Larry W. Moreland, MD
Professor of Medicine
Department of Medicine, Division of Immunology/Rheumatology
The University of Alabama at Birmingham
Birmingham, Alabama

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Glucosamine and chondroitin have little effect on the pain of knee osteoarthritis, according to the largest study ever conducted of the widely used dietary supplements. The National Institutes of Health sponsored the randomized double-blind Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) to answer questions about safety and effectiveness of supplements.

Previous studies of glucosamine and chondroitin, often sold in combination for symptomatic relief of osteoarthritis, have offered conflicting findings, and clinicians have criticized many of these for their small size and lack of scientific quality. “The literature contains a number of reports of glucosamine and chondroitin reducing pain or slowing structural deterioration of osteoarthritis,” says UAB rheumatologist Larry W. Moreland, MD, who served as principal investigator for the UAB arm of the GAIT trial. “But many of these studies are controversial, often because of potential bias from industry sponsorship or methodological flaws, such as failure to follow intention-to-treat standards.”

Despite this lack of clear scientific evidence, consumers spend big money on the supplements — more than $730 million in 2004, according to an annual nutrition industry overview (Nutrition Business J. 2005;X:6-7). Osteoarthritis affects more than 20 million Americans and about 1 in 4 adults older than 55 years. Current therapies are aimed at easing patients’ joint pain and inflammation, and all have limitations, including lack of efficacy and uncertain long-term safety, Moreland says.

Mainstays of therapy include nonsteroidal anti-inflammatory drugs (NSAIDS) and cyclooxygenase-2 (COX-2) inhibitors, which studies have linked to increased risk of cardiovascular events, resulting in withdrawal of two popular drugs, valdecoxib (Bextra) and rofecoxib (Vioxx). “These agents usually work to some degree for most individuals, but are less effective as the disease progresses,” he says.

GAIT Trial Results

The 5-year, $12.5 million, placebo- and celecoxib-controlled GAIT trial involved 1538 participants at 16 US academic medical centers. Investigators randomized participants to 1 of 5 treatment groups: glucosamine hydrochloride, chondroitin sulfate, a combination of glucosamine and chondroitin, celecoxib, or placebo. As an approved medication for management of osteoarthritis pain, celecoxib was chosen as the active control, because patients respond to it in a predictable manner. Participants had both X-ray evidence of disease and at least mild knee pain, determined by a standard questionnaire that assesses osteoarthritic symptoms of pain, stiffness, and physical function. Patients took medications for 24 weeks, with evaluations at baseline and 4, 8, 16, and 24 weeks. Investigators defined a positive response as 20% improvement in knee pain compared with baseline measurements.

For the majority of study participants, neither supplement alone, nor a combination of the two, achieved significantly better results than placebo. Overall, 70% of patients responded to celecoxib, 64% to glucosamine alone, 65% to chondroitin alone, and 60% to placebo, while the combination of supplements produced a 66% response rate (N Engl J Med. 2006;354:795-808).

As expected, celecoxib significantly outperformed placebo. But Moreland points out, “the placebo response was extremely robust. Patients taking celecoxib improved, but almost as many patients responded to placebo. When patients have only mild pain, as did most individuals in GAIT, measuring treatment response is challenging, confounded by patients’ subjective reports of very small changes that are difficult to measure accurately.”

Among GAIT participants, 78% had mild knee pain, while the remaining 22% had moderate-to-severe pain. Overall, GAIT investigators found supplements had no effect on pain, yet individuals with moderate-to-severe baseline pain did experience statistically significant relief while taking the combination of chondroitin and glucosamine. Within this subgroup, the supplement combination reduced pain in 79.2% of patients versus 54.3% of individuals taking placebo (P=0.002). Celecoxib relieved pain for 69.4% of individuals in this group.

Moreland, however, cautions against placing too much emphasis on this preliminary subgroup finding. “The subgroup did not contain a large number of participants. Although supplements may possibly help certain individuals with severe pain, further research is needed before we have a definitive answer,” he says. “The bottom line for most patients is that a large, rigorously conducted, federal study found no difference in pain reduction among patients taking placebo and patients taking the supplements. At this time, based on these results and data from other studies, I do not see any justification for recommending chondroitin, glucosamine, or the combination to patients for treatment of osteoarthritis.”

Although Moreland considers GAIT a negative study, he is aware of anecdotal reports of pain relief among patients who use the supplements. “The good news for these people is glucosamine and chondroitin do not appear to be associated with any significant adverse effects,” he says. GAIT study authors note adverse events “…were mild, infrequent, and evenly distributed among the groups.”

“Although they do not appear to be harmful, chondroitin and glucosamine are expensive,” Moreland says, noting consumers can spend between $30 to $50 a month on the supplements. Besides a relatively high cost and, according to GAIT findings, no efficacy for pain relief, supplement quality varies widely, making it difficult for consumers to gauge potency of the many products on the market.

GAIT was conducted under an investigational new drug application, with study agents subject to pharmaceutical regulation by the Food and Drug Administration (FDA). Investigators found many discrepancies among commercially produced supplements and raw products before identifying suppliers who could provide ingredients of sufficient purity, potency, and quality. For example, an evaluation of chondroitin quality conducted for GAIT found that among 32 commercially available dietary supplements, chondroitin content ranged from 0% to 115% of the labeled claim (J Am Pharm Assoc. 2006;46[1]:14-24).

In the United States, production and marketing of dietary supplements are not subject to strict regulations governing pharmaceutical manufacturing, and physicians should advise consumers to exercise caution when choosing such products.

Although chondroitin and glucosamine failed to reduce osteoarthritic knee pain for the majority of patients in GAIT, Moreland notes future GAIT analyses will assess X-ray progression of disease. “Other studies have suggested that while glucosamine and chondroitin have little effect on pain and swelling, they may slow or prevent cartilage destruction.”

A randomized placebo-controlled trial of glucosamine sulphate found individuals taking 1500 mg of the supplement once a day for 3 years had no significant tibiofemoral joint-space loss, while those taking placebo experienced progressive joint-space narrowing (Lancet. 2001;357:251-256). An editorial in the same issue of Lancet noted that while important, results raised a number of questions, including the accuracy of joint-space narrowing measurements, which might be biased because patients experiencing significant pain cannot fully extend their knee for imaging, and whether such an evaluation provides the most meaningful measure of osteoarthritic severity. The editorialist notes that compared with pain and physical function, radiographic severity is one of the least important predictors of disease outcome (Lancet. 2001;357:247-248).

GAIT investigators plan to compare baseline X-rays of participants’ knees with imaging studies done at years 1 and 2. “We need to evaluate these results before concluding the supplements have no value for treatment of osteoarthritis,” he says. “One of the key reasons for skepticism regarding these supplements is there is no clear mechanistic explanation of how glucosamine and chondroitin could affect the disease process.”

Both substances are produced by the body and found in joints. Naturally occurring glucosamine is an amino sugar distributed in cartilage and other connective tissue and is believed to play a role in cartilage growth and repair. Chondroitin sulfate, a complex carbohydrate, promotes water retention in cartilage, providing elasticity.

“The body quickly breaks down oral glucosamine,” Moreland says. “Very little reaches the joints. The same thing occurs with chondroitin. Joints are complex systems — naturally occurring glucosamine and chondroitin work in concert with other substances in the body to build and repair cartilage.”

Osteoarthritis affects many older adults, but also can occur in younger individuals with occupational risk factors, such as jobs that involve lifting and bending. In some individuals, the condition improves or remains stable, while others gradually worsen, with some eventually requiring total joint replacement. “We now understand that osteoarthritis is a group of disorders with different initiating mechanisms,” Moreland says. “Regardless of cause, disease progression can impede walking and other routine activities.”

Relieving pain, correcting mechanical malalignment, identifying joint instabilities, and delaying the need for total joint replacement are goals of current osteoarthritis treatment. The American College of Rheumatology (ACR) recommends acetaminophen, which causes less gastrointestinal toxicity than NSAIDS, as first-line treatment for osteoarthritis, but notes patients often do not get sufficient pain relief to maintain their normal lifestyle. While NSAIDS and COX-2 inhibitors are used frequently as osteoarthritis therapy, these medications have adverse effects. A recent New England Journal of Medicine article notes combining NSAIDS with misoprostol or proton pump inhibitors reduces the incidence of gastrointestinal bleeding (2006;354:841-848).

Intraarticular injections of corticosteroids have powerful anti-inflammatory effects, but side effects limit use, and efficacy often wanes after several injections. Long-acting steroids can be combined with local anesthesia and injected directly into inflamed joints and may be useful for flares of knee osteoarthritis, according to clinical trials. Meta-analyses of scientific data show limited effectiveness for FDA-approved hyaluronic acid injections, and pain usually returns within weeks or months. Opiates provide more pain relief than other analgesics, but cause sedation and may result in dependancy.

Lifestyle changes can improve symptoms of osteoarthritis, Moreland says. “Exercise is often challenging for people with osteoarthritis but can help when targeted toward strengthening muscles people use in daily activities.” Low-impact aerobic exercise such as swimming or using an exercise bike or elliptical trainer can decrease pain and disability, as can weight loss. ACR notes patients who participate in self-management plans, such as the Athritis Foundation’s Self-Management Program, report decreases in joint pain and arthritis-related physician visits and improvements in daily functioning and quality of life. The Centers for Disease Control and Prevention provide information about evidence-based programs, along with an interactive tool that helps patients locate resources in their state. Visit www.cdc.gov/arthritis/intervention for more information.

“More research is needed to dissect mechanisms of osteoarthritis,” Moreland says. “NIH has begun a large initiative to develop a public research resource. Investigators are following 5000 individuals for 7 years, looking for biomarkers that predict osteoarthritis. Efforts to better understand the condition’s pathology will hopefully lead to more effective treatments.”

For more information:

Dr. Larry Moreland
1-800-UAB-MIST
mist@uabmc.edu

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