The effects of Glucosamine Sulphate on OA of the knee joint

Date First Published:
June 28, 2005
Last Updated:
May 8, 2008
Report by:
Michael Callaghan, Research Physiotherapist (Manchester Royal Infirmary)
Search checked by:
Stephanie Pye, Manchester Royal Infirmary
Three-Part Question:
In [adults with OA of the knee] do [Glucosamine Sulphate tablets] improve [Pain and Function]
Clinical Scenario:
A middle aged lady is receiving physiotherapy for her OA knee. She mentions that her husband has heard that Glucosamine tablets are great for arthritis and is thinking of buying some from a health-food shop. She asks what you think about them. Before imparting wise words, you decide to check the evidence first.
Search Strategy:
MEDLINE 1966-01/08, CINAHL 1982-01/08, AMED 1985-01/08, SPORTDiscus 1830-01/08, EMBASE 1996-01/08, via the OVID interface. In addition, the Cochrane database and PEDro database were also searched in January 2008.
Search Details:
Medline, CINAHL, AMED, EMBASE, SPORTSDiscus: [{(exp.glucosamine OR glucosamine sulphate.mp OR glucosamine sulfate.mp) AND (exp.arthritis OR exp.osteoarthritis OR arthropathy.mp OR osteoarthrosis.mp OR gonarthritis.mp) AND (exp knee OR exp knee joint)}] LIMIT to human AND English language.
Outcome:
The search retrieved a Cochrane review last substantially amended in February 2005. There were two systematic reviews, one with a meta-analysis studying heterogeneity in trials and another that analysed the long-term effect on disease progression but not clinical efficacy. There were three other randomised controlled trials (RCT) published since but not included in the Cochrane. There was another RCT in which data collection finished in March 2006 but it has not published full results.
Relevant Paper(s):
Study Title Patient Group Study type (level of evidence) Outcomes Key results Study Weaknesses
Glucosamine therapy for treating osteoarthritis Towheed ML, Anastassiades,T, Shea B, Houpt J, Robinson V, Hochberg M, Wells,G 2005 Uk 20 RCTs
19 published
1 unpublished
English Lang.
N = 2570		 Cochrane review
Level 1		 Pain GS v placebo. 15 RCTs. Moderate Effect size 0.61: 28% improvement from baseline in favour of GS. GS v NSAIDs. Small Effect size –0.24 In favour of GS 65% of RCTs in review used GS preparation by Rotta Pharmaceutical Co. for EU. Other preparations may not be as pure & so skew RCT results.
Function GS v placebo (Lequesne Index) Moderate Effect size 0.51. 21% improvement from baseline in favour of GS. (WOMAC) Effect size –0.15 NSS. GS v NSAIDs: (Lequesne Index) effect size –0.36 NSS.
XRay changes 2 studies: Effect size 0.24. GS slows rate of cartilage loss
Side effects(adverse reaction & toxicity) Incidence: GS 26% & 4%. Placebo 32% & 5%
Glucosamine, Chondroitin Sulfate and the two in combination for painful knee osteoarthritis. Clegg DO, Reda DJ, Harris CL, Klein MA, et al. USA 2006 N = 1583;>40yrs; OA knee pain for >6mths;knee OA on XRay; WOMAC score 125-400;ARA Class I,II or III
5 groups
Gp1.Glucosamine (G) 1500mg/day n = 317
Gp2.chondroitin sulphate (C) )1200mg/day
n = 318
Gp3. G & C
n = 317
Gp4. Celecoxib 200mg/day
n = 318
Gp5. placebo
n = 313
Acetaminophen 4g/day as rescue analgesia		 Multi centre double blinded Placebo RCT
6 month F.U.		 Primary: WOMAC pain subscale.Rate of response compared to placebo All patients(n=1583)<br><br>Gp1=3.9% (p=0.3). Gp2=5.3%(p=0.17). Gp3=6.5%(p=0.09). Gp4=10%(p=0.008) 60% placebo response and mild pain at baseline in may limit or dilute any treatment effect
Secondary (sig differences only compared to placebo): Patients with mod-severe pain(n=354)<br><br>Gp1=11.4%(p=0.17).Gp2=7.1%(p=0.39). Gp3=24.9%(p=0.002). Gp4=15.1%(p=0.06).
OMERACT-OARSI response rates Gp3=8.7%(p=0.02) Gp4=10.4%(p=0.007)
effusion/joint swelling Gp2=7.5%(p=0.01). Gp4=6.5%(p=0.03)
Glucosamine/chondriotin combined with exercise for the treatment of knee osteoarthritis: a preliminary study. Messier SP, Mihalko SD, Loeser RF, et al. 2006, N = 89 50 years knee OA K–L grade II/III
Gp 1: GH 1500 mg/CS 1200 mg daily
Gp 2: Placebo
Phase 1 (for 6 months): Gp1: vs Gp2
Phase 2 (further 6 months): Gp 1 + exercise/lifestyle advice vs Gp 2 + exercise/lifestyle advice		 Double blinded placebo controlled RCT
FU: 6 months after phase I and 12 months after phase II		 WOMAC physical function NSS improvement between groups at 6 and 12 months 20% Difference between groups in mean function at baseline
Pill compliance >85%
No a priori sample size calculation
WOMAC pain NSS at 6 and 12 months
6 Min walk NSS at 6 and 12 months
Knee length Extension: NSS at 6 and 12 months. Flexion: placebo group 17% better at 12 months (p = 0.05)
Balance Placebo group 10% better at 6 (p = 0.01) and 12 months (p = 0.05)
Comparison of glucosamine sulphate and a polyherbal supplement for the relief of osteoarthritis of the knee: a randomised controlled trial. Mehta K, Gaala J, Bhasale S, et al. 2007, India N = 95 >50 years
K–L grade II/III
ARA class II/III
Gp 1: GS 1500 mg daily
Gp 2: Reparagen 1800 mg daily 8 weeks treatment		 Multicentre double blinded RCT WOMAC at 8 weeks For 20% decrease in WOMAC pain: GS = 89.4%. Reparagen = 93.7%. NSS between groups No a priori sample size calculation
VAS at 8 weeks 49% decrease GS Gp versus 45% decrease reparagen Gp. NSS between groups
Glucosamine sulfate in the treatment of knee osteoarthritis symptoms. Herrero-Beaumont G, Roman Ivorra JA, Trabado MC, et al. 2007, Spain N = 318
K–L grade II/III
Gp 1: GS 1500 mg daily
Gp 2: paracetamol 3 g daily
Gp 3: placebo 6 months treatment		 Multicentre double blinded, double dummy, placebo and reference controlled RCT WOMAC total index Post hoc analysis for pill or exercise compliance: >85% compliance = greater improvement in pain and mobility<br><br>p = 0.039 between Gp 1 and Gp 3 Effect size Gp 1/Gp 3 = 0.31 BMI lower than other OA knee trials (? generalisability)
Lequesne index p = 0.032 between Gp 1 and Gp 3 Effect size Gp 1/Gp 3 = 0.32
OARSI—A Response rates compared with placebo Gp 1: 39.6% (p = 0.004) Gp 2: 33.3% (p = 0.047)
OARSI—B Response rates compared with placebo Gp 1: 35.8% (p = 0.004) Gp 2: 32.4% (p = 0.047)
Author Commentary:
The 2005 Cochrane update has 20 RCT with decreased pain by 28% and function by 21%, but this depends if a Lequesne index or WOMAC is used. Studies differed in methods of administration (oral ± IA ± IM). Most RCT show superiority of glucosamine over placebo in osteoarthritis. The five negative RCT did not use the Rotta brand of glucosamine, which raises issues about different types of glucosamine preparations being sold that may not be equally effective.

The new RCT added contradictory evidence of glucosamine efficacy against placebo, paracetamol or a natural polyherb.

Side effects from glucosamine or chondroitin alone or in combination are mild and infrequent.
Bottom Line:
There is still controversy about the efficacy of glucosamine alone or in combination with chondroitin for the treatment of moderate to severe pain in osteoarthritis of the knee.
Level of Evidence:
Level 3: Small numbers of small studies or great heterogeneity or very different population
References:
  1. Towheed ML, Anastassiades,T, Shea B, Houpt J, Robinson V, Hochberg M, Wells,G. Glucosamine therapy for treating osteoarthritis
  2. Clegg DO, Reda DJ, Harris CL, Klein MA, et al.. Glucosamine, Chondroitin Sulfate and the two in combination for painful knee osteoarthritis.
  3. Messier SP, Mihalko SD, Loeser RF, et al.. Glucosamine/chondriotin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
  4. Mehta K, Gaala J, Bhasale S, et al.. Comparison of glucosamine sulphate and a polyherbal supplement for the relief of osteoarthritis of the knee: a randomised controlled trial.
  5. Herrero-Beaumont G, Roman Ivorra JA, Trabado MC, et al.. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms.