April 1, 2015

Can Chondroitin and Glucosamine Rival Cox-2 Inhibitors for Osteoarthritis?

Study suggests superiority of natural agents in pain relief
Surprising results of a European trial suggest a combination of chondroitin sulfate and glucosamine hydrochloride offers better pain relief for knee osteoarthritis than celecoxib.


Hochberg MC, Martel-Pelletier J, Monfort J, et al. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis. 2015 Jan 14. [Epub ahead of print]


Randomized, double-blind, noninferiority trial


As part of the Multicentre Osteoarthritis interVEntion trial with Symptomatic slow-acting drugs for osteoarthritis (MOVES), 606 patients with radiographic evidence of knee arthritis and moderate to severe pain were selected from 42 clinics in France, Germany, Poland, and Spain. The mean age of participants was 63 years; 84% were women, and 99% were white.  


MOVES patients were randomized to receive either 400 mg chondroitin sulfate (CS) plus 500 mg glucosamine hydrochloride (GH) 3 times per day or 200 mg COX-2 selective inhibitor celecoxib (Celebrex) once a day for 6 months. Acetaminophen, up to 3 g per day, was permitted as needed.

Primary Outcome Measures

The primary outcome measure was the change in the Western Ontario and McMaster osteoarthritis index (WOMAC) pain score at 6 months. Secondary measures included stiffness, joint swelling, and use of acetaminophen. All measures were evaluated at 1, 2, 4, and 6 months.

Key Findings

At 1, 2, and 4 months, celecoxib was more effective than CS+GH in lowering the WOMAC pain score. Correspondingly, acetaminophen use was higher in the CS+GH group at 1 month. At 6 months, however, the mean change from baseline in WOMAC pain score was ‒186.8 (a 50.2% decrease) in the celecoxib group and ‒185.7 (a 50.1% decrease) in the CS+GH group. These results demonstrated noninferiority of CS+GH to celecoxib at 6 months.

Practice Implications

The results of this study were surprisingly impressive: a combination of CS+GH was equally effective at reducing pain as the popular COX-2 inhibitor celecoxib.

The current study used a combination protocol, but there is no way to know whether the positive results should be attributed to chondroitin, glucosamine, or their synergistic effect. 

A cursory review of recent studies on chondroitin and glucosamine would not predict such a robust finding.1,2 Conclusions of published meta-analyses of chondroitin, glucosamine, or their combination have been conflicted. Even the study that was used as a model for the current trial was inconclusive: the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) was a large randomized controlled trial (RCT) that demonstrated no benefit of CS+GH over placebo in the overall GAIT population and only “possible benefit” vs placebo in the subgroup of patients with moderate to severe pain.3
Most studies have evaluated a combination of chondroitin plus glucosamine, making it difficult to distinguish their individual effects. Recent trials on glucosamine alone have failed to demonstrate its efficacy; these trials include 1 published in 2010 in the Journal of the American Medical Association and another published in 2014 in Arthritis & Rheumatology.4,5 In contrast, a 2015 Cochrane review of 43 randomized trials concluded that chondroitin is superior to placebo at improving pain in patients with osteoarthritis (OA).6 The current study used a combination protocol, but there is no way to know whether the positive results should be attributed to chondroitin, glucosamine, or their synergistic effect. 
Another confounding factor in the current study’s design was the form of glucosamine used—GH. A 2013 meta-analysis concluded that glucosamine sulfate (GS) but not GH may reduce pain and improve function in patients with knee OA.7 The Osteoarthritis Research Society International also concluded that GS produces more consistent results than GH.8 The authors of the current study provide no explanation for the choice of glucosamine, bringing into question whether any of the clinical effect can be attributed to glucosamine or should be attributed to chondroitin alone.  
Finally, the primary outcome measure in the current study was symptomatic improvement, a measure that may not fully reflect the benefits of chondroitin and glucosamine. Because these compounds provide a source of glycosaminoglycans for the production of collagen and synovial fluid, they might have tissue-modifying effects in OA. Two recent RCTs have demonstrated that a combination of GS+CS significantly reduced cartilage loss and joint space narrowing when taken for 2 years.9,10 In 1 of these trials, the radiographic evidence did not correlate with symptomatic improvement,9 and in the other trial, the outcome was measured by quantitative magnetic resonance imaging rather than the more standard x-ray.10 Interestingly, in patients taking glucosamine for 12 weeks, there was a reduction in immunoreactivity in collagen type I and a reduction in receptors for advanced glycation end products when compared to those taking nonsteroidal antiinflammatory drugs or placebo.11 Taken together, these studies suggest that chondroitin and glucosamine may have tissue-modifying effects that are detected only when the outcome measures aim to do so.   
Standard pharmaceutical treatments for OA aim for relief of symptoms.12 Chondroitin and glucosamine are unique in their potential to offer tissue-modifying effects. Results of the current study suggest that these natural agents, when taken for at least 6 months, may also offer symptomatic relief in patients with moderate to severe knee arthritis.  
The current study used a combination protocol, an inferior preparation of glucosamine, and outcome measures based only on symptomatic improvement. Despite these weaknesses, results demonstrated noninferiority of CS+GH as comparedto a COX-2 inhibitor after 6 months. These results are impressive and should not be ignored. Chondroitin and glucosamine are natural agents with good safety profiles, whereas COX-2 inhibitors carry both gastrointestinal and cardiovascular risk. 

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  9. Fransen M, Agaliotis M, Nairn L, et al; on behalf of the LEGS study collaborative group. Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens. Ann Rheum Dis. 2014 Jan 6. [Epub ahead of print] 
  10. Martel-Pelletier J, Roubille C, Abram F, et al. First-line analysis of the effects of treatment on progression of structural changes in knee osteoarthritis over 24 months: data from the osteoarthritis initiative progression cohort. Ann Rheum Dis. 2015;74(3):547-556.
  11. Mattiello-Sverzut AC, Petersen SG, Kjaer M, Mackey AL. Morphological adaptation of muscle collagen and receptor of advanced glycation end product (RAGE) in osteoarthritis patients with 12 weeks of resistance training: influence of anti-inflammatory or glucosamine treatment. Rheumatol Int. 2013;33(9):2215-2224.
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