Pharmacotherapeutic aspects of treating knee osteoarthritis with glucosamine sulfate

doi:10.4236/health.2010.27107

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Vol.2, No.7, 705-707 (2010)

doi:10.4236/health.2010.27107

Health

Pharmacotherapeutic aspects of treating knee

osteoarthritis with glucosamine sulfate

Steven Simoens*, Gert Laekeman

Research Cent re for Pharma ceut ic al Ca re an d Phar maco-ec onomic s, Katholie ke Univ er sitei t Leu ven , Onde rwij s en Navo rsi ng,

Leuven, Belgium; *Corresponding Author: [email protected]

Received 5 February 2010; revised 11 March 2010; accepted 15 March 2010.

ABSTRACT

Glucosamine sulfate is a natural constituent of

cartilage and is used in the treatment of knee

osteoarthritis. The aim of this study is to pro-

vide a short but comprehensive pharmaco-

therapeutic update on treating knee osteoarthri-

tis with glucosamine sulfate. A literature search

was conducted of PubMed, Centre for Reviews

and Dissemination databases, Cochrane Re-

views and EconLit up to January 2010. The lit-

erature review indicated that the mechanism of

action of glucosamine sulfate is based on hy-

pothesis, but its treatment effects in knee os-

teoarthritis are symptomatic. With steady-state

peak concentrations at the 1,500 mg dosage in

the range of 10 µM, it is estimated that only 2%

of glucosamine is incorporated in the cartilage.

A once-daily dosage of 1,500 mg of glucosa-

mine sulfate is licensed for the treatment of

symptomatic osteoart hritis and has been shown

to reduce pain, improve function and exhibit

similar safety to placebo. Glucosamine sulfate

is likely to be a cost-effective treatment of knee

osteoarthritis. In conclusion, a once-daily dos-

age of 1,500 mg of glucosamine sulfate is likely

to be a safe, effective and cost-effective treat-

ment of knee osteoarthritis as compared to

placebo.

Keywords: Pharmacotherapy; Glucosamine

Sulfate, Knee Osteoarthritis; Pharmacokinetics;

Indication; Safety; Effectiveness;

Cost-Effectiveness

1. INTRODUCTION

Knee osteoarthritis is associated with significant mor-

bidity, impaired quality of life, and sub stantial health care

costs [1]. Pharmacological treatment of knee osteoarthri-

tis includes analgesics, non-steroidal anti-inflammatory

drugs (NSAIDs), corticosteroids and opiods, and gluco-

samine sulfate. Glucosamine sulfate is a natural subs-

tance that is a constituent of cartilage. Glucosamine sul-

fate is sold as a dietary supplement in the United States,

but is registered as a medicine throughout much of

Europe.

To date, there is uncertainty over various pharmaco-

therapeutic aspects of treating knee osteoarthritis with

glucosamine sulfate. Therefore, the aim of this study is

to provide a short but comprehensive pharmacothera-

peutic update on treating knee osteoarthritis with gluco-

samine sulfate.

2. METHOD

2.1. Search Strategy

A literature search was conducted of PubMed, Centre for

Reviews and Dissemination databases, Cochrane Data-

base of Systematic Reviews and EconLit up to January

2010. Additionally, the bibliography of included studies

was checked for other relevant studies. Search terms

included “knee osteoarthritis”, “knee joint”, “glucosa-

mine sulfate”, “pharmacokinetics”, “bioavailability”, “in-

dications”, “dosage”, “safety”, “effectiveness”, “cost-

effectiveness”, “economic evaluation” alone and in com-

bination wi t h each ot her.

The literature search included articles published in

peer-reviewed journals and congress abstracts. Also, the

researchers contacted manufacturers of glucosamine

sulfate for any unpublished studies. The review was lim-

ited to studies published in English for practical reasons.

2.2. Inclusion and Exclusion Criteria

The review was limited to the use of glucosamine sulfate

in its indication of knee osteoarthritis.

To explore the pharmacotherapy of glucosamine sul-

fate from a multidisciplinary perspective, the literature

review assessed the following aspects: pharmacokinetics,

S. Simoens et al. / HEALTH 2 (2010) 705-707

706

indications and dosage, safety and effectiveness, and

cost-effectiveness. Evidence about cost-effectiveness was

derived from economic evaluations. An economic ev alu a -

tion was defined as a study comparing glucosamine sul-

fate with an alternative treatment in terms of both costs

and consequences.

3. RESULTS

3.1. Search Results

The results of the literature search are displayed in Fig-

ure 1. The review summarized three studies on pharma-

cokinetics, a Cochrane literature review on safety and

effectiveness, and three economic evaluations of gluco-

samine sulfate in knee osteoarthritis.

3.2. Pharmacokinetics

A literature review analysed the absorption, distribution,

metabolism and excretion of different administration

forms of glucosamine sulfate [2]. The absolute bioavail-

ability of oral glucosamine sulfate amounted to 44%.

The fecal excretion was 11.3% of the dosage, indicating

that at least 88.7% of the dosage was absorbed through

the gastrointestinal tract. With an absolute bioavailability

of 44% calculated after oral 14C-glucosamine, a first-

pass effect can be hypothe sized.

A study examined the dosage-proportionality of glu-

cosamine sulfate in 12 healthy volunteers [3]. The phar-

macokinetics were linear in the 750 mg and 1,500 mg

dosages, but not at 3,000 mg, where the plasma concen-

tration-time profiles were less than expected based on

dosage-proportionality. More recent research showed

that glucosamine concentrations in plasma and synovial

fluid were correlated [4]. There remains controversy

over whether steady-state peak concentrations at the

1,500 mg dosage were in line with those found to be

effective in selected in vitro studies.

117 articles identi-

fied and abstracts

retrieved

11 full articles

retrieved

Exclusion because of:

- animal model of glucosamine sulfate

- disease other than knee osteoarthritis

- study not involving glucosamine

sulfate

- absence of data on pharmacokinetics,

safety, effectiveness or

cost-effectiveness

- study measuring resource use (but

not costs)

7 articles included

Figure 1. Flow chart of literature search.

3.3. Indications and Dosage

The indication of glucosamine sulfate in Europe is lim-

ited to the symptomatic treatment of knee osteoarthritis.

An expansion of indication to osteoarthritis of the hip,

spine, hands and other locations was refused, as a result

of which some companies have refused to register their

preparation as a medicine. Glucosamine sulfate can be

used alone or in combination with NSAIDs. The li-

censed dosage is 1,500 mg, once daily. Symptom relief

may not be experienced until after several weeks of

treatment, and optimal effects on joint mobility have

been observed aft e r 12 wee ks of administrat ion .

3.4. Safety and Effectiveness

A Cochrane review assessed randomized controlled trials

(RCTs) evaluating the effectiveness and toxicity of glu-

cosamine in osteoarthritis up to the end of 2008 [1]. Of

the 25 studies included in the review, 20 RCTs focused

on the knee exclusively and five RCTs examined os-

teoarthritis at other or multiple sites. All studies were

double-blinded randomized parallel-group trials, enroll-

ing a total of 4,963 patients (mean age of 60.7 years,

69% were female). Fourteen RCTs had affiliations with

Rotta Pharmaceuticals (an Italian manufacturer of glu-

cosamine sulfate).

A pooled analysis of the relevant RCTs showed that,

as compared to baseline, glucosamine sulfate taken

orally in amounts of 1,500 mg/day produced an increase

in the total score of the Lequesne Index (a multidimen-

sional index measuring knee pain or discomfort, activi-

ties of daily living and maximum distance walked) of

11% (standardized mean difference of –0.47; 95% con-

fidence interval: –0.82 to –0.12). A subgroup analysis of

the Rotta preparation showed significant benefit over

placebo in terms of pain (standardized mean difference

of –1.11; 95% confidence interval: –1.66 to –0.57) and

in terms of the total score of the Lequesne Index (stan-

dardized mean difference of –0.47; 95% confidence in-

terval: –0.82 to –0.12). Studies using a non-Rotta prep a-

ration failed to show benefit over placebo in terms of

pain and function as measured by the Western Ontario

and McMaster Universities Index (a disease-specific

index measuring pain, stiffness and function). Two RCTs

suggested that the Rotta preparation of glucosamine sul-

fate may slow radiological progression of knee os-

teoarthritis over a three-year period (average difference

of 0.32; 95% confiden ce interval: 0.05 to 0.58).

Glucosamine therapy exhibited a safety profile similar

to placebo in terms of the number of patients with

side-effects (relative risk ratio of 0.99; 95% confidence

interval: 0.91 to 1.07) and significantly better than

NSAIDs (relative risk ratio of 0.29; 95% confidence

interval: 0.19 to 0.44).

S. Simoens et al. / HEALTH 2 (2010) 705-707

707

3.5. Cost-Effectiveness

A Belgian economic evaluation indicated that treatment

of knee osteoarthritis with glucosamine sulfate for at

least one year and up to three years was associated with

a lower incidence of total knee replacement over an ob-

servation period of eight years [5]. Costs of glucosamine

sulfate treatment were offset by lower hospitalization

costs, resulting in overall savings. To tal costs per patient

amounted to € 1,103 in the placebo group and € 901 in

the glucosamine sulfate group. In other words, treatment

of knee osteoarthritis with glucosamine sulfate for up to

three years is associated with savings of € 202 per pa-

tient during the over all observation period of eight years

(i.e. up to three years of treatment and five years of fol-

low-up). This study indicated that glucosamine sulfate

treatment was more effective and less expensive than

placebo in knee osteoarthritis. If costs of other os-

teoarthritis medicines and other health care resource use

are taken into account, the cost-effectiveness of gluco-

samine sulfate would even be more favourable.

Openly accessible at

The National Institute for Health and Clinical Excel-

lence in England and Wales compared the likely cost-

effectiveness of selected treatments for knee osteoarthri-

tis [6]. This study did not provide a full economic

evaluation, but presented UK healthcare costs alongside

the effectiveness of each treatment option. The scope of

costs was limited to treatment costs (such as medicine

costs), but did not include other healthcare costs such as

adverse event costs or decreased use of other medical

resources. The results suggested that glucosamine sulfate

(1,500 mg/day) is likely to be cost-effective as compared

with placebo.

A recent US analysis explored the cost-effectiveness

of glucosamine sulfate treatment versus placebo in a

hypothetical cohort of 100,000 patients who were 65

years old and had knee osteoarthritis for five years [7]. A

hybrid Markov-decision tree model was constructed us-

ing published effectiveness data and US fee schedules.

Treatment with a daily dosage of 1,500 mg of glucosa-

mine sulfate turned out to be more effective and less

expensive than placebo by delaying time to joint re-

placement surgery. However, cost-effectiveness results

were sensitive to changes in several input parameters

and the authors recommended additional research to

inform decision making.

4. CONCLUSIONS

This study provided a pharmacotherapeutic update on

treating knee osteoarthritis with glucosamine sulfate.

Additionally, an economic evaluation explored the cost-

effectiveness of treating knee osteoarthritis with gluco-

samine sulfate in Belgium. The main messages can be

summarized as follows. The mechanism of action of

glucosamine sulfate is based on hypothesis, but its

treatment effects in knee osteoarthritis are symptomatic.

A once- daily dosage of 1,500 mg of glucosamine sulfate

has been licensed for the symptomatic treatment of knee

osteoarthritis. Glucosamine sulfate has been shown to

reduce pain and improve function of patients with knee

osteoarthritis. Glucosamine sulfate therapy exhibits a

safety profile similar to placebo and significantly better

than NSAIDs. Finally, glucosamine sulfate is likely to be

a cost-effective treatment of knee osteoarthritis.

5. ACKNOWLEDGEMENTS

No funding was provided to support this study. The authors have no

conflicts of interest that are relevant to the content of this manuscript.

REFERENCES

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