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Introduction:

In the late 1990s, St. John’s wort (SJW) extract rocketed to tremendous success in the United States and Europe as a natural anti-depressant, but a dubious 2002 study funded by the drug company giant Pfizer, led to a crushing 97% drop in its popularity that year and it has never recovered. Pfizer’s drug, Zoloft, was the number one selling antidepressant at the time. Many experts felt that the researchers stacked the deck against SJW especially since several double-blind studies afterwards showed that SJW is more effective and have fewer side effects than Zoloft and other antidepressant drugs. In fact, a 2008 Cochrane Database Review concluded based on the results from over 30 double-blind studies with SJW extract that it is: “ a) is superior to placebo in patients with major depression; b) is similarly effective as standard antidepressants; c) and has fewer side effects than standard antidepressants.”

Two of the most popular and clinically proven natural products are glucosamine sulfate and chondroitin sulfate, used alone or in combination in the prevention and treatment of osteoarthritis. Products containing glucosamine or chondroitin sulfate represent about $800 million in annual sales in the United States, while over-the-counter drugs like aspirin, ibuprofen and related non-steroidal anti-inflammatory drugs (NSAIDs) including prescription forms like Celebrex, produce approximately $8 billion in annual sales.

It seems like the drug companies are taking the “St. John’s wort approach” to try to curb sales of glucosamine and chondroitin products based upon a recent study that was funded in part by drug companies like Pfizer; Novartis; Merck; and GlaxoSmithKline. Why else would these drug companies invest in studying the effects of a natural product that is a direct competitor to their highly profitable drugs?

Background Data:

Glucosamine and chondroitin are naturally produced in the body, but as some people age they may lose the ability to manufacture sufficient levels of these critical components of cartilage leading to osteoarthritis (OA). Extensive preclinical and clinical research, including long-term double-blind studies, support a rationale and role for glucosamine, as well as chondroitin sulfate, as an effective treatment of OA.

In fact, numerous head-to-head double-blind studies have shown glucosamine sulfate (GS) to produce much better results compared with NSAIDs or acetaminophen in relieving the pain and inflammation of OA. While some of the studies comparing GS to NSAIDs or acetaminophen show similar reduction in pain and symptom scores, only GS improves measures of joint function or markers showing improvement of cartilage structure. Typically the advantages of GS over these other treatments is seen after 4-6 weeks of use, but there is some evidence that the longer GS is used, the greater the therapeutic benefit.

The two longest placebo-controlled trials with GS are of three years in duration. The results from these studies show quite convincingly that GS slows down the progression of osteoarthritis, and in many cases, produces regression of the disease, as noted by x-ray improvements, and significantly reduces the need for total joint replacement even after as much as 5 years after GS discontinuation.

GS may also have a role as a preventive measure against the development of OA, especially in athletes subjected to joint strain as shown in recent clinical trials.

While GS has shown significant clinical benefit, unfortunately several large, well-publicized studies utilized the hydrochloride form (glucosamine hydrochloride) and failed to show benefit. It is thought that the sulfur component is critical to the overall effect of GS.

In regards to chondroitin sulfate (CS), while many studies have combined it with glucosamine, it also has shown benefits in the treatment of osteoarthritis on its own and has also shown to promote healthier cartilage.

New Data:

The new data was not from a new study, but rather it involved sifting through the 4-year follow-up data from the Osteoarthritis Initiative study that involved subjects with or at risk of developing OA of the knee. The researchers identified 1,625 subjects who were not using glucosamine or chondroitin products at baseline. During the 4-year period, 18% of these participants began using glucosamine or chondroitin products. Using detailed clinical assessments and then adjusting the data for potential confounders, the researchers stated they found no clinically significant differences between those subjects who used of glucosamine or chondroitin versus those that never-used the products in terms of pain scores, joint function, and structural progression of the disease confirmed by x-ray. But, there appears to be more to the story.

Commentary:

While this analysis has received considerable attention, the media has for some reason ignored the sponsors of the study and failed to ask even the most basic questions if they even bothered to look at the data. Most of the time these sorts of studies hit the newswire or Internet they are not critically analyzed. So, let me offer some insight here.

It is important to distinguish that this study is one that is classified as an uncontrolled observational study. These sorts of studies are generally used to note trends so that properly conducted randomized, controlled double-blind studies can be performed. These are exactly the type of studies that have already been conducted with glucosamine/chondroitin.

Perhaps the first question to be answered is why did some of the subjects start taking glucosamine/chondroitin? You can probably guess the right answer. It is because their joint pain was getting worse. This situation makes it very hard for researchers to compare groups because it may simply be that they are comparing outcomes in people who were getting worse, to people who were not getting worse. The researchers tried to control for this confounding variable, but it is still an issue no matter how much math is involved.

The next question is how were subjects identified as using glucosamine or chondroitin products? They were asked in a questionnaire “During the past 6 months, did you use the following health supplements for joint pain or arthritis?” with separate questions for glucosamine and chondroitin sulfate use. A participant was considered as taking glucosamine or chondroitin if he/she reported using it for at least 4 days per week, and not taking the supplement if they reported not using it or using it for less than 4 days per week.

On the surface, this categorization seems reasonable even though there is no clinical difference between taking glucosamine/chondroitin 3 vs. 4 days a week. But, my feeling is that the biggest shortcoming was not getting a better idea of dosage. In my experience, I have found many consumers do not take the proper dosage of natural products. In the analysis, there was no indication of form or dosage of the products used. This shortcoming alone makes the data meaningless in my opinion.

Nonetheless, let’s take a look at the data. But first, let me ask another question. Does the data support the conclusion that the researchers “found no clinically significant differences between those subjects who used of glucosamine or chondroitin, versus those that never-used the products?” I don’t believe so. Here is why. Their stated conclusion is preceded in the article by the statement acknowledging it was made “after adjustment for potential confounders with marginal structural models.” In other words, they adjusted the data to create their conclusion

The key finding of the analysis that is briefly mentioned in the study that clearly shows there was benefit noted was that there was an absolute reduction in joint space narrowing in the knee in those subjects taking glucosamine/chondroitin products. The narrowing of the joint space is one of the key signs of progression of the disease process of osteoarthritis. Compared to never-users, those who reported previous use of glucosamine/chondroitin for three yearly assessments had on average 0.11mm wider joint space of the knee. To me, that is a clear sign of benefit and reason alone to take glucosamine/chondroitin. However, the researchers concluded that the average of 0.11 mm wider joint space in the users was not clinically significant because it did not reach what they considered the meaningful value of 0.2 mm wider. But, it is important to point out that the range increased with each yearly assessment meaning many of the subjects achieved improvements much greater than 0.2 mm wider. Compared to never-users, those who reported previous use for three, two and one assessments had a range in joint width of -0.21 to 0.44 mm (average 11 mm); -0.07 to 0.35 mm (average 14 mm); and -0.16 to 0.10 mm (average -0.03), respectively. This clearly shows a treatment effect in many of these users. It would have been interesting to see the median as opposed to the average. Again, keep in mind that this study was an observational study and not a clinical trial looking for specific treatment outcomes. In two separate long-term controlled trials (i.e., 3-year double-blind studies) with glucosamine sulfate there was significant clinical evidence on improving joint space width (a sign of healthier cartilage), thereby showing a significant effect on reducing the progression of osteoarthritis. This effect of preventing joint space narrowing led to GS being referred to as possessing a “structure modifying effect” in the treatment of osteoarthritis. Chondroitin sulfate alone and in combination with glucosamine has also shown positive effects on cartilage health and structure as also produces a structure modifying effect.

The bottom line is that while the headlines are claiming no benefit noted, this uncontrolled observational study should not blind anyone to the benefits noted in well-designed, controlled clinical trials. In addition, looking at the objective data instead, it is clear that the reported use of glucosamine/chondroitin products by some of these subjects was associated with a significant effect on modifying the progression of the disease, as the joint space width was considerably greater in some of these users of these supplements compared to non-users.

Keep in mind that although nonsteroidal anti-inflammatory drugs (NSAIDs) provide short-term symptomatic relief, they may actually increase the rate of degeneration of the joint cartilage. Experimental studies have shown that aspirin and other NSAIDs inhibit collagen matrix synthesis and accelerate cartilage destruction. Some retrospective clinical studies have shown that NSAID use is associated with acceleration of osteoarthritis and increased joint destruction.

The paragraph above is important because people that are in pain due to osteoarthritis are both most likely to use NSAIDs and natural products containing glucosamine/chondroitin. My recommendation is to avoid NSAIDs at all costs in osteoarthritis as they are a classic example of a drug suppressing a symptom while at the same time fueling the progression of the disease process. Fortunately, there are safe and effective natural alternatives.

Reference:

Yang S, Eaton CB, McAlindon TE, Lapane KL. Effects of glucosamine and chondroitin on treating knee osteoarthritis: An analysis with marginal structural models. Arthritis Rheumatol. 2014 Nov 4. doi: 10.1002/art.38932. [Epub ahead of print]

Dr. Michael Murray
12/3/2014

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