Joanna Cosgrove10.01.07
Alternative Osteoarthritis Remedies Panned
Systematic review deems glucosamine and chondroitin no more effective than placebos but counters with a call for better quality research.
By
Joanna Cosgrove
Online Editor
In stark contrast to legions of satisfied consumers, a recent systematic review released by the Department of Health & Human Services' (HHS) Agency for Healthcare Research and Quality (AHRQ) found glucosamine and chondroitin “to be no more effective than placebos,” in the treatment of knee pain caused by osteoarthritis. The review also failed to find convincing evidence of benefit from hyaluronan preparations and arthroscopic surgery to clean the knee joint with or without removal of debris and loose cartilage.
Osteoarthritis is a widespread, costly disease that wears away the cartilage cushioning the knee joint, causing pain and reducing mobility. Arthritic diseases, which include osteoarthritis, affect an estimated 46 million people in the United States, and at age 64 and older, one in 10 Americans is estimated to have osteoarthritis of the knee. Osteoarthritis and related arthritic conditions cost more than $81 billion a year in medical care, lost wages and other expenses.
The review, titled “Treatment of Primary and Secondary Osteoarthritis of the Knee,” was requested by The American Academy of Orthopedic Surgeons, funded by HHS’ Centers for Disease Control and Prevention, and executed by the AHRQ- supported Blue Cross and Blue Shield Association Evidence-based Practice Center in Chicago. The study authors, who were led by David J. Samson, M.S., associate director of the AHRQ, reviewed findings from 53 randomized clinical trials of glucosamine, chrondroitin and injections with hyaluronan preparations and 23 studies of arthroscopy. The review scrutinized individual studies concerned with these treatments' effects as well as meta-analyses that analyzed the combined evidence of groups of studies.
But, the report stated, “evidence is uncertain because of variation in study quality and difficulty determining whether changes in scores translate into real clinical improvements for patients.” According to Mr. Samson, better quality randomized clinical trials are needed to clarify whether these treatments are beneficial. However, given the aging of the population and increasing prevalence of obesity—both risk factors for osteoarthritis of the knee—“research on new approaches to prevention and treatment of osteoarthritis of the knee should be a high priority.”
The Industry Responds
Needless to say, glucosamine and chondroitin ingredient suppliers were none too pleased with this review’s findings. “The report is in sharp contrast to the benefit related by so many consumers who take these supplements,” commented Ronald Kettenacker, D.V.M., manager, technical services and support, Nutramax Laboratories, Inc. of Edgewood, MD. “If they did not feel the benefit, they would not continue to purchase the products. Apparently, the results of the individual published studies are more in alignment with what consumers as a whole experience with glucosamine and chondroitin sulfate supplements.
“Additionally,” added Mr. Kettenacker, “I am not certain how well the authors of this report understand the chemistry of the compounds they discussed. The authors stated, ‘Table 35 shows that in single-agent RCTs, chondroitin was given as the sulfate salt….’ Chondroitin sulfate is a disaccharide composed of glucuronic acid and galactosamine sulfate and is generally available as a sodium salt, sodium chondroitin sulfate. The attached sulfate structure is what gives chondroitin sulfate the ability to retain large quantities of water in the cartilage matrix.”
Mr. Samson said his team was very surprised by the results of this study, given the overwhelming consumer approval of these products versus the clinical data that spoke to the contrary. “One of the most important messages I took away [from reviewing decades of research] is that it would be really beneficial if there were better quality studies conducted to give us greater confidence in the results,” he said. “One of the more important studies was the GAIT trail [the NIH-funded, multi-centered Glucosamine/Chondroitin Arthritis Intervention Trial which Researchers found ‘overall, there were no significant differences between the other treatments tested and placebo’] and although the results did not show clear benefits in favor of the supplements it did raise some possibilities of some benefit in a specific subgroup of patients but that’s more a suggestion that was raised that could be further investigated with more high quality studies.”
“But we saw very clearly that there were some real problems with the quality of much of the rest of the literature,” concluded Mr. Samson. “Those kinds of quality issues can result in findings that may not be trustworthy. The kinds of problems that occurred can give results that exaggerate whatever effects there really might be.”
Mr. Kettenacker took issue with many specific aspects of the review, pointing out that several of the studies were designed to measure disease modification as the primary outcome, not pain reduction which demonstrated a heterogenicity in the studies that complicates this systematic review. With regard to the review of GAIT, he said, the significant findings of the moderate-to-severe pain patients receiving the combination of glucosamine HCl and chondroitin sulfate was dismissed as not of importance. “What the authors have not appreciated is that individuals with mild OA pain generally will self-medicate with over-the-counter remedies and analgesics. They are not the ones seeking medical attention,” he pointed out. “It is the individuals with moderate-to-severe OA pain, who seek out medical care, and those are the ones who best responded to glucosamine and chondroitin sulfate, and they responded better than those receiving celecoxib!”
Jason Theodosakis, M.D., a medical advisor for Missoula, MT-based TSI Health Sciences who served on the GAIT oversight committee, concurred with Mr. Kettenacker and said the supplement industry has been “subjected to a grave disservice,” in that he’s yet to see and accurate description of the GAIT study in the media. “GAIT is being used improperly to wrongly disparage glucosamine and chondroitin,” he said, noting that the misinterpreted results from GAIT have been used in at least two, “review” articles - one on glucosamine and one on chondroitin. He asserted that this AHRQ article also improperly used GAIT.
“The review articles on glucosamine and chondroitin fail to properly report the beneficial structural effects of these supplements which appear to occur independent of pain relief. Mildly affected patients who did not have significant pain relief still were able to virtually halt cartilage loss, as measured by quantitative x-ray, when using the supplements for two years or longer,” said Dr. Theodosakis. “In summary, failure to recognize the true conclusions of GAIT results in faulty negative conclusions about glucosamine and chondroitin. Since these supplements are virtually non-toxic, and cost only a fraction of the prescription agents for osteoarthritis, the risk/benefit ratio for the supplements is exceedingly favorable. Because of the structure modifying effects, failure to recommend glucosamine/chondroitin for osteoarthritis may one day be considered medical malpractice.”
Mr. Kettenacker also noted that it’s been reported that the cost of treating OA pain with prescription non-steroidal anti-inflammatory drugs is close to the cost of treating the side effects caused by their use. It has also been reported that over 16,000 deaths per year are attributed to the use of these drugs. It seems that the pharmaco-economic and social impact has been overlooked when down playing exceptionally safe supplements that so many people find effective and which are regularly prescribed by rheumatologists in a number of European countries. These compounds were classified by the European League Against Rheumatism (EULAR) in their 2003 recommendations as level of 1A for evidence and ‘A’ for recommendation.”
Ruling Out Bias
One of the top concerns surrounding this review was its origin and the possibility of bias, given that it was conducted by Blue Cross Blue Shield which, as a third party payer conducting the review, could somehow influence the outcome and thus the financial impact if the therapies and supplements reviewed in the study were accepted to be covered by medical insurance—a claim Mr. Samson explicitly denied. “Blue Cross Blue Shield Association Technology Evaluation Center is a contractor with the AHRQ. Our relationship with Blue Cross Blue Shield has no effect on how we evaluate the evidence. The systematic review is done according to very rigorous methods that are planned in advance to make sure we are giving the most fair and accurate reading of what the evidence tells us,” he explained. “From our point of view, the technical evaluation center of Blue Cross Blue Shield is very much interested in looking at the evidence and not being concerned about payment issues. Our methods of reviewing the evidence would be the same no matter what type of intervention it is, whether it would be considered alternative medicine, mainstream medicine, etc. We try to evaluate the quality and consistency of the results of clinical trails and studies.”
He added that Blue Cross Blue Shield’s Evidenced-Based Practice Center is assigned a variety of different topics to review each year. “The way these topics are chosen is that interested parties can nominate topics and the agency then screens them for their importance and the interest they hold for different parties,” he said.
Mr. Samson said his team’s literature search stretched back into the 1960’s. “We were very thorough in this systematic review,” he continued. “The project was conducted according to a pre-specified protocol that guides all of the methods we use for executing the review. This includes the search for studies, how we look at the results of the search, the way we pull information from the selected studies, how we synthesize the evidence—all of it is spelled out in advance. This was a very objective and unbiased look at the totality of the evidence.”
To view a full copy of the 270-page Treatment of Primary and Secondary Osteoarthritis of the Knee, visit http://www.ahrq.gov/clinic/tp/oakneetp.htm.