Doi:10.1016/j.yrtph.2006.07.004

Regulatory Toxicology and Pharmacology 47 (2007) 78–83 Risk assessment for glucosamine and chondroitin sulfate ଝ Council for Responsible Nutrition, 1828 L Street, NW, Suite 900, Washington, DC 20036-5114, USA Abstract
Glucosamine and chondroitin sulfate are two popular dietary ingredients present in dietary supplements intended to support joint health. A large body of human and animal research suggests that oral intakes of these ingredients, either alone or in combination, reducesjoint pain and improves mobility in persons with osteoarthritis. The increased awareness and use of these ingredients in dietary supple-ments warrant a comprehensive review of their safety. Systematic evaluation of the research designs and data do not provide a basis forrisk assessment and the usual safe upper level of intake (UL) derived from it unless the newer methods described as the observed safe level(OSL) or highest observed intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence strongly supports safetyat intakes up to 2000 mg/d for glucosamine, and 1200 mg/d for chondroitin sulfate, and these levels are identiWed as the respective OSL.
These values represent the highest levels tested in human clinical trials. The complete absence of adverse eVects at these levels supports aconWdent conclusion of their long-term safety.
2006 Elsevier Inc. All rights reserved.
Keywords: Glucosamine; Chondroitin sulfate; Upper level of intake (UL); Observed safe level (OSL) 1. Introduction
have investigated the eYcacy of oral glucosamine com-pounds, often in combination with chondroitin sulfate, in Glucosamine is an aminomonosaccharide and it is the individuals with osteoarthritis. Long-term (3 year) clinical principal component of O-linked and N-linked glycosami- noglycans, which form the matrix of all connective tissues, orally administered glucosamine compounds may be eVective in ameliorating pain due to osteoarthritis has ). Dietary supplements in the United States may con- port the eYcacy and safety of oral gluco- tain glucosamine hydrochloride, glucosamine sulfate, or samine in osteoarthritis. In general, the evidence suggests N-acetyl-glucosamine. The raw material for glucosamine that glucosamine, at the range of dosages commonly con- supplements has historically been derived from extraction sumed, is not toxic and produces no recognizable pattern of chitin, a component of shellWsh (shrimp, crab, and lob- of adverse eVects. Most of the data relate to a single ster). Recent technological advances have led to a more intake level, namely 1500 mg/d, although this is sometimes eYcient means of production of a vegetarian source by divided into three or more individual doses. While most published studies have been on the sulfate form, a fewhave used the hydrochloride form. One 12-week clinicaltrial involved a daily dose of 2000 mg of glucosamine ଝ No funding was speciWc to the production of this manuscript. The sala- ries for authors were provided by the aYliated organization.
* Corresponding author. Fax: +1 202 204 7980.
Chondroitin sulfate is a glycosaminoglycan with a poly- E-mail address: (J.N. Hathcock).
merized disaccharide base linked to a sulfate group, and is 0273-2300/$ - see front matter 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.yrtph.2006.07.004 J.N. Hathcock, A. Shao / Regulatory Toxicology and Pharmacology 47 (2007) 78–83 found in the proteoglycans of articular cartilage ( (b) Assess the dose–response relationship for the identiWed hazard.
). As a dietary supplement, chondroitin sulfate is (c) Consider uncertainty and assign an uncertainty factor (UF).
(d) Derive a UL from the no observed adverse eVect level (NOAEL) or usually derived from bovine trachea, although other lowest observed adverse eVect level (LOAEL), and the UL D sources such as ovine or porcine trachea and shark skele- tons (shark cartilage) are also used in some dietary supple- 2. If no data establish adverse eVects in humans, the above procedure ments). The concept that orally administered cannot be used. In these circumstances, the highest intake level with chondroitin sulfate, along with glucosamine, might slow the suYcient evidence of safety is identiWed as a value named the OSL byCRN and the HOI by FAO/WHO. Uncertainty is considered in selec- process of osteoarthritis has also been recognized for tion of the OSL value and the selection is made with suYcient conser- decades. Numerous clinical trials have investigated the vatism to justify assignment of UF D 1.0.
eYcacy of oral chondroitin sulfate and/or glucosamine inindividuals with osteoarthritis. Meta-analysis tends to sup- We applied the Wrst procedure to the glucosamine and chondroitin sul- fate human trial data and found no basis for a NOAEL or LOAEL, andthus could not derive a classical UL. Consequently, we applied the OSL procedure to the clinical trial data, with the results described in the sec- ). In general, the evidence suggests that chondroi- tin sulfate, at the range of dosages commonly consumed Due to the nature of the raw material sources for these two ingredi- (usually 1200 mg/d), is not toxic and produces no recogniz- ents, there is little, if any dietary contribution, and therefore the OSL able pattern of adverse eVects. Most of the data relate to value identiWed from the trials does not require correction for dietaryintakes, and the OSL can be identiWed as a safe upper level for supple- single intake levels, and no systematic study of the dose– response relationship has been conducted.
The increase in both public awareness and usage of these ingredients in dietary supplements warrants a comprehen- 3. ScientiWc evidence related to safety—glucosamine
sive review of their safety. Most upper safe levels of nutri-ents and related substances are based on widely applicable risk assessment models used by the US Food and NutritionBoard (FNB) in its Dietary Reference Intakes documents Publications on the clinical trials of glucosamine for eVec- tiveness in osteoarthritis also contained much useful infor- mation relating to safety. None of the clinical trials have reviews are a formalization and extension of the quantita- found signiWcant patterns of adverse eVects related to gluco- tive methods widely used earlier in risk assessment of other substances, and by the food and dietary supplement indus- tries. Because of the systematic, comprehensive and author- itative character of the FNB risk assessment method for of three years duration, substantial numbers of several nutrients, this approach has gathered widespread support diVerent adverse health events occurred in both the placebo and adoption by others such as the European Commission and the treatment groups, but none of the small diVerences in adverse event frequency approached statistical signiW- , the United Kingdom Expert Group on Vita- clusions from these studies are further supported by the and more recently by the Food and Agriculture Organiza- absence of signiWcant adverse eVects in other clinical trials tion/World Health Organization project report A Model for Establishing Upper Levels of Intake for Nutrients and Related Substances ( with some slight modiWcations. All these reports reXect the concepts and trial data have shown no cause for concern about the safety procedures established much earlier for the risk assessment of oral glucosamine at current and plausible intakes Speculation over a causal relationship between gluco- samine intake and diabetes has led to the investigation of 2. Methods
the possible eVects on insulin function and glucose metab-olism, but not always with an appropriate experimental The safety evaluation method applied to orally administered glucosa- protocol. Infused glucosamine can increase the hexosa- mine or chondroitin sulfate is that of the Council for Responsible Nutri- mine pathway Xux, suggesting a potential adverse eVect of tion (CRN) Vitamin and Mineral Safety, 2nd ed), whichcontains the basic features of the FNB method and also the observed safe level (OSL) modiWcation recently adopted as a highest observed intake ). The hexosamine pathway activation leads to deteri- oration of pancreatic -cell function, thereby posing the Overall, this risk analysis was derived from the human clinical trial possibility that glucosamine could enhance the risk of dia- database through the following major steps: 1. Derive a safe upper level of intake (UL) if the data are appropriate: Concerns about a possible adverse eVect of glucosamine (a) Search for data that identify a hazard related to excessive intake.
on glucose homeostasis or diabetes have prompted direct J.N. Hathcock, A. Shao / Regulatory Toxicology and Pharmacology 47 (2007) 78–83 evaluation of these endpoints in clinical trials. One clinical 2700 mg/kg in rats and 2149 mg/kg in dogs ( trial administered a daily dose of 1500 mg glucosamine hydrochloride for 90 days and found no eVects on hemo- 1500 mg daily dose in humans amounts to 25 mg/kg, and globin A concentrations in diabetic subjec the 2000 mg dose equals 33 mg/kg. Thus, extrapolation of ), and another found no eVects of 1500 mg/d of the extensive data obtained from the animal and in glucosamine sulfate on blood glucose or serum insulin in in vitro toxicology studies suggests that adverse eVects are Thorough review of the evidence on this relation of gluco-samine to glucose metabolism and function reveals no 4. Human NOAEL or OSL (HOI)—glucosamine
adverse eVect). Thus, concernsabout a possible diabetogenic eVect of glucosamine that arose from biochemical studies have been investigated inclinical trials, and the human data directly demonstrate None of the clinical trials found adverse eVect related to that this eVect does not occur in normal or diabetic subjects glucosamine administration in any form, and therefore who consume 1500 mg/d of glucosamine for up to 12 weeks.
there is, by deWnition, no basis for identifying a LOAEL. In Because of the small size of the clinical trials involved, the the absence of a LOAEL, a NOAEL is not usually set.
possibility of an eVect in sensitive individuals cannot be Without either of these two values the establishment of a The highest glucosamine dosage utilized in a double- blind, placebo-controlled, randomized clinical trial was2000 mg of glucosamine hydrochloride/d for 12 weeks in subjects with osteoarthritis of the knee (Subjects (24 assigned to glucosamine and 22 to pla- The glucosamine dosage that was utilized in most clini- cebo) were monitored for the side eVects of nausea/vomit- cal trials seems to be 1500 mg/d. The one clinical trial that ing, gastrointestinal upset/cramps, headache, bloating, dry used 2000 mg of glucosamine hydrochloride found no mouth, and tenderness in the knee. The total side eVects adverse eVects. There are ample data to identify 1500 mg reported were similar, with 11 among the 24 subjects in the of glucosamine sulfate as the OSL. The absence of adverse glucosamine group and 10 among the 22 placebo controls, eVects in clinical trial at 2000 mg of glucosamine hydro- with no signiWcant diVerences in any category.
chloride, together with the huge margins of safety indi- The NIH-sponsored glucosamine/chondroitin arthritis cated by animal studies and the direct evidence against a intervention trial (GAIT) involved more than 1500 osteoar- diabetogenic eVect in humans is suYcient grounds for set- thritis patients who ingested 1500 mg/d glucosamine hydro- ting the OSL at 2000 mg of glucosamine hydrochloride.
chloride, 1200 mg/d chondroitin sulfate, the combination of Further, the diVerences in glucosamine content and bio- the two, 200 mg/d of the prescription pain medication availability allow this OSL to be applied to glucosamine Adverse eVects were closely monitored throughout the In one placebo-controlled, double-blind randomized study period. A total of 634 patients were exposed to gluco- clinical trial of glucosamine hydrochloride (1500 mg) in samine hydrochloride. Results showed no signiWcant diVer- combination with chondroitin sulfate (1200 mg) two sub- ence in the incidence of adverse eVects between any of the jects in the active group experienced allergic responses, compared with none in the placebo group ( The glucosamine fraction of total weight is higher with combined treatment prevents attribution of the the hydrochloride than with the sulfate; the bioavailability eVect to a speciWc ingredient, but allergic responses related of both forms exceeds 90%, with glucosamine hydrochlo- to glucosamine of shell Wsh origin have been reported previ- ucts containing glucosamine from this source are required bioavailability similarities, the safety conclusions reached for hydrochloride can be appropriately and conWdently sources would not need such warnings.
IdentiWcation of 2000 mg/d as the OSL for oral con- sumption of glucosamine (either the hydrochloride or the sulfate) carries little uncertainty, due to the conWdencegained from substantial safety in animal and in vitro tests.
The large number of animal and in vitro studies The subjects in the clinical trials would have been con- addressing the safety as well as the metabolism and meta- suming little-to-no glucosamine in their diet, and there- bolic eVects of glucosamine have been reviewed in detail fore the quantities of glucosamine added in clinical trials discussed were supplemental amounts well above the very chloride is greater than 5000 mg/kg, and the NOAEL is small quantities potentially consumed in foods. Therefore, J.N. Hathcock, A. Shao / Regulatory Toxicology and Pharmacology 47 (2007) 78–83 no correction is required for glucosamine in the food sup- 1500 mg/d glucosamine hydrochloride, 1200 mg/d chon- ply and this risk assessment represents a direct approach droitin sulfate, the combination of the two, 200 mg/d of the to the safe upper level for supplements (ULS). No correc- prescription pain medication Celebrex™, or placebo for 24 tion is needed for the glucosamine in the food supply. The weeks (. Adverse eVects were closely mon- OSL for glucosamine set at 2000 mg is also identiWed as itored throughout the study period. A total of 635 patients the ULS. Allergic warnings are appropriate and required were exposed to chondroitin sulfate. Results showed no sig- only for products including glucosamine of shell Wsh niWcant diVerence in the incidence of adverse eVects between any of the treatment arms. None of the clinical tri-als found any adverse eVects on clinical chemistry (blood NOAEL and LOAEL: No toxicological basis.
and urine) or hematological measurements resulting from OSL: 2000 mg glucosamine compound (hydrochloride The clinical trial evidence has been the subject of four 5. ScientiWc evidence related to safety—chondroitin sulfate
and one review/commentar Thesepublications focused primarily on the beneWts of oral chondroitin sulfate in limiting the progression of osteoar-thritis, but they also have relevance to the safety of this Several clinical trials have involved the oral administra- ingredient. The meta-analyses support the safety of oral chondroitin sulfate at 1200 mg/d, the highest intake sys- ). The age, health conditions, dosage, dura- tion, and monitoring and evaluation methods have diVeredgreatly. For conWdence in the results, those studies with The absence of adverse eVects at any of the dosages used stronger designs carry more weight regarding a conclusion in the clinical trials does not support identiWcation of a of safety at that dosage. In a risk assessment, the studies LOAEL or NOAEL. The evidence indicates no adverse with strong designs and involving higher dosages deserve eVect of 1200 mg/d of oral chondroitin sulfate, but does not greater weight in identifying the highest dosage that can be suggest at what dosage adverse eVects might occur. There- conWdently concluded to carry no identiWable risk of fore there is, by deWnition, no basis for identifying a LOAEL. In the absence of a LOAEL, a NOAEL is not usu- ally set. Without either of these two values the establish- tered in published clinical trials is 1200 mg/d ( 6. Human NOAEL or OSL (HOI)—Chondroitin sulfate
of subjects in the trials varied from 12 to 635, and the clin-ical monitoring capable of detecting adverse eVects The highest chondroitin sulfate dosage that has been ranged from sparse to extensive (e.g., self-reports of possi- utilized in clinical trials is 1200 mg/d. There are suYcient ble adverse eVect to clinical evaluation combined with data at this level to identify it as the OSL. The nearly com- extensive hematological and clinical chemistry indices).
plete absence of any adverse eVects of chondroitin sulfate None of these clinical trials found any signiWcant adverse within the range of the clinical trials reviewed (800– 1200 mg/d) suggest that the highest level, 1200 mg/d, is not a true NOAEL and that any LOAEL is likely to be much higher. The single case of gastritis among hundreds of safety of oral chondroitin sulfate. It involved 165 subjects subjects treated suggests that this one case is not causally treated for 3 years with an oral dose of 1200 mg/d. The related to chondroitin sulfate, or that the individual had a monitoring included examination by three physicians. The very unusual sensitivity, and should not inXuence the out- only adverse eVect reported was a single case of gastritis in come of the risk assessment. IdentiWcation of 1200 mg/d as one chondroitin sulfate-treated subject. The subject with- the OSL for oral consumption of chondroitin sulfate up drawals were fewer among those treated with chondroitin to three years by adults carries little uncertainty—there sulfate compared with placebo-treated controls. These are no known adverse eVects to be avoided. Due to the rel- results are consistent with the most recent trial conducted atively low consumption of chondroitin sulfate in the diet, on chondroitin sulfate. The NIH-sponsored glucosamine/ this risk assessment represents a direct approach to the chondroitin arthritis intervention trial (GAIT) involved ULS. Therefore, the OSL of 1200 mg is identiWed as the more than 1500 osteoarthritis patients who ingested J.N. Hathcock, A. Shao / Regulatory Toxicology and Pharmacology 47 (2007) 78–83 Drovanti, A., Bignamini, A.A., Rovati, A.L., 1980. Therapeutic activity of oral glucosamine sulfate in osteoarthrosis: a placebo-controlled dou-ble-blind investigation. Clin. Ther. 3, 260–272.
Because the human clinical trial data are judged suY- Edelist, D.D., Evans, M.F., 2001. Do glucosamine and chondroitin treat cient to support identiWcation of an OSL value, the data the symptoms of osteoarthritis? Can. Fam. Physician 47, 275–277.
from animal experiments were not reviewed.
ScientiWc Committee on Food, 2001. Guidelines of the ScientiWc Commit- tee on Food for the Development of Tolerable Upper Intake Levels for Vitamins and Minerals. European Commission, Brussels, Belgium.
FAO/WHO, 2006. A Model for Establishing Upper Levels of Intake for Nutrients and Related Substances. In: FAO/WHO Technical Work- shop on Nutrient Risk Assessment, Geneva, Switzerland.
Food Standards Agency, 2003. Expert Group on Vitamins and Minerals, 7. Conclusions
2003. Safe Upper Levels for Vitamins and Minerals. Food StandardsAgency, United Kingdom.
Food and Nutrition Board, Institute of Medicine, 1997. Dietary Reference Glucosamine and chondroitin sulfate are two dietary Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluo- ingredients whose use continues to increase among Ameri- ride. National Academy Press, Washington, DC.
cans in the form of dietary supplements. While a substantial Food and Nutrition Board, Institute of Medicine, 1998a. Dietary Refer- body of evidence exists supporting the beneWcial eVects of ence Intakes for Thiamin, RiboXavin, Niacin, Vitamin B6, Folate, Vita-min B12, Pantothenic Acid, Biotin and Choline. National Academy these on joint health, oYcial documentation of their safety using risk assessment has not, to our knowledge, yet been Food and Nutrition Board, Institute of Medicine, 1998b. Dietary Refer- published. The present review of the available published ence Intakes: A Risk Assessment Model for Establishing Upper Intake human clinical trial data involving glucosamine and chon- Levels for Nutrients. National Academy Press, Washington, DC.
droitin sulfate, along with several published meta-analyses, Food and Nutrition Board, Institute of Medicine, 2000. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids. National provide for a high level of conWdence in the safety of these ingredients. The absence of a well-deWned critical eVect for Food and Nutrition Board, Institute of Medicine, 2001. Dietary Reference either ingredient precludes the selection of a NOAEL or Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Cop- LOAEL, and therefore required use of the observed safe per, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium level (OSL) or highest observed intake (HOI) approach and Zinc. National Academy Press, Washington, DC.
Harris, E.D., Budd, R.C., Firestein, G.S., Genovese, M.C., Sergent, J.S., established by FAO/WHO to conduct this risk assessment.
Ruddy, S., Sledge, C.B. 2005. Structure and Function of Bone, Joints, Evidence from well-designed randomized, controlled and Connective Tissue, Kelley’s Textbook of Rheumatology.
human clinical trials indicates that the ULS for is 2000 mg/ Hathcock, J., 2004. Vitamin and Mineral Safety. Council for Responsible d for glucosamine and 1200 mg/d for chondroitin sulfate.
Institute of Medicine, 2005. Glucosamine: Prototype Monograph Sum- mary. Dietary Supplements: A Framework for Evaluating Safety.
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