DOSAGE AND ADMINISTRATION: The usual dose used by those with osteoarthritis is l,500 milligrams daily in divided doses.

The amount of glucosamine base varies with the supplemental form. Pure glucosamine hydrochloride is about 83% in glucosamine base, pure glucosamine sulfate is about 65% in glucosamine base, and pure N-acetyl glucosamine, about 75% in glucosamine base. It is important that all clinical studies standardize the glucosamine dose of the form used to glucosamine base.

It usually takes several weeks of supplementation before effects, if any, are noted.

Mechanism of action: Until the specific actions of supplemental glucosamine are determined, the mechanism of action in relieving arthritic pain and in repair of cartilage is a matter of speculation. However, we do know a great deal about the biochemistry of the molecules in which glucosamine is found. Biochemically, glucosamine is involved in glycoprotein metabolism. Glycoproteins, known as proteoglycans, form the ground substance in the extra-cellular matrix of connective tissue. Proteoglycans are polyanionic substances of high-molecular weight and contain many different types of heteropolysaccharide side-chains covalently linked to a polypeptide-chain backbone. These polysaccharides make up to 95% of the proteoglycan structure. In fact, chemically, proteoglycans resemble polysaccharides more than they do proteins.

The polysaccharide groups in proteoglycans are called glycosaminoglycans or GAGs. GAGs include hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin and heparan sulfate. All of the GAGs contain derivatives of glucosamine or galactosamine.

Glucosamine derivatives are found in hyaluronic acid, keratan sulfate and heparan sulfate. Chondroitin sulfate contains derivatives of galactosamine.

The glucosamine-containing glycosaminoglycan hyaluronic acid is vital for the function of articular cartilage. GAG chains are fundamental components of aggrecan found in articular cartilage. Aggrecan confers upon articular cartilage shock-absorbing properties. It does this by providing cartilage with a swelling pressure that is restrained by the tensile forces of collagen fibers. This balance confers upon articular cartilage the deformable resilience vital to its function.

In the early stages of degenerative joint disease, aggrecan biosynthesis is increased. However, in later stages, aggrecan synthesis is decreased, leading eventually to the loss of cartilage resiliency and to most of the symptoms that accompany osteoarthritis.

During the progression of osteoarthritis, exogenous glucosamine may have a beneficial role. It is known that, in vitro, chondrocytes do synthesize more aggregan when the culture medium is supplemented with glucosamine. N-acetylglucosamine is found to be less effective in these in vitro studies. Glucosamine has also been found to have antioxidant activity and to be beneficial in animal models of experimental arthritis.

The counter anion of the glucosamine salt (i.e. chloride or sulfate) is unlikely to play any role in the action or pharmacokinetics of glucosamine. Further, the sulfate in glucosamine sulfate supplements should not be confused with the glucosamine sulfate found in such GAGs as keratan sulfate and heparan sulfate. In the case of the supplement, sulfate is the anion of the salt. In the case of the above GAGs, sulfate is present as an ester. Also, there is no glucosamine sulfate in chondroitin sulfate.

CONTRAINDICATIONS: There are no known contraindications to glucosamine supplementation.

DESCRIPTION: Glucosamine is an amino monosaccharide found in chitin, glycoproteins and glycosaminoglycans (formerly known as mucopolysaccharides) such as hyaluronic acid and heparan sulfate. Glucosamine is also known as 2-amino-2-deoxyglucose, 2-amino-2-deoxy-beta-D-glucopyranose and chitosamine.

Glucosamine is available commercially as a nutritional supplement in three forms: glucosamine hydrochloride or glucosamine HCl, glucosamine sulfate and N-acetyl-glucosamine.

At neutral as well as physiologic pH, the amino group in glucosamine is protonated, resulting in its having a positive charge. Salt forms of glucosamine contain negative anions to neutralize the charge. In the case of glucosamine hydrochloride, the anion is chloride, and in glucosamine sulfate the anion is sulfate. N-acetylglucosamine is a delivery form of glucosamine in which the amino group is acetylated, thus neutralizing its charge. To date, most of the clinical studies examining the effect of glucosamine on osteoarthritis have been performed with either the sulfate or the chloride salts of glucosamine. All three forms are water soluble.

The glucosamine used in supplements is typically derived from marine exoskeletons. Synthetic glucosamine is also available.

ACTIONS

The actions of supplemental glucosamine have yet to be clarified. It may play a role in the promotion and maintenance of the structure and function of cartilage in the joints of the body. Glucosamine may also have anti-inflammatory properties.

CLINICAL PHARMACOLOGY:

 PHARMACOKINETICS

Pharmacokinetics of glucosamine are derived primarily from animal studies. About 90% of glucosamine administered orally as a glucosamine salt gets absorbed from the small intestine, and from there it is transported via the portal circulation to the liver. It appears that a significant fraction of the ingested glucosamine is catabolized by first-pass metabolism in the liver. Free glucosamine is not detected in the serum after oral intake, and it is not presently known how much of an ingested dose is taken up in the joints in humans. Some uptake in the articular cartilage is seen in animal studies.

RESEARCH SUMMARY

Two recent meta-analyses have confirmed that glucosamine is useful in the treatment of osteoarthritis. One of these meta-analyses included all double-blind, placebo-controlled trials that lasted four weeks or longer. This meta-analysis also included trials that studied the effects of chondroitin sulfate. In all, there were l3 of these studies (six involving glucosamine and seven involving chondroitin sulfate).

All l3 studies found positive results in hip or knee osteoarthritis. The authors of the meta-analysis judged a trial positive if there was 25% or more improvement in the treatment group compared with placebo. The Levesque Index and global pain scores were used to assess improvement. Very significant improvement was associated with both glucosamine (39.5%) and chondroitin sulfate (40.2%), compared with placebo.

In another recent meta-analysis of nine randomized, controlled trials of glucosamine, glucosamine was significantly superior to placebo in seven of the studies and was superior to ibuprofen and equal to ibuprofen in the other two studies.

Recently, a long-term, randomized placebo-controlled trial of glucosamine sulfate's effects on osteoarthritis ended with the conclusion that the supplement halts progression of structural joint damage and reduces symptoms of those with osteoarthritis of the knee. The study involved 212 patients 50 years or older who received 1500 milligrams of glucosamine sulfate daily or placebo.

Radiographic evidence, at a three-year follow up, showed joint space narrowing--the prime indicator of arthritic joint damage--in the placebo group consistent with what has been documented to be typical in untreated osteoarthritis. The glucosamine-supplemented subjects, on the other hand, showed only a non-significant increase in joint space at the same three-year follow up.

There has been one study demonstrating an apparent synergistic effect using glucosamine and chondroitin together. The combination was more effective than either substance alone in inhibiting progression of degenerative cartilage lesions in an experimental study.

Clinical research is needed to determine if this effect is truly synergistic, additive or non-existent. The National Institutes of Health has started a large, multi-center study that may shed further light on this issue.

It is probably not surprising that glucosamine may be helpful in osteoarthritis. Glucosamine is crucial for the construction of glycosaminoglycans (GAGs) in articular cartilage. Reduced GAG content in osteoarthritic cartilage matrix corresponds with the severity of osteoarthritis. Oral glucosamine appears to be capable of prompting the chondrocytes to secrete more GAGs. This knowledge, derived from animal and in vitro studies, has prompted clinical trials of glucosamine in osteoarthritis.

WARNINGS & PRECAUTIONS:

 Glucosamine may increase insulin resistance. Glucosamine increases insulin resistance in normal and experimentally diabetic animals. In these animals, intravenous glucosamine significantly decreases the rate of glucose uptake in skeletal muscle. In animals given oral glucosamine, this is not observed.

Those with type 2 diabetes and those who are overweight and have problems with glucose tolerance should have their blood sugars carefully monitored if they use glucosamine supplements. Because of insufficient safety data, children, pregnant women and nursing mothers should avoid using glucosamine.

Drug Interactions:

Glucosamine may increase insulin resistance and consequently affect glucose tolerance. Diabetics who, under medical advisement, decide to use glucosamine supplements will need to monitor their blood glucose and may need to adjust the doses of the medications they take to control blood glucose. This needs to be done under medical supervision. No other drug, nutritional supplement, food or herb interaction is known.

SIDE EFFECTS:

Side effects that have been reported are mainly mild gastrointestinal complaints such as heartburn, epigastric distress and diarrhea. No allergic reactions have been reported including sulfa-allergic reactions to glucosamine sulfate.

How Supplied: Pack of 60 capsuless in a bottle.

stotage: Store at 25°C (77°F); excursions permitted to 15-30°C.

Reference:

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.

Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulfate in osteoarthritis, a placebo-controlled double-blind investigation. Clin Ther. 1980; 3:260-272.

Houpt JB, McMillan R, Wein C, Paget-Dello SD. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol. 1999; 26:2423-2430.

Leffler CT, Philippi AF, Leffler SG, et al. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized double-blind, placebo-controlled pilot study. Mil Med. 1999; 64:85-91.

McClain DA, Crook, ED. Hexosamines and insulin resistance. Diabetes. 1996; 45:l003-l006.

Noack W, Fischer, M., Forster, KK, et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage. 1994; 2:51-59.

Pujalte JM, Llavore EP, Ylescupidez FR. Double-blind evaluation of oral glucosamine sulfate in the basic treatment of osteoarthritis. Curr Med Res Opin. 1980; 7:110-114.

Reichelt A, Forster K, Fisher M, et al. Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee. A randomized, placebo-controlled, double-blind study. Arzneimittelforschung. 1999; 44:75-80.

Setnikar I, Giacchetti C, Zanolo G. Pharmacokinetics of glucosamine in the dog and in man. Arzneimittelforschung. 1986; 36:729-735.

Setnikar I, Palumbo R, Canali S, Zanolo G. Pharmacokinetics of glucosamine in man. Arzneimittelforschung.1993; 43:1109-1113.

Towheed TE, Anastassiades TP. Glucosamine and chondroitin for treating symptoms of osteoarthritis. Evidence is widely touted but incomplete. JAMA. 2000; 283:1483-1484.

Towheed TE, Anastassiades TP. Glucosamine therapy for osteoarthritis. Editorial. J Rheumatol l999; 26:2294-2297.

For more information; please refer to this web-page: http://altmed.creighton.edu/glucosamine/mechanism.htm