NUTRACEUTICALS Editors: Gil Hardy, PhDErick Valencia, MD

Glucosamine: Con or Cure?Louise Sutton, MPharm, Lisa Rapport, MPhil, MRPharmS, and

Brian Lockwood, PhD, MRPharmSFrom the School of Pharmacy and Pharmaceutical Sciences, University of Manchester,

Manchester, United Kingdom

In our modern world, with rapidly devel-oping technology and great advances inmedical care, some people increasingly

rely on particular traditional remedies totreat their illnesses. In recent years herbal,homeopathic, and other alternative treat-ments have become increasingly popular;glucosamine, a nutraceutical, is one of thosealternative treatments. Nutraceuticals arenot new treatments; they have been used forat least 20 y. In fact, there is evidence thatglucosamine was being examined as a ther-apeutic agent for osteoarthritis as long agoas 1969. However, they are now causing alot of interest within the medical professionsand the public.1

Glucosamine is an aminosaccharidebased on the sugar glucose and is made inthe body by a reaction involving glutamicacid and glucose. It is found in abundance incartilage tissues and in smaller amounts intendon and ligament tissues. Glucosamine isan essential substrate in the natural forma-tion of the glycoaminoglycan matrix, whichis the main component of cartilage tissue,and chains of the matrix form aggrecan andother proteoglycans. Aggrecan is importantbecause it is required to give cartilage tissueits necessary hydrophobicity. The pressurecreated by aggrecan is opposed by the pullof collagen fibers. This is essential so thatthe correct pressure is maintained in tissue.These competing forces keep the cartilagestructure strong and help to protect it foreveryday wear and tear.2 Without this struc-ture, the cartilage is useless and the jointwill not be able to perform its normal func-tions. With the aging process and constantuse, damage develops to the matrix andproblems become apparent with the joint.

Glucosamine is synthesized in onlysmall amounts in the body and it is thoughtthat the ability of the body to do this de-creases with aging. Glucosamine is notfound in any common foodstuffs and socannot be obtained in this way, and if thebody is not synthesizing glucosamine in suf-

ficient quantities, then supplements may berequired.

OSTEOARTHRITIS

Glucosamine is thought to be useful in thetreatment of arthritic conditions, especiallyosteoarthritis. Osteoarthritis is a degenera-tive disorder involving destruction of jointsin the body; its incidence increases with ageand affects more than 10% of the populationolder than 65 y.3 As people age the numbersof chondrocytes within the structure de-crease to about 5%, with the aqueous matrixbeing approximately 95%. The aqueous ma-trix consists of proteoglycans, namely gly-cosaminoglycans. Chondrocytes are in-volved in the production of theproteoglycans and this is necessary to re-place those lost by natural metabolism anddegradation.4 Loss of chondrocytes or lossof function leads to poor-quality cartilage.

When cartilage tissue deteriorates, thebones in the joint becomes exposed; thesethen rub together causing pain and damage.Bones may chip or become fractured; thisthen leads to the formation of osteophytes,which are protrusions of bone. Hypertrophyalso occurs, which is an increase in the sizeof the tissue due to enlargement of cells.The joint becomes very painful and mobilityis affected; this is unpleasant for the suffererwhose normal life is disrupted.

Osteoarthritis can be extremely painfuland is made worse during activity, whichcan cause patients with the disease to be-come depressed and feel generally unwell.

The main aim of the various types ofdrug therapies available, mainly rubefa-cients and non-steroidal anti-inflammatorydrugs (NSAIDs), is to increase flexibility ofthe joint and to relieve pain so that thepatient is as comfortable as possible. How-ever, there is a high incidence of unwantedside effects with the latter group of drugs.5

An alternative agent for the treatment ofosteoarthritis is needed. The agent ideallywould treat the symptoms of the disease andprevent further progression. Cartilage canrepair itself given time, but to speed up theprocess an external agent is required.6Chondroprotective agents are one such classof drugs. Chondroprotection involves inser-tion of synthetic glycosaminoglycans into

the affected joint so that they can be used bychondrocytes for synthesis of cartilage com-pounds. Examples of such agents are glu-cosamine, chondroitin sulfate, and hyal-uronic acid. Many trials were performed onthe use of glucosamine to treat osteoarthritisin the early 1980s. It is now being examinedfurther because satisfactory alternatives toconventional drugs have not beendeveloped.

Glucosamine exists naturally in thebody; it is a small compound with molecularweight of 179. Because it is small, it isabsorbed easily into the body; and onceabsorbed, it is preferentially taken up intothe tissues such as cartilage and other jointstructures. In vivo, when glucosamine sul-fate is absorbed into the body, the sulfategroup breaks off from the compound. Theglucosamine molecule then moves into themucopolysaccarides. Here the glucosaminecan act as a substrate for the enzyme in-volved in the catalysis of transfer of phos-phate groups. Glucosamine therefore be-comes glucosamine-6-phosphate that isfurther incorporated into the biochemicalpathway. This leads to the synthesis of com-pounds used in the cartilage structure. Thereare some experimental data2 showing thatglucosamine has the ability to prevent fur-ther degradation of proteoglycans and canrebuild damaged cartilage. There is furtherevidence7 that glucosamine may also inhibitthe release of proteolytic enzymes such asthe elastase enzyme and lysosomal en-zymes; however, it has no effect on therelease of prostaglandin. Elastase has beenlinked to deterioration in cartilage structure,but levels of inhibition have been shown tobe affected by the dose of glucosamineused.7 Glucosamine is therefore attackingthe disease process and should halt the de-velopment of damage and reverse it. Ratherthan just blocking the pain of the disease,this treatment works on the actual cause,thus alleviating pain.8

CLINICAL TRIALS

A trial carried out recently looked at thelong-term effects of glucosamine sulfate onosteoarthritis progression.9 It was a random-ized, double-blind, placebo trial involving212 patients with osteoarthritis of the knee.

Correspondence to: Brian Lockwood, PhD, MR-PharmS, School of Pharmacy and PharmaceuticalSciences, University of Manchester, Manchester,M13 9PL, UK. brian.lockwood@man.ac.uk

Nutrition 18:534–536, 2002 0899-9007/02/$22.00©Elsevier Science Inc., 2002. Printed in the United States. All rights reserved. PII S0899-9007(02)00759-1

The trial results showed no significant de-crease in joint space in those subjects takingglucosamine. In contrast, the patients takingthe placebo exhibited a narrowing of thejoint space. A symptom score also assessedthe patients; this was a simple questionnaireabout how they rated their osteoarthritissymptoms and any changes that had oc-curred. The patients taking glucosamine hadpositive results; there was a 24% improve-ment in symptoms compared with only 10%in the placebo group. There were no differ-ences between the groups in relation tosafety issues. The conclusion from this trialfound that long-term administration of glu-cosamine over 3 y could prevent joint struc-ture changes and significantly improvesymptoms of the disease.

It was thought that chondroitin sulfatecould also be of benefit in treating the dis-ease. This is a much larger molecule thanglucosamine and has a more complex chem-ical structure. It has a molecular weight of50 000, which is 250 times that of glu-cosamine, and this results in it being poorlyabsorbed from the gastrointestinal tract,with only approximately 13% gettingthrough. Clinical trials showed no addi-tional benefit to the patient when chon-droitin sulfate was given in combinationwith glucosamine compared with glu-cosamine alone.10

What makes glucosamine even more ex-citing is its apparent lack of side effects.Because the compound is synthesized natu-rally by the body, no toxicity occurs eventhough it is given in much higher doses thanis normally present. It has a therapeutic mar-gin 10 to 30 times more favorable thanNSAIDs.8

Most of the data from the many clinicaltrials showed positive effects for glu-cosamine in the treatment of osteoarthritis.There have been many types of trials in-volving glucosamine, comparing it with pla-cebo and alternative treatments such asNSAIDs. A trial performed in 1982 com-pared the use of glucosamine and ibuprofento treat osteoarthritis. Forty patients weregiven 1.5 g of glucosamine or 1.2 g ofibuprofen daily over a period of 8 wk. Theresults showed that both treatments wereeffective and generally well tolerated. It wasnoted that ibuprofen relieved pain morequickly, but its effects leveled off as treat-ment continued. The beneficial effects ofglucosamine were slower but overtook theibuprofen in pain relief scores by the end ofthe study.11 It may be beneficial to start apatient on both treatments and then with-draw the NSAID once the glucosamine hashad time to become effective.4

PROBLEM POINTS

Glucosamine is prepared from chitin ob-tained from seashells or manufactured syn-thetically. Because glucosamine is not clas-

sified as a medicinal product, itsmanufacture is not regulated. Regulation ofits production is essential if it is to be usedas a viable form of treatment for osteoar-thritis. Many companies are now producingglucosamine compounds that are availablefor general sale in pharmacies. The wayeach company formulates its product is notthe same and this will lead to variationsbetween products. To ensure patient safety,standardization of glucosamine raw materialand resulting products is required so that all:

● contain the same active ingredient● contain the same concentration of ac-

tive ingredient● have known bioavailabilty per deliv-

ery system● state correct information on packaging

The standard dosage of glucosamine sulfateis 1500 mg in divided doses. Pure glu-cosamine is not particularly stable and itbreaks down in the presence of water andair. Therefore, to stabilize the compound, itis often combined with sodium or potas-sium, which increases the total weight of thecompound. There are different forms of thecompound available for sale such as glu-cosamine sulfate, glucosamine hydrochlo-ride, N-acetyl glucosamine, and the chlorhy-drate salt of glucosamine. There is noguarantee as to exactly what is contained inthe product. This is an important issue be-cause patients tend to self-medicate. Inves-tigators at the University of Maryland ana-lyzed 23 glucosamine products; many didnot contain what was stated on the label.The only form recommended is glu-cosamine sulfate because the sulfur in thesulfate is also important. Sulfur is an impor-tant nutrient used in joint tissue, its mainfunction being to stabilize the connectivetissue matrix within the cartilage struc-ture.10 It is not uncommon to find that peo-ple suffering from osteoarthritis also havelow sulfur levels in their joints and blood.

Patients using glucosamine need to bemade aware that this supplement does nothave immediate success. Positive results us-ing glucosamine may not become apparentfor some time and the benefits will not reacha maximum for several weeks.

The clinical trials that have been per-formed on glucosamine have produced sat-isfactory results and have shown it to besafe; however, there are indications that thetrials have not been carried out in an unbi-ased way. A recent article stated that “meth-ods of treatment and assessment of resultshave been considered unsatisfactory.”12 It isthought that further independent trials arenecessary to prove the efficacy of glu-cosamine. Moreover, many of the trials todate have had sponsorship from companiesthat manufacture glucosamine supple-ments.13 This may have an effect on anyresults and will favor biased results towardglucosamine rather than toward placebo oran alternative treatment. For those reasons,

all information relating to the effects of glu-cosamine needs to be treated with caution.

The change in disease state is very hardto measure; different people have differentlevels of pain threshold and what is unbear-able to one person may be bearable to an-other. It is also hard to measure pain on astandard scale; it is very hard to make anadequate or accurate comparison of painexperienced at different times. When peopleundertake a new treatment, they want to seeimprovement in their symptoms and willrelate any initial change to it. There are nonerves in articular cartilage, so pain is notdirectly associated to it. When x-rays showchanges in joint space, it cannot be linkeddirectly to the severity of pain that the pa-tient is suffering because it is not directlyrelated to the disease. It would also be morehelpful if the same outcome measures wereused in each trial because some use changein joint space whereas others use aquestionnaire.

When patients show improvement intheir symptoms, it is sometimes hard to re-late this to the therapy involved. Peoplehave different lifestyles, do differentsamounts of exercise, and have different di-ets. All these factors influence the diseaseprocess. A change in body weight will alsogreatly affect the results; even a small de-crease in weight can have profound effectson load-bearing joints.3 This latter point isof increased significance in women due todepletion of bones as they age.

There are a few situations where glu-cosamine use is not suitable or may needmonitoring. The standard dose needs to beincreased in patients who are obese and inthose currently taking diuretics.10 It alsomay be contraindicated in patients with di-abetes because there are concerns that itmay have an effect on insulin secretionwithin the body. This is important becausemost patients taking glucosamine are el-derly who are more prone to being over-weight and, hence, at risk for developingtype 2 diabetes. The mechanism involved iscomplex. High levels of glucose in theblood results in glucose toxicity, whichmeans there in less insulin secreted from theislet cells due to a decrease in their function.This change in function is thought to berelated to an increase in flow of thehexosamine–phosphate pathway, which isstimulated by glucosamine.2,14 The data forthis are debatable because the trial usedinjectable forms of glucosamine rather thanoral preparations. Higher plasma levels ofglucosamine occur with these preparationscompared with the oral form. Glucosaminealso may cause gastrointestinal disturbancessuch as upset stomach, nausea, heartburn,and diarrhea in some patients, but advisingthe patient to take the supplement with foodcan usually control such disturbances.

Glucosamine needs to be regulated andundergo more clinical testing to ascertainthe optimum dose and route of administra-

Nutrition Volume 18, Number 6, 2002 535Glucosamine: Con or Cure?

tion. These trials should be independent ofany company. No extreme long-term studieshave been carried out, so there is no indica-tion of any long-term side effects that thissupplement could have, nor does anyoneknow how long it should be taken for. Itwould be useful to perform trials using dif-ferent doses to find out if the patient shouldalways take 1.5 g/d or whether a lowermaintenance dose is suitable to controlsymptoms.

REFERENCES

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2. Adams M. Hype about glucosamine. Lancet 1999;354:353

3. Krska J. The treatment of arthritic conditions. PharmMagazine 2000;6:17

4. Kayne SB, Wadeson SK, MacAdam A. Is glu-cosamine an effective treatment for osteoarthritis? Ameta-analysis. Pharm J 2000;265:759

5. BMA/RPSGB. British National Formulary 2001;41:461

6. Franzen P. Arthritis with nutritional rehabilitation.A case report. Sports Chiropract Rehabil 1998;12:21

7. Kamel M, Hanafi M, Bassouni M. Inhibition ofelastase enzyme release from human polymorpho-nuclear leukocytes by N-acetyl-galactoseamine andN-acetyl-glucosamine. Clin Exp Rheumatol 1991;9:17

8. Webb M. Glucosamine sulphate: superior toNSAIDs in arthritic conditions. J Altern Comple-ment Med 1995:13

9. Reginster JY, Deroisy R, Rovati LC, et al. Longterm effects of glucosamine sulphate on osteoarthri-tis progression: a randomised, placebo-controlledclinical trial. Lancet 2001;357:9252

10. Glucosamine sulphate: nature’s arthritis cure. Avail-able from: http//www.chiropage.com/glucosamine-sulphate.htm

11. Vaz AL. Double blind clinical evaluation of therelative efficacy of ibuprofen and glucosamine sul-phate in the management of osteoarthritis of theknee in outpatients. Curr Med Res Opin 1982;8:145

12. Mc Alindon T. Nutraceuticals have some efficacy inOA, meta analysis shows. Pharm J 2001;264:533

13. Dieppe P, Chard J. Glucosamine for osteoarthritis:magic, hype or confusion? BMJ 2001;322:1439

14. Monauri T, Zenti MG, Cretti A. Effects of glu-cosamine infusion on insulin secretion and action inhumans. Diabetes 2000;49:926

536 Sutton et al. Nutrition Volume 18, Number 6, 2002