Glucosamine and Chondroitin - Dushan Atkinson FRCS Tr & Orth 10/1/2006

OA and glucosamine

Osteoarthritis is a disease that involves damage to, and loss of articular cartilage.

Among the components of articular cartilage are glycosaminoglycans,

One of these is glucosamine, a sulphated amino-monosaccharide (sugar), one of the constituents of the disaccharide units present in articular cartilage proteoglycans.

In vitro work has shown that glucosamine can alter chondrocyte metabolism, oral glucosamine is well absorbed from the gut, and animal models suggest that circulating glucosamine canlocalise in cartilage.

This is the rationale usually given for its use in osteoarthritis

Glucosamine supplements are sold as either glucosamine hydrochloride or sulphate - supplements are either derived from shells of shellfish or produced synthetically

It appears well tolerated,at least in the short term; usual GI upset, rash, some have drowsiness,insomnia etc Shell fish allergy

NO DRUG INTERACTIONS TODATE!

Cautions: pregenancy and breast feeding (no data for or against)

Can alter insulin sensitivity in diabetics

A dose of 1500-2000mg a dayis recommended and can take 3-6 weeks to provide benefits.

psycho babble.....

Glucosamine sulphate cannot be practically used as such for the preparation of medicinal products or dietary supplements because, for chemical reasons, it is a highly unstable compound. The Rotta Research Group has invented and patente d several years agoa method to stabilize glucosamine sulphate, through a chemical process of co-precipitation with sodium chloride, thus obtaining Crystalline Glucosamine Sulphate.Crystalline Glucosamine Sulphate is the active ingredient in DONA and the original and only glucosamine sulphate that has been investigated in more than150 pre-clinical and clinical studies, and to which over 90% of the scientific literature refers

Early Meta-analysis Effectiveness of glucosamine and chondroitin sulphate in osteoarthritis:

• A systematic review (McAlindonTE, La Valley MP, Gulin JP, et al (2000). Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA, 283, 1469-75

McAlindon et al included studies that were randomised controlled, double blind, trials that compared oral or parenteral glucosamine sulphate, glucosamine hydrochloride, or chondroitin sulphate with placebo for > 4 weeks with placebo in patients with osteoarthritis of the hip or knee. )

They found that there was evidence that glucosamine and chondroitin are effective for improving function and relieving pain in patients with osteoarthritis, though that the the magnitude of the effect of these treatments was unclear because of inconsistencies in study methods and dependence on industry support for study execution

POSSIBLY GOOD comment about poor studies

Interesting!... Lancet.2001 Jan 27;357(9252):251-6. Reginster JY, Deroisy R, et al. Long-termeffects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Belgium

BACKGROUND:Treatment of osteoarthritis is usually limited to short-term symptom control. We assessed the effects of the specific drug glucosamine sulphate on the long-term progression of osteoarthritis joint structure changes and symptoms.

METHODS:We did a randomised, double-blind placebo controlled trial, in which 212patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oralglucosamine or placebo once daily for 3 years.

Weightbearing, anteroposterior radiographs of each knee in full extension were taken at enrolment and after 1 and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width--ie, at the narrowest point--was measured by visual inspection with a magnifying lens
Symptoms were scored by the Western Ontario andMcMaster Universities (WOMAC) osteoarthritis index.

FINDINGS:The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss
after 3 years of -0.31 mm (95% CI -0.48 to -0.13).

Therewas no significant joint-space loss in the 106 patients on glucosamine sulphate : -0.06 mm (-0.22 to 0.09). Similar results were reported with minimum joint-space narrowing.

Asassessed by WOMAC scores, symptoms worsened slightly in patients on placebo compared with the improvement observed after treatment with glucosamine sulphate. There were no differences in safety or reasons for early withdrawal between the treatment and placebo groups.

INTERPRETATION:The long-term combined structure-modifying and symptom-modifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in osteoarthritis.

IS THIS REALLY TRUE?

UK Recommendations

• Drug and Therapeuticsreview (Drug and Therapeutics Bulletin (2002), 40(11),81-3.)

Concluded that 'oral glucosamine sulphate 1,500mg daily probably provides modest symptom relief inpatients with osteoarthritis of the knee and its efficacy appears similar to that of NSAIDs..On current evidence, it seems reasonable to suggest glucosamine sulphate 1,500 mg daily as a treatment option of patients with kneeosteoarthritis..'

......BUT A LOT OF CONTROVERSY

From The Cochrane Library,Issue 2, 2005. Chichester, UK: John Wiley & Sons, Ltd. All rights reserved.

• Glucosamine therapy for treating osteoarthritis (Cochrane Review)

Towheed TE, Maxwell L,Anastassiades TP, Shea B, Houpt J, Robinson V, Hochberg MC, Wells G

A substantive amendment to this systematic review was last made on 23 February 2005. Cochrane reviews are regularly checked and updated if necessary.

Background: Osteoarthritis (OA) is the most common form of arthritis, and it is often associated with significant disability and an impaired quality of life.

Objectives: To review all randomized controlledtrials (RCTs) evaluating the effectiveness and toxicity of glucosamine in OA.

Search strategy: We searched MEDLINE, PREMEDLINE, EMBASE, AMED, ACP Journal Club, DARE, CDSR, and the CCTR. We also wrote letters to content experts, and hand searched reference lists of identified RCTs and pertinent review articles. All searches were updated in January 2005.

Selection criteria: Relevant studies met the following criteria: 1) RCTs evaluating the effectiveness and safety of glucosamine in OA,2) Both placebo controlled and comparative studies were eligible, 3) Both single blinded and double blinded studies were eligible.

Data collection and analysis: Data abstraction was performed independently by two investigators and the results were compared for degree of agreement. Gotzsche's method and a validated tool (Jadad 1996) were used to score the quality of the RCTs. Continuous outcome measures were pooled using standardized mean differences (SMD) as the measure of effect size. Dichotomous outcome measures were pooled using relative riskratios (RR).

Main results:

Analysis restricted to eight studies with adequate allocation concealment failed to show benefit of glucosamine forpain and WOMAC function.

Collectively, the 20 analyzed RCTs found glucosamine favoured placebo with a 28% (change from baseline) improvement in pain (SMD -0.61, 95% CI -0.95, -0.28) and a 21%(change from baseline) improvement in function using the Lequesne index (SMD-0.51 95% CI -0.96, -0.05).

Lequesne Index This includes the measurement of pain (5 questions), walking distance (1 question),and activities of daily living (4 questions), with versions available for thehip and knee.

Scores for each questionare added together to provide a combined disease severity score. Scores of 14 are classified as mild osteoarthritis, 57 moderate, 810 severe, 1113 verysevere, and 14 as extremely severe osteoarthritis

However, the results are not uniformly positive, and the reasons for this remain unexplained. WOMAC pain, function and stiffness outcomes did not reach statistical significance.

In the 10 RCTs in which the Rotta preparation of glucosamine was compared to placebo, glucosamine was found to be superior for pain (SMD -1.31, 95% CI -1.99, -0.64) and function using theLequesne index (SMD -0.51, 95% CI -0.96, -0.05).

Pooled results for pain(SMD -0.15, 95% CI -0.35, 0.05) and function using the WOMAC index (SMD 0.03,95% CI -0.18, 0.25) in those RCTs in which a non-Rotta preparation ofglucosamine was compared to placebo did not reach statistical significance.

In the four RCTs in which the Rotta preparation of glucosamine was compared to an NSAID, glucosamine was superior in two, and equivalent in two.

Two RCTs using the Rotta preparation showed that glucosamine was able to slow radiological progression of OA of the knee over a three year period (SMD 0.24, 95% CI 0.04, 0.43).

Glucosamine was as safe as placebo in terms of the number of subjects reporting adverse reactions(RR=0.97, 95% CI, 0.88, 1.08).

Authors' conclusions: This update includes 20 studies with 2570 patients. Pooled results from studies using a non-Rotta preparation or adequate allocation concealment failed to show benefit in pain and WOMAC function
those studies evaluating the Rotta preparation show that glucosamine was superior to placebo in thetreatment of pain and functional impairment resulting from symptomatic OA .

WOMAC outcomes of pain,stiffness and function did not show a superiority of glucosamine over placebo for both Rotta and non-Rotta preparations of glucosamine.

Recent papers Other preparations?

• Zhonghua YiXue Za Zhi. 2005 Nov;85(43):3067-70. Qiu GX et al

A multi-central, randomized, controlled clinical trial of glucosamine hydrochloride /sulphate in the treatment of knee osteoarthritis

142 pateints with knee OA randomised. There were no significant differences inefficacy and safety between Glucosamine Hydrochloride and glucosamine sulphate groups in the treatment of knee OA (p<0.05). Glucosamine hydrochloride was as effective and safe as glucosamine sulphate.

A considerable improvement in OA symptoms and a reduction of total Lequesne's score were observed in both groups after the 4-week treatment.

Pharmakokinetics?

• Osteoarthritis Cartilage. 2005 Dec;13(12):1041-9. Persiani S et al . Glucosamine oral bioavailability and plasmapharmacokinetics after increasing doses of crystalline glucosamine sulphate in man.

12 healthy male subjects. Plasma collection. Rapid absorption after intake. Linear concentration with increasing dose. Estimated half life of 15 hours.Glucosamine is bioavailable after oral administration of crystalline glucosamine sulphate, persists in circulation, and its pharmacokinetics support once-daily dosage. Steady state peak concentrations at the therapeutic dose of1,500 mg were in line with those found to be effective in selected in vitro mechanistic studies. This is the only glucosamine formulation for which pharmacokinetic, efficacy and safety data are now available

Another systematic review

• Ann Pharmacother. 2005 Jun;39(6):1080-7. Poolsup N, Suthisisang C, Channark P,Kittikulsuth W. Thailand Glucosamine long-term treatment and the progression of knee osteoarthritis: systematic review of randomized controlled trials.

OBJECTIVE:To investigate the structural and symptomatic efficacy and safety of glucosamine in knee osteoarthritis (OA). DATA SOURCES: Clinical trials of glucosamine were identified through electronic searches (MEDLINE, EMBASE,BIOSIS, EMB review, the Cochrane Library) using the key words glucosamine,osteoarthritis, degenerative joint disease, degenerative arthritis,osteoarthrosis, gonarthrosis, knee, disease progression, and clinical trial.The bibliographic databases were searched from their respective inception dates to August 2004. We also hand-searched reference lists of relevant articles.

STUDY SELECTION AND DATA EXTRACTION: Studies were included if they were double-blind,randomized, controlled trials that evaluated oral glucosamine long-term treatment in knee OA; lasting at least one year; and reporting as outcome measures the symptom severity and disease progression as assessed by jointspace narrowing. Two authors interpreted data independently. Disagreements were resolved through discussion.

DATASYNTHESIS: Glucosamine sulphate was more effective than placebo in delaying structural progression in knee OA. The risk of disease progression was reduced by 54% (pooled RR 0.46; 95% CI 0.28 to 0.73; p = 0.0011). The number-needed-to-treat was 9 (95% CI 6 to 20). The pooled effect sizes for pain reduction and improvement in physical function were 0.41 (95% CI 0.21 to 0.60;p < 0.0001) and 0.46 (95% CI 0.27 to 0.66; p < 0.0001), respectively, in favor of glucosamine sulphate. Glucosamine sulphate caused no more adverse effects than placebo.

CONCLUSIONS: The available evidence suggests that glucosamine sulphate may be effective and safe in delaying the progression and improving the symptoms of knee OA. Due to the sparse data on structural efficacy and safety, further studies are warranted.

REASONABLY WELL DONE STUDY BUT NOT PARTICULARLY ENLIGHTENING

What about

Chondroitin sulphate ?

Also well studied, chondroitin sulphate is demonstrated to be effective forfunction, pain and mobility in osteoarthritis. In a multi-centre, double-blind study ¹⁸ , 146 patients with osteoarthritis of the knee were randomised to chondroitin sulphate or diclofenac or placebo. While patients on diclofenac demonstrated immediate pain relief, symptoms reappeared after treatment was discontinued. In the chondroitin group, the therapeutic result appeared later but persisted for up to three months after the end of thetreatment. The recommended dose of chondroitin sulphate is about800-1200mg/day. Like glucosamine, it forms part of the proteoglycan matrix structure of the cartilage and also has a structure-modifying effect on cartilage. Chondroitin sulphate is generally well tolerated and has low toxicity, although more research is required.

Interestingly, topical applications of the above substances may also be useful.A randomised controlled trial ¹⁹ of 63 patients over two months found that a combined glucosamine and chondroitin cream applied topically to osteoarthritic knees provided 50% reduction in pain and improved quality oflife when compared to placebo. Unlike oral use, topical use showed beneficial effects within days.

18. Journal of Rheumatology 1996; 23(8):1385-91.

19. Journal of Rheumatology 2003; 30(3):523-28.

BRAND NEW DATA. Largest trial todate

The National Center for Complementary and Alternative Medicine and the National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS/NCCAM) have funded a multicenter five arm placebo controlled study called The Glucosamine Arthritis Intervention Trial (GAIT). GAIT spanned 24 weeks, enrolling 1588 subjects, at 13 centers comparing the efficacy of glucosamine sulphate,chondroitin sulphate, glucosamine with chondroitin, to placebo and compared tocelecoxib for knee OA.

Participants in the GAIT study were randomly assigned to placebo, glucosamine HCL 500mg 3times/day, sodium chondroitin sulfate 400mg 3 times/day, glucosamine plus chondroitin sulfate at the above doses, or celecoxib.

.Good News for Knees: NIH GAIT Study Announcement Shows Pharmaceutical Grade Glucosamine/Chondroitin Sulfate Combination Effective in Moderate to Severe Knee Pain

November 14th at the American College of Rheumatology Conference (ACR) in San Diego, California. According to the abstract results posted on the ACR website (www.rheumatology.org/annual/abstracts/search.asp), the combination of pharmaceutical grade chondroitin sulfate and glucosamine HCl was effective for moderate to severe knee pain.

BUT FUNNILY ENOUGH

The chondroitin sulfate selected for use in the GAIT study is ONLY found in Cosamin(R)DS, a combination of glucosamine HCl and chondroitin sulfate,marketed by Nutramax Laboratories, Inc. The pharmaceutical grade chondroitinsulfate is supplied by Bioiberica SA under an exclusive agreement with NutramaxLaboratories, Inc.

CONCLUSION STILL STANDS FROM

• BMJ 2001;322:1439-1440 ( 16 June ) Editorial Glucosamine for osteoarthritis: magic, hype, or confusion?

Osteoarthritisis a heterogeneous condition .the origin of pain caused by osteoarthritisis unclear, and regional joint pain in older people is often due to periarticular lesions or referred pain rather than articular problems there is littlerelation between the severity of the radiographic changes and the severity of symptoms.

There is confusion about what we are trying to do when we treat people with osteoarthritis,epitomised by the glucosamine literature. A reasonable objective is the reduction of pain, stiffness, and other symptoms that arise from a joint as aresult of osteoarthritis, with the plausible goal of a secondary reduction in disability. But why should we expect an agent that affects articular cartilage to have any effect on symptoms? There are no nerves in articular cartilage.10 In addition, examination of the glucosamine literature shows that investigators have used several different patient related outcome measures, often mixing up different domains of outcome. An agent that affects cartilage might conceivably affect the radiographic changes of osteoarthritis, but why should we want to try to alter the radiographic changes when there is no relation between their severity and the clinical expression of the disease?11

So how good is the evidence that glucosamine alters either the symptomatic expression of osteoarthritis or its radiographic progression? Actually, not very good. Indeed, something amusing seems to be happening as a result of our evidence based approach to new therapies. Glucosamine may become the first agent about which we have more published systematic reviews, editorials,meta-analyses, and comments than we do primary research papers. Our literature search identified nine reviews (and many editorials and comments), but only 24 primary studies (three of which were on combined therapies that included glucosamine). Other overviews, including a Cochrane systematic review, are in the pipeline. Perhaps we could have got away with examining other peoples' reviews, but we have studied most of the trial publications as well.

We agree with McAlindon et al12 and Delafuente,13 who complain that most of the primary studies are poor and most of the trials too small. To be fair, the reviews and meta-analyses are dominated by trials done several years ago, many of which were particularly poor, and the quality of more recent studies is clearly better. But we have two additional concerns about the existing evidence. Firstly, much of the research is sponsored by companies making glucosamine. Company sponsorship affects the likelihood of positive results in trials of non-steroidal anti-inflammatory drugs, 14 15 and the same bias will probably exist with glucosamine. We identified 12 trials with clear involvement by a company producing the product: all these trials gave positive results.Nine other studies reported positive findings but we could not ascertain the source of funding. Conversely, of the three trials that reported a negative effect, only one reported commercial funding. Secondly, most reviews have not been able to take account of the possible effects of publication or language bias. 12 16 17 So, though much of the research points to glucosamine being a safe and effective treatment for osteoarthritis, problems with bias and quality mean that these results must be treated with caution.

We conclude that there is more confusion and hype than magic about glucosamine.The rationale for its use is unclear, the best dose and route of administration unknown, and the published trials do not allow any conclusion about its efficacy (let alone its effectiveness or cost effectiveness). In its defence it does seem to be very safe and any safe, effective compound used for osteoarthritis could do much good, even if the effect size is small. However,given the confusion we cannot recommend its wholesale use. We need large clinical trials, without company interference.