Kicking Glucosamine to the Evidence Curb

Today’s post is from pharmacist and SBP contributor Avicenna. Here’s his bio and his prior posts.

As a community pharmacist, I’m frequently asked about over-the-counter (OTC) and natural health products (NHPs) for the treatment of different chronic conditions. This consultation can be complicated by a reluctance for consumers to seek a physician’s advice (and a diagnosis) before beginning therapy. As a partner in the health care system it’s important to give both credible, science-based advice, while ensuring a patient’s primary care physician is aware of the consultation and recommendations.

Arthritis pain is a common complaint, and I’m regularly asked about glucosamine, and sometimes chondroitin (which it is often co-packaged with). As is true for most natural products, glucosamine’s popularity is not related to persuasive clinical evidence. Rather it seems to be secondary to perceptions of efficacy, driven by personal experience, anecdotes and persuasive marketing.  However, unlike many other supplements, glucosamine has been extensively studied in clinical trials, and is at least plausible as a pain reliever for conditions affecting joint articulations, such as osteoarthritis (OA).  The evidence, unfortunately, is largely contradictory, and on balance, disappointing.

Anatomy of an Articulation

Osteoarthritis is a common debilitating condition of a certain type of joint, called synovial joints. These joints make up most of the movable articulations of the body and are characterised by an articular capsule and synovial lining that surrounds the fluid-filled synovial cavity. This fluid functions much like motor oil; It’s the joint’s lubricant. The opposing ends of the two articulating bones are lined by cartilage which acts like a shock absorbent and reduces friction between bones. If you sample a piece of cartilage and observe it under a microscope, you’d see cells called chondrocytes bathing in a matrix composed of collagen fibers, a substance rich in proteoglycans and elastin fibers. Now these proteoglycans are themselves composed of a protein bound to glycoaminoglycans (GAG)  – a chain of repeating carbohydrates compound (e.g., hyaluronan).  The role of proteoglycans is to act as binding force in articular tissue. GAGs include chondroitin, heparin and keratan.

What is Osteoarthritis?

Osteoarthritis is the most common joint disorder. In older adults, around one in three have knee arthritis. Although its cause is not well understood, osteoarthritis seems to be caused mostly by articulation “wear and tear”, such that nearly everyone by age 70 has some degree of OA. Other factors for OA include genetic inheritance, behavior influences, and obesity. Chronic pain in the knee, hip, fingers and of the lower back are typical symptoms of osteoarthritis. Joints in the as wrists, elbows and ankles are less commonly affected.

After injury (e.g., trauma or repetitive joint overuse), changes start to occur in the articulation itself. First, cartilage cells, called chondrocytes, start to change their metabolism and cause an overall depletion in proteoglycan that leads to damage to the collagen matrix. Then the cartilage swells and loses its ability to absorb joint pressure.  As a consequence of cartilage loss, the bone surfaces of the articulation start to wear off which result in deformed bone structures of the joint.

Pain from OA is activity-related, with onset during or just after joint use, and then gradual  resolution. In the early phase of the condition, pain is episodic and happens after a day or two of overuse of the affected articulation. In severe OA, pain can be continuous. Occasionally, morning stiffness can occur, typically resolving within 30 minutes.  While some patients may have physical changes in the joint  –  particularly joint space narrowing  –  that can be seen on x-rays, a diagnosis of mild to moderate OA is usually based on a physical examination only.

The important and measurable outcomes in OA are global pain as measured by a visual analog scale (VAS), pain function as measured by the WOMAC or the Lequesne Index, and occasionally, joint space narrowing (JSN) as measured using x-ray imaging. It should be noted that the physical changes seen on x-rays do not accurately predict the severity of symptoms and little is known about the natural progression of radiological evidence of OA.  For these reasons, most trials use pain outcomes as clinically important outcomes to treat.

What are Glucosamine and Chondroitin?

Part of the glycoaminoglycans (GAGs) family of substances found in various connective tissues but concentrated in cartilages, glucosamine and chondroitin are oral or topical supplements available without a prescription (in most countries) and traditionally used for osteoarthritis, rheumatoid arthritis, temporomandibular joint arthritis, knee or back pain.  While chondroitin is typically formulated as the sulfate form (CS), glucosamine is formulated either as the sulfate (GS) or hydrochloride form (GH).  Glucosamine is a molecule of an amino sugar (amino-monosacharide), extracted from shrimp, lobster and crab shells, that the body uses to link another sugar (monosacharide or hexose) to form a unit of a long chain which are GAGs.  Chondroitin is the name of a specific GAG, which does not contain a glucosamine as an amino sugar.

The purported (but not demonstrated) mechanism of action is as follows:

• keratan and hyaluronic acid in cartilage (which contain glucosamine) and synovial fluid are reduced in OA patients
• replacing these with glucosamine supplements might alter chondrocyte metabolism or otherwise have protective effects on cartilage tissue.

Potential mechanism of actions include direct stimulation of chondrocytes, incorporation of sulfur into cartilage, and protection against degradative processes within the body through altered gene expression.  However, these are theoretical mechanisms, based on in vitro or animal studies. In humans, it not even known if supplementation has any effect on the joint concentrations of glucosamine or chondroitin.

We do know that oral forms of glucosamine is well absorbed into the system and chondroitin isn’t, but not much else is known about the pharmacology of these products. The bottom line is this: glucosamine is not an essential compound since our body produces nearly all of it; small additional amounts ingested are not expected to make much difference; it is not known if ingested glucosamine reaches the chondrocytes; we do not know the preferred route of administration (topical, oral or injection) or the optimal dose; and the exact mechanism of action is yet unknown.  A lot of “ifs” for a product without clearly demonstrated efficacy.

Confusingly, some scientists believe that glucosamine is not the active part: the sulfate form the glucosamine sulfate (GS) oral product might be the key. This is quite possible, as was pointed out at Science-Based Medicine, the amount of glucosamine found in supplements represents about 0.001 to 0.0001% of the total amount naturally produced by the body.  Supplements are truly just drops in the bucket.

Strength of Evidence

The confidence we have in the effectiveness of any treatment, drug or otherwise, depends on the strength of the evidence. A prescription medication that would typically be considered proven effective typically has a moderate to large effect size, consistently seen in rigorous placebo controlled trials for varying types of conditions and outcomes. Conversely, a medication that is deemed ineffective usually has no significant effect, compared to placebo, for most conditions and clinically important outcomes. In addition to studies demonstrating a favorable safety profile, this is the general standard of evidence required  for approval by regulatory agencies of prescription drugs. However, it’s important to keep in mind that much, much lower standards exist for products approved as supplements (USA) or “Natural Health Products” (Canada) where there is effectively no efficacy standard in place.

Health professionals have a professional and ethical practice with the limits of science. So while we agree that medications aren’t perfect, and the process we use to evaluate them has it’s problems and limitations, using unproven or inconclusive treatments is not an acceptable or appropriate substitute. A treatment that does not have convincing evidence has no place in an science-based practice.  And this point is critical: medications that work typically have consistent benefits clearly seen in the large majority of trials.

What does the evidence tell us?

Although the plausibility of glucosamine’s therapeutic effect remains to be established, we’d be willing to look past this if, having been evaluated, the data were very persuasive. There have been numerous trials done since the 1980’s but most of them are plagued by major limitations, such as weak methods, industry funding, and usually small sample sizes.  Seperating these flawed studies, we are left with about two dozen reasonable  trials that examine glucosamine’s efficacy.

A  2000 JAMA review by McAlinder et al. found an overall moderate to large effect in terms of pain relief and functional improvements in 15 trials, of which most are plagued by limitations (inadequate allocation concealment and manufacturer sponsorship).  Most importantly, the authors found less of an effect when they included above average-quality trials.  In contrast, a 2001 Cochrane review (updated as of 2008) found inconclusive positive effects if they considered all trials on some outcomes of pain and functionality scores (Lequesne Index, but not WOMAC scores), but ultimately found insignificant differences when they analysed only the better trials (adequate allocation concealment and intention-to-treat protocol) or when they analysed data from trials using a non-Rotta glucosamine product (potential sponsor bias).  Initially it seemed the evidence was mixed; one review still found benefit after excluding the weaker trials while a second didn’t.

But that’s not the end of the evidence trail: in 2003, Reginster, MD, published a meta-analysis of 15 trials  –  7 for glucosamine sulfate and 8 for chondroitin sulfate  –  which showed beneficial effects in global pain (VAS) and functionality (WOMAC,LI), but minimal joint protection; to the point of being clinically insignificant (0.27 mm less JSN).  Critically, this review included poor chondroitin trials and most glucosamine trials were either medium quality (JADAD score of 3) or had very high drop-out rates.  Unlike the JAMA and Cochrane reviews, no separate analysis was done to see if the effects diminished in the best trials.  Also, the authors failed to disclose previous industry funding from a manufacturer (Rotta Research Laboratorium, Italy) of glucosamine products.  Despite (or possibly because of) these limitations, this review does suggest benefit.

What does the latest and best evidence show us?

Revealing analyses by Vlad et al. on glucosamine, and concurrently by Reichenbach et al. for chondroitin, looked at the studies and their methods, industry involvement or sponsorship, industry-affiliated authorship, or other factors could explain why the effect sizes are so varied from study to study.  Despite finding a significant benefit for glucosamine or chondroitin, the high heterogeneity  –  strong differences in methods, treatments or results  –   between the trials make the pooling of results for meta-analysis inappropriate, because it casts doubt on the size or direction of the observed effect.

Specifically, Vlad et al. found:

There is sufficient information to conclude that glucosamine hydrochloride lacks efficacy for pain in OA. Among glucosamine sulfate trials, enough heterogeneity existed such that no definitive conclusion about efficacy is possible. This heterogeneity appeared to be most prominent among trials with industry involvement. Explanations for the effect of industry involvement in trials include differing efficacy of glucosamine sulfate preparations (including the possibility that the Rottapharm glucosamine sulfate product is more efficacious than others), inadequate allocation concealment in trials with positive results, unidentified factors that we did not investigate, and bias due to industry involvement.

Reichenbach et al. reached similar conclusions.  The implications of this evidence suggest that there are many confounders which likely exaggerate the effects seen in most trials of glucosamine and chondroitin, including the formulation used, industry involvement or poor methodology.  This means that the positive effects seen may, at least in part, be due to poor quality trials: They are identifying an effect when none likely exists.

Lastly, a recent 2011 BMJ review found 10 large and most rigorous trials which had absence of global pain effects (VAS) for glucosamine and chondroitin alone, or when taken together, and no difference in joint space narowing (JSN).  The authors decided to include trials with 100 or more patients per treatment arm because they calculated that sample size this large would be powered enough to find a small to moderate effect size equivalent to a 1 cm  difference in a 10 cm visual analog scale (10-pt VAS).

It is also worth highlighting the results of undoubtedly the largest and rigorous of the glucosamine and chondroiting studies: the GAIT trials. These studies looked at patients taking glucosamine and chondroitin sulfate for 2 years, to treat knee OA, and found that they did not affect WOMAC pain measures or preserve joint space. To summarize it all quite simply: the bulk of the best evidence  –  multiple meta-analysis and at least one very large rigorous RCT  –  suggest that there is no difference between glucosamine or chondroitin and placebo effects.

Safety Profile

The main side effects from glucosamine are mild gastrointestinal (GI) symptoms such as gas, abdominal bloating, and cramps.  Initial concerns based on case reports and preliminary evidence suggested that it might affect blood sugars, however clinical evidence does not support adverse metabolic effects in type 2 diabetics.  Even if glucosamine is extracted and purified from seafood, there seems to be some evidence that people with shellfish allergies can take glucosamine products, especially if we consider that since the antigen responsible is found in the meat of the shells. However, people with diabetes or severe shellfish allergies may wish to seek advice from a health professional.

Importantly, glucosamine increases the blood-thinning effect of anticoagulants (e.g., warfarin) and has led to cases of increased INR, bruising and major bleeding episodes. It should be used with caution and monitoring, if taken at all.  Some chemotherapy may also be affected by glucosamine.

Glucosamine has been evaluated to be safe in studies for up to 2 years, but caution is advised in patients with renal dysfunction, active bleeding disorders (e.g. ulcers) or people taking aspirin or anti-inflammatories.  It is also advisable to discontinue use  14 days before any dental or surgical procedures. There is an absence of safety data in children and pregnant or breastfeeding women: it should be avoided.

Summary

There’s little data on what glucosamine does in the body and how it’s used. There are several unsupported theories about how it might protect the joints, but none with regards to pain relief.  One might reasonably ask how glucosamine relieves OA pain if its actions are supposedly located only in cartilage tissues, while pain sensations are thought to generate from extra-articular tissues (i.e. surrounding tendons, muscle, etc).

While safe and reasonably inexpensive, (year supply 75-150 CAN$), there’s no persuasive evidence to suggest this product has any meaningful effects.  Interestingly, arthritis sufferers can avoid the expense entirely.  This rather ingenious randomized double-blind discontinuation trial showed that patients deemed “responsive” to glucosamine, did not fare worse when they were switched to a placebo.

At first glance, the studies are contradictory. It’s a cherry picker’s dream. But when we consider all the evidence, a science-based evaluation suggests the following:  Although earlier studies suggested glucosamine might have an effect, they were of such poor methodologic quality that their results were questionable. The highest quality evidence contradicts earlier studies and suggests that this product has no meaningful effects. This is unfortunate – we’d all like a safe and effective product to treat the pain osteoarthritis. Glucosamine isn’t it.