Glucosamine for osteoarthritis: magic, hype, or confusion?
BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7300.1439 (Published 16 June 2001) Cite this as: BMJ 2001;322:1439
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REPLY TO THE EDITORIAL WRITTEN BY P. DIEPPE IN THE BMJ
Glucosamine Sulphate: an old new drug
I am a usual reader of papers coming from the authors of this
editorial (June 16th, 2001)(1) and they have always seemed to me very
clear and accurate. This time I was deeply disappointed. In fact, the
content of this editorial is contradictory with the claimed purpose. The
editorial spreads confusion where there is (fortunately) increasing
evidence.
The first issue to clarify is that the glucosamine sulphate (GS) used
in my country is a prescription drug indicated exclusively in the
symptomatic treatment of osteoarthritis. We are using it for more than 15
years, based on increasing evidence coming from clinical trials. These
trials have always been in accordance to the “state-of-art” methodology,
which has been evolving along the years. That is why I feel comfortable
with the GS data. Meanwhile, I (and many of my colleagues) acquired a
significant expertise with the use of this drug and along those years we
clearly pointed out that this drug is a very useful tool when integrated
in a global approach to osteoarthritis.
As far as all the Science and Research fields are concerned, our
demands, in terms of evidence, has increased in the last couple of
decades. It is therefore current to state that the methodology used some
years ago is not perfect or even incorrect and that the study duration or
subjects are insufficient. The last GS clinical trials seems to put aside
some of these concerns.
Glucosamine sulfate (GS) is a drug that has demonstrated in in vitro
and in vivo (2,3,4,5,6,7,8,9,10,11) research that it is well absorbed by
oral and intramuscular administration and incorporated in the chondrocyte
metabolism. Glucosamine sulphate has several mechanisms of actions that
include anticatabolic actions and pro-anabolic ones in what concerns to
the cartilage matrix. Those actions can explain GS efficacy in symptom
relief (pain and inflammation) and the possible slowing of osteoarthritis
progression.
I do agree with the authors for the need of further research to find
the optimal dosing and administration route. On the other side, we cannot
ignore the cumulative experience with millions of patients treated with GS
confirmed by the majority of the clinical trials performed, that has been
highlighting the evidence that this drug is active and effective in the
symptomatic control of osteoarthritis, with a persistent long-lasting
effect, even after the withdrawal of the treatment. The safety of
glucosamine sulphate is outstanding, whether if you compare it to placebo
or to NSAIDs.
These facts were known from the results of several short-term
clinical trials (12,13,14) as mentioned at the recently published Cochrane
Review (15). Those were even extended and reinforced by the last two long
-term trials (16,17) which brings to a new striking point: it is possible
to slow the progression of joint space narrowing which reflects the
cartilage deterioration characteristic of the osteoarthritis process.
Once again I share the opinion of those who claim the need for
further research to extend these studies to other joints and to identify
which patients can obtain more benefits from this treatment, reflecting
possible differences in the pathogenic processes and stages of the
disease.
Concluding, I am convinced that glucosamine sulphate is an active and
useful drug, with a very appropriate safety profile to long-term
treatment, even in older and polimedicated patients. I also agree that OA
management should benefit from an integrated approach adapted to the
disease presentation and stage, in which the pharmacological treatment is
only one part of a broader and multidisciplinary care strategy (18).
Rui André, M.D.
Rheumatologist
Military Hospital,
Lisbon,
Portugal
Consultant of Rotta Farmacêutica - Portugal
References:
(1) Chard J. Dieppe P. Glucosamine for osteoarthritis: magic, hype,
or confusion? BMJ 2001; 322: 1439-40
(2) Setnikar I, Giachetti C, Zanolo G. Absorption, distribution and
excretion of radioactivity after a single intravenous or oral
administration of [14C]-glucosamine to the rat. Pharmatherapeutica, 1984;
3:538-550
(3) Setnikar I, Giachetti C, Zanolo G. Pharmacokinetics of glucosamine in
the dog and in man. Arzneim-Forsch, 1986; 36: 729-735.
(4) Dodge GR, Regatte RR, Hall JO, Borthhakur A, Sarme A, Callaway DA,
Reddy R. The fate of oral glucosamine traced by 13C-labeling in the dog.
Abstract. ACR Meeting, San Francisco, November 2001.
(5) Basleer C, Rovati L, Franchimont P. Stimulation of proteogycan
production by glucosamine sulfate in chondrocytes isolated from human
ostearthritic articular cartilage in vitro. Osteoarthritis Cartilage,
1998; 6: 427-434
(6) Piperno M, Reboul P, Hellio Le Graverand MP, et al. Glucosamine
sulfate modulates dysregulated functions of human osteoarthritic
chondrocytes in vitro. Osteoarthritis Cartilage, 2000; 8: 207-212.
(7) Jimenez SA, Dodge GR. The effects of glucosamine sulfate (GSO4) on
human chondrocyte gene expression. Osteoarthritis Cartilage, 1997; 5: 72.
(8) Setnikar I, Cereda R, Pacini MA, et al. Antireactive properties of
glucosamine sulfate. Arzneim.-Forsch./Drug Res., 1991; 41: 157-161
(9) Setnikar I, Pacini MA, Revel L. Antiarthritic effects of glucosamine
sulfate studies on animal models. Arzneim.-Forsch./Drug Res., 1991; 41:
542-5.
(10) Conrozier T, Mathieu P, Piperno, et al. Glucosamine sulfate
significantly reduced cartilage destruction in a rabbit model of
osteoarthritis. Arthritis Rheum 1998; 41: 147
(11) Pellettier JP, Jovanovic D, Lascau-Coman V, et al. Relevance of
animal models to clinical disease. Glucosamine sulfate reduces the
structural changes in dog experimental osteoarthritis: beneficial effect
through suppression of the expression of collagenase-1. Presented at the
XIV EULAR Congress, held in Glasgow, Scotland, in June 1999.
(12) Müller-Fassbender H, Bach GL, Haase W, et al. Glucosamine sulfate
compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis
Cartilage, 1994; 2: 61-9
(13) Qiu GX, Gao SN, Giacoveli G, et al. Efficacy and safety of
glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis.
Arzneim.-Forsch./Drug Res., 1998; 48(I): 469-74.
(14) Rovati LC. The clinical profile of Glucosamine sulfate as a
selective symptom-modifying drug in osteoarthritis: current data and
perspectives. Osteoarthritis Cartilage, 1997; 5 (Supp. A): 72.
(15) Towheed TE, Anastassiades TP, Shea B, Houpt J, Welch V, Hocberg MC.
Glucosamine therapy for treating osteoarthritis (Cochrane Review): In:
The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
(16) Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O,
Giacovelli G, Henrotin Y, Dacre JE, Gossert R, Long-term effects of
glucosamine sulphate on osteoarthritis progression: a randomised, placebo-
controlled clinical trial. Lancet, 2001; 357: 251-6
(17) Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati
LC. A long-term, randomised, placebo-controlled, confirmatory trial on
the effects of glucosamine sulfate on knee osteoarthritis progression.
Arthritis Rheumat., 2000; 43: 9 (S1908).
(18) Dieppe P. Management of Osteoarthritis. In: Klippel JH, Dieppe P,
eds Rheumathology, 2nd Ed., London: Mosby – Year Book Europe Limited;
1997.
Competing interests: No competing interests
Sir,
In the June 16 editorial of your journal, Chard and Dieppe referenced but
almost ignored the results of a clinical trial published recently in THE
LANCET (1) of which I am the principal investigator. The study has been
quoted by independent experts (2) as "a landmark in OA research, not only
for its scientific results, but also for highlighting vexing issues in
this area". The author of this comments, T. McAlindon, Arthritis Center,
Boston University Medical Center, Boston, USA, also said that this study
showed many hallmarks of a well-conducted study, including a state-of-the
-art methodology, rigorous description of the results and validated and
accepted outcome measures for both Osteoarthritis symptoms and structure.
He qualifies the results as impressive and consistent with previous
glucosamine studies, in presence of a safety profile similar to placebo.
As the principal investigatgor of the study, I guarantee that the study
was performed strictly according to the ICH guidelines for clinical
research and in a totally independent way from the study sponsor, as it is
the rule in today's modern, serious, clinical research. Thus, it is not
by chance that THE LANCET accepted it for publication and the American
College of Rheumatology had previously accepted it for presentation in
plenary session (3) and also at the official ACR press conference during
their 1999 annual meeting. THE LANCET, the ACR and McAlindon independence
is out of question. A second, independent study, on the Glucosamine
sulfate effect on OA disease progression has recently been presented by
its principal investigator, K. Pavelka (4). This study confirmed the
findings of the study that I co-ordinated. The EULAR and Prof. Pavelka
independence are also out of any question. Contrary to what your
editorial authors stated, the evidence that glucosamine alters either the
symptomatic expression of osteoarthritis or its radiographic progression,
is not only "not very good" but it is very solid, at least, based on the
current standard measurements for evidence-based medicine, accepted by the
international scientific community.
Jean-Yves REGINSTER
Director, Departement of Epidemiology and Public Health, University of
Liège, Liège, Belgium
Head, University Center for Investigation in Bone and Articular Cartilage
Metabolism, University of Liège, Liège, Belgium
Director, WHO Collaborating Center for Public Health Aspects of Rheumatic
Disorders (Non communicable diseases)
References
1. Reginster JY, Rovati LC, et al. Long-term effects of glucosamine
sulphate on osteoarthritis progression : a randomised, placebo-controlled
clinical trial. THE LANCET 2001, 357:251-256
2. McAlindon T. Glucosamine for osteoarthritis : dawn of a new era ? THE
LANCET 2001,357:247-248
3. Reginster JY, et al. Glucosamine sulfate significantly reduces
progression of knee osteoarthritis over 3 years : a large, randomised,
placebo-controlled, prospective trial. Arthritis Rheum 1999;42(Suppl):400
4. Pavelka K et al. Glucosamine sulfate decreases progression of knee
osteoarthritis in a long-term, randomized, placebo-controlled,
independent, confirmatory trial. Arthritis Rheum 2000;43(Suppl):1908
Competing interests: No competing interests
Sir.
Just a short comment about Chard and Dieppe’s editorial on Glucosamine for
Osteoarthritis in the last BMJ issue(1).
Osteoarthritis is traditionally treated with NSAIDS and analgesics, just
covering up symptoms but doing nothing to actually improve the disease.
Worst of all, NSAIDS alone cause over 16,500 deaths and over 103,000
hospitalizations per year in the US, according to a review article
published in the New England Journal of Medicine(2).
Regarding Evidence Based Medicine, these are the Reviewers' conclusions of
the Cochrane Review on NSAIDS for osteoarthritis of the knee(3): “In spite
of the large number of publications in this area, there are few randomized
controlled trials. Furthermore, most trials comparing two or more NSAIDs
suffer from substantial design errors. From the results of this review it
is concluded that no substantial evidence is available related to
efficacy, to distinguish between equivalent recommended doses of NSAIDs.
Had studies employed appropriate doses of comparator drug, most would have
been sufficiently powerful to detect clinically important differences in
efficacy. As differences in efficacy between NSAIDs have not been
recorded, the selection of an NSAID for prescription for OA knee should be
based upon relative safety, patient acceptability and cost.”
On the other hand, a recent Cochrane Review on Glucosamine(4), gave the
following main results:” Collectively, the 16 identified RCTs provided
evidence that glucosamine is both effective and safe in OA. In the 13 RCTs
in which glucosamine was compared to placebo, glucosamine was found to be
superior in all RCTs, except one. In the four RCTs in which glucosamine
was compared to an NSAID, glucosamine was superior in two, and equivalent
in two.”
Additionally, new evidence was recently reported in a clinical trial
published last January, 2001 on The Lancet(5), showing that glucosamine
can beneficially modify the osteoarthritis disease process, both from
symptom and structure point of view. These results have already been
confirmed in an independent trial, presented last November, 2000 at the
64th annual meeting of the American College of Rheumatology, held in
Philadelphia(6).
This drug is currently the only substance known that can both help with
the symptoms of osteoarthritis and improve the course of the disease,
without showing any harmful effect for the patient: despite its supplement
status in certain countries, the evidence tells us that glucosamine must
be taken seriously.
Davide Sonnino, M.D.
Medical Dept.
Rottapharm Italy
Email: davide.sonnino@rotta.com
References:
1.Chard J, Dieppe P. Glucosamine for osteoarthritis: magic, hype, or
confusion?BMJ 2001; 322: 1439-1440
2.Wolfe MM, et. al. Gastrointestinal toxicity of nonsteroidal
antiinflammatory drugs. NEJM 1999;340(24):1888-99
3.Watson MC, et. al. Non-aspirin, non-steroidal anti-inflammatory drugs
for treating osteoarthritis of the knee (Cochrane Review). In: The
Cochrane Library, 2, 2001. Oxford: Update Software.
4.Towheed TE, et. al. Glucosamine therapy for treating osteoarthritis
(Cochrane Review): In: The Cochrane Library, Issue 2, 2001. Oxford: Update
Software.
5.Reginster JY, et. al. Long-term effects of glucosamine sulphate on
osteoarthritis progression: a randomized, placebo-controlled clinical
trial. Lancet 2001;357:251-256.
6.Pavelka K, et. al. A long-term, randomized, placebo-controlled,
confirmatory trial on the effects of glucosamine sulfate on knee
osteoarthritis progression. Arthritis Rheumat 2000;43:9(S1908).
Competing interests: No competing interests
Sir.
I’m simply astonished about Chard and Dieppe’s editorial on
Glucosamine for Osteoarthritis in this journal June 16 issue. Their
editorial on Glucosamine is misleading, incomplete and biased. First of
all, the authors are not well documented: they wonder how an agent that
affects articular cartilage should have an effect on symptoms. Obviously,
they haven’t read all the available literature on this subject:
Glucosamine sulfate not only inhibits the action of metalloproteinases and
stimulates the synthesis of proteoglycans, but also has an effect on the
synovial IL-1B, on the inhibition of the activity of lisosomal enzymes and
on other inflammation mediators, including NO inhibition, according to the
currently available evidence1,2,3,4. Secondly, they underestimate the
importance of the most recent clinical trials performed with Glucosamine
sulfate. A number of well-conducted, controlled, clinical trials on
symptoms were published in Osteoarthritis and Cartilage in the mid
nineties5,6, and well-conducted, state-to-the-art, clinical trials either
have been recently published in THE LANCET7 or are in their way to be
published in first level peer-reviewed journals8. I agree with Chard and
Dieppe in that the older studies might lack of a reasonably good
methodology, to our days standards. Clinical research and medical
publications have changed a good deal over the last two decades. But this
is certainly not true for all the above referenced studies.
They are also
partial when they quote, for instance, McAlindon. They pointed out some
negative aspects highlighted by McAlindon in his JAMA meta-analysis but
they forgot to include some of the remarks by McAlindon in his comments to
the Reginster study recently published in THE LANCET: a landmark in OA
research, he quoted. They also seem to forget that according to the EULAR
recommendations for OA management9, Glucosamine not only ranks for 1B-
CATEGORY OF EVIDENCE and A-STRENGTH OF RECOMMENDATION, but it could well
move to 1A / A in the light of the latest publications released after the
work of the EULAR experts had finalized. The Cochrane review on
Glucosamine10 is almost ignored by Chard and Dieppe. This review concludes
that Glucosamine sulfate available evidence for its use in Osteoarthritis
is high and even superior to NSAIDs. Is this another industry-induced
bias?.
And this is exactly the last point I wanted to analyze. Are the
authors of the editorial going to ask for further “industry-independent”
studies to Merck (Alendronate, Rofecoxib), Aventis (Leflunomide),
Pharmacia/Pfizer (Celecoxib), Centocor (Infliximab), Immunex Co.
(Etanercept), and Lilly (Raloxifene) to support the real efficacy of these
compounds? (just to limit the list to some widely accepted and even
innovative products). Or only to Rotta Research Lab?. But, for us, a small
multinational Italian company, with a long tradition and vocation for
clinical research, there might even be something positive in the Chard and
Dieppe’s editorial: possibly, the next time that the EULAR experts (who
did a great job by delivering the EULAR Recommendations For OA
Management)independently sit down again and revise their findings and
recommendations, will include the above quoted THE LANCET publication and
the Cochrane review on Glucosamine, according to their parameters to
support both the Category of Evidence and the Strength of Recommendation.
P. Dieppe was one of the experts working out the recommendations published
last year.
C. Gonzalez.
Corporate Medical Dep.
Rotta Research Laboratorium.
References.
1. Bassleer C, Rovati L, Franchimont P. Osteoarthritis Cartilage,
1998; 6: 427-434
2. Piperno M, Reboul P, Hellio Le Graverand MP, Peschard MJ, Annefeld M,
Richard M, Vignon E. Osteoarthritis Cartilage, 2000; 8: 207-212
3. Jimenez SA, Dodge GR. Osteoarthritis Cartilage, 1997; 5 (suppl. A): 72
4. Yaron I et al. Ann. Rheum Dis, 2001, 60 (Suppl. 1), OP 0025.
5. Müller-Faßbender H, Bach GL, Haase W, Rovati LC, Setnikar I.
Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee.
Osteoarthritis Cartilage 1994; 2: 61–69.
6. Noack W, Fischer M, Förster KK, Rovati LC, Setnikar I. Glucosamine
sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage, 1994; 2:
51–59.
7. Reginster JY, Rovati LC, et al. THE LANCET 2001, 357: 251-256.
8. Pavelka K et al. Arthritis Rheum, 2000; 43 (Suppl): 1908.
9. EULAR recommendations for the management of knee osteoarthritis. Ann.
Rheum Dis 2000; 59:936-944.
10. Towheed et al. Glucosamine Therapy for treating osteoarthritis
(Cochrane review). In: The Cochrane Library, Issue 1, 2001.
Competing interests: No competing interests
EDITOR-Chard and Dieppe open their editorial on glucosamine for
osteoarthritis (1) saying that "perhaps we are just confused ". Indeed,
they are. Actually, they claim that this "may become the first agent about
which we have more published systematic reviews, editorials, meta-analyses
and comments than we do primary research papers": in order not to reverse
this deplorable trend, they produced another useless comment, which is
further confusing their mind and (hopefully not) the mind of several
readers in good faith. This is at least strange from a man like Paul
Dieppe who has been and still is one of the leading scientists in the
osteoarthritis field, a teacher for everybody and, I hope, a personal
friend.
In my capacity of proud co-author of most of the recent original
research on glucosamine sulfate in osteoarthritis (luckily not of
editorials or comments) and of proud Director of Clinical Research of the
pharmaceutical company that developed the original and only glucosamine
sulfate available for the treatment of osteoarthritis, I will try to clear
some of the confusion in Chard and Dieppe's mind. In doing that, of
course, I openly declare my conflict of interests for the readers'
consideration and I wish some academic experts could do the same, from
time to time.
First of all, as most of the experts from the anglo-american world,
Chard and Dieppe confuse what they call "glucosamine" with the original
glucosamine sulfate whose effects are described in over 90% of the
available clinical studies. While the former includes a multitude of
undefined, uncontrolled and questionable compounds freely available in
health food shops, the latter identifies the one and only prescription
drug approved for osteoarthritis by Health Authorities in over 40
countries of the world. I believe it makes a difference and I hope it
clarifies to Chard and Dieppe how they should classify the substance
reported in the serious literature: it is a prescription drug, whose most
appropriate dose and route of administration (1500 mg/day by the oral
route) is well described and approved.The fact that it may be available as
a nutraceutical in some countries (together with the multitude of
uncontrolled "glucosamines") due to a questionable legislation, does not
change this evidence.
Chard and Dieppe correctly remember that one of the main
pharmacological activities of glucosamine sulfate is to affect articular
cartilage metabolism, but they pretend to ignore the pharmacological
evidence supporting also its effects on osteoarthritis symptoms. Indeed,
the drug has been described for example to possess mild antiinflammatory
effects (prostaglandin independent), possibly by inhibiting the generation
of superoxide radicals (2), and to inhibit the synthesis of inducible
nitric oxide (3), while new studies on the effects on the cytokine
systems are about to be published. These effects may be enough to justify
the significant improvement of symptoms even over short-term treatments,
well described in the recent Cochrane Review (4). On the other hand, it is
not unconceivable that also the activities on the cartilage may, at least
in part, be responsible for the long-term symptomatic effect,
irrespectively of the radiographic changes, since they may modify the
whole joint environment. Actually, Chard and Dieppe deliberately forget to
mention that the recent report in The Lancet (5) not only describes the
glucosamine sulfate-induced favourable modification of the radiographic
progression of osteoarthritis, but also a significant amelioration of
symptoms after 3 years, clearly evident in both the pain and the function
domains (where is the confusion in the domains of outcome?). These results
have been recently replicated in a second, 3-year, randomised, placebo-
controlled trial whose final results were presented last week at the
European League Against Rheumatism (EULAR) meeting (6).Furthermore,Tim
McAlindon (7) defined the Lancet report (5) a "landmark study" , but Chard
and Dieppe seem to agree with McAlindon only on his previous report (8) on
the inauspicious influence of the pharmaceutical industry in the drug
development. I hope that the latter is not referred only to glucosamine
sulfate, since to my knowledge all modern drugs have been developed by
pharmaceutical companies, who have the expertise and the funds to do that.
The industry has certainly its bias, but thanks to the high quality
standards it has to respect, this may be less than artfully suspected, in
a way that offends thousands of scientists, by Chard and Dieppe.
Finally, the recent Cochrane Review (4) states that glucosamine
trials were collectively as good (if not better) than NSAID trials in
osteoarthritis, with the quality of the most recent studies being very
high: thus the argument of the poor quality of the older trial does not
hold and it would be nice if scientists of the importance of Paul Dieppe
could look fairly at the evidence available.
I look forward to seeing a large, independent clinical trial on
glucosamine sulfate performed by Chard, Dieppe and coworkers: I will be
happy to provide them with the drug supply, provided that they do not
interpret it as a company interference. But probably it was easier for
them to play the role of the censors and stay at the window.
Lucio C Rovati, MD
Chief, Department of Clinical Pharmacology
Rotta Research Laboratorium,
20052-Monza (MI)- Italy
lucio.rovati@rotta.com
References
1. Chard J and Dieppe P. Glucosamine for osteoarthritis: magic, hype, or
confusion? BMJ 2001; 322: 1439-40.
2. Setnikar I, Cereda R, Pacini MA, Revel L. Antireactive properties
of glucosamine sulfate. Arzneimittelforschung 1991; 41: 157-61.
3. Shikhman AR, Alaaeddine N, Lotz MK. N-acetylglucosamine prevents
IL-1 mediated activation of chondrocytes. Arthritis Rheum 1999; 42
(suppl): S381.
4. Towheed TE, Anastassiades TP, Shea B, Houpt J, Welch V, Hochberg
MC. Glucosamine therapy for treating osteoarthritis (Cochrane Review). In:
The Cochrane Library, Issue 1, 2001. Oxford: Update Software.
5. 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: 251-56.
6. Pavelka K, Gatterova J, Olejarova M, Machacek S, Gonzalez C,
Giacovelli G, Rovati LC. Glucosamine sulfate as an osteoarthritis disease
modification agent: a confirmatory, long-term, randomised, placebo-
controlled, independent study. Ann Rheum Dis 2001; 60 (Suppl 1): 57.
7.McAlindon T. Glucosamine for osteoarthritis: dawn of a new era?
Lancet 2001; 357: 247-48.
8. McAlindon TE, La Valley MP, Gulin JP, Felson DT. Glucosamine and
chondroitin for treatment of osteoarthritis: a systematic quality
assessment and meta-analysis. JAMA 2000; 283: 1469-75.
Competing interests: No competing interests
EDITOR-Chard and Dieppe in their editorial (BMJ 2001;322:1439-1440)
conclude "that there is more confusion and hype than magic about
glucosamine". Surely there is confusion, and the editorial is indeed a
good example of this confusion.
It is a gross error defining glucosamine as a "sulphated amino-
monosaccharide". Glucosamine is not "sulphated" and the Authors confound
this chemical entity with the sulphate salt of glucosamine used in the
original proprietary drug to improve the chemical stability of the active
principle. In the disaccharide units of some glycosaminoglycans such as
the chondroitin sulphates, glucosamine or acetylglucosamine may be
sulphated with an ester bond, but these are different chemical entities
and should not be confused with glucosamine.
The Authors state that "it is unclear whether oral glucosamine can
reach chondrocytes in vivo". An early and preferential uptake of
radioactivity was found in the cartilage of the femoral head after oral
administration of uniformly 14C labeled glucosamine in the rat1 and in the
dog2, and recently confirmed in the dog3 using glucosamine traced by 13C.
Rather outdated is the statement that the osteoarthritic cartilage
should not be cured because there are no nerve endings and therefore it is
not the origin of pain. Have the Authors never heard about cytokines
released from damaged tissues that produce pain and inflammation?
Bizarre is the statement that "the most appropriate dose and route of
administration is still unknown" apparently based on the fact that some
clinical trials were conducted also with injectable and local
preparations. The efficacy of glucosamine in daily oral doses of 1500 mg
(of glucosamine sulfate) on the symptoms of osteoarthritis is well
documented by several clinical trials4 and even recently by two 3-year
studies4,5 in which also a structure-modifying effect was demonstrated.
The Authors admit that they do not know how to classify glucosamine:
"Is it a drug, a food supplement, a nutriceutical, or a complementary
therapy?" A minimum of familiarity with international regulation would
have solved their doubt, because glucosamine in the different nations is
classified in one or in another of the mentioned categories. The pivotal
clinical trials were made with glucosamine sulphate regulated as a drug,
i.e. with Health Authority controlled and approved quality and with full
preclinical and clinical documentation, with an approved protocol and with
the results registered in the CRFs. In several nations, including the UK
and the USA, glucosamine as sulfate or hydrochloride is freely available
also as food supplement. As such it is not assessed or guarantied for
quality and content and the promotion in the lay press is often cheeky and
magic. As clinicians, the Authors should have been able to discern the
therapeutic merits of glucosamine based on scientific evidence from the
hypes of unregulated non-medical fantastic promotion. An editorial based
on sound and unbiased chemical, pharmacological, pharmacokinetic and
clinical knowledge would have surely contributed to clear much of the
confusion on glucosamine. Unfortunately this was not the case.
Ivo Setnikar
scientific director
Rotta Research Laboratorium, 20052 Monza, Italy
e-mail: ivo.setnikar@rotta com
1. Setnikar I, Giachetti C, Zanolo G. Absorption, distribution and
excretion of radioactivity after a single intravenous or oral
administration of [14C]-glucosamine to the rat. Pharmatherapeutica
1984;3:538-550.
2. Setnikar I, Giachetti C, Zanolo G. Pharmacokinetics of glucosamine in
the dog and in man. Arzneim-Forsch 1986;36:729-735.
3. Dodge GR, Regatte RR, Hall JO, Borthhakur A, Sarme A, Callaway DA,
Reddy r. The fate of oral glucosamine traced by 13C-labeling in the dog.
Abstract. ACR Meeting, San Francisco, November 2001.
4. Towheed TE,Anastassiades TP, Shea B, Houpt J, Welch V, Hocberg MC.
Glucosamine therapy for treating osteoarthritis (Cochrane Review): In: The
Cochrane Library, Issue 2, 2001. Oxford: Update Software.
5. Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O,
Giacovelli G, Henrotin Y, Dacre JE, Gossert R. Long-term effects of
glucosamine sulphate on osteoarthritis progression: a randomized, placebo-
controlled clinical trial. Lancet 2001;357:251-256.
6. Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati
LC. A long-term, randomized, placebo-controlled, confirmatory trial on the
effects of glucosamine sulfate on knee osteoarthritis progression.
Arthritis Rheumat 2000;43:9(S1908).
Competing interests: No competing interests
Dear Sir,
Chard and Dieppe rightly suggest that larger clinical trials are
needed to clarify the role of glucosamine in osteoarthritis. However,
their points about possible publication bias and drug company sponsorship
of studies surely applies equally to many expensive and potentially toxic
new pharmaceutical agents which come to the marketplace. At least
glucosamine appears relatively cheap and safe. Furthermore, there is no
monopoly on its production. As regards hype, one only has to glance at
pharmaceutical company adverts in medical journals to encounter this. One
also recalls the hype in the not so distant past over new drugs such as
opren and osmosin and their traumatic legacies. Perhaps there is more hope
than hype when it comes to glucosamine.
Competing interests: No competing interests
Being a GP, I have been prescribing glucosamine sulfate for several
years and I can say that most of my patients get moderately but
consistently better. The studies conducted with GS, especially the recent
ones, just confirm what I was observing in my daily practice – a relief in
pain and an improved function.
If additionally I can increase my patient’s probability of having a
slower progression of their OA, it will be great!
Not only my patients, but myself included (I have used glucosamine since
1990) say that glucosamine is a wonderful drug, reducing the pain and
other symptoms associated to the OA.
For the moment I will keep using the drug, glucosamine sulfate, with
the most consistent data for OA treatment and keep looking at all the new
developments.
In conclusion and based on my daily clinical practice, overall I do
not agree with the authors, regarding the value of glucosamine sulfate but
I hope that this discussion will contribute to bring further evidences
into the treatment of osteoarthritis.
Competing interests: No competing interests
Disappointments with any magic bullet intervention might one day
compel what's called medical science to accept that research standards and
retail clinical process needn't operate on exactly the same track. Over-
leaning on clinical study provings that arise from within a midset of
biochemical routines based a highly successful but limited perspective
models create a process skew at the healthcare endpoint..this is within
the actual mind and living bodies of the clients. Solving osteoarthritis
with this agent or probably any other is a poor joke from step one. As one
respondent points out..discourage coagulation and you get benefit
symptomatically. Let's not keep chasing these fairy tales as if they were
a central direct part of the primary task of delivering useful service to
our patients. There are all kinds of sensible ways to address the various
stages of osteoarthritis. Glucosamine might have a role for some but our
market systems so urgent for ego, entertainment and profit keep spinning
nonsense and the public grows more despairing in their pains...
Competing interests: No competing interests
Glucosamine sulphate in osteoarthritis is effective and safe
Editor- In their editorial on glucosamine [1], Chard and Dieppe
complain about the confusion and the inconsistencies in the literature on
the efficacy of glucosamine in osteoarthritis. For instance they do not
understand how glucosamine can cure symptoms of osteoarthritis because
"there are no nerves in articular cartilage". Apart of this curious view
on the origin of osteoarthritis symptoms, the editors seem to ignore that
glucosamine inhibits metalloproteinases, synovial IL-1B, lysosomal enzymes
and the release of NO radicals [2,3,4]. The statement of the editors: "the
published trials do not allow any conclusion about its efficacy” must be
interpreted as personal view based on the first and outdated clinical trials published in the 70 - 80s. The Cochrane Systematic Review [5]
updated
till 1999 comes to a different conclusion, i.e. "There is good evidence
that glucosamine is both effective and safe in treating osteoarthritis".
Consistently the EULAR recommendations (2000) state: “Glucosamine appears
to
be effective for both pain reduction ... and for functional improvement”.
Also the editors neglect the evidence of symptom
modification, in addition to structure modification, found in two long
term studies [6, 7]. Based on this evidence, in my clinic I use
glucosamine sulphate at the daily dose of 1500 mg, as recommended for the
original product, which in Germany is a regularly authorized drug. It is
safe and generally effective, especially in osteoarthritis in not advanced
stage.
Certainly it is not a "miracle" drug, but in the scientific literature I
was unable to find claims of miracles as well as hyperbolic statements.
Frankly I do not understand where the editors have found hype and magic in
the scientific clinical and preclinical literature on the original
glucosamine sulphate. Possibly this occurs in the British mass media and
regards undefined glucosamine preparations available in the UK as food
supplements.
If this is the case, the editors should clearly address their critics
to this abuse and avoid to confuse it with evidence based information. For
this
very reason, it would have been perhaps more appropriate to publish the
article in a tabloid rather than a respected scientific journal.
Prof. Dr. med. Joachim Grifka
Director,
Orthopedic clinic of University Regensburg in BRK Rheuma-
Zentrum,
St. Josef-Hospital, Kaiser-Karl-V.-Allee 3, 93077 Bad Abbach - Germany
e-mail: j.grifka@rheumazentrum-brk.de
[1] BMJ 2001;322:1439-1440
[2] Piperno M, et al. Osteoarthritis Cartilage, 2000;8:207-212
[3] Jimenez SA, Dodge GR. Osteoarthritis Cartilage, 1997;5 (Suppl. A):72
[4] Yaron I et al. Ann. Rheum Dis, 2001,60 (Suppl. 1),OP 0025
[5] Towheed TE et al. The Cochrane library Oxford: Update Software 2001;2
[6] Reginster JY et al. Lancet 2001;357:251-256
[7] Pavelka K et al. Arthritis Rheumat 2000;43:9(S1908)
Competing interests: No competing interests