By Sharon L. Kolasinski, MD, FACP, FACR
Glucosamine sulfate continues to be one of the most frequently taken dietary supplements in the United States. Principally those with symptomatic osteoarthritis (OA) take glucosamine, often in combination with chondroitin sulfate or other ingredients, in oral as well as topical forms. Glucosamine is widely available in retail pharmacies and in nutrition and health food outlets, or can be ordered by mail or via the Internet.
Osteoarthritis is the most common form of arthritis and is a leading cause of pain and disability, including lost time from work. Symptomatic knee OA affects more than 6% of those older than age 30,1 and OA can be found in the majority of people older than age 70.2
The pathophysiologic processes of OA include local and systemic factors. Systemic factors like age, sex, and inherited susceptibility to OA probably influence the vulnerability of cartilage to injury and the capacity for cartilage repair. The effects of growth factors and cytokines on chondrocytes and their production of cartilage matrix constituents, like proteoglycan, are among the mechanisms through which systemic factors exhibit their influence. Local biomechanical factors act on this background of cartilage vulnerability and include repetitive trauma, obesity, and muscle weakness.1 As a building block of proteoglycan and hyaluronic acid, glucosamine has an obvious appeal as a potential treatment for OA.
Current treatment guidelines include nonpharmacologic approaches, as well as the use of injectable medications, analgesics, and nonsteroidal anti-inflammatory drugs (NSAIDs).3 Each has its limitations, including the potential for considerable toxicity due to NSAIDs, and interest remains high in identifying chondroprotective or disease-modifying agents in OA that might help prevent or reverse degenerative changes. Controversy persists as to whether glucosamine is such an agent. This newsletter summarized a segment of the available studies on glucosamine in 2001;4 this article will review some of the additions to the basic science and clinical literature since.
Pharmacokinetics
Previously summarized reports have shown that glucosamine is rapidly absorbed in animals and humans and has numerous effects in chondrocyte cultures.4 It has been somewhat more difficult to demonstrate that orally administered glucosamine has a direct action on chondrocytes. One report showed that 14C could be detected in rat cartilage four hours after ingestion of 14C-labeled glucosamine.4 A new report using a dog model has been published in abstract form.5 It documents a dose-dependent increase in 13C in the cartilage of dogs that received two different doses of oral glucosamine. Ingestion of 250 mg/d of glucosamine for three weeks led to an increase of 1.6% in 13C in cartilage compared to control, whereas ingestion of 500 mg/d for two weeks was associated with a 2.6% increase. The authors suggested that the amount of radioactivity detected was consistent with what would be expected given the isotope stability and normal rate of biosynthesis if the 13C were incorporated into proteoglycan. They further suggested that these results convincingly demonstrated for the first time that oral glucosamine is bioavailable to chondrocytes and therefore could have an effect on proteoglycan biosynthesis.
Mechanism of Action
Clinical use of glucosamine antedated a substantial amount of the basic science research that is now elucidating its potential mechanisms of action. The importance of glucosamine as a principal component of glycosaminoglycans (GAGs) has been well established. A protein core combines with GAGs to make proteoglycan, of which cartilage is composed. It is presumed that glucosamine has positive beneficial effects due to its role in supporting the production of proteoglycan. Evidence continues to emerge that glucosamine has other physiological effects that may be relevant to the treatment of osteoarthritis, in addition to its role as a cartilage building block.
Further reports have been published that glucosamine can reverse the effects of interleukin-1 (IL-1). IL-1 is a significant mediator of cartilage destruction in OA. It stimulates the transcription of many genes by activation of transcription factors like NF-kB, increases activity in catabolic pathways, and inhibits matrix macromolecule biosynthesis. Investigators have demonstrated that glucosamine can prevent the inhibitory effects of IL-1 on proteoglycan synthesis.6 Glucosamine also can interfere with the upregulation by IL-1 of the destructive matrix metalloproteinases-3 (MMP-3).6,7 These actions may be mediated by effects of glucosamine on both the production of IL-1 receptors, as well as inhibition of NF-kB.8
New evidence of a potential anti-inflammatory mechanism came in a report that glucosamine suppressed numerous inflammatory effects of neutrophils in a dose-dependent manner.9
Clinical Studies
Previously summarized reports demonstrated short-term analgesic efficacy for glucosamine comparable to that of NSAIDs, but with less toxicity.4 One long-term study remains controversial in its conclusion that glucosamine may modify the course of OA.10 Although this three-year prospective, randomized, placebo-controlled study suggested that glucosamine could halt the radiographic progression of knee OA, it has been criticized because the radiographic technique used is subject to variation in interpretation. In a recently published extension of this work, the authors performed additional analyses on this same study cohort. Their reanalysis suggests that patients may vary in their response to glucosamine based on the severity of their OA.11 Subjects with less severe OA at the outset were the most likely to progress, as measured by the percentage change in radiographic joint space narrowing. However, glucosamine had a larger effect on subjects with less severe disease than in those with more severe disease. In the highest quartile of baseline mean joint space width (least severe OA), joint space narrowing of 14.9% was seen in the placebo group after three years, but only 6% in the glucosamine group.
A second, three-year study recently has been published that supports the conclusions of the Reginster trial.12 Among the authors of this paper are two scientists from Rotta Research Laboratories, manufacturers of the glucosamine preparation used in both trials. They also were among the authors of the Reginster paper. The Pavelka study recruited subjects at a single center in Prague and 202 participants were randomized to receive either glucosamine 1,500 mg/d or placebo. Radiographs of the knees were obtained in full extension and positioning was fluoroscopically guided. Two independent radiologists blinded to treatment assignment read them. In subjects completing each year of treatment with placebo there was progressive loss of joint space (total loss after three years = 0.36 mm). However, there was no loss in the glucosamine group. In addition, the number of subjects experiencing severe joint space loss (> 0.5 mm) and worsening osteophyte scores was significantly greater in the placebo group. Pain and functional limitation measured by the Lequesne Index and WOMAC scores decreased in both treatment groups. However, the improvements were significantly larger in the glucosamine group. There was no statistically significant difference in side effects between the groups.
An additional meta-analysis has recently been published,13 but adds little to the contribution of numerous previous, similar studies4 in terms of conclusions about glucosamine (and chondroitin). It concludes, on the basis of data from 1,775 subjects, that use of glucosamine leads to statistically significant pain relief and improvement in function. It does provide a particularly comprehensive and up-to-date reference list.
The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), a large, National Institutes of Health-sponsored, multicenter study remains ongoing. This trial is being carried out to address some of 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, in addition to an NSAID-treated group. A subset of patients will be followed radiographically to help assess the purported disease-modifying ability of glucosamine.
An interesting case report was recently published regarding the use of glucosamine for symptomatic degenerative disc disease.14 A 56-year-old man with a 15-year history of back pain noted a gradual improvement in range of motion and pain over a six-month period after taking 1,500 mg glucosamine and 1,200 mg chondroitin daily. Magnetic resonance imaging of the lumbar spine was obtained at baseline and after one and two years of supplementation. After two years, brightening of the T2-weighted signal of the disc cartilage was noted, suggesting increased water content, and a protrusion at the L3-4 disc decreased along with an increase in disc height of 5-10%. The authors suggest that the proteoglycan content of the extracellular matrix of the nucleus pulposus may be regenerated by glucosamine supplementation. This anecdote is entirely speculative, both with regard to causation of the subject’s improvement and the possible mechanism by which this might occur. However, an older abstract had suggested that the pain and decreased flexibility of lumbar spinal OA might be improved by glucosamine as well.15
A final noteworthy clinical trial is the first to demonstrate analgesic efficacy for a topical glucosamine preparation.16 In this single-center, randomized, double-blind trial, 59 subjects were randomized to apply either a placebo cream (with a small amount of peppermint oil) or a commercially available product containing glucosamine sulfate 30 mg/g, chondroitin sulfate 50 mg/g, shark cartilage 140 mg/g, camphor 32 mg/g, and peppermint oil 9 mg/g. Participants were instructed to apply as necessary; the placebo group did so 2.7 times/d while the active group did so 2.4 times/d. The calculated absorbed dose of glucosamine was 60-120 mg/d (in addition to 156-300 mg/d chondroitin). Visual analog scores for pain were the primary outcome measure and improved in both groups. However, there was a statistically significant decline in pain in the active group (-3.3 cm) compared to controls (-1.6 cm). None of the secondary outcome measures (WOMAC, SF 36) improved in the active group compared to controls.
Adverse Effects
Investigators continue to conclude that glucosamine use is safe. Virtually all trials report rates of side effects that cannot be distinguished from those of placebo. In the Cochrane review,17 only 14 study participants withdrew from glucosamine trials due to toxicity out of more than 1,000 subjects included in the review.
Some controversy remains over whether taking glucosamine might have an effect on glucose homeostasis18 since animal data have suggested that insulin resistance could develop with high-level parenteral glucosamine exposure. However, a recent single-center trial of patients with Type 2 diabetes offers some reassurance.19 In this prospective, randomized, double-blind study, 38 participants received either placebo or commercially available capsules containing a total of 1,500 mg glucosamine hydrochloride, 1,200 mg chondroitin sulfate, 15 mg manganese, and 198 mg ascorbic acid daily. Baseline and 90-day follow-up levels of hemoglobin A1c were not significantly changed for either the placebo or the treatment group.
A single case report of an asthma exacerbation thought to be related to use of a combination glucosamine/chondroitin supplement recently has been published.20 A 52-year-old woman with longstanding asthma experienced increased symptoms over a several-week period associated with initiation of glucosamine and chondroitin supplementation for OA of the knees and hips. Her symptoms persisted despite an increase in albuterol inhaler use and a tapering course of oral steroids until she discontinued her supplement. She refused rechallenge with the supplement. She later recalled an exacerbation of asthma while in graduate school after dissecting a shark. The authors hypothesized that several observations could implicate the supplement as a possible cause of the asthma exacerbation. These include the fact that glucosamine antigen preparations can be allergenic to those with sea squirt allergy; antibodies to chondroitin sulfate are found in higher concentrations in the airways of persons with asthma than in those without; deposition of chondroitin in the airways is significantly increased in asthmatics compared to controls; and the degree of proteoglycan immunoreactivity is correlated significantly with airway responsiveness in persons with asthma.
Contraindications and Precautions
Some authors have suggested that patients with seafood allergies should avoid taking glucosamine. Glucosamine is derived from chitin in crustacean shells. However, no case reports of cross-reactivity have been published. The risk from taking a glucosamine sulfate preparation in patients who have sulfa allergy is unknown. No case reports of this cross-reactivity have appeared.
Theoretical concerns have been raised about the safety of chondroitin sulfate, often used in combination with glucosamine, in the setting of prostate cancer; we await further studies to elucidate any potential risk.21
Dosage
Virtually all published clinical trials have used oral glucosamine sulfate at a dose of 1,500 mg/d. It is available over the counter in pill and powder forms, as well as in topical preparations.
As with all over-the-counter preparations, quality assurance remains a concern when purchasing glucosamine. Because the Dietary Supplement Health and Education Act of 1994 severely limits federal regulatory control over supplements, there currently are no clear mechanisms for assuring product quality. However, Consumer Reports recently tested several brands of glucosamine and the glucosamine content was quite reliable. Information on additional independent testing also can be obtained on-line from Consumerlab.com regarding a variety of products, including glucosamine.
Conclusion
Glucosamine has been in use for the treatment of OA for more than 30 years. Despite the limitations (small size, short duration) of the numerous, randomized, placebo-controlled trials, meta-analyses have convincingly demonstrated that glucosamine can be effective for relief of pain, stiffness, and functional disability due to OA. The potency of glucosamine appears to be equivalent to that of an NSAID with substantially less toxicity. Longer-term trials support the safety and efficacy of glucosamine, but do not yet convincingly demonstrate a disease-modifying effect. In part, this is because the ability to assess disease progression in OA is limited.
Recommendation
Glucosamine remains a reasonable addition to the treatment regimen for symptomatic OA that includes weight loss, exercise and physical modalities, and assistive devices as appropriate.3 Glucosamine might be used as an alternative to NSAIDs, especially for the patient who is concerned about taking prescription medications or who has experienced adverse effects due to NSAIDs, most notably gastrointestinal bleeding, peripheral edema, or exacerbation of hypertension.
The total daily dose of glucosamine sulfate is 1,500 mg/d in two or three divided doses (available both in 500 mg and 750 mg tablets). A trial of at least six weeks seems appropriate to assess whether the patient experiences significant pain relief. Glucosamine also is appropriate to use along with an NSAID in a patient with an incomplete response.
Glucosamine cannot be recommended to prevent the onset of OA at this time.
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
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2. Peyron JG, Altman RD. The epidemiology of osteoarthritis. In: Moskowitz RW, et al, eds. Osteoarthritis: Diagnosis and Medical/Surgical Management. 2nd ed. Philadelphia, PA: WB Saunders; 1992:15-37.
3. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 2000;43:1905-1915.
4. Kolasinski SL. Glucosamine for treatment of osteoarthritis. Altern Med Alert 2001;4;73-76.
5. Dodge GR, et al. The fate of oral glucosamine traced by 13C-labeling in the dog. Arthritis Rheum 2001;44:S308.
6. Gouze JN, et al. Interleukin-1b down-regulates the expression of glucuronosyltransferase I, a key enzyme priming glycosaminoglycan biosynthesis. Arthritis Rheum 2001;44:351-360.
7. Dodge GR, Jimenez SA. Glucosamine sulfate modulates the levels of aggrecan and matrix metalloproteinases-3 synthesized by cultured human osteoarthritis articular chondrocytes. Osteoarthritis Cartilage 2003;11:424-432.
8. Gouze J-N, et al. Glucosamine modulates IL-1-induced activation of rat chondrocytes at a receptor level, and by inhibiting the NF-kB pathway. FEBS Letters 2002;510: 166-170.
9. Hua J, et al. Inhibitory actions of glucosamine, a therapeutic agent for osteoarthritis, on the functions of neutrophils. J Leukoc Biol 2002;71:632-640.
10. Reginster JY, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomized, placebo-controlled clinical trial. Lancet 2001;357:251-256.
11. 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.
12. Pavelka K, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis. Arch Intern Med 2002;162:2113-2123.
13. Richy F, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis. Arch Intern Med 2003;163:1514-1522.
14. Blitterswijk WJ, et al. Glucosamine and chondroitin sulfate supplementation to treat symptomatic disc degeneration: Biochemical rationale and case report. BMC Complement Altern Med 2003;3:2-9.
15. Foerster KK, et al. Efficacy of glucosamine sulfate in osteoarthritis of the lumbar spine: A placebo-controlled, randomized, double-blind study. Arthritis Rheum 2000; 43:S384.
16. Cohen M, et al. A randomized, double-blind, placebo-controlled trial of a topical cream containing glucosamine sulfate, chondroitin sulfate, and camphor for osteoarthritis of the knee. J Rheumatol 2003;30:523-528.
17. Towheed TE, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2001;1: CD002946.
18. Towheed TE. Current status of glucosamine therapy in osteoarthritis. Arthritis Rheum (Arthritis Care Res) 2003;49:601-604.
19. Scroggie DA, et al. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. Arch Intern Med 2003:163:1587-1590.
20. Tallia AF, Cardone DA. Asthma exacerbation associated with glucosamine-chondroitin supplement. J Am Board Fam Pract 2002;15;481-484.
21. Ricciardelli C, et al. Elevated levels of peritumoral chondroitin sulfate are predictive of poor prognosis in patients treated by radical prostatectomy for early-stage prostate cancer. Cancer Res 1999;59:2324-2328.
Kolasinski S. Glucosamine for osteoarthritis: An update. Altern Med Alert 2003;6(11):121-125.
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