Few specialty dietary supplements have enjoyed the life span and consistent success of glucosamine sulfate and glucosamine hydrochloride. Glucosamine sulfate and glucosamine hydrochloride have been studied in two separate multiyear randomized controlled trials and have shown promising disease-modifying effects. Although glucosamine seems to sell itself, wise retailers will want to know the latest clinical evidence on glucosamine salts and be able to differentiate between the sulfate and hydrochloride forms.
Chemical Shell Game
Shrimp and other shellfish exoskeletons contain a versatile carbohydrate called chitin. Chitin is a polymer of D-glucosamine, with randomly assigned D-glucosamine monomers having a chemically bonded "acetyl" group, giving rise to N-acetyl-D-glucosamine units. In addition to serving as the raw material for chitosan manufacture, chitin can be chemically modified with hydrochloric acid digestion and deacetylation to yield rather pure D-glucosamine HCl monomers. Mixing glucosamine HCl with sulfuric acid yields glucosamine sulfate. The most widely tested form of glucosamine sulfate includes a cocrystallization step with sodium chloride to produce a glucosamine sulfate—sodium chloride complex. Potassium chloride also can be used as the cocrystal-lization agent. These chloride salts curtail oxidation and prevent glucosamine sulfate from absorbing moisture. Glucosamine HCl, which typically does not require salts for crystallization, also absorbs airborne moisture1 and thus is commonly granulated; polyvinylpyrrolidone and corn syrup are often used as binders for granule formation.2
As its name implies, glucosamine is glucose with an added amino group. Because glucose is a biological "starter" for glucosamine, a novel source of the HCl form is fermented corn-derived glucose. Arkion BioSciences of Wilmington, Del., is producing this glucosamine and is slated to offer the shellfish-allergen-free (corn-related allergenicity is unknown) form sometime in 2003, but it is unclear whether it will contain a genetically modified organism (as described in the patent). Minneapolis-based Cargill will be offering Regenasure in 2003, a shellfish-free glucosamine product not derived from a genetically modified organism. Soy tempeh is an underappreciated fermented food source of glucosamine.3
Mechanisms Of Action
Despite the numerous animal and cell-culture studies exploring glucosamine salt bioactivity, the definitive mode of action associated with analgesic and possible cartilage-stimulating effects remain enigmatic. Both in vitro and in vivo (administered intravenously) studies in animals show glucosamine HCl inhibits inflammation-stimulated nitric oxide production.4 In a recent study, researchers found glucosamine (presumably the HCl form) exerts immunosuppressive effects at high doses (both in vitro and in vivo).5 These authors suggested if adequate concentrations of glucosamine entered inflamed arthritic locations, joint repair may proceed unimpeded. Adding either glucosamine or N-acetylglucosamine (the latter being more potent) to human cartilage in vitro reduced inflammatory changes and gene expression induced by two different cytokines (interleukin 1-ß and tumor necrosis factor).6
Other evidence suggests glucosamine can stimulate joint cartilage growth. In a study with a tagged, nonradioactive glucosamine, researchers administered the substance to bovine knee joints and monitored them for 13 days. There was a substantial increase in N-acetylgalactosamine, a constituent of proteoglycans, in the cartilage.7 This is the most compelling line of in vitro evidence to date supporting the presumed mechanism of bioprecursor activity, but still does not explain how glucosamine salts operate in vivo in humans.
Another theory focuses on glucosamine's companion in its commercially available forms. Because sulfation (adding sulfur groups to biomolecules) is an active metabolic process in cartilage, some have argued that glucosamine sulfate is preferable to sulfate-free forms. In one recent study, researchers explored sulfate's role by administering either glucosamine sulfate (1 gram) or sodium sulfate to healthy subjects.8 After measuring serum increases in sulfate, researchers found only subjects who received glucosamine sulfate displayed a significant increase in serum sulfate despite the elemental sulfate dose being doubled. Additionally, when subjects took glucosamine sulfate with acetaminophen, serum sulfate levels decreased. Acetaminophen metabolism involves sulfation, and thus, the authors suggested it consumed the sulfate provided by glucosamine sulfate. Cartilage lacks a definitive blood supply, so the synovial fluid that bathes cartilage tissue is the reservoir for nutrients and metabolic substrates. Thus, researchers measured the serum and knee synovial fluid sulfate concentrations in osteoarthritis patients and found virtually identical concentrations in both compartments. They interpreted this finding to suggest that blood sulfate supplies the synovial fluid free sulfate, presumably used in proteoglycan sulfation, and that glucosamine sulfate may exert its salutary effects by delivering sulfate to the serum and then synovium. Additionally, these findings raise the concern that glucosamine efficacy may be blunted by concurrent acetaminophen use.
The Cochrane Collaboration assessed 16 randomized controlled glucosamine trials involving 1,000 patients with osteoarthritis and reported only 16 adverse events requiring withdrawal from investigation.9 This tolerability earned glucosamine an "excellent" safety profile. This review did not incorporate the results of two separate three-year studies done with glucosamine sulfate in people with osteoarthritis. In the first study, 106 patients assigned to receive 1.5 g glucosamine sulfate once daily showed no greater incidence of adverse events than the 106 subjects in the placebo group.10 The second study reported similar findings.11
Most of the side effects described in the clinical trials involving oral glucosamine salts are stomach or gastrointestinal disturbances, which most often are transient and self-limiting. One case report describes an allergic reaction to glucosamine sulfate in a 76-year-old woman with hypertension and osteoarthritis. The reaction could be related to glucosamine's shellfish origin, but this was not explored.12 A second case report associated low-dose glucosamine use (form not disclosed) with impaired kidney function in a 79-year-old woman with myasthenia gravis who was also receiving corticosteroid and immunosuppressive drug treatment.13 Her kidney function normalized after discontinuing glucosamine.
One concern with glucosamine supplementation is impaired insulin action. Numerous animal studies have shown glucosamine injections produce acute insulin resistance.14,15 A recent study indicated a protein that transports glucose, or GLUT 2, has a higher affinity for glucosamine in vitro,16 suggesting glucosamine could affect blood glucose disposal. Two studies of infused glucosamine found either no effect17 or a modest effect on pancreatic insulin release and whole-body insulin sensitivity.18 In what appears to be the only oral supplementation study examining this phenomenon, six nondiabetic subjects with chronic low-back pain received 500 mg glucosamine sulfate three times daily for 12 weeks. The subjects showed a significant increase in fasting insulin concentrations compared with baseline concentrations and relative to a similar group of nine subjects who received placebo.19 No change in blood glucose was noted. Further research examining the effect of chronic oral glucosamine supplementation among those with impaired glucose tolerance and insulin resistance is needed.
More than two dozen clinical trials involving glucosamine salts have been conducted and published. The meta-analysis published in the Journal of the American Medical Association in 2000 critically reviewed five clinical trials using oral glucosamine salts (and seven clinical trials using oral chondroitin sulfate preparations).20 All of the reviewed trials used the unique glucosamine sulfate sodium chloride salt DONA by Rotta Pharmaceuticals in New Jersey. The conclusion was glucosamine appears to be safe and effective, but the magnitude of its effectiveness may be exaggerated. The latter conclusion was due to lax study designs, study design descriptions in the individual studies, and the fact that the majority of the trials to date have been sponsored by companies marketing the ingredient. The Cochrane Collaboration systematic review also provides a thorough examination of clinical evidence supporting glucosamine salt efficacy.9 The authors conclude glucosamine (again as glucosamine sulfate, DONA) is safe and effective for osteoarthritis, yet they question its long-term safety and efficacy. Additionally, the review raises the still-unanswered concern of whether other forms of glucosamine are equally effective. The lone published clinical trial involving glucosamine HCl (500 mg three times daily), cited in both reviews, found no statistically significant improvement compared with placebo.21
Since these reviews, a few additional clinical trials have been published, including the two three-year clinical trials mentioned above. The first of the two clinical trials equally randomized 212 patients older than 50 with mild to moderate knee osteoarthritis to receive either placebo or 1.5 g DONA once daily (note the single daily dose).10 In earlier studies, researchers used 500 mg three times daily, the same dose recommended for most commercially available products. Acetaminophen was one of several "rescue" drugs patients were permitted to use. The primary outcomes were JSW, or joint space width, in the knee (determined by X-ray—higher scores mean less cartilage degradation), an index of cartilage erosion and symptom scores on a research-validated questionnaire (WOMAC). After three years, 71 subjects on placebo and 68 on glucosamine sulfate completed the full intervention. Researchers noted a statistically significant reduction of cartilage (defined as reduced joint space narrowing) in the placebo group compared with those taking glucosamine sulfate. Indeed, the glucosamine group on average showed no joint space width loss—a result accompanied by statistically superior symptom scores (including pain and function) compared with placebo. Symptoms worsened for patients in the placebo group. Secondary analyses of this study indicated baseline presupplementation JSW had no bearing on glucosamine sulfate efficacy,22 and those with less severe osteoarthritis-mediated structural knee damage were likely to show the most aggressive cartilage erosion as determined by X-ray.23 This latter finding suggests cartilage structure-modifying (chondroprotective) agents such as glucosamine sulfate may be more appropriate than analgesic agents alone.
In the second three-year study, 202 patients aged 45 to 70 with mild to moderate knee osteoarthritis were assigned to either glucosamine sulfate (DONA) or placebo.11 Acetaminophen was the only "rescue" drug offered. As with the previous three-year trial, JSW and WOMAC symptom scores were the primary outcomes. Additionally, researchers assessed a functional index (Lequesne). Sixty-six placebo and 55 glucosamine sulfate patients finished the intervention. The results of this trial also showed no average reduction in JSW in the glucosamine sulfate group; there was a statistically significant reduction in JSW among those receiving placebo. Compared with placebo, the glucosamine sulfate group had significant improvements in joint pain symptoms and function.
In a recent six-month study involving 80 osteoarthritis patients—of whom a greater percentage displayed more advanced disease—researchers found a proprietary glucosamine sulfate complex had no statistically significant effect on WOMAC or pain scores.24 Patients in the glucosamine sulfate group took Health Perception High Strength Glucosamine three times daily; each tablet contains 500 mg glucosamine potassium chloride salt combined with 300 mg ascorbic acid, 300 mg calcium carbonate and 5 mg manganese.
In a recent trial involving 50 people aged 20 to 70 with unspecified chronic knee pain (osteoarthritis was not a required diagnosis), those randomized to receive 2 g glucosamine HCl (Musashi from Australia) once daily for 12 weeks showed a statistically significant reduction in pain scores and an increased quality of life, but no significant improvements in functional measures.25 Those taking glucosamine experienced a 30 percent reduction in knee pain scores at week eight compared with a 9.7 percent reduction among those receiving placebo. After 12 weeks, the percentages were 25 for the glucosamine group and 21.4 for placebo. The difference was statistically significant at eight weeks.
The original rationale suggesting glucosamine supplementation elicits chondroprotective or chondrotherapeutic effects stems from the notion that consumption of like biological materials (cartilage) will deliver necessary nutrients for health and healing.26 Given the prevalence of osteoarthritis and chronic knee pain in North America, agents offering sustained pain relief with minimal side effects are desirable. The joint-remedy duo of glucosamine and chondroitin is popular in the United States27—retail sales of these products exceeded $700 million in 2002.28 The evidence supporting these products rests primarily with one brand of glucosamine sulfate and limited evidence with glucosamine HCl alone. Additionally, the long-term effects of glucosamine supplements among people with diabetes remain unknown. Customers should consult their health care practitioner to closely monitor short- and long-term markers of blood glucose control.
The continuing National Institutes of Health-sponsored GAIT study pits Waukegan, Ill.-based ingredient manufacturer Pfanstiehl's glucosamine HCl against a specific, proprietary, clinical research-validated chondroitin sulfate (Bioiberica from Spain); the two combined; the COX-2 inhibitor Celebrex; and placebo. This may illuminate the difference, if any, between glucosamine HCl and chondroitin sulfate, but will leave unanswered the question of glucosamine sulfate versus chondroitin sulfate. Moreover, it may raise the ante for combination products that include other ingredients, the vast majority of which lack safety and efficacy data. As retailers, the safe harbor may be where the evidence resides.
Anthony L. Almada, MSc, is a nutritional and exercise biochemist and is the president and chief scientific officer of IMAGINutrition Inc. He has collaborated on two clinical trials assessing the influence of specific natural products in osteoarthritis.
Tim McAlindon, M.D., MPH, MRCP, is a rheumatologist at Tufts-New England Medical Center who has a broad research interest in the epidemiology of rheumatic disorders. He has performed systematic reviews of glucosamine and chondroitin treatment for osteoarthritis and is completing an online trial of gluco-samine for knee osteoarthritis symptoms.
DISCLOSURES: Almada is a paid consultant to BioEssentials Inc., marketers of Motion Potion, a glucosamine sulfate-containing beverage. McAlindon is founder of Internet Clinical Trial Systems Inc., and is named on a pending patent application filed by Boston University relating to Online Clinical Trials.
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2. Ebube NK, et al. Preformulation studies and characterization of proposed chondroprotective agents: Glucosamine HCl and chondroitin sulfate. Pharm Dev Technol 2002;7:457-69.
3. Sparringa RA, Owens JD. Glucosamine content of tempe mould, Rhizopus oligosporus. Int J Food Microbiol 1999;47:53-7.
4. Meininger CJ, et al. Glucosamine inhibits inducible nitric oxide synthesis. Biochem Biophys Res Comm 2000;279:234-9.
5. Ma L, et al. Immunosuppressive effects of glucosamine. J Biol Chem 2002;277:39343-9.
6. Shikhman AR, et al. N-Acetylglucosamine prevents IL-1ß-mediated activation of human chondrocytes. J Immunol 2001;166:5155-60.
7. Noyszewski EA, et al. Preferential incorporation of glucosamine into the galactosamine moieties of chondroitin sulfates in articular cartilage explants. Arthritis Rheum 2001;44:1089-95.
8. Hoffer LJ, et al. Sulfate could mediate the therapeutic effect of glucosamine sulfate. Metabolism 2001;50:767-70.
9. Towheed TE, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev Issue 4, 2002.
10. Reginster JY, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357:251-6.
11. Pavelka K, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis. Arch Intern Med 2002;162:2113-23.
12. Matheu V, et al. Immediate-hypersensitivity reaction to glucosamine sulfate. Allergy 1999;54:643.
13. Guillaume MP, Peretz A. Possible association between glucosamine treatment and renal toxicity: comment on the letter by Danao-Camara. Arthritis Rheum 2001;44:2943-4.
14. Balkan B, Dunning BE. Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. Diabetes 1994;43:1173-9.
15. Shankar RR, et al. Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism 1998;47:573-7.
16. Uldry M, et al. GLUT2 is a high-affinity glucosamine transporter. FEBS Lett 2002;524:199-203.
17. Pouwels MJ, et al. Short-term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab 2001;86:2099-103.
18. Monauni T, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49:926-35.
19. Almada AL, et al. Effect of chronic oral glucosamine sulfate upon fasting insulin resistance index (FIRI) in nondiabetic individuals. FASEB J 2000;14:A750.
20. McAlindon T, et al. Glucosamine and chondroitin for treatment of osteoarthritis. A systematic quality assessment and meta-analysis. JAMA 2000;283:1469-75.
21. Houpt J, et al. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol 1999;26:2423-30.
22. Bruyere O, et al. Radiologic features poorly predict clinical outcomes in knee osteoarthritis. Scand J Rheumatol 2002;31:13-6.
23. 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 Cart 2003;11:1-5.
24. Hughes R, Carr A. A randomized, double-blind placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology 2002;41:279-84.
25. Braham R, et al. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med 2003;37:45-9.
26. Buckwalter JA, et al. From oranges and lemons to glucosamine and chondroitin sulfate: clinical observations stimulate basic research. J Bone Joint Surg 2001;83A:1266-8.
27. Blakeley JA, Ribeiro V. A survey of self-medication practices and perceived effectiveness of glucosamine products among older adults. Complement Ther Med 2002;10:154-60.
28. Rea P. Nutrition Business Journal, San Diego, CA. Personal communication, March 2003.
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