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GLUCOSAMINE FOR OSTEOARTHRITIS: PART II, BIOLOGIC AND METABOLIC CONTROVERSIES

Medicine and Health Rhode Island, Jun 2004 by Biggee, Beth Anne, McAlindon, Timothy

Osteoarthritis (OA) is the most common arthritis in the United States. Glucosamine is a popular nutritional supplement used by consumers to treat osteoarthritis. The exact mechanism of action of glucosamine remains unknown. How does glucosamine exert biological effect in the human after standard oral doses?

BIOLOGIC CONTROVERSIES

BIOLOGICAL EFFECTS OF GLUCOSAMINE?

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Glucosamine is an amino sugar which is rapidly degraded in the liver during first pass metabolism. How then would enough intact glucosamine ever reach the joint to exert biologic effect? In the late 1980s and early 1990s, Setnikar et al studied the pharmacokinetics of glucosamine sulfate. They used radiolabled oral glucosamine sulfate and tested this in rats, dogs, and man.1,2,3 They found that radiolabeled oral glucosamine was absorbed from the GI tract quite rapidly and then incorporated into plasma proteins. However they did not detect any radioactivity in deproteinized plasma nor did they detect any free glucosamine in plasma even after giving doses equivalent to 6,000mg of glucosamine. They found the pharmacokinetics of glucosamine difficult to investigate because it was rapidly degraded in the body and their assay methods had insufficient sensitivity to detect small quantities of glucosamine. They did find low levels of radioactivity in the urine.1,3 Furthermore, they found some radioactivity within joint cartilage; however, they also found such radioactivity in many other tissues and organs.1 Detection of radioactivity in joints does not necessarily mean that glucosamine itself was incorporated. This radioactivity was found nonspecifically in many different tissues and organs because radioactivity can very rapidly diffuse into most tissues and organs. Another independent investigator also found that glucosamine is extensively degraded in the GI tract.4 No other study has measured glucosamine in the plasma of man.

Glucosamine is a ubiquitous endogenous amino-sugar. However, it is very unlikely that exogenous glucosamine is essential for biosyntheisis of cartilage proteoglycans and glycosaminoglycans because it can enter the glycosaminoglycan biosynthetic pathway by endogenously converting to UDP-N-galactosamine, which is used to incorporate N-acetyl-galactosamine into chondroitin sulfate. (Figure 1). Despite endogenous glucosamine being ubiquitous, in vitro studies on cultured cells have shown increased proteoglycan synthesis after addition of exogenous glucosamine sulfate. 5,6 However, one study on the effects of exogenous glucosamine hydrochloride on proteoglycan concentration of rabbit articular temporaomandibular disc showed no effect.7

BIOLOGICAL EFFECTS OF SULFATE?

Most clinical trials have studied glucosamine sulfate rather than other forms of glucosamine. Towheed et al. in his systematic review emphasized that the first negative study among the earlier set of glucosamine trials tested glucosamine hydrochloride rather than glucosamine sulfate. 8,9 Some in vitro experiments on cultured cells suggest that increases in serum sulfate concentration enhance glycosaminoglycan synthesis. 10,11 Glucosamine is ubiquitous in the human yet sulfate is readily depleted when ingesting low-protein diet or by drugs metabolized through sulfation such as acetaminophen. It may be possible that the sulfate component of glucosamine sulfate rather than glucosamine itself acts as a substrate for proteoglycan synthesis. Hoffer et al in 2001 investigated this by measuring sulfate levels in humans after oral glucosamine sulfate ingestion. 12 This study did find that sulfate levels transiently increased after oral ingestion in healthy volunteers. They found that this effect was reversed when glucosamine sulfate was co-ingested with 1.0gm of acetaminophen, which is metabolized in the liver through sulfation and glucuronidation. They also measured sulfate levels after subjects ingested sodium sulfate but this failed to increase the serum sulfate concentrations in all subjects. The authors speculate that perhaps the intestinal absorption of sulfate was improved when co-ingested with glucosamine. They further hypothesize that it may be exogenous sulfate rather than glucosamine that the human needs for glycosaminoglycan synthesis. Recently others have performed experiments on sulfate ingestion and excretion in healthy volunteers and proposed the same hypothesis.13

METABOLIC CONTROVERSIES

SIDE EFFECTS OE GLUCOSAMINE METABOLISM - DIABETES?

Human safety data from clinical trials reveal that participants who took glucosamine supplement experienced the same number of side effects as those taking a harmless placebo. Ingestion of glucosamine sulfate has not been associated with any serious side effects in clinical trials to date. Side effects were minor such as GI discomfort and headache. No severe allergic reactions were reported in large multi-centered clinical trials that used chemically purified glucosamine sulfate.14,15 In addition, no participant developed diabetes while in clinical trials, but many trials excluded those with diabetes.

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GLUCOSAMINE FOR OSTEOARTHRITIS: PART II, BIOLOGIC AND METABOLIC CONTROVERSIES

Medicine and Health Rhode Island, Jun 2004 by Biggee, Beth Anne, McAlindon, Timothy

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