By Dónal P. O’Mathúna, PhD
Osteoarthritis is the most common form of arthritis and a leading cause of disability in the United States and other developed countries.1 The aging of the world’s population is leading to increased incidence of the disease, soon expected to account for 30% of doctors’ office visits.2 It is estimated that almost everyone 75 years of age or older is affected by osteoarthritis in at least one joint. However, only about half of the people who show evidence of the disease on X-ray report having any symptoms. Most people develop symptoms as a result of general use and aging, although some are predisposed genetically to osteoarthritis. In others, the disease appears years after traumatic injury or surgery because of incomplete healing at the joint. Osteoarthritis tends to affect women at an earlier age than men, making it an important area of investigation for women’s health.
Background
Medically speaking, osteoarthritis refers to a disease in which the cartilage inside joints gradually degenerates. This exposes the bone inside the joint and causes narrowing of the joint-space leading to stiffness and pain. In the end, the joint may become so immobile and painful that joint replacement surgery is the best alternative. (See Figures 1 and 2.) Osteoarthritis is only one of a number of arthritic diseases, resulting in the term arthritis being used commonly to refer to any pain and stiffness in the muscles and joints. For this reason, some who have osteoarthritis refer to it as arthritis. Technically speaking, arthritis involves inflammation in the joints and osteoarthritis is a non-inflammatory degenerative disease. It should be noted that all of the studies to be reviewed here were carried out with older adults diagnosed with osteoarthritis.
At the present time there is no cure for osteoarthritis.3 Management of symptoms includes weight control, pain relief, maintaining and improving the range of movement and stability of the joints, and limiting the impairment of functional abilities. Frequently, drug therapy, including analgesics like acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), is needed. The newer cyclooxygenase-2 (COX-2) inhibitors are recommended widely as being safer than older NSAIDs. Although all of these are important for managing symptoms, they do not treat the underlying pathology.
Concerns about the toxicity and side effects of pharmaceutical drugs have fueled interest in complementary approaches to managing osteoarthritis symptoms, with some dietary supplements also claiming to actually treat the underlying condition.1 Foremost among these are glucosamine sulfate and chondroitin sulfate. Although the two sometimes are taken together, this review will focus on the use of glucosamine sulfate alone.
Glucosamine occurs naturally in the body as one component of the cartilage and synovial fluid found within joints.4 It is formulated as the salt, glucosamine sulfate, for oral consumption. As a central building block in the formation of cartilage, it is assumed that glucosamine supplementation facilitates the production and regeneration of cartilage.
Clinical Studies
Clinical studies have been conducted on glucosamine sulfate for osteoarthritis for more than 20 years, primarily in Europe. It is available with prescription for the treatment of osteoarthritis in many countries in Europe and elsewhere, but is available as a dietary supplement in the United States.5 A systematic review and meta-analysis of studies examining the effectiveness of glucosamine or chondroitin for treating osteoarthritis was published in 2000.6 This review identified six double-blind, randomized, controlled trials (RCTs) in which glucosamine sulfate was administered for at least four weeks. The trials were conducted between 1980 and 1997 and all evaluated knee osteoarthritis symptoms. The analysis revealed moderate-to-large benefits from taking glucosamine sulfate. However, all of the trials were of relatively short duration and had methodological limitations that are known to exaggerate beneficial effects.
Since that review was published, two long-term, high-quality studies that examined the impact of glucosamine on symptoms and also on disease progression have been published. In the first, 212 subjects with knee osteoarthritis were assigned randomly to receive either 1,500 mg glucosamine sulfate daily or placebo for three years.5 Symptoms were assessed using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. This showed statistically significant improvement in symptoms between baseline and end of study for those taking glucosamine while those taking placebo worsened. The final difference between the two groups was highly significant (P = 0.016). Subjects were permitted to use analgesics or NSAIDs if required for pain and most did, on an average of once a week. There were no differences between the two groups in rescue drug usage.
To examine disease progression, X-ray studies were performed on all subjects’ knees at baseline and after one and three years. Narrowing of the space within the joint is an accepted measure of the degree of osteoarthritis disease progression and was measured two ways using validated methods. One was a computer-generated measurement of mean joint-space width and the other required visual inspection of the X-rays and measurement of the narrowest space within the joint. Both measures showed no average joint-space loss for those taking glucosamine sulfate, while those taking placebo showed statistically significant narrowing (annual average of 0.1 mm). However, those with the severest joint-space narrowing at baseline responded similarly to either glucosamine sulfate or placebo, while those with the mildest baseline osteoarthritis showed much more narrowing with placebo (14.9%) compared to glucosamine (6.0%).7
In terms of adverse effects, there were no significant differences between the frequency or types of adverse events experienced by those taking glucosamine sulfate or placebo. Routine lab tests revealed no metabolic ab- normalities, including no changes in glycemic homeostasis, which has been proposed as a potential problem from taking such large doses of glucosamine.
The second of the long-term X-ray studies had a very similar design with 202 patients with mild-to-moderate knee osteoarthritis randomized to receive either placebo or 1,500 mg glucosamine sulfate once daily.4 The same European prescription-grade glucosamine sulfate product was used. The minimum joint-space was measured visually on X-rays by blinded radiographers. After three years, those taking placebo had significant joint-space narrowing (average 0.19 mm) while those taking glucosamine sulfate had no change. The difference between the two groups was statistically significant (P = 0.001). Symptoms improved in both groups according to the WOMAC and Lequesne indices. However, the changes were significantly better with glucosamine sulfate, with subjects reporting an average 20-25% improvement from baseline. No differences were reported in adverse events between the two groups.
Of particular interest to women’s health is an analysis of how women fared in the two previous studies.8 Of the 414 participants in the two trials, 319 were postmenopausal women. In the X-ray analyses, women taking placebo experienced a mean joint-space narrowing of 0.33 mm while those taking glucosamine sulfate had no change. In the WOMAC symptom scores, those taking placebo deteriorated by 5.4% while those taking glucosamine sulfate improved by 14%. The results demonstrated that glucosamine sulfate is beneficial in postmenopausal women, the population most frequently affected by knee osteoarthritis.
A more recent meta-analysis has been published incorporating only the highest-quality trials, including the two studies involving X-ray analyses.9 The results confirmed that glucosamine sulfate has a structure-modifying effect on knee osteoarthritis and that it is tolerated well.
Adverse Effects
Concerns have been raised that glucosamine might interfere with glycemic control in diabetic patients since animal models have demonstrated such effects. In a double-blind RCT, 34 Type 2 diabetes patients received either placebo or 1,500 mg glucosamine sulfate and 1,200 mg chondroitin sulfate.10 After 90 days, no changes occurred in glycemic control as measured by HbA1c levels.
Concerns also have been raised about allergic reactions since glucosamine sulfate is obtained from chitin, extracted from marine exoskeletons. Therefore, in those with seafood allergies, it should be tried carefully, if at all, depending on the severity of the allergy.3
Conclusion
Overall, glucosamine sulfate has demonstrated itself to be the first structure-modifying treatment for knee osteoarthritis. Studies in other joints are still needed, and also examination of the very long-term outcomes in terms of need for joint replacement or avoidance of debilitating disability. Glucosamine sulfate also appears to be of more benefit with mild osteoarthritis rather than the more severe stages. Studies still need to be conducted on whether it has a role in preventing osteoarthritis.
Although the results to date are positive, it should be noted that the same European prescription-grade product was used in the two X-ray trials (Dona, Viatril-S, or Xicil; Rotta Pharmaceuticals). Glucosamine sulfate is classified as a dietary supplement in the United States and therefore may vary in quality. In addition, although glucosamine sulfate is very well-tolerated, in the two most recent trials, subjects still needed rescue medication for severe bouts of pain. As with any treatment, glucosamine sulfate should not be touted as something that will eliminate all symptoms. Control of weight, exercise, and other symptom-relieving strategies still play an important role in the overall management of osteoarthritis.
Dr. O’Mathuna, Lecturer, School of Nursing, Dublin City University, Ireland, is on the Editorial Advisory Board of Alternative Therapies in Women’s Health.
References
1. Curtis CL, et al. Biological basis for the benefit of nutraceutical supplementation in arthritis. Drug Discov Today 2004;9:165-172.
2. Markenson JA. Osteoarthritis: Old facts and new ideas. December 2003. Available at: http://rheumatology.hss.edu/phys/diseaseReviews/osteoArth/osteoArth_phys.asp#. Accessed May 7, 2004.
3. Grainger R, Cicuttini FM. Medical management of osteoarthritis of the knee and hip joints. Med J Aust 2004;180:232-236.
4. Pavelká K, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: A 3-year, randomized, placebo-controlled, double-blind study. Arch Int Med 2002;162:2113-2123.
5. Reginster JY, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomized, placebo-controlled clinical trial. Lancet 2001;357: 251-256.
6. McAlindon TE, et al. Glucosamine and chondroitin for treatment of osteoarthritis: A systematic quality assessment and meta-analysis. JAMA 2000;283: 1469-1475.
7. Bruyere O, et al. Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate. Osteoarthritis Cartilage 2003;11:1-5.
8. Bruyere O, et al. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: Evidence from two 3-year studies. Menopause 2004;11:138-143.
9. Richy F, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: A comprehensive meta-analysis. Arch Intern Med 2003;163:1514-1522.
10. Scroggie DA, et al. The effect of glucosamine- chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: A placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587-1590.
Concerns about the toxicity and side effects of pharmaceutical drugs have fueled interest in complementary approaches to managing osteoarthritis symptoms, with some dietary supplements also claiming to actually treat the underlying condition. Foremost among these are glucosamine sulfate and chondroitin sulfate. Although the two sometimes are taken together, this review will focus on the use of glucosamine sulfate alone.
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