Glucosamine for Treatment of Osteoarthritis
July 2001; Volume 4; 73-77
By Sharon L. Kolasinski, MD, FACP, FACR
Although glucosamine has been used clinically in europe since the 1960s, only recently has it become one of the most frequently taken dietary supplements in the United States. In vitro and animal studies performed decades ago in the United States resulted in little interest in this dietary supplement. Glucosamine gained popularity in this country only after the publication of The Arthritis Cure by Jason Theodosakis, MD, in 1997.1 Since then, it has become one of the most commonly used supplements for osteoarthritis (OA).
Most adults age 40 and older experience some degenerative joint abnormalities and OA symptoms are present almost universally by age 75.2 OA is a leading cause of pain and disability, including lost time from work. Current OA treatments provide only symptomatic relief and the traditionally prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with serious toxicities. Measures aimed at prevention or reversal of OA are not yet available.
OA results in loss of the articular surface. Cartilage loss reflects underlying biochemical, mechanical, and immunological changes, and particularly the loss of proteoglycan. As a naturally occurring building block of proteoglycan, glucosamine has received considerable attention in the treatment of OA. The best evidence indicates that glucosamine ameliorates OA pain as well as some NSAIDs with fewer short-term side effects, and can be considered for initial OA therapy along with appropriate lifestyle measures. Glucosamine also might be of benefit as adjunctive therapy for patients experiencing an incomplete response from current prescription OA medications.
Pharmacokinetics
Laboratory and animal studies show that more than 50% of glucosamine sulfate is non-ionized at the pH of the small intestine, which allows rapid absorption. In rats, 90% of glucosamine sulfate is absorbed and about 10% remains in the tissues. Autoradiographs demonstrate C14 in rat cartilage four hours after ingestion of C14-labeled glucosamine.3 Limited human studies have documented the absorption and metabolism of glucosamine. Six healthy volunteers ingested radiolabeled glucosamine—two orally, two intravenously, and two intramuscularly—and had serum radioisotope levels measured at various subsequent time points.4 Absorption occurred rapidly; radiolabeled glucosamine could be identified in the serum as early as six hours after ingestion. Intramuscular administration resulted in higher serum concentrations than oral administration. Furthermore, radioactivity could be detected in the serum as late as five days later. Data are not available, however, to identify whether intact glucosamine is incorporated into human articular cartilage.
Mechanism of Action
Glucosamine is a normal component of virtually all human tissues. It is the principal component of O-linked and N-linked glycosaminoglycans, which form the extracellular matrix of connective tissue. An amino-monosaccharide, it is acetylated, and then becomes a building block of hyaluronan, keratan sulfate, and heparan sulfate.
In vitro studies have shown glucosamine affects chondrocyte gene expression and that addition of glucosamine to human chondrocyte culture leads to a dose-dependent increase in proteoglycan synthesis.5,6 In the rabbit model, there has been a suggestion that glucosamine sulfate slows the progression of cartilage lesions.7
Though glucosamine’s effectiveness as an analgesic is well known, the mechanism by which that occurs still is unknown. Pain relief in OA may be related to an anti-inflammatory effect, but unlike NSAIDs, glucosamine has no effect on cyclooxygenase-dependent prosta- glandin synthesis.8
Glucosamine may have several other mechanisms of action. In animal models of arthritis, glucosamine has been demonstrated to stabilize cell membranes, reduce the generation of oxygen-free radicals by macrophages, and inhibit lysosomal enzymes. Glucosamine may interact with cytokine-mediated pathways on chondrocytes or other inflammatory pathways as well. It may inhibit interleukin-1-induced nitric oxide activity, which mediates chondrocyte cell death. Glucosamine also may inhibit interleukin-1-induced increases in aggrecanase activity, which could lead to preservation of proteoglycan.9,10
Clinical Studies
Numerous short-term studies have suggested that glucosamine is effective in treating OA pain. Placebo- controlled trials have demonstrated short-term efficacy in terms of reduced pain, reduced stiffness, and increased range of motion. To identify how many patients might be expected to respond to glucosamine vs. placebo, a large, multicenter, randomized, double-blind, placebo-controlled trial (RDBPCT) was conducted.11 In this study, 155 patients with symptomatic OA of the knee were randomized to either 400 mg/d of intramuscular glucosamine or placebo. Patients were followed for six weeks. The investigators found that 55% of patients taking glucosamine (compared with 33% in the placebo group) improved based on the Lesquesne index. This measurement instrument provides a composite score that takes into account pain, walking distance, and ability to carry out activities of daily living (ADLs).
In trials comparing glucosamine to NSAIDs, comparable efficacy in pain relief and functional improvement has been demonstrated. The analgesic effect of glucosamine, however, is delayed compared with that of NSAIDs and is longer lasting than that of NSAIDs after discontinuation of the treatment.12-15 In one of the most frequently cited recent trials, 200 ambulatory patients with knee OA undergoing inpatient rehabilitation were randomized into two groups.14 The double-blind design resulted in patients receiving either 1,500 mg/d glucosamine sulfate or 1,200 mg/d ibuprofen. After four weeks, both groups had improvements in pain and reduced limitations on ADLs. However, the glucosamine group achieved these improvements one to two weeks after the ibuprofen group. Side effects occurred in 35% of the ibuprofen group, but in only 6% of the glucosamine group.
A recent meta-analysis addressed some of the criticisms of studies to date, particularly criticisms of small size and short duration.16 The authors surveyed the MEDLINE and Cochrane databases as well as other sources and identified six RDBPCTs comparing glucosamine to placebo. The meta-analysis also assessed a series of equally well-designed trials evaluating chondroitin sulfate. The investigators found that the trials showed moderate to large effects, but that interpretation was limited by inconsistencies in study methods and potential for bias from industry sponsorship. Nonetheless, the authors concluded that "overall, it seems probable that these compounds do have some efficacy in treating OA symptoms and that they are safe."
Considerable controversy persists about the chondroprotective effects of glucosamine. The most definitive study to date is a three-year Belgian radiographic study.17 Two hundred twelve patients with OA were assigned randomly to receive either 500 mg oral glucosamine sulfate tid or placebo. Baseline and one- and three-year follow-up radiographs of the knees were compared. The data showed a mean joint space loss of 0.31 mm in the placebo-treated patients, but no cartilage loss in the patients on glucosamine sulfate. Symptomatically, patients in the glucosamine group improved in pain and physical function measures compared to baseline, while those in the placebo group worsened. Interestingly, though, symptom improvement did not correlate with radiographic findings. Radiographic progression in OA is known to be slow and variable.
This latter study has been criticized because the radiographic technique used is subject to variation in interpretation. However, it is the longest glucosamine trial to date and the safety profile for glucosamine did not differ from that of placebo. In particular, the authors noted that glucosamine did not affect annual fasting blood sugar levels.
Ongoing Clinical Research
A large, NIH-sponsored, multicenter trial is being carried out to address the unanswered questions about glucosamine and its possible role in chondroprotection. The placebo-controlled trial includes a glucosamine arm, a chondroitin arm, and a combination glucosamine-chondroitin arm, as well as an NSAID-treated group. It will be conducted over the next several years and a subset of subjects will be followed radiographically to help answer the remaining questions regarding prevention of OA progression. The study will enroll 1,500 subjects at 13 U.S. locations and will have a $12 million budget.
Formulation
In the United States, glucosamine often is sold in the hydrochloride form,8 which is 99.1% pure and contains no sodium, unlike the sulfate form. In addition, the hydrochloride form provides 81.3% bioreactive glucosamine vs. 47.8% bioreactive glucosamine from the sulfate form. Thus, theoretically, about 860 mg of the hydrochloride form delivers the same amount of glucosamine as 1,500 mg of the sulfate form. It is not known if the sulfate moiety is essential to the action of glucosamine in OA. No head-to-head comparisons of the two types of glucosamine preparations have been published.
Adverse Effects
No serious adverse effects have been reported, though the longest published experience with glucosamine is three years.17 Side effects related to long-term exposure are unknown. Many short-term glucosamine trials have reported a side effect profile indistinguishable from placebo. Some studies have made note of gastrointestinal complaints (nausea, vomiting, abdominal pain, change in bowel habits) and sleepiness.15 Dropout rates in glucosamine groups generally have been low.
Contraindications and Precautions
Some authors have suggested exercising caution when recommending glucosamine to patients with diabetes mellitus.18 Considerable in vitro and animal data suggest that glucosamine can enter the hexosamine biosynthetic pathway and cause insulin resistance. However, the clinical relevance of these observations and the risks of long-term glucosamine use by diabetics are unknown. Short-term studies in non-diabetic subjects have had equivocal results. One report on 10 healthy subjects showed that glucosamine did not affect insulin levels but did increase fasting plasma glucose levels.19 A more recent study of 18 healthy subjects showed that glucosamine had no effect on insulin-induced glucose uptake.20 The U.S. Food and Drug Administration web site for the Special Nutritionals Adverse Event Monitoring System lists a case of hyperglycemia after glucosamine ingestion, but no details are provided. The three-year Belgian study included annual measurement of fasting glucose levels.17 The authors reported, "there was no change in glycaemic homoeostasis, with fasting plasma glucose concentrations decreasing slightly in the glucosamine sulphate group." The ongoing NIH study is monitoring glucose levels repeatedly and should provide further information.
Patients with seafood allergies should avoid glucosamine, which is derived from chitin in crustacean shells. No case reports of cross-reactivity have been published.
Dosage
Virtually all published clinical trials have used oral glucosamine sulfate at a dose of 500 mg tid. As noted previously, however, many preparations available in health food stores and pharmacies are in the hydrochloride form. Because of its superior bioavailability, the hydrochloride form may require a lower dose to achieve the same efficacy, but this has not been demonstrated in pharmacokinetic or clinical studies. However, given that the sulfate form has been used in the bulk of available research, it seems reasonable to favor this preparation.
Conclusion
Glucosamine has been used to treat OA for more than 30 years. A large accumulated clinical experience and numerous positive, randomized, placebo-controlled trials have demonstrated the effectiveness of glucosamine preparations for relief of pain, stiffness, and functional disability caused by OA with a potency equivalent to that of NSAIDs. Based on generally short-term data, glucosamine appears to be substantially less toxic than NSAIDs and has been associated with only minor and infrequent side effects. Furthermore, meta-analyses have suggested efficacy as well, despite methodologic limitations to existing trials.
Recommendation
Glucosamine is a reasonable addition to the symptomatic OA treatment regimen that includes weight loss, exercise and physical modalities, and assistive devices as appropriate. Glucosamine might be used as an alternative to NSAIDs, especially for patients who are concerned about taking prescription medications or who have experienced adverse effects—including gastrointestinal bleeding, peripheral edema, or exacerbation of hypertension—from NSAIDs. The total daily dose of glucosamine sulfate is 1,500 mg in divided doses bid or tid. A trial of at least six weeks seems appropriate to assess whether the patient experiences significant pain relief. Glucosamine also is appropriate to use in conjunction with NSAIDs in patients with incomplete response. A trial of 1,500 mg/d for six weeks also would be appropriate under these circumstances. However, glucosamine cannot be recommended to guard against the onset of OA or as an agent that might prevent the progression of early OA.
Dr. Kolasinski is Assistant Professor of Medicine; Director, Rheumatology Fellowship Program; and Chief of Clinical Service, Division of Rheumatology at the University of Pennsylvania School of Medicine in Philadelphia.
References
1. Theodosakis J, et al. The Arthritis Cure. New York: St. Martin’s Press; 1997.
2. Moskowitz RW, et al. Genetics and osteoarthritis. Bull Rheum Dis 1992;41:4-6.
3. van der Kraan PM, et al. Inhibition of glycosaminoglycan synthesis in anatomically intact rat patellar cartilage by paracetamol-induced sulfate depletion. Biochem Pharmacol 1988;37:3683-3690.
4. Setnikar I, et al. Pharmacokinetics of glucosamine in man. Arzneimittelforschung 1993;43:1109-1113.
5. Bassleer C, Reginster JY. Effects of glucosamine on differential human chondrocytes cultivated in clusters [abstract]. Rev Esp Rheumatol 1993;20(Suppl 1):95.
6. Jimenez SA, Dodge GR. The effects of glucosamine sulfate on human chondrocyte gene expression [abstract]. Presented at: ILAR Congress, Singapore; June 8-13, 1997.
7. Conrozier T, et al. Glucosamine sulfate significantly reduced cartilage destruction in a rabbit model of osteoarthritis. Arthritis Rheum 1998;41:S147.
8. Deal CL, Moskowitz RW. Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheum Dis Clin North Am 1999;25:379-395.
9. Shikhman AR, et al. N-acetylglucosamine prevents IL-1-mediated activation of chondrocytes [abstract]. Arthritis Rheum 1999;42(Suppl):S381.
10. Sandy JD, et al. Control of chondrocyte aggrecansase by glutamine supply. In: Program of 44th Annual Meeting of the Orthopaedic Research Society: New Orleans; March 1998;16-19.
11. Reichelt A, et al. Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee. A randomised, placebo-controlled, double-blind study. Arzneimittelforschung 1994;44:75-80.
12. Lopes Vaz A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulfate in the management of osteoarthritis of the knee in out-patients. Curr Med Res Opin 1982;8:145-149.
13. Noack W, et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2:51-59.
14. Muller-Fabender H, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2:61-69.
15. Qiu GX, et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung 1998;48:469-474.
16. McAlindon TE, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum 1996;39:648-656.
17. Reginster JY, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomised, placebo-controlled clinical trial. Lancet 2001;357: 251-256.
18. Felson DT, McAlindon TE. Glucosamine and chondroitin for osteoarthritis: To recommend or not to recommend? Arthritis Care Res 2000;13:179-182.
19. Monauni T, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49:926-935.
20. Pouwels MJ, et al. Short-term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab 2001;86:2099-2103.
July 2001; Volume 4; 73-77
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