Do Osteoarthritis Supplements Work?

Did you know that billions are spent on glucosamine supplements every year. Do they work? Are they safe? Let’s find out.

Global sales of glucosamine supplements are estimated at $2 billion. Glucosamine is a precursor to two of the major components of cartilage, though at the marginal blood levels achieved by supplementation, one would not expect it to contribute much to cartilage formation directly. There are marked inconsistencies in the clinical research literature as to whether it works at all. The most potent predictor of trial results? Industry funding. Studies sponsored by the product makers themselves showed their patented products were beneficial. But independently-funded studies showed glucosamine had no effect. This has raised serious concerns about “publication bias,” the suspicion that the glucosamine industry quietly shelved rather than published any studies that didn’t go their way to give an overly rosy picture in the medical literature. This is what led in part to the current American College of Rheumatology guidelines strongly recommending against the use of glucosamine.

The proscription against glucosamine is echoed by some expert consensus guidelines––for example, the American Academy of Orthopedic Surgeons and Osteoarthritis Research Society International, but not others, such as the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases, which allows an exception for pharmaceutical-grade glucosamine. Only this patented so-called “crystalline” glucosamine, sold as a prescription-only drug in Europe, has been decisively shown to improve osteoarthritic joint pain or function, whereas the over-the-counter glucosamine supplements sold in the U.S. offered mixed results with no overall effect, presumably because quality control analyses by Consumer Reports and others found glucosamine supplements sometimes contained no glucosamine at all. An investigation of over a dozen glucosamine supplements found that only one contained the claimed dose on the label.

So, maybe the inconsistency in findings is less a matter of funding bias, and more a reflection of the efficacy of using genuine glucosamine. I’d feel more confident in the industry results if they were more transparent with their participant-level results. A request for data sharing was reportedly denied by the owner of the crystalline glucosamine trials, which “raises concerns about the robustness of their study findings.”

Regardless, the effect size of the pain relief found even in the best studies of crystalline glucosamine can be considered relatively small. Effect size can be quantified as a “standardized mean difference.” An effect size of 0.2 is considered small, 0.5 moderate, and 0.8 large. The effect size of the best studies of crystalline glucosamine, 0.27, representing a small effect. So, prescription glucosamine works better than Tylenol, but on par with placebo injections, and less than the NSAID drugs like ibuprofen. Now, glucosamine is safer than NSAIDs, but the most tantalizing possibility is that it could offer more than just symptomatic relief.

Two industry-funded randomized controlled trials found that those with knee osteoarthritis randomized to take the prescription glucosamine for three years experienced less progression of their disease compared to placebo, as quantified by x-ray measurements. Those on the glucosamine had a 62 percent reduction in osteoarthritis progression, as measured by joint space narrowing, compared to those randomized instead to placebo. However, two subsequent non-industry-funded studies found no benefit on osteoarthritis disease progression, resulting in no benefit overall when all four were combined. But, how’s this for a purported potential side-effect: a longer life?

Glucosamine supplementation extends the lifespan of both microscopic worms and aging mice. What about people? In 2012, the Vitamins and Lifestyle cohort was the first to report on the relationship between glucosamine use and mortality. About 75,000 Washington State residents aged 50 to 76 were followed for about seven years, and those taking glucosamine were 18 percent less likely to die in that period. In 2020, two other cohort studies were published on the matter, including the enormous UK Biobank study that followed nearly a half million people for nine years. Glucosamine users were 15 percent less likely to die, and in a 2020 national U.S. study, users had 27 percent lower risk of death. Since glucosamine use has been associated with lower CRP blood levels, researchers suggested that this may be an anti-inflammatory effect. But when actually put to the test, glucosamine doesn’t appear to affect CRP at all. A more likely explanation may be the so-called “healthy user effect.”

Those who choose to take supplements tend to be healthier than those who don’t. Studies show dietary supplement users are more likely to be female, more educated, and make healthier diet and lifestyle choices, such as exercising more and smoking less, and being less sick. So, presumably, that’s why observational studies found that those who take vitamins may have lower mortality rates, but when put to the test in interventional studies, there was no benefit, or worse. One of the most dramatic examples of the healthy user effect is the finding that elders who take flu vaccines appear to cut their risk of all-cause winter mortality by 50 percent, when seasonal flu itself rarely causes more than 10 percent of excess winter deaths. That’s why randomized controlled trials are so critical to establishing cause and effect, and we have no such data as of yet for glucosamine. The cohort studies did try to adjust for factors such as age, obesity, exercise, education, and smoking status, but it’s not possible to control for unmeasured lifestyle confounders.

In our next story, we ask – why some clinical guidelines recommend chondroitin supplements but others do not?

Chondroitin is a structural component of cartilage commonly used as a dietary supplement for osteoarthritis that shares a similar story with glucosamine. There’s a large heterogeneity in outcomes, with the industry-funded studies showing a benefit for symptomatic relief, and the non-industry-funded studies showing no effect, with a small effect size similar to glucosamine. Considering just the largest, best-run studies, the benefit of chondroitin was found to be “minimal or non-existent” and its use “therefore [should] be discouraged.”

Like glucosamine, the current American College of Rheumatology guidelines “strongly recommend against” the use of chondroitin for knee or hip osteoarthritis, along with the American Academy of Orthopedic Surgeons and Osteoarthritis Research Society International, whereas the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases again allow for the use of pharmaceutical-grade, prescription-only chondroitin.

Chondroitin is typically extracted from animal cartilage—shark fins, bovine and chicken windpipes, or pig noses—and slaughterhouse supply chains are not known for their “good manufacturing practices.” The lack of purity and presence of contaminants is blamed in part for the lack of consistent reproducibility. A study of 32 chondroitin supplements on the market found that only five contained the labeled amount, and some contained none. Terms like “quality tested” or retail price were found to provide no basis for judging quality. Some of the cheapest and the most expensive chondroitin on the market contained less than 10 percent actual chondroitin.

When the National Institutes of Health set out to design the esteemed GAIT trial, the Glucosamine/Chondroitin Arthritis Intervention Trial, they ruled out 20 different commercial products for issues like quality control before giving up and just deciding to have it specially-made themselves. More than 1,500 patients with symptomatic knee osteoarthritis were randomized to take standard daily doses of glucosamine, chondroitin, both glucosamine and chondroitin, an NSAID anti-inflammatory drug, or a placebo for six months. Only the drug beat out placebo for pain management. Neither glucosamine and chondroitin alone or in combination reduced pain effectively, and neither did they have any significant effect on delaying disease progression on x-ray. Chondroitin also failed in another two-year study. But two other trials found that by year two, objective benefits could be found, and a third using more sensitive imaging (MRI) could pick up protective effects by six months. If you want to give it a try, there is now a purified non-animal source of chondroitin made from scratch that should be free from contaminants.

In the U.S., chondroitin and glucosamine are almost always sold in a combination pill. Like in the GAIT trial, a meta-analysis of studies pitting both against osteoarthritis found no clinically significant benefit. However, there had never been a trial in which pharmaceutical-grade, prescription-only preparations of both were used together, until finally one was published in 2017. The multicenter randomized, double-blind, placebo controlled clinical trial had to be stopped prematurely because one group was doing so much better than the other that it was deemed unethical to continue. But that superior treatment was the placebo! Unexpectedly, when the code was broken, it turned out that the placebo group did better! In other words, the industry-funded study found that their own pharmaceutical-grade chondroitin/glucosamine was making the pain significantly worse compared to a sugar pill. In the sugar pill group, 47 percent had at least a 50 percent improvement in pain or function, compared to just 28 percent in the chondroitin/glucosamine group. What the chondroitin/glucosamine users did get was more side effects, such as diarrhea and abdominal pain; so, doctors may want to tell their patients to stop taking their glucosamine and chondroitin as it is less effective than placebo.