Healthy Skepticism Library item: 13737

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Publication type: news

Symbion glucosamine complaint
Pharmacy Daily (Australia) - registration required 2008 May 26
http://www.pharmacydaily.com.au

Notes:

Details of Dr Harvey’s complaint to the CRP

The advertisement (appended) said:
“Glucosamine. The facts made simple.”

It claimed:
“A review of a number of clinical trials using X-rays to measure improvement concluded glucosamine
could reduce the risk of osteoarthritis progression by 54%1.”
Choice Magazine2 found about 75% of their online members who were arthritis sufferers claimed they were experiencing a benefit from using glucosamine.”
“One thing we can conclude with confidence is that extensive research proves there can be a significant benefit in taking glucosamine for relief of osteoarthritis.”

Reference cited:
1. Poolsup N, Suthisisang C, Channark P, Kittikulsuth W. Glucosamine long-term treatment and the progression of knee osteoarthritis: systematic review of randomized controlled trials. Ann Pharmacother. 2005 Jun;39(6):1080-7. http://www.theannals.com/cgi/content/abstract/39/6/1080.
2. Choice > Home > Health > Medicines > Glucosamine (05/08):
http://www.choice.com.au/viewArticle.aspx?id=106316&catId=100231&tid=100008&p=1&title=Glucosamine

I believe that this advertisement breaches Section 42C(1) and 42DM(1)&/or 42DP of the Therapeutic Goods Act 1989 because:
• The advertisement lacks a CHC approval number while clearly advertising glucosamine in mainstream print media (all the companies named in the advertisement market various formulations of glucosamine);
• It makes generic claims about an ingredient of listed therapeutic goods (glucosamine) which, in my opinion, do not comply with the Therapeutic Goods Advertising Code 2007.

In particular, I believe that this advertisement breaches Section 4(1)(a); 4(1)(b); 4(2)(a); 4(2),(c); 6(4) of the Therapeutic Goods Advertising Code 2007 because:
• The claims made about the efficacy of glucosamine are not in accord with a balanced view of all the scientific literature available. In particular, Symbion Health have failed to critically appraise the article they cite (see below);
• The quotation from Choice magazine was selectively and misleadingly taken out of context from the
overall thrust of this article which concluded, “The scientific evidence for glucosamine or
glucosamine/chondroitin makes it seem doubtful that it’s effective at relieving the pain of osteoarthritis”.

This large misleading advertisement was published in major metropolitan newspapers by Symbion Health Limited in response to an independent review of glucosamine preparations by CHOICE (the Australian Consumers’ Association) 2. It was clearly designed to undermine the balanced information and advice given by CHOICE.

Because of this, if the Complaint Resolution Panel agrees with my concerns, I believe the strongest penalties should apply:
• A fine of 60 penalty units as laid out under Section 42Dm &/or 42DP of the Therapeutic Goods Act 1989;
• A corrective advertising order specifying that a retraction is placed in the same major metropolitan newspapers as the offending advertisement and in a font size filling the same space.

My detailed concerns about this advertisement’s misrepresentation of the scientific literature follow:

Reference 1 (above) was a 2005 systematic review from the Pharmacy School of Silpakorn University, Thailand. The authors identified two controlled clinical studies that had investigated radiological narrowing of the joint space in 212 and 202 patients respectively, randomized into receiving either 1500 mg glucosamine sulphate (Rotta) or a placebo, once a day, for a 3 year period 3-4. Both studies were supported by a research grant from the Rotta Research Group, Monza, Italy.

The pooled results of both studies (414 patients) were then reported in terms of relative risk of disease progression; defined by the authors as the proportion of patients with joint space narrowing >0.5 mm in the glucosamine group relative to the placebo group and risk difference 1. There were 21 such patients in the glucosamine group and 46 in the placebo group giving a relative risk ratio of 0.46 (95% confidence intervals 0.28 to 0.73).

The authors noted (as did the authors of the original papers):
• “It has yet to be demonstrated that such a delay in progression of joint space narrowing provides clinically beneficial effects to the patients”.
• “Glucosamine is considered a nutritional supplement in the US and Europe and is available as the sulfate, hydrochloride, N-acetyl, or chlorohydrate salts. It is not known whether different forms of glucosamine are associated with differences in efficacy. Moreover, the relative purity and content of glucosamine may vary among different preparations. High-quality, placebo-controlled, long-term trials of nonsulfate salt of glucosamine are needed”.

They authors concluded:
• “Further long-term trials and trials evaluating different forms of glucosamine are warranted before its usefulness and safety can be clearly established”.

The abstract of this paper did state:
• “The risk of disease progression was reduced by 54%”.

However, I argue that this statement does not fit the facts contained in either the systematic review or the original papers.

First, it is inappropriate (as the authors of all these papers admit) to extrapolate from a radiological reduction in joint space to claim a reduction in osteoarthritis disease progression when studies have repeatedly shown that symptom and structure changes are poorly correlated in osteoarthritis, and even the long-term effects of glucosamine sulfate use on symptoms occur irrespective of the outcome on joint space width.

Second, it is inappropriate to translate an arbitrarily defined relative risk ratio (0.46), relating only to a sub-set of patients, into an inverse percentage risk reduction (54%) for the whole population. Absolute numbers and percentages should have been used, together with a more cautious conclusion. For example,
• Of 207 patients in the glucosamine group 21 (10%) showed radiological evidence of joint space narrowing >0.5 mm compared to 46 of 207 (22%) in the placebo group. The clinical significance of this 12% difference is uncertain.

Third, I argue that the claim, “extensive research proves there can be a significant benefit in taking glucosamine for relief of osteoarthritis” is also not in accord with the current literature.
The best evidence of efficacy for glucosamine in osteoarthritis is for the Rotta formulation of glucosamine sulphate. Symbion Consumer markets many formulations of both glucosamine hydrochloride and glucosamine sulphate (to which they sometimes add other ingredient of even more dubious efficacy). To my knowledge, Symbion Consumer has not demonstrated the efficacy of their products in osteoarthritis by appropriately conducted clinical trials nor have they demonstrated bioequivalence of their glucosamine sulphate products with the Rotta formulation (see letter from Rottapharm, Italy). This is also why my colleagues and I recommended that the TGA should check the
analysis of listed products more thoroughly and only allow sponsors to use clinical trial evidence relating to other products where their own product has been shown to be therapeutically equivalent (see: Harvey KJ, Korczak VS, Marron LJ, Newgreen DB. Commercialism, choice and consumer protection: regulation of complementary medicines in Australia. MJA 2008; 188 (1): 21-25.
http://www.mja.com.au/public/issues/188_01_070108/har10522_fm.html).

Because of this, I believe that the implication in their promotion that consumers with osteoarthritis will derive “significant benefit” from taking Bio-Organics, Nature’s Own, Cenovis, Golden Glow and Microgenics brands of glucosamine is misleading and in breach of the Therapeutic Goods Advertising Code.

The scientific evidence follows:

1. An updated 2005 Cochrane Review of glucosamine trials in osteoarthritis (OA) was summarized as follows:
This update includes 20 studies with 2570 patients. Pooled results from studies using a non-Rotta preparation or adequate allocation concealment failed to show benefit in pain and WOMAC function while those studies evaluating the Rotta preparation show that glucosamine was superior to placebo in the treatment of pain and functional impairment resulting from symptomatic OA. WOMAC outcomes of pain, stiffness and function did not show a superiority of glucosamine over placebo for both Rotta and non-Rotta preparations of glucosamine. Glucosamine was as safe as placebo.
Towheed TE, Maxwell L, Anastassiades TP, Shea B, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD002946. DOI: 10.1002/14651858. CD002946.pub2. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD002946/frame.html

2. A 2006 Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) study enrolled nearly 1,600 participants with documented osteoarthritis of the knee into a randomized, placebo- and celecoxib-controlled trial of 1500 mg of glucosamine hydrochloride daily, 1200 mg of chondroitin sulfate daily, or the two in combination. This US$12.5 million trial was funded () by the National Center for Complementary and Alternative Medicine and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. See: http://nccam.nih.gov/news/2006/022206.htm
The results failed to demonstrate a significant difference in the percentage of patients who reached the primary outcome between any of the three supplement groups and the placebo group. The percentage of patients with a response in the celecoxib group did differ significantly from that in the placebo group, providing internal validity for the study. However, a smaller subgroup of study participants with moderate-to-severe pain did show significant relief with the combined supplements.
See also: Hochberg MC. Editorial: Nutritional Supplements for Knee Osteoarthritis – Still No Resolution. New Eng J Med. 2006; 354: 858-991. http://content.nejm.org/cgi/content/extract/354/8/858

3. A 2007 Belgium WHO Collaborating Center study made an exhaustive and critical analysis of the literature from 1980 to 2005 (Medline, PubMed and manual search within the bibliography of retrieved manuscripts).
Results: Despite multiple controlled clinical trials of the use of glucosamine in osteoarthritis (mainly of the knee), controversy on efficacy related to symptomatic improvement continues. Differences in results originate from the differences in products, study design and study populations. Symptomatic efficacy described in multiple studies performed with glucosamine sulphate support continued consideration in the osteoarthritis therapeutic armamentarium. The most compelling evidence of a potential for inhibiting the progression of
osteoarthritis is also obtain with glucosamine sulphate.
Conclusions: glucosamine sulphate has shown positive effects on symptomatic and structural outcomes of knee osteoarthritis. These results should not be extrapolated to other glucosamine salts or preparations (overthe-counter or food supplements) in which no warranty exists about content, pharmacokinetics and pharmacodynamics of the tablets.
From: Reginster JY, Bruyere O, Neuprez A. Current role of glucosamine in the treatment of osteoarthritis.
Rheumatology (Oxford). 2007 May;46(5):731-5. Epub 2007 Mar 31
http://rheumatology.oxfordjournals.org/cgi/content/full/kem026v1

4. A 2008 randomized, controlled trial from the Erasmus Medical Center, Rotterdam, and Leiden
University Medical Center, Leiden, the Netherlands.
Background: The effectiveness of glucosamine sulfate as a symptom and disease modifier for osteoarthritis is still under debate.
Objective: To assess whether glucosamine sulfate has an effect on the symptoms and structural progression of hip osteoarthritis during 2 years of treatment.
Setting: Primary care in the Netherlands. Patients: 222 patients with hip osteoarthritis who were recruited by their general practitioner. Patients were eligible if they met the American College of Rheumatology clinical criteria for hip osteoarthritis.
Intervention: 2 years of treatment with 1500 mg of oral glucosamine sulfate or placebo once daily. The glucosamine used in this study was provided by Numico Research BV (Wageningen, the Netherlands) but was manufactured by Nutricia Manufacturing USA (Greenville, South Carolina). It contained 2000 mg of Dglucosamine sulfate 2-potassium chloride, which results in a net content of 1500 mg of glucosamine sulfate per 2 pills. The supplier conducted a quality check before delivery of the trial medication to ensure that study pills contained the required amount of active ingredients.
Measurements: Primary outcome measures were Western Ontario and McMaster Universities (WOMAC) pain
and function subscales over 24 months and joint space narrowing after 24 months. The main secondary
outcome measures were WOMAC pain, function, and stiffness after 3, 12, and 24 months.
Results: At baseline, both groups were similar in demographic and clinical variables. Overall, WOMAC pain did not differ (mean difference [glucosamine sulfate minus placebo], –1.54 [95% CI, –5.43 to 2.36]), nor did WOMAC function (mean difference, –2.01 [CI, –5.38 to 1.36]). Joint space narrowing also did not differ after 24 months (mean difference, –0.029 [CI, –0.122 to 0.064]). Only 1 of the sensitivity analyses, based on extreme assumptions regarding missing assessments due to total hip replacement, provided results consistent with a glucosamine effect.
Limitations: Twenty patients had total hip replacement during the trial. Half of the patients had a Kellgren and Lawrence score of 1.
Conclusion: Glucosamine sulfate was no better than placebo in reducing symptoms and progression of hip osteoarthritis.
[N.B. This study was not funded by Rotta Research Group, Monza, Italy and did not use their product].
Rozendaal RM, Koes BW, van Osch GJVM, et al. Effect of Glucosamine Sulfate on Hip Osteoarthritis: A
Randomized Trial. Ann Intern Med. 2008;148:268-277. http://www.annals.org/cgi/content/abstract/148/4/268

Additional references:
3. Reginster JY, Deroisy R, Rovati LC. Long-term effects of glucosamine sulphate on osteoarthritis
progression: a randomised, placebo-controlled clinical trial. Lancet 2001; 357: 251–56.
4. Pavelka´ K, Gatterova´ J, Olejarova´ M, et al. Glucosamine Sulfate Use and Delay of Progression of Knee Osteoarthritis. Arch Intern Med. 2002;162:2113-2123

Full text:

LA TROBE University’s Ken Harvey has submitted another official complaint to the Therapeutic Goods Complaints Resolution Panel.

This time he’s taken exception to the advertisements published by Symbion last week defending glucosamine (PD 21 May) after a CHOICE report which claimed there was little evidence that the
supplement was effective apart from as a placebo (PD 08 May).

Harvey claims the Symbion ad breached the Therapeutic Goods Act because it makes generic claims about glucosamine which “are not in accord with a balanced view of all the scientific literature available.”

He said Symbion Health has failed to critically appraise the article cited as clinical evidence
for glucosamine, which related to a particular formulation of glucosamine sulfate made by an Italian company called Rotta.

Harvey said the “large misleading advertisement was… clearly designed to undermine the balanced information and advice given by CHOICE” and asked for the strongest penalties to apply.