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New Published Study - 2/19/08

Effect of Glucosamine Sulfate on Hip Osteoarthritis

Rianne M. Rozendaal, Bart W. Koes, et. al. Annals of Internal Medicine Vol 148, no. 4, (2008) pp. 268-277.

Introduction: Researchers from the Netherlands recruited 222 patients with mild hip osteoarthritis pain to receive either 1,500 mg of glucosamine sulfate or a placebo for 2 years. 207 patients completed the study. At baseline, 29% of the patients assigned to the glucosamine group were on daily medication to control pain (only 19% in the placebo group).

Measurements: The principle outcome measures were the WOMAC pain and function subscales and joint space narrowing (as determined by quantitative x-ray measures) before and after the two year study period.

Results: Reduction in pain, improvement in function and x-ray changes were similar in the two groups. In this study, glucosamine sulfate was no better than placebo for hip osteoarthritis for either pain and function improvement or joint space width on x-ray. At the end of the 24 month study, those in the glucosamine group were 29% less likely to use arthritis medication (but this was not considered to be statistically significant).


Dr. Theo's Comments
:


I have to wonder if this study was designed to fail.

When you pick patients who don't have much pain to start, they don't have much room to improve. Then when you pick patients whose joints are stable and have very little disease, your won't see significant changes on x-ray in two, short years.

It's the perfect formula to make it look like glucosamine doesn't work.

Perhaps the authors thought they were doing the right thing. They did design this study in 2003 or 2004, before we knew that this kind of design is all but useless. Granted, it's a lot easier to see where the researchers went wrong after the study was complete, I admit. But don't buy the results of this study just yet until you read on. There are some big problems with this study.

The doctors who wrote the editorial in the Annals of Internal Medicine did a pretty good job of exploring the problems with the study. I would have to agree with them on most of the points.

What happened?

There is a major mistake in the design of this study that renders it partially or fully invalid. It is clearly indicated that half of the patients in the study had very mild disease (classified as Kellgren and Lawrence (KL) grade 1. KL is a x-ray grading system for osteoarthritis that varies from 1 (mild) to severe (grade 4). Most modern osteoarthritis studies (including GAIT) utilize only patients with KL grades 2 and 3.

It's improper to include KL grade 1 patients in a long-term cartilage structure assessment, such as this study. Doing so may lead to false negative results (doesn't look like a treatment works when in fact it does).

The guidelines for performing studies on cartilage structure with x-ray evaluation (enacted all the way back in 1998) are very clear in this matter. Take a look (Adobe Acrobat reader required).

What's so bad about using KL grade 1 patients?


KL grade 1 patients don't have significant disease (you can't see any abnormal, disease related changes on x-ray). These patients often don't have much pain, but more importantly, they aren't in the phase of the disease where they are losing cartilage fast enough to detect a change in a two-year study.

As a result, of course the authors wouldn't find a difference between glucosamine and placebo - the patients they were using wouldn't be expected to show a difference.

The cartilage in patients with KL grade 1 is relatively inactive. But you need activity to see changes. It's like saying that Grizzly bears are not dangerous to humans. It does no good to make such an assessment when examining the bears during hybernation. To get an accurate assessment, examine the bears while they're awake. Cartilage is essentially "hybernating" in KL grade 1. Want proof? In this glucosamine study, the patients (who were made up of 50% KL grade 1 patients) lost only 0.16 mm of joint space over the two-year period versus the expected loss of 0.25 mm. With the numbers of patients used, and the x-ray techniquie employed, there was no way this study could have detected a difference on x-ray between the glucosamine sulfate treated group and the placebo group.

The authors of the study go on to say that they did a separate analysis looking at patients who had osteoarthritis grades 2 and 3 (KL scores of 2 and 3) and found no significant variation from the outcome reported for all of the patients. There's a problem with this analysis, however. More than half of the patients enrolled were KL grade 1, and only 207 patients completed the study. Therefore, only about 50 patients per group (glucosamine sulfate or placebo) who had KL grades 2 and 3 were available for this sub-analysis. This is an insufficient number of patients to actually make the statement that glucosamine sulfate was not effective in preventing loss of joint space. The authors did say that patients in the study lost joint space at rates below what were expected. This exemplifies the fact that patients with KL 1 grade osteoarthritis shouldn't be included in this type of study. The rate of loss of cartilage is not enough to detect a significant difference over a two-year period of time.

If the authors had 207 patients with KL grade 2 and 3 disease, and followed the patients long enough, this study might have been OK.


This is why the main governing body for European pharmaceutical research on long-acting treatments for osteoarthritis discourages the use of patients with KL 1 grade disease. The authors clearly violated these guidelines and published a study that looks impressive, and does have some features of a high quality clinical study, but actually may not be valid. They didn't measure what they were supposed to measure.

I must admit that I don't expect the average health reporter to understand the intricacies of clinical research, especially as it relates to the esoteric nature of long-term osteoarthritis studies. It's no surprise that most publications will report that glucosamine sulfate had no effect on osteoarthritis of the hip. The headline for this article should be that the authors made a mistake in choosing their patients.

In this study, we really can't tell anything about the effect, or lack of effectiveness of glucosamine sulfate versus placebo in treating patients with osteoarthritis of the hip based on this study.

Continued...



 
 

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