We cannot recommend using glucosamine and chondroitin for patients with symptomatic osteoarthritis of the knee.

Twenty-one studies were included as evidence for this recommendation; all were prospective. Twelve focused on glucosamine alone, eight on chondroitin sulfate alone, and one (Clegg et. al86) assessed both. Sixteen were of moderate-strength and five were of high-strength.
Among the studies, eleven of 52 outcomes were statistically significant in favor of glucosamine when compared to placebo. WOMAC pain and function subscales scores and VAS pain were the critical outcomes and were not associated with statistical significance at any treatment duration period. When meta-analyses were run for WOMAC pain, function, stiffness and total subscale scores, all meta-analyses showed that the overall effect of glucosamine compared to placebo was not statistically significant.
Two studies compared glucosamine to active treatments. Glucosamine was compared to reparagen87 (a poly-herbal supplement), and enzymatic hydrolyzed collagen.88  Glucosamine was found to have no significant effect on pain compared to these treatments.
Figure 31 presents the meta-analysis results comparing chondroitin sulfate to placebo in pain scores on the VAS. The weighted mean difference revealed that scores were 11.89 points lower in the chondroitin group than in the placebo group. However, the difference was not clinically important.
At this time, both glucosamine and chondroitin sulfate have been extensively studied. Despite the availability of the literature, there is essentially no evidence that minimum clinically important outcomes have been achieved compared to placebo, whether evaluated alone or in combination. The strength of the recommendation is based on lack of efficacy, not on potential harm.
One of our search terms was neutraceuticals and we initially maintained a broad focus. However, the original guidance was to evaluate methylsulfonylmethane, omega-3, gelatin, vitamin D, dimethylsulfoxide, antioxidants, and coenzyme Q10. The general term was intended to guide the search of the specific terms. Additionally, the evidence for neutraceuticals was variable and could not be easily summarized. Two moderate-strength studies89;90comparing ginger extract to placebo arose in the included evidence.  The only improvement in pain associated with both statistical significance and clinical importance was measured using WOMAC stiffness. Clinical importance could not be determined for four other pain measures, or they did not meet the minimum clinically important improvement threshold. The findings on outcomes of function were contradictory and low in count, which rendered them inconclusive. Glycosaminoglycan polysulfuric acid (GAGPS)91 produced a true negative finding statistically and clinically, and gubitong was associated with higher WOMAC total scores than glucosamine in a non-control matched study where clinical importance could not be determined.
  1. (41) Meunier PJ, Sebert JL, Reginster JY et al. Fluoride salts are no better at preventing new vertebral fractures than calcium-vitamin D in postmenopausal osteoporosis: the FAVOStudy. Osteoporos Int 1998;8(1):4-12.
  2. (86) Clegg DO, Reda DJ, Harris CL et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354(8):795-808. PM:16495392
  3. (87) Mehta K, Gala J, Bhasale S et al. Comparison of glucosamine sulfate and a polyherbal supplement for the relief of osteoarthritis of the knee: a randomized controlled trial [ISRCTN25438351]. BMC Complement Altern Med 2007;7):34. PM:17974032
  4. (88) Trc T, Bohmova J. Efficacy and tolerance of enzymatic hydrolysed collagen (EHC) vs. glucosamine sulphate (GS) in the treatment of knee osteoarthritis (KOA). Int Orthop 2010. PM:20401752
  5. (89) Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum 2001;44(11):2531-2538. PM:11710709
  6. (90) Zakeri Z, Izadi S, Bari Z, Soltani F, Narouie B, Ghasemi-Rad M. Evaluating the effects of ginger extract on knee pain, stiffness and difficulty in patients with knee osteoarthritis. Journal of Medicinal Plant Research 2011;5(15):3375-3379.
  7. (91) Pavelka K, Jr., Sedlackova M, Gatterova J, Becvar R, Pavelka K, Sr. Glycosaminoglycan polysulfuric acid (GAGPS) in osteoarthritis of the knee. Osteoarthritis Cartilage 1995;3(1):15-23. PM:7536623
  8. (92) Cibere J, Kopec JA, Thorne A et al. Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Rheum 2004;51(5):738-745. PM:15478160
  9. (93) Mazieres B, Combe B, Phan VA, Tondut J, Grynfeltt M. Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study. J Rheumatol 2001;28(1):173-181. PM:11196521
  10. (94) Pavelka K, Coste P, Geher P, Krejci G. Efficacy and safety of piascledine 300 versus chondroitin sulfate in a 6 months treatment plus 2 months observation in patients with osteoarthritis of the knee. Clin Rheumatol 2010;29(6):659-670. PM:20179981
  11. Bourgeois P,Chales G,Dehais J,Delcambre B,Kuntz JL,Rozenberg S. Efficacy and tolerability of chondroitin sulfate 1200mg/day versus chondroitin sulfate 3 x 400 mg/day versus placebo. Osteoarthritis Cartilage 1998;6 Suppl A:25-30.
  12. Bucsi L,Poor G. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Osteoarthritis Cartilage 1998;6 Suppl A:31-36.
  13. Das A,Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000;8(5):343-350.
  14. Houpt JB,McMillan R,Wein C,Paget-Dellio SD. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol 1999;26(11):2423-2430.
  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) 2002;41(3):279-284.
  16. Kahan A,Uebelhart D,De VF,Delmas PD,Reginster JY. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2009;60(2):524-533.
  17. McAlindon T,Formica M,Lavalley M,Lehmer M,Kabbara K. Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an internet-based randomized double-blind controlled trial. Am J Med 2004;117(9):643-649.
  18. Moller I,Perez M,Monfort J,Benito P,Cuevas J,Perna C,Domenech G,Herrero M,Montell E,Verges J. Effectiveness of chondroitin sulphate in patients with concomitant knee osteoarthritis and psoriasis: a randomized, double-blind, placebo-controlled study. Osteoarthritis Cartilage 2010.
  19. Noack W,Fischer M,Forster KK,Rovati LC,Setnikar I. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2(1):51-59.
  20. Pavelka K,Gatterova J,Olejarova M,Machacek S,Giacovelli G,Rovati LC. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162(18):2113-2123.
  21. Rai J,Pal SK,Gul A,Senthil R,Singh H. Efficacy of chondroitin sulfate and glucosamine sulfate in the progression of symptomatic knee osteoarthritis: A randomized, placebo-controlled, double blind study. Bulletin, Postgraduate Institute of Medical Education and Research, Chandigarh 2004;38(1):18-22.
  22. Reginster 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(9252):251-256.
  23. Rindone JP,Hiller D,Collacott E,Nordhaugen N,Arriola G. Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee. West J Med 2000;172(2):91-94.
  24. Uebelhart D,Malaise M,Marcolongo R,De VF,Piperno M,Mailleux E,Fioravanti A,Matoso L,Vignon E. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage 2004;12(4):269-276.