (Washington, DC), was careful not to overstate the GAIT study’s results in a November 13, 2005, press release. “The body of science demonstrates that these supplements are both safe and beneficial for joint health,” he said. “We believe that the results from this well-executed, NIH-sponsored study not only indicate that more research is needed to determine the full potential of glucosamine and chondroitin, but also to reconfirm that these supplements can help the growing number of Americans with joint problems reduce the pain of arthritis.”

Future studies on glucosamine and chondroitin, as well as other natural ingredients, should go a long way toward addressing these unresolved issues.

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