Dietary Supplements Glucosamine and/or Chondroitin Fare No Better than Placebo in Slowing Structural Damage of Knee Osteoarthritis

The dietary supplements glucosamine and chondroitin sulfate, together or alone, appeared to fare no better than placebo in slowing loss of cartilage in osteoarthritis of the knee, researchers from the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) team report in the October issue of Arthritis & Rheumatism.[1] Interpreting the study results is complicated, however, because participants taking placebo had a smaller loss of cartilage, or joint space width, than predicted. Loss of cartilage, the slippery material that cushions the joints, is a hallmark of osteoarthritis and its loss is typically measured as a reduction in joint space width—the distance between the ends of bones in a joint as seen on an X-ray.

“While these results are of interest, we cannot draw definitive conclusions about the utility of glucosamine or chondroitin in reducing joint space width loss, in part because the placebo group fared better than anticipated based on prior research results,” said Josephine P. Briggs, M.D., director of the National Center for Complementary and Alternative Medicine, at the National Institutes of Health (NIH), one of the study’s funders. “The results of the study provide interesting insights for future research.”

The NIH-supported study was led by University of Utah School of Medicine’s Allen D. Sawitzke, M.D., and Daniel O. Clegg, M.D. This study was an ancillary, or additional, trial conducted by the GAIT team with a subset of participants from the original GAIT study. The original GAIT study sought to determine whether these dietary supplements could treat the pain of knee osteoarthritis and found that overall the combination of glucosamine plus chondroitin sulfate did not provide significant relief from osteoarthritis pain among all participants. However, a smaller subgroup of study participants with moderate-to-severe pain showed significant relief with the combined supplements. These results were reported in 2006.[2]

To study whether the dietary supplements could diminish the structural damage of osteoarthritis, interested GAIT patients were offered the opportunity to continue their original study treatment in the ancillary trial for an additional 18 months, for a total of two years. The randomly assigned study treatments were 500 milligrams glucosamine hydrochloride three times daily, sodium chondroitin sulfate 400 milligrams three times daily, the combination of glucosamine plus chondroitin sulfate, placebo, or celecoxib 200 milligrams daily. The research team enrolled 572 GAIT participants for the ancillary study. Participants entering the ancillary study had X-ray evidence of moderate (grade 2) or severe (grade 3) knee osteoarthritis in one or both knees using a scale that measures osteoarthritis severity called the Kellgren-Lawrence scale. At the end of the ancillary study, the team had gathered data on 581 knees.

“At two years, no treatment showed what we determined to be a clinically important reduction in joint space width loss,” said Dr. Sawitzke, associate professor of medicine and lead investigator for the ancillary study. “While we found a trend toward improvement among those with milder, Kellgren-Lawrence grade 2 osteoarthritis of the knee in those taking glucosamine alone, we were not able to draw any definitive conclusions.”

The joint space width in the knee, or knees, of the patients was measured with a specific X-ray protocol on entering the ancillary study and at one and two years to determine any loss in joint width. The X-ray technique required images of the knees be taken in a standardized, weight-bearing position.

The GAIT researchers expected patients in the placebo group to have a joint space width loss of approximately 0.4 millimeters over two years, based on results of previously published large studies. The study team hypothesized that a loss of 0.2 millimeters or less would show a slowed rate of cartilage loss. The final results, adjusted for baseline joint space width, gender, and other factors, showed:

* glucosamine alone group had the least average joint space width loss of 0.013 millimeters
* chondroitin alone group had an average loss of 0.107 millimeters
* glucosamine plus chondroitin group had an average loss of 0.194 millimeters
* celecoxib group had an average loss of 0.111 millimeters
* placebo group had an average loss of 0.166 millimeters.

In addition to measuring average loss of joint space width, the study also measured the percentage of participants with progression (worsening) of their osteoarthritis — defined as a joint space width loss of more than 0.48 millimeters over the two years. Overall, those with grade 2 (moderate) knee osteoarthritis were least likely to have progression of osteoarthritis compared to those with more severe disease. Approximately 24 percent of participants taking the combination of glucosamine plus chondroitin sulfate showed disease progression, which was similar to placebo, but greater than either glucosamine or chondroitin sulfate alone. The researchers theorize that this may reflect interference in absorption of the two supplements when taken together.

“Research continues to reveal that osteoarthritis, the most common form of arthritis, appears to be the result of an array of factors including age, gender, genetics, obesity, and joint injuries,” said Stephen I. Katz, M.D., director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, co-funder of the study. “Because osteoarthritis affects nearly 21 million Americans, we are seeking ways to not only treat pain, but also address the structural effects of the condition.”

The researchers note that the study has limitations, such as a greater-than-expected variability in measurement of joint space width loss and a less-than-expected loss of joint space width in the placebo group. However, the team also notes that not only was the study designed to investigate whether glucosamine and chondroitin sulfate, either together or alone, may have an effect on structural damage, it was also designed to test the method of measuring joint space width loss and learning more about the natural progression of osteoarthritis.

“Despite the ancillary study’s limitations, it has provided us with new insights on osteoarthritis progression, the techniques to use to more reliably measure loss of joint space width, the possible effects of these dietary supplements, and the characteristics of osteoarthritis patients that may best respond, all of which will assist investigators in future studies,” said Dr. Clegg, professor of medicine and chief of rheumatology and principal investigator for GAIT.

The nine GAIT centers that recruited patients for the ancillary structural study were

* The Arthritis Research and Clinical Centers, Wichita, Kan.
* University of Arizona, Tucson
* Case Western Reserve University, Cleveland, Ohio
* Cedars-Sinai Medical Center, Los Angeles
* Indiana University, Indianapolis, Ind.
* University of California, Los Angeles
* University of California, San Francisco
* University of Pittsburgh, Pittsburgh, Pa.
* University of Utah, Salt Lake City.

The National Center for Complementary and Alternative Medicine’s mission is to explore complementary and alternative medical practices in the context of rigorous science, train CAM researchers, and disseminate authoritative information to the public and professionals. For additional information, call NCCAM’s Clearinghouse toll free at 1-888-644-6226, or visit the NCCAM Web site at nccam.nih.gov.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases, a component of the National Institutes of Health, DHHS, supports research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For additional information, call NIAMS’s clearinghouse at (301) 495-4484 or visit NIAMS’s Web site at www.niams.nih.gov.
The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov. References:
1 Sawitzke AD, Shi H, Finco MF, et al. The Effect of Glucosamine and/or Chondroitin Sulfate on the Progression of Knee Osteoarthritis: A Report from the Glucosamine/Chondroitin Arthritis Intervention Trial. Arthritis & Rheumatism, 2008; 58(10):3183-3191.

2 Clegg D, Reda DJ, Harris CL, et al. Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis. New England Journal of Medicine, 2006;354:795-808.