The rise and (sort of) fall of glucosamine

From alternative medicine golden child to class-action goldmine, what happened to glucosamine?

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A decade ago, glucosamine was the bees’ knees as far as over-the-counter treatments for joint pain and osteoarthritis went.

At one stage, around 20% of Australians aged 45 and over were using it, and 85% of GPs and 95% of community pharmacists recommended it.

The problem, as we know now, is that it doesn’t actually work. Early research showed promise for some formulations, but it was not borne out in subsequent studies. Doubt about those initial results started creeping in. The quality of the early trials was questioned. Were there really any significant benefits?

Numerous papers (including some in veterinary science, because pets commonly suffer from osteoarthritis) came to different conclusions: yes, no, potentially. It depends on the formulation. Given the relatively low cost and safety, many said, it was worth a shot for a limited time to see whether it worked for individuals.

Subsequent independent research, such as a 2014 study led by Sydney University’s Associate Professor Marlene Fransen looking at joint-space narrowing and pain for knee osteoarthritis, found no greater effect from glucosamine than placebo.

An Australian review led by rheumatologist Dr Xiaoqian Liu, also of Sydney University, examined evidence for dietary supplements used for treating osteoarthritis. The review found that some natural therapies (Boswellia serrata extract, curcumin and methylsulfonylmethane, or MSM) had clinically important and large effects in the short term. But glucosamine, which again showed no greater effect than placebo, wasn’t among them.

There’s research – and there’s research

It turned out that those early studies, the ones that showed such promise, were often of very low quality and had a high risk of bias – perhaps not surprising given they were frequently funded by industry.

“The original paper was from Rottapharm [the company that made crystalline glucosamine sulfate], suggesting that crystalline glucosamine sulfate was effective for pain, for cartilage loss, and even for joint replacement,” says Professor Graeme Jones, head of the musculoskeletal unit at the Menzies Institute for Medical Research. Professor Jones has also looked into glucosamine efficacy and found it no better than a placebo.

“But other authors have tried to reproduce that data over many years with glucosamine sulfate, which is similar, and glucosamine hydrochloride, with really very little in the way of success.”

He says what concerns him most is that Rottapharm had declined to have their data independently verified.

“I don’t see why they’ve got any reason to be scared,” he says. “If you’ve got a data set and you’ve analysed it correctly, what is there to fear from sending it to someone else to have a look at it? I’ve certainly done that with some of my trials.”

The glucosamine story has a geographical dimension too. Initially, prescription-formulated crystalline glucosamine sulfate was recommended in Europe. But it was not recommended in the US, where it was an over-the-counter medication, and where they conducted their own “very, very expensive” trial, the NIH Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) amid what Melbourne-based rheumatologist Dr Daniel Lewis describes as “a political storm”.

“All the studies up to then had been done with glucosamine sulfate. And for reasons which no one still can explain, they did the expensive American trial with glucosamine hydrochloride. So, of course, when it didn’t work, the nutraceutical companies said, ‘well, of course it didn’t work. You should have used sulfate’. And they’d spent so much money that the clinical trial was never done with glucosamine sulfate.”

And that’s how it went for a while, recalls Dr Lewis – industry trials, largely done without placebo, said it worked, and independent trials showed that it didn’t.

The end of the affair (sort of)

This lack of good-quality evidence supporting its efficacy eventually led to peak medical and arthritis bodies and guidelines to more or less shut the door on glucosamine as a treatment for osteoarthritis (some more firmly than others), if they hadn’t already done so.

In Europe, the use of glucosamine sulfate was in EULAR’s list of 10 recommendations for management of knee osteoarthritis in 2003. In its 2018 update for hand OA it was framed as “more of a suggestion than a recommendation to use”.

The Osteoarthritis Research Society International (OARSI) designated it as a “treatment … of uncertain appropriateness” in 2014 and didn’t even mention it in its 2019 update.

The American College of Rheumatology was always sceptical. Its 2000 guideline update stated it was premature to recommend glucosamine because there were “considerations” about the methodology and design of existing studies.

In 2012, it made the then controversial move to conditionally recommend that patients with knee OA should not use glucosamine. And it went further in its 2019 guideline: “Glucosamine is strongly recommended against in patients with knee, hip, and/or hand OA.” Studies that showed an effect were often sponsored by industry, it said, and those with least bias didn’t show any advantage over a placebo.

Peak bodies followed suit. The Australian Rheumatology Association and Arthritis Australia have both said in a recent statement that glucosamine “does not help people with osteoarthritis”.  To make it perfectly clear, “high-quality evidence shows little or no benefit from glucosamine or chondroitin for OA”, Arthritis Australia says on its website.

And the RACGP guideline tells GPs not to bother with it for patients with knee and hip OA. “With pooling (where possible) of results from the nine available RCTs, no benefit for pain, function or joint space narrowing was demonstrated,” the RACGP says.

Still popular – just check the shelves

Glucosamine is still wildly popular, regardless. A search on the Australian Register of Therapeutic Goods (ARTG) brings up hundreds of individual listings. And it’s set to make manufacturers more money than ever – they can feel it in their bones. Market research on the exact size of the expected windfall varies, ranging from an anticipated global market value of more than $200 million to a massive $830 million by 2027.

“The market is witnessing a shift toward the use of nutraceutical and dietary supplements such as glucosamine to treat arthritis without side effects,” one glucosamine forecast report states. This, they say, is driven by ageing populations, the use of “combination therapies” and health industry e-commerce. Another company cites the increase in obesity and sedentary lifestyles related to developing economies.

“It’s still incredibly commonly used,” says Professor David Hunter, co-director of the Sydney Musculoskeletal Health Flagship at the University of Sydney. “We did a survey 12 to 18 months ago of a large community-based sample and I would say 30-40% of people have tried or are on glucosamine for osteoarthritis.”

The association between glucosamine and osteoarthritis pain relief is tenacious, despite the evidence. Professor Hunter says his patients tell him it’s been recommended by their peers, and others by someone in their local chemist.

However, he says he doesn’t see the same number of “outlandish claims” made about the substance as there were even five years ago.

Mixed messages: the role of pharmacy

With vitamins and dietary supplements being sold through pharmacies, both the Pharmacy Guild and the Pharmaceutical Society of Australia (PSA) have clear positions on complementary medicines.

The PSA Complementary Medicines Position Statement cites the Code of Ethics for Pharmacists that “a pharmacist will only purchase, supply or promote any complementary medicine or herbal remedy where there is credible evidence of efficacy and the benefit of use outweighs the risk”. And it says “the pharmacist must ensure the consumer is provided with the best available information about the current evidence for efficacy”. It adds that pharmacy assistants should also be supported in understanding the role of evidence.

The Pharmacy Guild’s policy on complementary medicines and therapies says: “[Pharmacists] … have a duty of care to be aware of available clinical evidence that supports the therapeutic and marketing claims made about all products sold in their pharmacies. Therefore, pharmacists should consider the efficacy and safety of complementary medicines sold within their pharmacy, using an evidence-based approach and utilising available clinical/traditional-use information.”  

Both the Pharmacy Guild and the PSA were invited to comment for this story. The Guild provided its existing statement and the PSA has not responded at time of publication.

In its statement, the Guild says that complementary medicines should be better regulated and it is particularly concerned about the lack of independent assessment prior to listing on the ARTG. It is not alone.

ARTG listing doesn’t mean it works

Unlike the rigorous process for prescription medicines, when it comes to listing most complementary medicines, there is no pre-market assessment of evidence and very little post-market surveillance.

However, any claims made are still supposed to be supported by evidence and comply with the Advertising Code.

Professor Harvey has complained to the TGA (though his experience suggests those complaints “never go anywhere”) that glucosamine supplements are still on sale, and still making unsubstantiated claims, despite the lack of evidence that they work.

“The companies just tick some boxes to say yes, yes, yes, we hold evidence and we’ve followed good manufacturing practice.”.

Meanwhile, he points out, glucosamine continues to be heavily marketed, regardless of the fact that the evidence no longer supports its use, and he believes they shouldn’t be listed on the ARTG.

“It’s hard for doctors to keep up to date. The irony is that the [previous] government has just defunded the National Prescribing Service, which was one way for doctors to do so.”

The same is true for pharmacists, he says, who, with all the goodwill in the world, may not have the time to keep up to date with the latest research and recommendations unless they have a specific interest in arthritis.

Time to bring in the law?

In the US, consumers have bitten back. In the most recent class action, against manufacturer Reckitt Benckiser, the company settled for US$53 million ($75 million) – reportedly “the largest dietary supplement class action settlement ever reached”.

The California- and New York-based plaintiffs said they bought the glucosamine product, Move Free Advanced, because the packaging said it treated joint pain and stiffness, but independent studies showed that glucosamine and chondroitin, alone or combined, did not in fact improve mobility, pain or quality of life.

The manufacturer argued it was impossible to gauge how consumers interpreted the ads, how satisfied they were with the product, and how it affected each one individually. But the science won out in this case. The judge said the plaintiffs did have a case, and in the end the manufacturer settled.

And that could happen here too, according to class actions expert Professor Michael Legg from the faculty of Law and Justice at the University of NSW.

“Australian class-action lawyers do have a history of seeing class actions brought in the United States in the product liability consumer space and replicating them in Australia,” he says, adding that there are Australian lawyers out there “perfectly capable of bringing this litigation”.

Professor Legg says Australian plaintiffs have a course of action via Section 18 of the Australian Consumer Law in terms of misleading and deceptive conduct. And Part IVa of the Federal Court of Australia Act, with similar regimes in NSW, Victoria, Queensland and Tasmania, allows for class actions.

What’s the harm?

Compared with the side effects of other treatments, glucosamine has relatively few. It can interact with blood thinners, may raise blood sugar levels in people with diabetes, negatively affect cholesterol and chemotherapy drugs, and could be linked to worsening asthma.

Glucosamine products may contain shellfish, which can have serious consequences for those who are allergic. An Adelaide University study found 366 adverse reactions to glucosamine and chondroitin (one of the many combinations available) between 2000 and 2011.

It was inadequate labelling about shellfish, rather than lack of evidence that glucosamine performs no better than a placebo, that briefly brought glucosamine manufacturers into the TGA’s sights. As a result, from 2016, products that contained shellfish had to say so, specifically and clearly, to prevent allergic reactions.

While Professor Hunter steers patients away from taking it if they ask, he doesn’t stop them if they’re already taking it and seeing some improvement.

“The evidence doesn’t support it, but if you can get a benefit out of the placebo, and the patient feels better as a consequence of that, well and good,” he says.

However, the $25 to $30 a month spent on supplements could be more wisely invested in exercise programs or doing something to lose weight, if need be, he says. And there is plenty of evidence-based advice that patients can be directed towards on the MyJointPain website, developed with Arthritis Australia.

But he doesn’t worry as much about glucosamine as he does about other medical therapies with a much greater cost and risk of harm, such as opioids or arthroscopy.

Dr Lewis agrees that there are worse things, and says placebos can have a very real, physiological effect. Furthermore, many things are done in medicine that aren’t evidence based.

“Lots of surgery is done without any evidence base. All the steroid injections to shoulders and so on are completely without evidence,” he says.

“There’s a bit of a debate in the medical profession as to whether it’s ethical to use placebo responses. I think most of what we do – giving people hope and encouragement and supporting them in their journey – is a fabulous placebo with no toxicity. Why not do it?”