[Mikey T]

gloucosomine in all it varied forms each touted as better than the next is general coupled with chondroitin sulfate in OTC supplements. Chondroitin Sulfate has been more extensively studied than gloucosomine and from the limited amount I have seen the results have been positive.

Results of a multicenter study of chondroitin sulfate (Condrosulf) use in arthroses of the finger, knee and hip joints"The decrease of pain was revealed to be statistically significant; serious side effects were not to be observed during the study. At the beginning of the observation period patients suffered from overall severe pain, and therefore the decrease of pain down to a level, which could not have been achieved by NSAID therapy alone to a greater extent, is of special interest. The results of this trial represent the first office based Austrian data on CS-therapy. In conclusion it could be demonstrated that a significant reduction of the daily NSAID consumption was possible by concomitant CS-therapy, without the risk of deterioration of the patients' symptoms. The 97% compliance does not give evidence for drop-out bias. Moreover, the results of this trial are comparable to other international double-blind, in part placebo-controlled studies, concerning CS-therapy, indicating beneficial results in the treatment of osteoarthritis."

Glucosamine, Chondroitin Sulfate Clinical Trials

Six of the 15 trials involved glucosamine and nine used chondroitin. The team used only trials of four or more weeks in duration because of evidence that it may take several weeks for the compounds to have a therapeutic benefit. Only one of the 15 trials was completely independent of manufacturer support.

The team's analysis of the trials had two key facets: a quality assessment to evaluate each of the clinical trials and a meta-analysis, which enabled them to integrate the data from different trials. The trials studied had many methodological flaws and biases, including those that tended to inflate the benefits of the compounds. The team was also concerned that trials having small or negative effects might not have been published, but after contacting study authors and other experts, they could locate no unpublished negative results.

Based on data from the trials, the researchers calculated an overall \"effect size\" for the two compounds: the figure 0.2 is considered a small effect; 0.5, moderate; and 0.8, large. The researchers calculated an effect size for glucosamine of 0.44 and for chondroitin sulfate of 0.78, but reported that these values \"were diminished when only high-quality or large trials were considered.\"

The study was published in the March 15, 2000, issue of the Journal of the American Medical Association (JAMA). Dr. McAlindon recommends that additional, rigorous, independent studies be done of these compounds to determine their true efficacy and usefulness.

Has any one seen any results from the NIH study

Effects of Oral Glucosamine on Insulin and Blood Vessel Activity in Normal and Obese People
"This study is currently recruiting patients."

 

[Mikey T]

"Studies that evaluate pain as an endpoint aren't all that useful--"

Aren't the most consumed and prescribed medications for osteoarthritis - pain relievers, without any possibility of joint repair? There are currently studies going on to see if Nsaid's while relieving pain actual contribute to joint degradation or the increased degradation associated with Nsaid's is because the joint is used more. A simple pain relief mechanism effective as Nsaids that does not have increased joint degradation, is a major advance in the treatment of arthritis and perhaps other causes of joint pain.


It is important to point out that Glucosamine has frequently become a generic term for A natural pain-reliever for joint pain. Most time any concoction referred to as Glucosamine also contains chondroitin Sulfate and some times MSM. It could be 1, some, all or none, of these products actual produces a scientifically verifiable result but when used in some combination new. This require quite extensive testing of all the permutations that won't be completed for some time.

Most of the studies have been of short duration also so other than pain it may not be possible to see measurable improvement or decline of the joint with use of the product. The NIH is conducting a phase three study of glucosamine, chondroitin sulfate both separately and combined against a placebo and celebrex as controls. When completed and published it should provide a clear understand of the value of these product

There are also various forms of Glucosamine such as Glucosamine HCL and Glucosamine Sulfate. Each with it's own proponents which just adds further confusion.

I have always found it curious the criticism of test/studies on alternative therapy's as flawed simply because they were conducted sponsored i.e. paid for by the manufacture of the product. Correct me if I'm wrong but isn't ever prescription drug ever OK'd by the FDA be done so either exclusively or mostly based on studied conducted, sponsored, paid for by the drug company? Yet we don't seem to have a problem with that.

 

[Mikey T]

for those interested links to studies on Glucosomine with other than pain as an endpoint
All done after 1998 and the meta-study by Timothy E. McAlindon, DM

Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial.
J. Reginster, R. Deroisy, L. Rovati, et al. The Lancet;357:251-256 (January 27, 2001). [Correspondence: Dr. Jean-Yves Reginster, Bone and Cartilage Metabolism Research Unit (WHO Collaborating Center for Public Aspects of Osteoarticular Disorders), University of Liege, B-4020 Liege Belgium.

"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). There was 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. As assessed 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."

Glucosamine Sulfate Use and Delay of Progression of Knee Osteoarthritis
A 3-Year, Randomized, Placebo-Controlled, Double-blind Study Karel Pavelká, MD, PhD; Jindriska Gatterová, MD; Marta Olejarová, MD; Stanislav Machacek, MD; Giampaolo Giacovelli, PhD; Lucio C. Rovati, MD Arch Intern Med. 2002;162:2113-2123.


And an explanation why glucosamine sulfate can work but not all glucosamines and some fators that might effect clinical trials of GS that have not been fully understood
Sulfate could mediate the therapeutic effect of glucosamine sulfate

These results do not prove that glucosamine sulfate improves osteoarthritis, but considered with other data, they do provide a plausible biochemical mechanism for its reported beneficial effects. This hypothesis is clinically relevant because it predicts that nonsulfate salts of glucosamine will be ineffective and that renal function, diet, and concurrent acetaminophen therapy could confound clinical trials of this therapy

[ January 16, 2004, 09:09 PM: Message edited by: Toughynutter ]

 

[Mikey T]

I don't think an sane person would conclude glucosamine a miracle cure but then again "miracle cure" has been associated with Nsaids the tradition even though studies link Nsaid use with increased joint degeneration cause because the cause is unknown and could be as reasonable and plausable the less pain=more use=more degeneration]
I don't know about you but if I were an OA sufferer I would be a bit concerned.


As noted earlier there are many reason a particular study may not reach a scientifically valid conclusion even though the trial was conducted with the best intention and at the time the best controls possible. Defferences in culture i.e. diet can play a role in how a drug is matablized, the age. and severity of the condition. In OA drugs that rely on rebuilding the joint may not fair as well with older more degerated joint than those with slight or moderate dengeration. In a smaller trial it is impossible to control for all the variable. So some failure and descrepencies are to be expected.

Hopefully the phase III large RCT trials of the NIH which I under stand might have some results by sometime in 2005 will put the matter to bed

 

[Mikey T]

That's exactly right! It's about what works, based upon sound evidence. Doesn't matter where or how it originated, if it's shown to be effective

If it were only that simple. I found the following three discussion/correspondence on Clinical Trials in specific clinical trials on CAM to be quite thought provoking. Of interest is the Notion of bias by scientifically oriented physicians to require less proof for the effectiveness of those therapy to which the understand how it works.
Complementary or alternative medicine: the need for plausibility
"The correct way to meet these challenges is to put CAM therapies though the same plausibility-building process that conventional therapies undergo before they come to the stage of definitive RCTs. The premise of this strategy is that a gain in plausibility is not proof. (Conversely, lack of proof does not exclude plausibility.,) Rather, as plausibility increases, the case for definitive RCT testing becomes stronger. The purpose of this research is to groom CAM therapies into serious candidates for definitive testing by RCTs"

I think it is safe to say that is the stage GS is currently in. It is plausable from the numerous but less than definitive trials that GS is effective. We just have to wait for the definitive RCT test that are going on now.


Response by Lloyd B. Oppel to Investigating CAM

L. John Hoffer response to Lloyd B. Oppel

 

[Mikey T]

All of these variables (diet, age, disease stage, cultural practices) are amenable to examination using randomized, controlled, double-blinded trials.

Certainly true but when the basic principles of how a therapy works are not clearly understood one can never be sure that every or even just the significant variables that may effect a particular therapy are controlled for. At best one can control for the factors that have proven in general to effect a large number of therapies.

"

Of interest is the Notion of bias by scientifically oriented physicians to require less proof for the effectiveness of those therapy to which the understand how it works.

This position doesn't appear to be well-supported by the author's arguments; "

While not well support with specific examples I do not think, however, the follow statement can be easily overlooked.

"But what formula determines which therapies are accepted and which ones rejected by conventional medicine? Generally speaking, a therapy joins the canon of conventional, accepted therapies either after its efficacy has been demonstrated in well-designed clinical trials, or because its biological rationale fits plausibly within the scientific biomedical conceptual framework, even if proof of its efficacy is lacking — it "makes biological sense." The latter stipulation is necessary, because many conventional therapies are unproven but still not considered CAM. "

The implication is very clear because we have a clear understanding of how a therapy should work it is not always necessary to prove it's effectiveness for it be consider a tradional therapy. That is certainly a much lower threshold of proof.

 When patients with the same disease stage were compared, glucosamine was not demonstrated to have a statistically significant effect in either the group with severe disease (defined as comparatively narrow joint space width at the beginning of the trial) or the group with mild disease (defined as comparatively greater joint space width at the beginning of the trial).

Maybe I am missing something from the abstract but I fail to see how this conclusion can be reached.
"In the highest quartile of baseline mean JSW (>6.2mm){mildest}, a joint space narrowing of 14.9%{mean} (17.9){Standard deviation} occurred in the placebo group after 3 years while patients from the glucosamine sulfate group only experienced a narrowing of 6.0%{mean} (15.1){sd}"

Note item's between{} added by me for clarification

It has been some time since I have been immersed in statistical analysis to calculate for myself whether the difference between a 14% joint space narrowing for placebo and only a 6.0% for GS is of statistical significance for a trial of this size. Unlike with the the most severe form of OA there is no mention that the results were not of statistical importance in the abstract. It does say "In patients with mild OA, i.e. in the highest quartile of baseline mean JSW, glucosamine sulfate use was associated with a trend (P=0.10) towards a significant reduction in joint space narrowing." This does not seem to support the conclusion that mild forms of OA were not positively effected by GS over and above that of a placebo.


It is far to early to come to a definative conclusion about the effecacy of GS. Learned and knowledgeable people can reach different well support opinions on what that outcome will eventually be. Given that the potential for an adverse reaction from GS is negligable, even for diabetics, see the use of GS with other therapies for the treatment of OA and/or other joint problems does not appear to be unwarranted. There is no evidence of it being harmful, or interfering with the effectiveness of other medications and it has demonstrated effectiveness in some studies.

More problematic than GS itself is that nutraceutical in general are not effectively regulate as to potency. Repeated studies on this clearly show that manufactures routine overstate the potency of the pills. This is true of supplements like GS and Vitamins which throws doubt into any therapy that uses nutaceuticals.

What You Need to Know When Buying Nutritional Supplements"A study of various vitamin E products by laboratory analysis showed that a large percentage of the supplements had less vitamin E than stated on the label. A few of the products had no vitamin E in them at all!"

 

[Mikey T]

Certainly, not all standard therapeutic practices are evidence-based, and much work remains to be done.

My opinion is that there's no \"unproven but not CAM\" category; there's simply proven and unproven.

I'm confused

Statistical significance is defined as a p value of <0.05. The use of the word \"trend\" is an acknowledgment that the findings did not reach the level of statistical significance.

Is it not fair to say that just because a RCT did not reach a the level of statistical significance that it is not proof of failure of a therapy. Factors like trial size greatly effect the needed degree of improvement require over a placebo to reach the level of statistical significance. Does not a finding that approaches but not reaches statistical signifacance merit further study?

"

Learned and knowledgeable people can reach different well support opinions on what that outcome will eventually be.

And so can people with crystal balls."

I am delighted to learn that you believe people with crystal ball can reach well supported opinions.

Of additional interest is the existence of bias against publication of negative studies. Negative findings are under-reported, leading to misleading meta-analyses and summary reviews.

It is not just negative finding but inconclusive ones as well. Meta-analysis of many similar inconclusive studies could be conclusive. Selective publication is a problem that is easily solved.

"as if this legitimizes the use of unproven modalities" Are not the use of unproven modalities acceptable when there is an absence of proven ones or in cases where proven modalities are ineffective? Is there no value in trying to illicit the placebo effect in conditions with no known cure? I think for the most part this is where GS use falls or has there been a therapy for OA that is proven to correct/or even moderate the condition other than just control pain and inflamation.

 

[Mikey T]

Certainly, not all standard therapeutic practices are evidence-based, and much work remains to be done.

My opinion is that there's no \"unproven but not CAM\" category; there's simply proven and unproven.

What would you call a unproven Standard Practice?
Is it not unproven but not CAM? Oh unproven. there are proven and unproven, There are those that there is evidence for and those that are unsupported by evidence. There are standard practices and there are CAM's and never can any of these categories be used together Such as Proven standard Practices, or Unproven Standard practices. standard practices supported by evidence, standard practices unsupported by evidence.

there are positive and negative trials; trials that support a hypothesis in a statistically significant manner or trials that don't.

When interpreting trial data I don't think the black and white is always the correct approach. To discount the results simply because the trial size is to small to prove to statistical significance is not appropriate, especially when considering what warrants further evaluation. It is important to note that A negative trial does not prove the ineffectiveness of a therapy, often times it is the result of an insufficient sample size as in the case of Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate. Where two subsets of a previously successful trial were examined and while difference were found they were not statistically significant. I don't think it is fair to say that in this particular case "upon re-analysis, become negative," When the subset, in a positive clinical trial with the largest positive effect, is examined on its own no longer yields statistical significant result, it is simply because the sample size had become to small to do so. It is a clear Indication that further investigation is needed.

If I'm not mistaken statistical significance is on the order of 97% certainty that the variance between two or more sets of data is not the result of normal randomness. Therefore a negative trial is not proof of failure of a therapy. Like the old adage "you can't prove a negative" it is difficult to prove a therapy is ineffective, only that it is not proven effective. Only when the results are worse than a placebo to a statistically significant order, harmful, can a therapy be called ineffective. To some extent this leads to the proliferation of quack medicine and the need for evidence based therapies but the question becomes what level of proof and degree of certainty is required. Certainly less than half the standard practices reach the level of proof by RCT while 75% or more have some evidence of effectiveness. GS has RCT evidence but not a large phase III trial that is consider by most as proof.

I enjoyed the links on Evidence based medicine.
is it not fair to say given the criteria accepted as evidence for some standard practices that there is evidence for prescribing GS for OA and/or joint pain? Evidence is not proof.

Are you agreeing with Biscuit, that the positive effects of glucosamine are due to placebo effect

Nope only that it is an unproven therapy that has some evidence to support its use to treat conditions that there is currently no proven cure.

Joint replacement. Edited to add that autologous osteochondral (bone and cartilage) grafting and chondrocyte (cartilage cells) implantation are also being investigated, as is the use of biphosphonates, a class of medication currently used in the treatment of osteoporosis, which modulate bone formation.

Given the invasiveness, pain, long term prognoses , ie. 10-20 life of replacement joint, Joint replacement is reserved of only the most severe cases and where other mitigate factors like patient's weight don't rule it out. While technically a cure it is one whose side-effects are so severe that its use is only warranted in the most severe cases. As for the other, how do they differ from GS where there is some evidence of effectiveness but not proof?

It's my opinion that it would be unethical to represent a practice known to be ineffective as effective, in an attempt to produce a placebo effect.

What if the practice is not know to be ineffective? Say an unproven therapy, one there is debate on it's effectiveness or one has doubt about it effectiveness.

Some patients who have exhausted their options elect to enroll in Phase I or II trials of possible new therapeutic interventions, which are under investigation, and by definition, unproven. These patients provide informed consent and these studies are reviewed and approved by IRB's.

Not all patience have access to trials or meet the criteria. I don't think it is inappropriate for a MD to prescribe a therapy for which there is some evidence but not proof of effectiveness, provide that the patient is made so aware. Nor is it the governments business to prevent its citizens from deciding what they consume.

purveyors of unproven practices and nostrums to prey upon patients with chronic, incurable conditions

it is not preying upon patients if they are made aware of the evidence for and against the effectiveness of a therapy. Hope is a factor in mitigating symptoms. To dismiss it is not being fair to the patient.


At some point it comes down to the eternal debate between the "Art" of medicine and the "science" of medicine. What is ethical and reasonable in the absence of or with limited scientific knowledge.

Selective publication is a problem that is easily solved.

Oops typo should have read "not" as was clearly pointed out in links provided by Betsy earlier

Not a battle from my perspective; rather, an opportunity for education.

Could not agree more, and doing I damn fine job of it