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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.
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.

Search 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)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Towheed 2005 Uk	20 RCTs 19 published 1 unpublished English Lang.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%
Clegg 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) 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) 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)
Messier 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)
Mehta 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
Herrero-Beaumont 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 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)

Comment(s)

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.

Editor Comment

BMI, body mass index; CS, chondroitin sulphate; FU, follow-up; G, glucosamine; GH, glucosamine hydrochloride; Gp, group; GS, glucosamine sulphate; NSAID, non-steroidal anti-inflammatory drug; OA, osteoarthritis; RCT, randomised controlled trial; VAS, visual analogue scale.

Clinical 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 The Cochrane Database of Systematic Reviews 2005; CD002946
2. Clegg DO, Reda DJ, Harris CL, Klein MA, et al. Glucosamine, Chondroitin Sulfate and the two in combination for painful knee osteoarthritis. New England Journal of Medicine 2006; 354 (8): 795 – 808.
3. Messier SP, Mihalko SD, Loeser RF, et al. Glucosamine/chondriotin combined with exercise for the treatment of knee osteoarthritis: a preliminary study. Osteoarthr Cartilage 2007; 15: 1256–66.
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. BMC Musculoskel Disord 2007; 7: 34.
5. Herrero-Beaumont G, Roman Ivorra JA, Trabado MC, et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms. Arthritis Rheum 2007; 5692: 555–67.