Glucosamine

• How It Works

  Conclusive evidence is lacking to support the effectiveness of glucosamine against arthritis.

  Cartilage is composed of collagen, elastin, and sugar-protein molecules, that make it gel-like, resilient, and act as a shock absorber. Osteoarthritis is characterized by progressive cartilage degeneration. Glucosamine may help with formation of the sugar-protein molecules, which would slow the degeneration of cartilage. However, clinical trials yielded mixed results. Glucosamine may reduce inflammation and protect cartilage from damage caused by NSAIDs and corticosteroids, but additional studies are needed. In addition, the American College of Rheumatology (ACR) conditionally recommends that patients avoid glucosamine for osteoarthritis.

• Purported Uses
  • To reduce inflammation
    Glucosamine may reduce inflammation in a way that is different from non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen.
  • To prevent osteoarthritis and treat disease progression
    Several clinical trials of glucosamine alone and in combination with chondroitin sulfate yielded mixed results. The differences in availability of formulas may also contribute to the lack of significant effect across studies and pooled analyses.
  • To treat temporomandibular joint disorder (TMJ)
    There is limited evidence to suggest glucosamine may be help for TMJ symptoms. Additional studies are needed.
• Patient Warnings
  • Patients with liver disease should avoid taking glucosamine, as there are case reports of liver injury/toxicity.
  • Patients who are taking blood-thinners or who have glaucoma or diabetes should tell their healthcare professionals if they are taking glucosamine. There is some preliminary evidence for potential side effects and related monitoring needs should be discussed.
• Do Not Take If
  • You are allergic to shellfish: Some glucosamine products are derived from chitin, the exoskeleton on shellfish. Ask your doctor if you might have an adverse reaction to glucosamine.
  • You have liver disease: There are several case reports of liver injury/toxicity in patients with liver disease.
• Side Effects

  Glucosamine tends to be safe and well tolerated, but caution should be exercised in certain populations (see Warnings and Interactions). Rare reactions include gastrointestinal complaints and allergic reactions.

  Case Reports

  • Kidney problems: In a 67-year-old patient with long-term use of glucosamine.
  • Increased warfarin effects or INR levels (related to blood-thinning medication monitoring): Occurred with glucosamine-chondroitin; lab tests returned to normal levels when glucosamine was discontinued.
  • Liver injury/toxicity and elevated lab values: In patients with liver disease.
  • Increased fluid pressure inside the eye: In older patients with osteoarthritis who took glucosamine supplements in a study. The meaning of this finding needs further evaluation.
  • Reduced glucose tolerance: From infusion and oral forms of glucosamine.
• Special Point
  • Glucosamine may have a limited effect, more likely in older patients who have arthritis that is more severe or when used for longer periods of time.
  • Glucosamine may take longer to act than NSAIDs, but once it does, its effects may last longer after treatment is stopped.
  • Although European treatment guidelines recommend a prescription formulation, this product is not available in the US and other guidelines generally do not recommend glucosamine for OA conditions.
  • Glucosamine has not been found effective in relieving back pain.
• Scientific Name

  2-Amino-2-deoxyglucose

• Clinical Summary

  Glucosamine is an endogenous aminomonosaccharide synthesized from glucose. Found in mucopolysaccharides, mucoproteins and chitin, a cellulose-like biopolymer in marine invertebrate exoskeletons, it is used in the biosynthesis of proteoglycans and glycosaminoglycans, which are sugar-protein molecules found in cartilage. Glucosamine has anti-inflammatory activity, and is marketed as a dietary supplement and often paired with chondroitin sulfate for joint health.

  Glucosamine has been mostly studied for osteoarthritis (OA) conditions. Although glucosamine/chondroitin supplementation was comparable to celecoxib in a large multicenter trial of patients with severe knee OA pain ⁽²⁾, other studies have not found benefit with glucosamine, chondroitin, or the combination for knee or hip OA ^{(3) (4) (5) (6) (7) (8) (9) (10)}. Data on chondroitin alone also suggest no significant benefit ^(10) (11). In addition, no efficacy was seen with glucosamine in relieving back pain ^(12) (13), degenerative lumbar OA ⁽¹³⁾, or improving glucose metabolism in type 2 diabetes ⁽¹⁴⁾. Any benefits with glucosamine may be limited to older patients who have arthritis that is more severe ⁽¹⁵⁾ or for longer periods of time ⁽¹⁶⁾.

  Meta-analyses of glucosamine trials are also somewhat mixed ^{(35) (36) (37) (38) (39)}. The American College of Rheumatology (ACR) conditionally recommends that patients avoid glucosamine for osteoarthritis ⁽⁴⁵⁾. In contrast, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment guidelines recommends a prescription glucosamine formulation as being superior to other forms, but this product is not available in the US  ⁽⁴⁰⁾. It is further suggested that these differences in availability and formulas have contributed to the lack of significant effect across studies and pooled analyses ⁽⁴⁶⁾.

  Studies on whether glucosamine can improve temporomandibular joint (TMJ) symptoms are limited and generally provide only low evidence of this effect ^(1) (41), although one study of oral glucosamine adjunctive to hyaluronic acid injection suggests long-term benefit ⁽⁴²⁾.

  Epidemiological studies suggest potential reduction for some cancer risks and mortality with long-term glucosamine/chondroitin supplementation, although limitations such as bias could not be ruled out and confirmatory studies are needed ^{(17) (18) (19)}.

  There are case reports of liver injury/toxicity related to glucosamine consumption ^(20) (21). Patients on antiplatelet or anticoagulant therapies should be monitored for interactions or increased INR levels ^(22) (23). Patients with poorly controlled diabetes or glucose intolerance should be monitored as glucosamine could worsen insulin resistance ^(24) (25).

• Purported Uses
  • Inflammation
  • Osteoarthritis
  • Temporomandibular joint disorder (TMJ)
• Mechanism of Action

  Progressive degeneration of cartilage glycosaminoglycans is evident in osteoarthritis. Glucosamine is the first step in glycosaminoglycan biosynthesis. In vitro, it increased production of monomeric proteoglycans capable of assembling into high molecular weight aggregates ⁽²⁶⁾. Glucosamine can protect cartilage from metabolic impairment by NSAIDs, corticosteroids, and by exerting anti-inflammatory effects ⁽²⁷⁾. It may promote cartilage repair by inducing tissue TGFβ1 and CTGF expression that regulates chondrocyte proliferation ⁽²⁸⁾. Long-term reductions in TMJ symptoms with adjunctive oral glucosamine may be due to TGF-beta stimulation and IL-1beta / IL-6 suppression ⁽⁴²⁾. Reduced systemic inflammation and cytokine activity found in a small randomized crossover study may explain potential reductions in mortality or cancer risk ⁽³⁰⁾.

  Although glucosamine is slow to act ⁽³¹⁾, its effects may persist after treatment cessation ⁽²⁶⁾.

  The rise in intraocular pressure associated with older patients in one study may relate to exogenous glycosaminoglycans effects on accumulations of extracellular matrix and thickening of the basement membrane, thereby compromising function of the trabecular meshwork ⁽²⁹⁾.

• Warnings
  • Patients with liver disease should avoid taking glucosamine, as it is extensively metabolized in the liver and there are case reports of liver injury/toxicity ^(20) (21).
  • Patients who are taking anticoagulants or antiplatelet drugs or who have glaucoma or diabetes should be monitored, as there is some preliminary evidence for potential side effects ^{(22) (23) (24) (25) (29)}.
  • Individuals should consult their doctor if allergic to shellfish ⁽³²⁾.
• Adverse Reactions

  Glucosamine tends to be safe and well tolerated ⁽⁴³⁾, but caution should be exercised in certain populations (see Warnings and Interactions).

  Rare reactions include gastrointestinal complaints ^(33) (41) and allergic reactions ⁽²⁰⁾.

  Case Reports
  Chronic tubulointerstitial nephropathy: In a 67-year-old patient who took glucosamine daily for 3 years for OA knee pain ⁽⁴⁴⁾.
  Increased intraocular pressure: In a randomized double-blind trial, glucosamine sulfate supplementation significantly increased intraocular pressure in older patients with OA ⁽²⁹⁾. The implication of this finding needs further evaluation.
  Liver injury/hepatotoxicity and elevated aminotransferase values: In patients with liver disease ^(20) (21).
  Reduced glucose tolerance: From infusion and oral forms of glucosamine ⁽³⁴⁾.

• Herb-Drug Interactions
  • Warfarin: Although more information is needed to define this interaction, glucosamine-chondroitin may potentiate warfarin effects and increase INR levels ⁽²²⁾.
  • Anticoagulants/Antiplatelets: Use of glucosamine may inhibit platelet aggregation ⁽²³⁾.
• Herb Lab Interactions
  • Blood glucose levels: May be affected by glucosamine ⁽³⁴⁾.
  • Increased International Normalized Ratio (INR): Glucosamine was associated with increased INR that return to normal levels when discontinued ⁽²²⁾.
  • Elevated aminotransferase values: In patients with liver disease ⁽²⁰⁾.
• References

  1. Nguyen P, Mohamed SE, Gardiner D, et al. A randomized double-blind clinical trial of the effect of chondroitin sulfate and glucosamine hydrochloride on temporomandibular joint disorders: a pilot study. Cranio. Apr 2001;19(2):130-139.

  2. Hochberg MC, Martel-Pelletier J, Monfort J, et al. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis. Jan 2016;75(1):37-44.

  3. Roman-Blas JA, Castaneda S, Sanchez-Pernaute O, et al. Combined Treatment With Chondroitin Sulfate and Glucosamine Sulfate Shows No Superiority Over Placebo for Reduction of Joint Pain and Functional Impairment in Patients With Knee Osteoarthritis: A Six-Month Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Arthritis Rheumatol. Jan 2017;69(1):77-85.

  4. Fransen M, Agaliotis M, Nairn L, et al. Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens. Ann Rheum Dis. May 2015;74(5):851-858.

  5. Kwoh CK, Roemer FW, Hannon MJ, et al. Effect of oral glucosamine on joint structure in individuals with chronic knee pain: a randomized, placebo-controlled clinical trial. Arthritis Rheumatol. Apr 2014;66(4):930-939.

  6. Cibere J, Kopec JA, Thorne A, et al. Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Rheum. Oct 15 2004;51(5):738-745.

  7. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. Feb 23 2006;354(8):795-808.

  8. Herrero-Beaumont G, Ivorra JA, Del Carmen Trabado M, et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis Rheum. Feb 2007;56(2):555-567.

  9. Sawitzke AD, Shi H, Finco MF, et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum. Oct 2008;58(10):3183-3191.

  10. Wandel S, Juni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ. Sep 16 2010;341:c4675.

  11. Reichenbach S, Sterchi R, Scherer M, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med. Apr 17 2007;146(8):580-590.

  12. Leffler CT, Philippi AF, Leffler SG, et al. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med. Feb 1999;164(2):85-91.

  13. Wilkens P, Scheel IB, Grundnes O, et al. Effect of glucosamine on pain-related disability in patients with chronic low back pain and degenerative lumbar osteoarthritis: a randomized controlled trial. JAMA. Jul 7 2010;304(1):45-52.

  14. Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med. Jul 14 2003;163(13):1587-1590.

  15. Hughes R, Carr A. A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology (Oxford). Mar 2002;41(3):279-284.

  16. Rindone JP, Hiller D, Collacott E, et al. Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee. West J Med. Feb 2000;172(2):91-94.

  17. Bell GA, Kantor ED, Lampe JW, et al. Use of glucosamine and chondroitin in relation to mortality. Eur J Epidemiol. Aug 2012;27(8):593-603.

  18. Pocobelli G, Kristal AR, Patterson RE, et al. Total mortality risk in relation to use of less-common dietary supplements. Am J Clin Nutr. Jun 2010;91(6):1791-1800.

  19. Satia JA, Littman A, Slatore CG, et al. Associations of herbal and specialty supplements with lung and colorectal cancer risk in the VITamins and Lifestyle study. Cancer Epidemiol Biomarkers Prev. May 2009;18(5):1419-1428.

  20. Cerda C, Bruguera M, Pares A. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease. World J Gastroenterol. Aug 28 2013;19(32):5381-5384.

  21. Smith A, Dillon J. Acute liver injury associated with the use of herbal preparations containing glucosamine: three case studies. BMJ Case Rep. 2009;2009.

  22. Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and MedWatch database. Pharmacotherapy. Apr 2008;28(4):540-548.

  23. Lin PC, Jones SO, McGlasson DL. Effects of glucosamine and Celadrin on platelet function. Clin Lab Sci. Winter 2010;23(1):32-36.

  24. Marshall PD, Poddar S, Tweed EM, et al. Clinical inquiries: Do glucosamine and chondroitin worsen blood sugar control in diabetes? J Fam Pract. Dec 2006;55(12):1091-1093.

  25. Pham T, Cornea A, Blick KE, et al. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci. Jun 2007;333(6):333-339.

  26. Bassleer C, Rovati L, Franchimont P. Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage. Nov 1998;6(6):427-434.

  27. Runkel DR, Cupp MJ. Glucosamine sulfate use in osteoarthritis. Am J Health Syst Pharm. Feb 1 1999;56(3):267-269.

  28. Ali AA, Lewis SM, Badgley HL, et al. Oral glucosamine increases expression of transforming growth factor beta1 (TGFbeta1) and connective tissue growth factor (CTGF) mRNA in rat cartilage and kidney: implications for human efficacy and toxicity. Arch Biochem Biophys. Jun 1 2011;510(1):11-18.

  29. Esfandiari H, Pakravan M, Zakeri Z, et al. Effect of glucosamine on intraocular pressure: a randomized clinical trial. Eye (Lond). Mar 2017;31(3):389-394.

  30. Navarro SL, White E, Kantor ED, et al. Randomized trial of glucosamine and chondroitin supplementation on inflammation and oxidative stress biomarkers and plasma proteomics profiles in healthy humans. PLoS One. 2015;10(2):e0117534.

  31. Muller-Fassbender H, Bach GL, Haase W, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage. Mar 1994;2(1):61-69.

  32. Dahmer S, Schiller RM. Glucosamine. Am Fam Physician. Aug 15 2008;78(4):471-476.

  33. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. Apr 18 2005(2):Cd002946.

  34. Monauni T, Zenti MG, Cretti A, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes. Jun 2000;49(6):926-935.

  35. Gregori D, Giacovelli G, Minto C, et al. Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis. JAMA. Dec 25 2018;320(24):2564-2579.

  36. Liu X, Machado GC, Eyles JP, et al. Dietary supplements for treating osteoarthritis: a systematic review and meta-analysis. Br J Sports Med. Feb 2018;52(3):167-175.

  37. Ogata T, Ideno Y, Akai M, et al. Effects of glucosamine in patients with osteoarthritis of the knee: a systematic review and meta-analysis. Clin Rheumatol. Sep 2018;37(9):2479-2487.

  38. Zhu X, Sang L, Wu D, et al. Effectiveness and safety of glucosamine and chondroitin for the treatment of osteoarthritis: a meta-analysis of randomized controlled trials. J Orthop Surg Res. Jul 6 2018;13(1):170.

  39. Simental-Mendia M, Sanchez-Garcia A, Vilchez-Cavazos F, et al. Effect of glucosamine and chondroitin sulfate in symptomatic knee osteoarthritis: a systematic review and meta-analysis of randomized placebo-controlled trials. Rheumatol Int. Aug 2018;38(8):1413-1428.

  40. Bruyere O, Altman RD, Reginster JY. Efficacy and safety of glucosamine sulfate in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin Arthritis Rheum. Feb 2016;45(4 Suppl):S12-17.

  41. Melo G, Casett E, Stuginski-Barbosa J, et al. Effects of glucosamine supplements on painful temporomandibular joint osteoarthritis: A systematic review. J Oral Rehabil. May 2018;45(5):414-422.

  42. Cen X, Liu Y, Wang S, et al. Glucosamine oral administration as an adjunct to hyaluronic acid injection in treating temporomandibular joint osteoarthritis. Oral Dis. Apr 2018;24(3):404-411.

  43. Honvo G, Reginster JY, Rabenda V, et al. Safety of Symptomatic Slow-Acting Drugs for Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. Drugs Aging. Apr 2019;36(Suppl 1):65-99.

  44. Gueye S, Saint-Cricq M, Coulibaly M, et al. Chronic tubulointerstitial nephropathy induced by glucosamine: a case report and literature review. Clin Nephrol. Aug 2016;86(2):106-110.

  45. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). Apr 2012;64(4):465-474. Full article available at https://www.aafp.org/afp/2013/0401/p515.html and https://www.aafp.org/afp/2013/0401/p515.pdf.

  46. Reginster JY, Cooper C, Hochberg M, et al. Comments on the discordant recommendations for the use of symptomatic slow-acting drugs in knee osteoarthritis. Curr Med Res Opin. May 2015;31(5):1041-1045.