Glucosamine sulphate, but not glucosamine hydrochloride, effective against osteoarthritis

Clarification is in order for the widely publicized findings of a recent BMJ article entitled: Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of the hip or knee: network meta-analysis.¹ The headline of the September 13, 2010, press release declaims: Popular supplements to combat joint pain do not work.²

Since numerous studies, including two recent Cochrane Reviews—long recognized as the gold standard in medical research analysis—have demonstrated that glucosamine (in the form of glucosamine sulfate) and chondroitin do effectively not only reduce pain, but promote restoration of healthy joint tissue, it seems advisable to take a closer look at the evidence presented in both the Cochrane reviews and in the latest BMJ paper whose authors are now pronouncing an opposite conclusion.

The first positive Cochrane review was published in 2001, and the results further confirmed in an updated review in 2005:

The 2001 Cochrane review identified 16 randomized controlled trials (RCTs) which provided evidence that glucosamine is both effective and safe in osteoarthritis (OA). Glucosamine was compared to placebo in 13 of these RCTs and was found to be superior in all except one. In four of the 16 RCTs, glucosamine was compared to an NSAID and was found to be superior in two and equivalent in two.

Of key importance, in their conclusion, the Cochrane reviewers noted, “Most of the trials reviewed only evaluated the Rotta preparation of glucosamine sulfate. It is not known whether different glucosamine preparations prepared by different manufacturers are equally effective in the therapy of OA.”³

The second Cochrane review (2005) included 20 RCTs and found glucosamine significantly better than placebo with, from baseline, a 28% improvement in pain and a 21% improvement in function.⁴ In the 10 RCTs in which the Rotta preparation of glucosamine (glucosamine sulfate [aka sulphate]) was compared to placebo, glucosamine was found to be superior for pain and function. In contrast, pooled results for pain and function in those RCTs in which a non-Rotta preparation of glucosamine (glucosamine hydrochloride) was compared to placebo did not reach statistical significance.

In the four RCTs in which the Rotta preparation (glucosamine sulfate) was compared to an NSAID, glucosamine was superior in two, and equivalent in two. Furthermore, two RCTs using the Rotta preparation showed that glucosamine was able to slow radiological progression of OA of the knee over a three year period. Unlike NSAIDs, which are well known to cause intestinal bleeding, peptic ulcers and cardiovascular thromboembolic events with long term use,⁵⁶ glucosamine was as safe as placebo.

In the article published in BMJ September 13, 2010, Jüni et al. analyzed the results of 10 published trials involving 3,803 patients with knee or hip osteoarthritis. While mentioned neither in the press release nor noted in the abstract of this paper, half of the trials chosen utilized glucosamine hydrochloride. Not surprisingly, in all of these studies, glucosamine hydrochloride produced marginal benefit compared to placebo. In contrast, in the 5 trials in which glucosamine sulfate (aka sulphate) was used, it was clearly superior to placebo. Combining the results of the 10 trials produced an “average” that drags down the overall value, washing out the benefit demonstrated by glucosamine sulfate. This then allowed Jüni et al. to claim they found no clinically relevant effect of chondroitin, glucosamine, or their combination on perceived joint pain or on joint space narrowing, despite the fact that the data presented in Figure 3 in their article clearly reveals this was not the case.

Chart Adapted from Jüni et al., Figure 3 Stratified analyses of differences (95% confidence interval) on 10 cm visual analogue scale (VAS) in pain intensity between experimental interventions and placebo. Shading represents area of clinical equivalence. Negative values indicate benefit of experimental interventions compared with placebo.

This misdirection is highly unfortunate since:

1. OA is the most common arthritis in the world. In 2000, symptomatic OA afflicted an estimated 9.6% of men and 18% of women over 60. Currently, ~25% of individuals >55 experience knee pain most days of the month. By 2050, 27% of the North American population and 33% of the European population and will be >60. Since age is the greatest risk factor for OA, the burden of disease will surely worsen. In those ≥80, a greater than 100% increase in OA is anticipated by 2050.⁷
2. OA of the hip or knee is a chronic condition for which the standard treatment–symptomatic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) remains the status quo despite questionable efficacy and significant risks, i.e., hemorrhage, peptic ulcer disease, renal failure, and thromboembolism.⁸

With the prevalence of OA expected to double in the next 20 years and NSAID-related gastropathy currently the second most deadly rheumatic disease,⁸ the need for treatment that safely provides not only palliative relief, but also beneficially impacts the underlying causes of OA and slows the progression of the disease, is becoming progressively more apparent. Not surprisingly, after the publication of the positive Cochrane reviews, general practitioners and rheumatologists have increasingly prescribed glucosamine and chondroitin to their patients. In addition, many individuals have purchased these supplements over the counter. In 2008, global sales of glucosamine supplements reached almost $2 billion, an increase of ~60% since 2003—a fact emphasized by Jüni et al. in the opening paragraphs of their BMJ meta-analysis.¹

From a monetary perspective—the perspective highlighted by Jüni et al.—a lot of prescriptions have been written, costing the health authorities in countries with socialized medicine and health insurers in countries with fee-for-service medicine a lot of money. Another “problem” singled out by Jüni et al. is that “Despite this [Jüni et al’s] finding, some patients [LMR comment: e.g., those taking glucosamine sulfate] are convinced that these preparations are beneficial.”

What to do? Jüni et al. suggest “patients continue these preparations as long as they perceive a benefit and cover the cost of treatment themselves [italics added]…but health authorities and health insurers should not cover the costs for these preparations, and new prescriptions to patients who have not received treatment should be discouraged.”

We suggest a bit of health-promoting skepticism and a thorough reading of the full paper when one highly publicized article asserts a finding that flies in the face of numerous respectable reviews.

In addition to the Cochrane reviews, a number of other reviews published since 2005 have confirmed that treatment with glucosamine sulfate and chondroitin should be recommended as first-line therapy for OA.

These include:

• Bruyere O, Reginster JY. (2007): a review that evaluated RCTs that have assessed the structure-modifying effect of glucosamine sulfate and chondroitin sulfate using plain radiography to measure joint space narrowing over years. The conclusion reached based on recent RCTs and meta-analyses: glucosamine sulfate (but not glucosamine hydrochloride) and chondroitin sulfate have small-to-moderate symptomatic efficacy in OA…there is compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of OA.⁹
• Black C, Clar C, Henderson R, et al (2009): a review of eight primary trials of >12 months’ duration, all of which showed evidence of statistically significant improvements in joint space loss, pain and function for glucosamine sulfate. In two studies of glucosamine sulfate, the need for knee arthroplasty was reduced from 14.5% to 6.3% at 8 years’ follow-up. The authors note, in a comment repeatedly seen in the research involving glucosamine, that for other preparations of glucosamine (i.e., glucosamine hydrochloride), chondroitin and combination therapy, there was less evidence to support a clinical effect.¹⁰
• Vangsness CT Jr, Spiker W, Erickson J. (2009): an excellent historical overview, this paper evaluates the research evidence presented over the last 40 years for the use of glucosamine and chondroitin sulfate in OA. A key point made in the introduction is that to do so, “It is necessary to evaluate each supplement independently (GS [glucosamine sulfate], GH [glucosamine hydrochloride], and CS [chondroiton sulfate]) and jointly as a pair (glucosamine plus CS).”

Among the many studies discussed by Vangsness et al., is the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), which was published in the New England Journal of Medicine early in 2006 and included 1,583 patients with OA. Despite the fact that glucosamine hydrochloride, which has repeatedly been shown to be less effective than glucosamine sulfate, was used in this trial, the primary outcome measure in the GAIT was a 20% decrease in the summed score for the WOMAC pain subscale from baseline to week 24. (WOMAC =Western Ontario and McMaster University Osteoarthritis Index, the standard index used in OA studies.) Vangsness et al.’s conclusion: “Many studies confirmed OA pain relief with glucosamine and chondroitin sulfate use. The excellent safety profile of glucosamine and chondroitin sulfate therapy should be discussed with patients, and these supplements may serve a role as an initial treatment modality for many OA patients.”⁸

In contrast, the most recent follow up on the GAIT showed little to no efficacy for glucosamine and chondroitin. This article—Sawitzke AD, Shi H, Finco MF, et al.(2010)¹¹—reports the negative outcome of a 24-month, double-blind, placebo-controlled study involving 662 patients that was conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT). Its stated purpose: to evaluate the efficacy and safety of glucosamine and chondroitin sulfate, alone or in combination, as well as celecoxib and placebo on painful knee OA over 2 years. Its results: Glucosamine produced pain relief comparable to celecoxib. Compared with placebo, the odds of achieving a 20% reduction in pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/chondroiton sulfate: 0.83 and CS alone: 0.69. The conclusion drawn: Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. Guess which form of glucosamine was used: glucosamine hydrochloride.

Why is glucosamine sulfate, but not glucosamine hydrochloride, likely to be effective in treating OA?

In all the papers in which the question is raised as to the mechanism of action through which glucosamine may serve as an effective treatment for OA, the “answer” given is that the mechanism is unknown. What do we know?

We know that glucosamine (2-amino-2-deoxy-β-d-glucopyranose, an endogenous amino-monosaccharide, is synthesized from glucose and utilized for the biosynthesis of glycoproteins and glycosaminoglycans (GAGs) found in hyaline cartilage.¹²

Although it is present in almost all human tissues, we know that glucosamine is concentrated in connective tissue, most highly in cartilage. And we know that while glucosamine can be found in several forms, including sulfate, hydrochloride, and N-acetylglucosamine, the vast majority of the peer-reviewed research indicates that glucosamine sulfate reduces osteoarthritis pain and reduces joint space loss, whereas glucosamine hydrochloride does not.¹²

Insufficient human studies have been conducted on N-acetyl-glucosamine to make a determination as to its efficacy, although hyaluronic acid (which is found in articular cartilage and synovial fluid) is composed of repeating dimeric units of glucuronic acid and N- acetylglucosamine, providing a mechanism through which it might be beneficial, and research has confirmed that exogenous N-acetyl-glucosamine can increase hyaluronic acid production by synovium tissue, while glucosamine hydrochloride does not.¹³  In fact, glucosamine hydrochloride actually inhibits hyaluronic acid and glycosaminoglycan synthesis in chrondocytes!¹⁴

(Chondroitin sulfate also increases hyaluronic acid production by human synoviocytes, which may be why the combination of glucosamine sulfate and chondroitin sulfate is more effective than either nutraceutical alone.)¹⁵

In humans, ~90 percent of an oral dose of glucosamine sulfate is absorbed and rapidly incorporates into articular cartilage. The sulfate salt of glucosamine sulfate forms one half of the disaccharide subunit of keratin sulfate, levels of which decrease in patients with OA.¹²

Possible mechanisms of action for the chondroprotective effect of glucosamine sulfate include:

Direct stimulation of chondrocytes: Treatment with glucosamine has been shown to enhance human mesenchymal stem cell chondrogenesis and maintain cartilage matrix gene expression in chondrocytes.¹⁶

Incorporation of sulfur into cartilage: Sulfate is required for glycosaminoglycan synthesis. Oral glucosamine sulfate (1 gram) has been shown to significantly increase serum and synovial fluid sulfate concentrations, which were found to be virtually identical. Of interest, when the same dose of glucosamine sulfate was ingested with 1 gram of the NSAID, acetaminophen, which is largely metabolized by sulfation, serum and synovial concentrations of sulfate significantly decreased. This research also shows that glucosamine is definitely an active partner for sulfate, since, unlike glucosamine sulfate, oral sodium sulfate—at a dose that provided twice the amount of sulfate as the dose of glucosamine sulfate–did not significantly increase the serum sulfate concentration.¹⁷

Protection against oxidative-stress related cartilage degradation: in patients with OA, levels of lipid and protein oxidation products have been shown to be much higher than in the healthy population. Increased levels of TNF-α, a cytokine involved in cartilage inflammation and degradation, and MMP-2, a matrix metalloproteinase involved in the destruction of articular cartilage via the breakdown and modification of extracellular matrix components including collagen, have been observed in the serum/plasma of OA subjects.¹⁸

Sulfur is an essential component of cysteine, the rate-limiting peptide in glutathione formation. Not only is glutathione acting as a reducing agent through its sulfhydryl (-SH) moiety, but many other key cellular enzymes use prosthetic groups ending with -SH moieties to handle reactions involving acyl-containing biochemicals: two examples, both of which are essential for healthy mitochondrial function, are coenzyme A and alpha-lipoic acid. Sulfur is also required for both glucuronidation and sulfation, key Phase II detoxification reactions that transform xenobiotic compounds (many drugs and environmental toxins) into a form in which they are able to be excreted from the body. NSAIDs are primarily detoxified via glucuronidation.

Given all of the above, it is not surprising that in their paper published in Metabolism in 2001, Hoffer et al. suggest that sulfate may be key to the therapeutic effect of glucosamine and conclude: “This hypothesis is clinically relevant because it predicts that nonsulfate salts of glucosamine [i.e. glucosamine hydrochloride] will be ineffective and that renal function, diet, and concurrent acetaminophen therapy could confound clinical trials of this therapy.”¹⁷

Conclusion

Treatment with Glucosamine Sulfate is a Reasonable Option for Patients with OA.

To quote Dahmer and Schiller in their August 2008 review of glucosamine in the American Family Physician: “If physicians have patients who wish to try glucosamine, it would be reasonable to support a 60-day trial of glucosamine sulfate, especially in those at high risk of secondary effects from other accepted treatments.”¹²

In the numerous trials that have demonstrated benefit versus OA with glucosamine, most utilized glucosamine sulfate (500 mg orally t.i.d.), and most noted improvements after 30 to 90 days of therapy.

References