- Email: [email protected]
Role of glucosamine in osteoarthritis
ARTICLE IN PRESS Current Orthopaedics (2007) 21, 386–389
Available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/cuor
THERAPEUTICS
Role of glucosamine in osteoarthritis R. Thakrala, U.K. Debnathb,, C. Dentc a
Department of Trauma and Orthopaedics, Adelaide and Meath Hospital Incorporating National Children’s Hospital, Tallaght, Dublin-24, Ireland b Department of Trauma and Orthopaedics, University Hospital Cardiff, Cardiff CF14 4XW Wales, UK c Department of Orthopaedics, University Hospital Cardiff, Cardiff CF14 4XW Wales, UK
KEYWORDS Glucosamine; Action; Cartilage; Arthritis
Summary Long-term follow-up studies on the effects of glucosamine preparations are still awaited. At present, only short-term results are available. They are known to relieve pain and decrease the rate of joint space narrowing clinically in osteoarthritis of knee, whilst the side effects are less when compared to the anti-inflammatory drugs and even placebos. It is probably safe – but there is no good evidence that it works. It would be ideal to have a medication that is a normal constituent of the human cartilage, which modifies the natural history of the disease. It is possible that long-term clinical studies with glucosamine may result in modifications to the indications for joint surgery or the time patients can live with osteoarthritis before developing substantial disability. & 2007 Published by Elsevier Ltd.
Introduction Glucosamine sulphate is a normal constituent of the extracellular matrix of mammalian articular cartilage and synovial fluid, which is required for synthesis of glycosaminoglycans (GAGSs).1 It also helps in synthesising mucin or mucous secretions, which act as lubricant or protective agents in human joints. In 1956, Lennart Roden from Stockholm first showed glucosamine HCL-stimulated production of chondroitin sulphate in cartilage matrix by at least three times its control value. It was not until the 1980s that clinical trials of
glucosamine as a therapeutic drug for osteoarthritis (OA) of knee began. Now, it is readily available for purchase from health/food shops and pharmacies in the UK, USA and throughout Europe, for the relief of musculoskeletal symptoms.2,3 The range of products that includes chondroitin sulphate, vitamins C, D and E, minerals and herbs, as well the oligoelements (such as zinc, selenium, manganese and copper) are together called nutripharmaceuticals.4 Glucosamine has gained popularity in the last two decades for the treatment of OA.5
Glucosamine and its properties Corresponding author. Present address: 23, Barons Court Road,
Cardiff CF23 9DF, UK. Tel.: +078 1116 5794. E-mail address: [email protected] (U.K. Debnath). 0268-0890/$ - see front matter & 2007 Published by Elsevier Ltd. doi:10.1016/j.cuor.2007.04.002
Glucosamine is an amino monosaccharide found in chitin, glycoproteins and in GAGSs (formerly known as mucopolysaccharides), such as hyaluronic acid and heparan sulphate.
ARTICLE IN PRESS Role of glucosamine in OA
387
CH:CH O H
H H CH
H
H
NH3+
HO
OH
2 Figure 1 Chemical structure of glucosamine.
It is the basic building block of the amino sugars and hence is an important constituent of the cell wall and interstitial proteins.6 The chemical structure of glucosamine is shown in Fig. 1. Glucosamine (2-amino-2-deoxyalpha-D-glucose) is one of the two hexosamine sugars (six carbon amino sugars) common in human cells. Structurally, glucosamine is modified glucose, with an –NH3 group replacing the –OH group found on carbon two (C-2). G6-P is an amino monosaccharide (amino sugar) produced in the body by the combination of glutamine with fructose, through the enzymatic action of glucosamine synthetase.6 Glucosamine is available commercially as a nutritional supplement in three forms: glucosamine HCl, glucosamine sulphate and N-acetyl-glucosamine. All three forms are water soluble, the salt acting as a delivery vehicle. At neutral and physiological pH, the amino group in glucosamine is protonated, resulting in a positive charge. Salt forms of glucosamine contain negative anions to neutralise the charge. In the case of glucosamine hydrochloride, the anion is chloride, and in glucosamine sulphate the anion is sulphate. N-acetylglucosamine is a delivery form of glucosamine in which the amino group is acetylated, thus neutralising its charge. To date, most of the clinical studies examining the effect of glucosamine on OA have been performed with either the sulphate or the chloride salts of glucosamine. The glucosamine used in supplements is typically derived from marine exoskeletons.7 Synthetic glucosamine is also available.
Pharmacokinetics 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.8 Healthy men have serum glucosamine concentrations of 0.04 mmol/L when they are not consuming supplemental glucosamine.9,10 Ingestion of recommended oral doses of glucosamine in humans achieves serum levels of approximately 0.06 mmol/L.11 It is not presently known how much of an ingested dose is taken up in the joints in humans. Most relevant clinical trials have used patented crystalline glucosamine sulphate in 1500 mg, once a day, soluble powder form.12,13 This is a prescription drug in most European and
non-European countries. However, the Dietary Supplement Health and Education Act of 1994 favoured the appearance of several undocumented glucosamine salts (e.g. hydrochloride), derivatives (e.g., N-acetyl-glucosamine) on the dietary supplement market in the USA and other countries, and various other dosage forms and regimens.14 Persiani et al.14 studied the pharmacokinetics of glucosamine and found that it is bioavailable after oral administration of crystalline glucosamine sulphate. This persists in circulation, and its pharmacokinetics support once-daily dosage. Steady-state peak concentrations after a therapeutic oral dose of 1500 mg show bioavailability at concentrations that are in line with those found to be effective in selected in vitro models, which may explain the favourable clinical results in OA.
Mechanism of action of glucosamine in human tissues Glucosamine is preferentially incorporated by chondrocytes into the components of the GAG chains in intact cartilage and stimulates the synthesis of physiological proteolglycans. It also decreases the activity of catabolic enzymes, including matrix metalloproteases (MMP).15-17 In certain tissues, glucosamine has a higher affinity for glucose transporters than glucose itself and is incorporated into glycoproteins faster than glucose.18 It also inhibits the degradation of equine articular cartilage induced by interleukin 1 and lipopolysaccaharides.19 This supports the suggestion that exogenous glucosamine acts mainly as a substrate for biosynthesis of mucopolysaccharides and biopolymers of joints and bones and, thus, contributes to restoration of damaged cartilage.8,20
Articular cartilage in OA of the knee The degenerative disease OA is a manifestation of an imbalanced synthesis of articular cartilage (AC) matrix and the associated growth factors.21 Knee cartilage defects, for example, may result in an increased rate of cartilage breakdown, leading to decreased cartilage volume and joint space narrowing. OA represents loss of homeostasis in the normal maintenance of articular cartilage by the degradation and synthesis of the matrix components. The inciting mechanisms are not fully understood, although the aetiology seems multifactorial.22 The end pathway is an imbalance between proteinases, which break down the matrix constituents, and proteinase inhibitors.
The role of glucosamine in OA of the knee The long-term combined structure-modifying and symptommodifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in OA.12 Besides synthesis of GAGs, it also exerts an anti-catabolic effect on AC by inhibiting the anti-inflammatory responses.23 The theory of synthesis of GAGs does not, however, explain the observed glucosamine mediated increase in collagen type II. The literature shows a positive effect of
ARTICLE IN PRESS 388 glucosamine on GAG production in human chondrocytes in cell culture, and the same anabolic effect is found in bovine and rat explants.16–18 TGF-b is considered to be a multifaceted cytokine that plays key roles in many downstream effects, such as mesenchymal differentiation, matrix production, stimulation of chondrocytes and controlled differentiation of stem cells.24,25 In adults, TGF-b’s are also believed to maintain a critical balance between the various anabolic and catabolic functions of chondrocytes for proper functioning of the cartilage. Varghese et al.26 provide evidence that glucosamine mediated increase in the production of specific matrix components involves TGF-b1 up-regulation, possibly through the hexosamine pathway in optimal concentrations of glucosamine. The effect of glucosamine on chondrocytes was found to be dependent upon the culture conditions. Is there an effect on gene expression, in both anabolic and catabolic activities of chondrocytes, in response to glucosamine treatment in the human OA explant model? Another study added a pre-culture experimental agent to human cartilage harvested during knee arthroplasty procedures. To this model, they added different concentration of glucosamine. They found that glucosamine (5 mM) addition to a human OA explant reduced the enzymatic breakdown of the cellular matrix.27 The authors of this study also suggested that chondroprotective properties of the glucosamine in vivo may be based on inhibiting further degradation due to catabolic activities, rather than on the ability to rebuild cartilage.28
Glucosamine in clinical practise Three rigorous meta-analyses show that individuals with OA of the knee or spine have significantly less symptoms while taking glucosamine than those taking placebo.29–31 McAlindon et al.28 conclude that glucosamine is moderately efficacious for the relief of symptoms of OA. Richy et al. conclude that glucosamine has highly significant effects on all aspects of knee OA.32 A recent randomized clinical trial included 414 post menopausal women followed for 3 years. The authors documented no decrease in joint space with glucosamine treatment whilst there was a decrease in the placebo group; the differences were significant (Po0.001).20 Reviewing the literature it appears that authors have looked at the knee, focussing on medial compartment arthritis, as a clinical substrate to analyse the effects of glucosamine treatment.12,31 Natural joint space narrowing in knee OA is slow (o0.1 mm/yr in average), but can be prevented by glucosamine sulphate, which concurrently induces a significant symptom improvement.31 When individual joint-space changes were analysed, twice as many patients receiving placebo had striking joint space narrowing, than those receiving glucosamine sulphate.11 Reginster et al.12 did a randomised , placebo-controlled clinical trial on 212 patients and found that joint space narrowing was significantly less when compared to the placebo group. They reported 20–25% improvement in symptoms. The joint space narrowing difference between the placebo and the glucosamine group was found to be 0.46 mm after 3 years. Pavelka et al.13 did a similar double
R. Thakral et al. blind study on 202 patients in Czech Republic. They also found a significant difference between the two groups (P ¼ 000.1) when they analysed the joint space narrowing at 3 years follow up. Cochrane reviews have concluded that glucosamine reduces the pain caused by OA but has not shown any effects on stiffness and improvements in function. High-quality preparations of glucosamine probably reduce pain in OA. A review on the efficacy of glucosamine in alleviating pain showed a significantly larger reduction in pain in patients who received glucosamine than in those who received placebo (15 RCTs, standardised mean difference 0.61%, 95% CI 0.95–0.28).32
Side effects Oral administration of glucosamine at very large doses (5000–15,000 mg/kg body weight) is well tolerated without documented toxicity.11 The most common symptoms reported with placebo and oral glucosamine are: mild gastrointestinal symptoms including constipation, diarrhoea, nausea, dyspepsia, excessive gas, abdominal distension and abdominal cramps. Headache and skin rash or pruritis are also known to occur. Some studies have also shown side effects such as increased musculoskeletal pain, urinary tract infection, vertigo, blood pressure fluctuation and depression.12,33 Although side effects occur with the use of glucosamine, it appears to be a generally safe compound when used in patients with OA. It favourably compares with the adverse effect profiles of other drugs used in the treatment of OA, such as analgesics and NSAIDs.12,31
Conclusion Long-term follow-up studies on the effects of glucosamine preparations are still awaited. At present, only short-term results are available. They are known to relieve pain and decrease the rate of joint space narrowing clinically in osteoarthritis of knee, whilst the side effects are less when compared to the anti-inflammatory drugs and even placebos. It is probably safe – but there is no good evidence that it works.31 It would be ideal to have a medication that is a normal constituent of the human cartilage, which modifies the natural history of the disease. It is possible that long-term clinical studies with glucosamine may result in modifications to the indications for joint surgery or the time patients can live with osteoarthritis before developing substantial disability.
References 1. Hamerman D. The biology of osteoarthritis. N Engl J Med 1989; 320:1322–30. 2. Briffa J. A critical review of the use of glucosamine sulphate in the treatment of osteoarthritis. Int J Alt Comp Med 1997;15: 15–6. 3. Baker CL, Ferguson CM. Future treatment of osteoarthritis. Orthopaedics 2005;28(Supp 2):227–34.
ARTICLE IN PRESS Role of glucosamine in OA 4. Hauselmann HJ. Nutripharmaceuticals for osteoarthritis, best practice and research. Clin Rhematol 2001;15(4):595–607. 5. Phoon S, Manolios N. Glucosamine A nutraceutical in osteoarthritis. Aus Fam Physician 2002;31(6):539–41. 6. Kelly GK. The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease. Alternative Med Rev 1998;3(1):27–39. 7. Lahiji A, Sohrabi A, Hungerford DS, Frondoza CG. Chitosan supports the expression of extracellular matrix proteins in human osteoblasts and chondrocytes. J Biomed Mater Res 2000; 51(4):586–95. 8. Setnikar I, Rovati LC. Absorption, distribution, metabolism and excretion of glucosamine sulfate. Rev Arzneimittelforschung 2001;51(9):699–725. 9. Monauni T, Zenti MG, Cretti A, Daniels MC, Targher G, Caruso B, Caputo M, McClain D, Del Prato S, Giaccari A, Muggeo RC, Bonora E, Bonadonna RC. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49(6):926–35. 10. Pouwels M, Jacobs JR, Span PN, Lutterman JA, Smits P, Tack CJ. Short-term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab. 2001;86(5):2099–103. 11. Anderson JW, Nicolosi RJ, Borzelleca JF. Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem Toxicol 2005;43:187–201. 12. Regnister JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE, Gossett C. Long term effects of glucosamine sulphate on osteoarthritis progression : a randomised, placebo-controlled clinical trial. Lancet 2001;357:251–6. 13. Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulphate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162(18):2113–23. 14. Persiani S, Roda E, Rovati LC, Locatelli M, Giacovelli GP, Roda A. Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man. Osteoarthr Cartilage 2005;13:1041–9. 15. Noyszewski EA, Wroblewski K, Dodge GR, Kudchodkar S, Beers J, Sarma AV, Reddy R. Preferential incorporation of glucosamine into the galactosamine moieties of chondroitin sulfate in articular cartilage explants. Arthr Rheum 2001;44:1089–95. 16. Bassleer C, Rovati LC, Franchimont P. Stimulation of proteoglycans production by glucosamine sulphate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthr Cartilage 1998;6(6):427–34. 17. Dodge GR, Jimenez SA. Glucosamine sulfate modulates the levels of aggrecan and matrix metalloproteinase- 3 synthesized by cultured human osteoarthritis articular chondrocytes. Osteoarthr Cartilage 2003;11(6):424–32. 18. Uldry M, Ibberson M, Hosokawa M, Thorens B. GLUT2 is a high affinity glucosamine transporter. FEBS Lett 2002;524(1–3): 199–203.
389 19. Takamiya Y, Friedlander RM, Brem H, Malick A, Martuza RL. Inhibition of angiogenesis and growth of human nervesheath tumors by AGM-1470. J Neurosurg 1993;78(3):470–6. 20. Bruyere O, Pavelka K, Rovati LC, Deroisy R, Olejarova M, Gatterova J, Giacovelli G, Reginster JY. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies. Menopause 2004;11(2):134–5. 21. Sokoloff L. Osteoarthritis as a remodeling process. J Rheumatol 1987;14:7–10. 22. Owens S, Wagner P, Vangsness Jr. CT. Recent advance in glucosamine and chondritin supplementation. J Knee Surg 2004; 17(4):185–93. 23. Chan PS, Charon JP, Orth MW. Short-term gene expression changes in cartilage explants stimulated with interleukin beta plus glucosamine and chondroitin sulfate. J Rheumatol 2006; 33(7):1329–40. 24. Lippeillo L. Glucosamine and chondritin sulphate: biological response modifier of chondrocytes under simulated conditions of joint stress. Osteoarthr Cartilage 2003;11(5):335–42. 25. Qiao B, Padilla SR, Benya PD. Transforming growth factor (TGF)beta-activated kinase 1 mimics and mediates TGF-beta-induced stimulation of type II collagen synthesis in chondrocytes independent of Col2a1 transcription and Smad3 signaling. J Biol Chem 2005;280(17):17562–71. 26. Varghese S, Theprungsirikul P, Sahani S, Hwang N, Yarema KJ, Elisseeff JH. Glucosamine modulates chondrocyte proliferation, matrix synthesis, and gene expression. Osteoarthritis Cartilage 2006; July 15 (Epub ahead of print). 27. Uitterlinden EJ, Jahr H, Koevoet JA, Jemmiskens YM, BiermaZeinstra SM, Degroot J, Verhaar JA, Weinans H, van Osch GJ. Glucosamine decreases expression of anabolic and catabolic genes in human osteoarthritic cartilage explants. Osteoarthr Cartilage 2006;14(3):250–7. 28. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. J Am Med Associat 2000; 283(11):1469–75. 29. Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensivemeta-analysis. Arch Intern Med 2003;163(13):1514–22. 30. Towheed TE, Maxwell L, Anastassiaides TP, Shea B, Houpt J, Robinson V, Hochberg MC, Wells G. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005;18(2): CD002946. 31. Chard J, Dippe P. Glucosamine for osteoarthritis: magic, hype, or confusion? Bri Med J 2001;322:1439–40. 32. Bazian Ltd. Glucosamine for osteoarthritis. Evidence-based Healthcare Pub Health 2005;9:322–31. 33. Hughes R, Carr A. A randomised, double-blind, placebo controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatomlogy 2002;41:279–84.
Available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/cuor
THERAPEUTICS
Role of glucosamine in osteoarthritis R. Thakrala, U.K. Debnathb,, C. Dentc a
Department of Trauma and Orthopaedics, Adelaide and Meath Hospital Incorporating National Children’s Hospital, Tallaght, Dublin-24, Ireland b Department of Trauma and Orthopaedics, University Hospital Cardiff, Cardiff CF14 4XW Wales, UK c Department of Orthopaedics, University Hospital Cardiff, Cardiff CF14 4XW Wales, UK
KEYWORDS Glucosamine; Action; Cartilage; Arthritis
Summary Long-term follow-up studies on the effects of glucosamine preparations are still awaited. At present, only short-term results are available. They are known to relieve pain and decrease the rate of joint space narrowing clinically in osteoarthritis of knee, whilst the side effects are less when compared to the anti-inflammatory drugs and even placebos. It is probably safe – but there is no good evidence that it works. It would be ideal to have a medication that is a normal constituent of the human cartilage, which modifies the natural history of the disease. It is possible that long-term clinical studies with glucosamine may result in modifications to the indications for joint surgery or the time patients can live with osteoarthritis before developing substantial disability. & 2007 Published by Elsevier Ltd.
Introduction Glucosamine sulphate is a normal constituent of the extracellular matrix of mammalian articular cartilage and synovial fluid, which is required for synthesis of glycosaminoglycans (GAGSs).1 It also helps in synthesising mucin or mucous secretions, which act as lubricant or protective agents in human joints. In 1956, Lennart Roden from Stockholm first showed glucosamine HCL-stimulated production of chondroitin sulphate in cartilage matrix by at least three times its control value. It was not until the 1980s that clinical trials of
glucosamine as a therapeutic drug for osteoarthritis (OA) of knee began. Now, it is readily available for purchase from health/food shops and pharmacies in the UK, USA and throughout Europe, for the relief of musculoskeletal symptoms.2,3 The range of products that includes chondroitin sulphate, vitamins C, D and E, minerals and herbs, as well the oligoelements (such as zinc, selenium, manganese and copper) are together called nutripharmaceuticals.4 Glucosamine has gained popularity in the last two decades for the treatment of OA.5
Glucosamine and its properties Corresponding author. Present address: 23, Barons Court Road,
Cardiff CF23 9DF, UK. Tel.: +078 1116 5794. E-mail address: [email protected] (U.K. Debnath). 0268-0890/$ - see front matter & 2007 Published by Elsevier Ltd. doi:10.1016/j.cuor.2007.04.002
Glucosamine is an amino monosaccharide found in chitin, glycoproteins and in GAGSs (formerly known as mucopolysaccharides), such as hyaluronic acid and heparan sulphate.
ARTICLE IN PRESS Role of glucosamine in OA
387
CH:CH O H
H H CH
H
H
NH3+
HO
OH
2 Figure 1 Chemical structure of glucosamine.
It is the basic building block of the amino sugars and hence is an important constituent of the cell wall and interstitial proteins.6 The chemical structure of glucosamine is shown in Fig. 1. Glucosamine (2-amino-2-deoxyalpha-D-glucose) is one of the two hexosamine sugars (six carbon amino sugars) common in human cells. Structurally, glucosamine is modified glucose, with an –NH3 group replacing the –OH group found on carbon two (C-2). G6-P is an amino monosaccharide (amino sugar) produced in the body by the combination of glutamine with fructose, through the enzymatic action of glucosamine synthetase.6 Glucosamine is available commercially as a nutritional supplement in three forms: glucosamine HCl, glucosamine sulphate and N-acetyl-glucosamine. All three forms are water soluble, the salt acting as a delivery vehicle. At neutral and physiological pH, the amino group in glucosamine is protonated, resulting in a positive charge. Salt forms of glucosamine contain negative anions to neutralise the charge. In the case of glucosamine hydrochloride, the anion is chloride, and in glucosamine sulphate the anion is sulphate. N-acetylglucosamine is a delivery form of glucosamine in which the amino group is acetylated, thus neutralising its charge. To date, most of the clinical studies examining the effect of glucosamine on OA have been performed with either the sulphate or the chloride salts of glucosamine. The glucosamine used in supplements is typically derived from marine exoskeletons.7 Synthetic glucosamine is also available.
Pharmacokinetics 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.8 Healthy men have serum glucosamine concentrations of 0.04 mmol/L when they are not consuming supplemental glucosamine.9,10 Ingestion of recommended oral doses of glucosamine in humans achieves serum levels of approximately 0.06 mmol/L.11 It is not presently known how much of an ingested dose is taken up in the joints in humans. Most relevant clinical trials have used patented crystalline glucosamine sulphate in 1500 mg, once a day, soluble powder form.12,13 This is a prescription drug in most European and
non-European countries. However, the Dietary Supplement Health and Education Act of 1994 favoured the appearance of several undocumented glucosamine salts (e.g. hydrochloride), derivatives (e.g., N-acetyl-glucosamine) on the dietary supplement market in the USA and other countries, and various other dosage forms and regimens.14 Persiani et al.14 studied the pharmacokinetics of glucosamine and found that it is bioavailable after oral administration of crystalline glucosamine sulphate. This persists in circulation, and its pharmacokinetics support once-daily dosage. Steady-state peak concentrations after a therapeutic oral dose of 1500 mg show bioavailability at concentrations that are in line with those found to be effective in selected in vitro models, which may explain the favourable clinical results in OA.
Mechanism of action of glucosamine in human tissues Glucosamine is preferentially incorporated by chondrocytes into the components of the GAG chains in intact cartilage and stimulates the synthesis of physiological proteolglycans. It also decreases the activity of catabolic enzymes, including matrix metalloproteases (MMP).15-17 In certain tissues, glucosamine has a higher affinity for glucose transporters than glucose itself and is incorporated into glycoproteins faster than glucose.18 It also inhibits the degradation of equine articular cartilage induced by interleukin 1 and lipopolysaccaharides.19 This supports the suggestion that exogenous glucosamine acts mainly as a substrate for biosynthesis of mucopolysaccharides and biopolymers of joints and bones and, thus, contributes to restoration of damaged cartilage.8,20
Articular cartilage in OA of the knee The degenerative disease OA is a manifestation of an imbalanced synthesis of articular cartilage (AC) matrix and the associated growth factors.21 Knee cartilage defects, for example, may result in an increased rate of cartilage breakdown, leading to decreased cartilage volume and joint space narrowing. OA represents loss of homeostasis in the normal maintenance of articular cartilage by the degradation and synthesis of the matrix components. The inciting mechanisms are not fully understood, although the aetiology seems multifactorial.22 The end pathway is an imbalance between proteinases, which break down the matrix constituents, and proteinase inhibitors.
The role of glucosamine in OA of the knee The long-term combined structure-modifying and symptommodifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in OA.12 Besides synthesis of GAGs, it also exerts an anti-catabolic effect on AC by inhibiting the anti-inflammatory responses.23 The theory of synthesis of GAGs does not, however, explain the observed glucosamine mediated increase in collagen type II. The literature shows a positive effect of
ARTICLE IN PRESS 388 glucosamine on GAG production in human chondrocytes in cell culture, and the same anabolic effect is found in bovine and rat explants.16–18 TGF-b is considered to be a multifaceted cytokine that plays key roles in many downstream effects, such as mesenchymal differentiation, matrix production, stimulation of chondrocytes and controlled differentiation of stem cells.24,25 In adults, TGF-b’s are also believed to maintain a critical balance between the various anabolic and catabolic functions of chondrocytes for proper functioning of the cartilage. Varghese et al.26 provide evidence that glucosamine mediated increase in the production of specific matrix components involves TGF-b1 up-regulation, possibly through the hexosamine pathway in optimal concentrations of glucosamine. The effect of glucosamine on chondrocytes was found to be dependent upon the culture conditions. Is there an effect on gene expression, in both anabolic and catabolic activities of chondrocytes, in response to glucosamine treatment in the human OA explant model? Another study added a pre-culture experimental agent to human cartilage harvested during knee arthroplasty procedures. To this model, they added different concentration of glucosamine. They found that glucosamine (5 mM) addition to a human OA explant reduced the enzymatic breakdown of the cellular matrix.27 The authors of this study also suggested that chondroprotective properties of the glucosamine in vivo may be based on inhibiting further degradation due to catabolic activities, rather than on the ability to rebuild cartilage.28
Glucosamine in clinical practise Three rigorous meta-analyses show that individuals with OA of the knee or spine have significantly less symptoms while taking glucosamine than those taking placebo.29–31 McAlindon et al.28 conclude that glucosamine is moderately efficacious for the relief of symptoms of OA. Richy et al. conclude that glucosamine has highly significant effects on all aspects of knee OA.32 A recent randomized clinical trial included 414 post menopausal women followed for 3 years. The authors documented no decrease in joint space with glucosamine treatment whilst there was a decrease in the placebo group; the differences were significant (Po0.001).20 Reviewing the literature it appears that authors have looked at the knee, focussing on medial compartment arthritis, as a clinical substrate to analyse the effects of glucosamine treatment.12,31 Natural joint space narrowing in knee OA is slow (o0.1 mm/yr in average), but can be prevented by glucosamine sulphate, which concurrently induces a significant symptom improvement.31 When individual joint-space changes were analysed, twice as many patients receiving placebo had striking joint space narrowing, than those receiving glucosamine sulphate.11 Reginster et al.12 did a randomised , placebo-controlled clinical trial on 212 patients and found that joint space narrowing was significantly less when compared to the placebo group. They reported 20–25% improvement in symptoms. The joint space narrowing difference between the placebo and the glucosamine group was found to be 0.46 mm after 3 years. Pavelka et al.13 did a similar double
R. Thakral et al. blind study on 202 patients in Czech Republic. They also found a significant difference between the two groups (P ¼ 000.1) when they analysed the joint space narrowing at 3 years follow up. Cochrane reviews have concluded that glucosamine reduces the pain caused by OA but has not shown any effects on stiffness and improvements in function. High-quality preparations of glucosamine probably reduce pain in OA. A review on the efficacy of glucosamine in alleviating pain showed a significantly larger reduction in pain in patients who received glucosamine than in those who received placebo (15 RCTs, standardised mean difference 0.61%, 95% CI 0.95–0.28).32
Side effects Oral administration of glucosamine at very large doses (5000–15,000 mg/kg body weight) is well tolerated without documented toxicity.11 The most common symptoms reported with placebo and oral glucosamine are: mild gastrointestinal symptoms including constipation, diarrhoea, nausea, dyspepsia, excessive gas, abdominal distension and abdominal cramps. Headache and skin rash or pruritis are also known to occur. Some studies have also shown side effects such as increased musculoskeletal pain, urinary tract infection, vertigo, blood pressure fluctuation and depression.12,33 Although side effects occur with the use of glucosamine, it appears to be a generally safe compound when used in patients with OA. It favourably compares with the adverse effect profiles of other drugs used in the treatment of OA, such as analgesics and NSAIDs.12,31
Conclusion Long-term follow-up studies on the effects of glucosamine preparations are still awaited. At present, only short-term results are available. They are known to relieve pain and decrease the rate of joint space narrowing clinically in osteoarthritis of knee, whilst the side effects are less when compared to the anti-inflammatory drugs and even placebos. It is probably safe – but there is no good evidence that it works.31 It would be ideal to have a medication that is a normal constituent of the human cartilage, which modifies the natural history of the disease. It is possible that long-term clinical studies with glucosamine may result in modifications to the indications for joint surgery or the time patients can live with osteoarthritis before developing substantial disability.
References 1. Hamerman D. The biology of osteoarthritis. N Engl J Med 1989; 320:1322–30. 2. Briffa J. A critical review of the use of glucosamine sulphate in the treatment of osteoarthritis. Int J Alt Comp Med 1997;15: 15–6. 3. Baker CL, Ferguson CM. Future treatment of osteoarthritis. Orthopaedics 2005;28(Supp 2):227–34.
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