Glucosamine Sulfate for the Treatment of Osteoarthritis

November 1998; Volume 1: 121-124

By David Schiedermayer, MD, FACP

Archeological studies of ancient humans reveal they had osteoarthritis (OA) of the lateral compartment of the knee (they were, like cowboys, bowlegged). Modern humans have OA primarily in the medial compartment (they are obese and have valgus deformity, knock-kneed).

This clinical fact, which I observe daily in my clinic, has always intrigued me as a teacher. We don’t know what causes OA, exactly, but we do know that it is associated with obesity, a profound problem for modern Americans. This should be the starting point for the discussion of any "pills," "natural" or "synthetic," which claim to have any effect on this disease. I have had several patients avoid or postpone hip replacements "simply" by losing 20-30 pounds.

Nonetheless, the prospect of a nutritional remedy for the treatment or prevention of OA is compelling, particularly because no specific medications currently halt disease progression. The problem is enormous, because more than four out of five persons older than the age of 65 show some clinical or radiological evidence of the disease. Glucosamine sulfate (GS) has been touted as a possible cure in The Arthritis Cure.1 Is there any merit to such a claim?

Pathogenesis and Current Treatment

OA, or degenerative joint disease (DJD), is a slowly progressive disease involving ongoing breakdown of articular cartilage and changes in the subchondral bone. The precise biochemical cause is unknown, but the process is characterized by a predominance of degradation (over repair) of cartilage proteoglycans and of subchondral bone. Over time, the continued catabolism of proteoglycans results in abrasion of the articular cartilage and the formation of new bone in the joint. This leads to functional deterioration, which results in stiffness, joint swelling, deformity, and crepitus. Synovitis can occur from the release of various inflammatory mediators, including collagenase, gelatinase, and activation of chondrocytes. Additional predisposing factors include aging, heredity, mechanical stress, obesity, crystalline deposits, previous inflammatory disease, and metabolic abnormalities. Given the involvement of cartilage in the process, "chondroprotective" agents are desirable.2

The current recommended treatment for OA is weight loss, physical therapy, and the use of pain relievers including acetaminophen and nonsteroidal anti-inflammatories (NSAIDS). NSAIDS have been reported to have positive and negative effects on cartilage metabolism. They prevent the activation of tissue-destroying enzymes by inhibiting cyclooxygenase, but they have been shown (in vitro) to reduce glycosaminoglycan synthesis in canine cartilage3 and indomethacin has been shown to speed the progression of OA in humans.4 NSAIDS and acetaminophen do not reverse OA.5


In vitro studies dating back to the 1950s have shown the addition of exogenous GS to cartilage-derived fibroblasts enhances secretion of mucopolysaccharides and collagen. The first studies used injectable GS preparations, but studies in humans in the early 1980s used the oral formulation of GS 500 mg and demonstrated mild effectiveness and virtually no toxicity.6

Mechanism of Action

GS is the salt of D-glucosamine, an amino sugar, with sulfuric acid. In solution, GS dissociates into the D-glucosamine ion and the sulfate ion. Most authors think that the glucosamine ion is the active principal, but at least some evidence suggests that a component of the GS activity is related to sulfur residues, because sulfur is an essential nutrient for the stabilization of connective tissue matrix.7

Controversy exists as to whether oral glucosamine avidly and preferentially seeks joint cartilage: proponents argue that the studies show that it is concentrated more in articular cartilage than any other tissue. This should be a provable hypothesis, using radiolabeling techniques, and it seems an important area for future research.


Glucosamine can pass through biological membranes easily because it has a molecular weight of only 179 daltons. It is found in vivo as glucosamine 6-phosphate and is required for the biosynthesis of glycolipids, glycoproteins, mucopolysaccharides, hyaluronic acid, and proteoglycans.

Glucosamine’s primary role is as a substrate for the glycosaminoglycans and the hyaluronic acid backbone used in the formation of the proteoglycans found in the structural matrix of joints.7 When taken by mouth, as would be the case with any simple sugar, a substantial portion is metabolized into H2O, CO2, and urea.

Clinical Studies and Use

In short-term controlled trials, glucosamine has been effective in relieving pain and increasing range of motion in OA patients.6 One four-week, double-blind trial in 252 patients with OA of the knee found oral GS 500 mg tid was more effective than placebo.8 In a four-week, double-blind trial of 200 patients, glucosamine sulfate was as effective as ibuprofen 400 tid from the second week onward.9 In a double-blind, eight-week study of 40 patients with OA, GS was as effective as ibuprofen 400 tid in relieving pain after two weeks, and by the end of the trial was more effective.10

Most of the current data are derived from European and Asian literature. The studies published to date have been done in small numbers of patients; adequate long-term trials examining the safety, efficacy, and optimal dosage requirements of glucosamine are lacking.2 However, six double-blind investigations in five countries all have documented statistically significant benefits, without side effects.

NSAIDS studies, in comparison, demonstrate significant side effect rates of 10-20%. A systematic review of 43 randomized controlled trials of NSAIDS and analgesic therapy in OA revealed that selection of the best NSAID for a particular patient is an art as well as a science. Remarkable variations in individual patient re-sponses, side effects, and preferences for individual NSAIDS existed. Four of the randomized clinical trials evaluated the efficacy of simple analgesia, but did not include any analysis of GS studies.11

Patient education interventions are also important in OA management. A meta-analysis of 19 patient education trials comprised of 32 treatment arms and 28 NSAID trials comprised of 46 treatment arms revealed that patient education interventions provide additional benefits that are 20-30% as great as the effects of NSAID treatment for pain relief and 40% as great for improvement in functional ability.12

Adverse Effects

In vitro studies have consistently demonstrated low toxicity; no LD50 has been established, since even at the very high levels of 5000 mg/kg, there is no mortality in mice and rats.

In human studies, less than a 4% incidence of GI effects, such as discomfort and nausea, have been reported, and severe side effects, such as edema and tachycardia, were reported in 0.08% of subjects.13 GS should not be consumed during pregnancy or childbearing years, and GS should not be consumed by young children until safety studies are performed. Diabetics should be cautious taking glucosamine, since it is an amino sugar, and they should check their glucose levels frequently (although documented hyperglycemia has not been a problem to date). Patients should not give up on proven pain management techniques, such as joint protection, exercise, and weight reduction.14

As in any therapeutic intervention, misdiagnosis is a potential problem. GS does not treat neuropathic pain, stress fractures, inflammatory arthritis, or other conditions. One must be sure that OA is the cause of pain.

Drug Interactions

No known drug-drug interactions exist, although if patients take preparations also containing chondroitin sulfate, a long chain of amino sugars which is similar in structure to heparin sulfate, possible additive anticoagulative effects may occur.


The source of GS is the chitin of crab shells. It is relatively inexpensive, depending on the formulation chosen. (See Table.) Glucosamine derivatives are available in pharmacies and health food stores as the sulfate, hydrochloride, n-acetyl, or chlorohydrate salt and as the dextrorotatory isomer. GS is sometimes combined with chondroitin sulfate, a glycosaminoglycan that has been reported to maintain viscosity in joints, stimulate cartilage repair mechanisms, and inhibit enzymes that break down cartilage.15 Chondroitin sulfate is derived from bovine trachea. Chondroitin sulfate, unlike GS, is poorly absorbed from the GI tract. The usual dose, and the one most studied, is glucosamine sulfate 500 mg po tid.

Product Name Amount of Glucosamine  
Contained in Each Dose
Dosage Form Bottle Size (n) Price Per Bottle* ($) Manufacturer
Enhanced Glucosamine Sulfate D-glucosamine sulfate 375 mg capsule 60, 90 $19.99  General Nutrition Corp.
Glucosamine Complex glucosamine HCl 250 mg and N-acetylglucosamine sulfate 250 mg capsule 90 28.95 Vitamin Research Products
Glucosamine Mega 1000 glucosamine HCl 1000 mg tablet 100 22.49 Jarrow Formulas
Glucosamine Sulfate glucosamine sulfate 750 mg capsule 60, 120 44.96 TwinLab
Glucosamine Sulfate glucosamine sulfate 500 mg capsule 60 13.99 Great Earth
Glucosamine Sulfate 500 glucosamine sulfate 500 mg capsule 100, 200 27.95 Jarrow Formulas
Glucosamine Sulfate 500 glucosamine sulfate 500 mg capsule 60, 120 15.95 The Vitamin Shoppe
Joint Factors glucosamine sulfate 375 mg capsule 60, 120 19.96 TwinLab
Nutri-Joint glucosamine HCl 300 mg and N-acetylglucosamine sulfate 100 mg capsule 90 38.95 Vitamin Research Products
Tyler Glucosamine Sulfate glucosamine sulfate 500 mg capsule 60, 120 38.00 Tyler Encapsulations
Ultra Maximum Strength glucosamine sulfate 600 mg tablet 60 24.95 Nature’s Plus Glucosamine Sulfate
*Prices vary, depending on bottle size Adapted from: C da Camara C, Dowless GV. Glucosamine sulfate for osteoarthritis. Ann Pharmacother 1998;32:580-587.


GS is a safe nutritional measure that supports proteoglycan synthesis, and it may offer a practical means of treating, preventing or postponing the onset of OA in older people.6 It is well absorbed and has a striking lack of side effects, but it also shows no evidence of being a "cure" for arthritis. About cure, The Berkeley Wellness Letter writes "Unlike bone, cartilage which has been injured has difficulty repairing itself. It is one of the most complex tissues in the body, and nobody knows how to restore it to its original shape. . .It is much too early to recommend GS and chondroitin sulfate as treatments, let alone call them a cure."16


Physicians should encourage weight loss, physical therapy, and regular exercise as the primary treatments for OA. For patients seeking pain relief, an 8-12 week trial of GS, 500 mg tid, appears to be much safer and at least as effective as ibuprofen 400 mg tid for many patients with mild-to-moderate OA of the weight bearing joints. Patients should not discontinue their weight loss and exercise programs if they choose to add glucosamine; whether they continue taking an NSAID or acetaminophen while on GS is an individual decision that a patient should make in consultation with his or her physician. v


1. Theodosakis J, et al. The Arthritis Cure. New York, NY: St. Martins’ Press; 1997.

2. C da Camara C, Dowless GV. Glucosamine sulfate for osteoarthritis. Ann Pharmacother 1998;32:580-587.

3. Palmoski MJ, Brandt KD. Effects of some nonsteroidal antiinflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arthritis Rheum 1980;23:1010-1020.

4. Rahad S, et al. Effect of non-steroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet 1989;2:519-522.

5. Barclay TS, et al. Glucosamine. Ann Pharmacother 1998;32:574-579.

6. McCarty MF. The neglect of glucosamine as a treatment for osteoarthritis—A personal perspective. Med Hypotheses 1994;42:323-327.

7. Kelly GS. The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease. Alt Med Rev 1998;3(1):27-39.

8. Noack W, et al. Osteoarthritis Cartilage 1994;2:51.

9. Muller-Fassbender H, et al. Osteoarthritis Cartilage 1994;2:61.

10. Vaz AL. Curr Med Res Opin 1982;8:145.

11. Towheed TE, Hochberg MC. A systematic review of randomized controlled trials of pharmacologic therapy in osteoarthritis of the hip. J Rheumatol 1997;24: 349-357.

12. Superio-Cabuslay E, et al. Patient education interventions in osteoarthritis and rheumatoid arthritis: A meta-analytic comparison with nonsteroidal antiinflammatory drug treatment. Arthritis Care Res 1996;9(4):292-301.

13. Tapadinhas MJ, et al. Oral glucosamine sulfate in the management of arthrosis: Report on a multi-centre open investigation in Portugal. Pharmatherapeutica 1982;3:157-168.

14. Horstman J. Glucosamine and chondroitin. Arthritis Today 1998;Sept-Oct:46-51.

15. Med Lett Drug Ther 1997;39:1010:91.

16. UC, Berkeley Wellness Lett 1997;13:8:1.