The dietary supplements chondroitin and glucosamine, separately or in combination, have been widely used to treat the pain of osteoarthritis of the knee. But do they work? When I wrote about glucosamine and chondroitin in 2008 and in 2015 the evidence was mostly negative. Some studies supported the combination of glucosamine and chondroitin, but many others didn’t; and there was little evidence that chondroitin alone had any effect. After reviewing all the published studies, the American Academy of Orthopaedic Surgeons recommended against the use of glucosamine and/or chondroitin.
A new study (the CONCEPT trial) published in the BMJ Annals of the Rheumatic Diseases contradicts several previous studies: it found that chondroitin was effective, as effective as celecoxib, a non-steroidal anti-inflammatory drug (NSAID). A common objection when a dietary supplement fails testing is that they didn’t use the right dose or the right formulation. This reasoning might be valid, but it could easily lead to an unending and unproductive proliferation of studies each using slightly different regimens. This new study avoided that objection by using the dose and the specific formulation that had been shown effective in the most positive studies.
Previous studies of chondroitin had suffered from idiosyncratic trial design. This new study followed the guidelines of the European Medicines Agency:
- a minimum 6-month study
- a three-arm design including a placebo and an active comparator (i.e. an oral NSAID)
- two primary endpoints evaluating pain and function
Is chondroitin really as effective as NSAIDs? If it is, it might be the best choice for osteoarthritis pain, since it doesn’t have the side effects that are problematic for other osteoarthritis medications. Should we discount the previous negative studies? Should we rely on this new study to guide clinical treatment? I’m skeptical.
The new study
604 patients with pain from knee osteoarthritis were recruited from 5 European countries. It was a prospective 6-month, double-blind, double-dummy trial of chondroitin sulfate (CS) vs. placebo vs. celecoxib. Subjects were randomly assigned to one of three groups:
- Real CS and placebo celecoxib
- Placebo CS and real celecoxib
- Placebo CS and placebo celecoxib
Meds were taken once daily for 6 months. CS tablets contained 800 mg of highly purified chondroitin 4 & 6 sulfate in a concentration not less than 95% (European patents E 1582214 and EP 1705192) Condrosulf (other brand name: Chondrosulf, Condral); IBSA Institut Biochimique SA; Pambio-Noranco, Switzerland.
The study was sponsored by the manufacturer of Condrosulf.
Results:
A 800 mg/day pharmaceutical-grade CS is superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee osteoarthritis (OA) patients. This formulation of CS should be considered a first-line treatment in the medical management of knee OA.
Previous double blind studies of chondroitin for knee osteoarthritis had mixed results
A 1998 pilot study found that Condrosulf 800 mg was an effective and safe slow-acting drug that reduced pain, increased mobility, and “might” be able to influence the natural course of osteoarthritis.
A 2005 study compared Condrosulf 800 mg to placebo. It had no effect on symptoms, but appeared to slow joint space narrowing on x-ray.
A 2009 study found that 800 mg of Condrosulf slowed joint space narrowing and improved pain faster than placebo.
A 2013 study used an Australian formulation of CS, 800 mg. along with glucosamine 1,500 mg. The combination didn’t relieve pain better than placebo, but it reduced joint space narrowing.
The GAIT trial was a multicenter double-blind placebo-controlled study of 1,583 patients with knee osteoarthritis published in the highly respected New England Journal of Medicine (NEJM) in 2006. It used 1,500 mg glucosamine hydrochloride and 1,200 mg sodium chondroitin sulfate. It found that “glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain.”
The MOVES trial (January 2016) was a large double blind trial using a combination of 400 mg chondroitin sulfate plus 500 mg glucosamine hydrochloride (Droglican, Bioiberica, S.A., Barcelona, Spain) three times a day or 200 mg celecoxib (Celebrex, Pfizer) every day for 6 months found comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile.
A Cochrane meta-analysis in 2007 found that trial quality was generally low, but “Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged.”
A Cochrane review in 2016 again found that many of the studies were low quality and heterogeneity was a problem. It found that after 6 months, chondroitin reduces pain by eight points on a 100-point scale compared to placebo. These differences persisted in some sensitivity analyses and not others.
Reasons for caution
If a medication is truly effective, that should become more and more obvious over time as more and better studies are done. And that hasn’t happened with chondroitin. The most recent Cochrane review said:
Studies published before 2000 showed that participants treated with chondroitin had significantly better pain scores than those in the placebo group while studies published after 2000 reported no statistically significant difference between chondroitin and placebo.
Studies of pharmaceuticals are frequently accused of bias because they are funded by the manufacturer. The Cochrane review said:
Studies funded by chondroitin sulfate manufacturers showed that participants in the chondroitin group had statistically significantly better pain scores than those in the placebo group, and the effect size was -0.52. Studies that did not specify their source of funding or with no pharmaceutical sponsorship did not report a statistically significant difference between participants in the chondroitin group and those in the placebo group.
Studies that found a positive effect tended to be low-quality, and outcomes other than pain were generally negative. The Cochrane review said:
among studies that found a statistically significantly positive effect with chondroitin for these various outcomes, heterogeneity was moderate, and factors that affect the study’s quality, such as size and independence of funding, were generally low quality.
In nearly all other outcomes, including physical function, stiffness, grip strength, morning stiffness, global assessment on VAS (mm), change in bone marrow lesion scores of several different compartments, OMERACT-OARSI, HAQ Disability, HAQ continuous, HAQ MCID scores, and both mental and physical components of SF-36, no statistically significant difference between chondroitin and placebo was noted.
Questioning the rationale
Proposed mechanisms of action include restoring the extracellular matrix of cartilage, preventing further cartilage degradation, and overcoming a dietary deficiency of sulfur-containing amino acids, which are essential building blocks for cartilage extracellular matrix molecules. This rationale is questionable.
In response to a Medscape article, a pathologist commented:
I doubt that dietary glucosamine or chondroitin sulfate are absorbed from the gut as such. Further, human cartilage contains N-acetyl galactosamine, not glucosamine. Depending on source, the dietary CS may have a different structure than human CS. Finally, the cartilaginous glycosaminoglycan matrix is synthesized by the chondrocytes, and it is naive to assume that dietary supplements will “home” to that avascular tissue. It is all placebo effect, making lots of money for manufacturers.
And our own editor emeritus Wallace Sampson wrote:
Glucosamine [and chondroitin] is not an essential nutrient like a vitamin or an essential amino acid, for which small amounts make a large difference. How much difference could that small additional amount make? If glucosamine or chondroitin worked, this would be a medical first and worthy of a Nobel. It probably cannot work.
What do you get when you buy “pharmaceutical grade” chondroitin sulfate?
Sources of chondroitin used in nutritional supplements include bovine trachea, pork byproducts, shark cartilage, and whale septum.
A 2015 study analyzed 16 preparations of pharmaceutical grade chondroitin sulfate and found that 11 of them contained less than 15% CS; five samples contained more than 90% CS, but their structures varied as to size and sulfation. Nine of the samples were from the US, one from Brazil, four from China, and two from Germany. The European brands used in the BMJ study are not available in the United States.
Conclusion: Maybe, but I’m not convinced
How do you know if a treatment works? Simple: you do a randomized, placebo-controlled, double-blind study. Only it’s not that simple. Ineffective or marginally effective treatments will yield a mixture of positive and negative findings, muddying the waters. Meta-analyses are no better than the studies they review: if the individual studies are poor quality it’s just GIGO (garbage in, garbage out). Studies comparing a treatment to usual care are almost guaranteed to give false positive results. The pragmatic “real world” studies favored by alternative medicine are unreliable and were never meant to evaluate the efficacy of a treatment. The new chondroitin study appears to be well-designed, but even the best-designed studies can yield false positive results.
The new study’s findings are encouraging. If chondroitin really works as well as NSAIDS and has practically no side effects, it would be the obvious drug of choice for osteoarthritis pain. And there is even a possibility that it might slow the progression of joint-space narrowing. But I’m not convinced. The new study must be considered along with previous research. Some of the previous studies used the same or even a higher dose of the same CS formulation and found no improvement of pain. The positive studies were funded by CS manufacturers, raising the issue of possible bias. The mechanism of action is questionable. My biggest concern is that the formulation that appears to be the most promising, Condrosulf, is not available in the US. If we just tell patients to buy pharmaceutical-grade chondroitin, they are likely to get an inferior product. For all these reasons, I wouldn’t feel justified in recommending chondroitin based on the current state of the evidence.
That said, I couldn’t argue with doctors choosing to recommend a trial of chondroitin before prescribing a drug with troublesome side effects. They can honestly tell patients there is some scientific evidence to support it, (although it would be more honest to explain that there was also reason to be skeptical). If it doesn’t work, patients can stop taking it. If their pain improves, we won’t know whether it is a placebo response or a true effect, but they will be better off than if they had taken an NSAID and risked serious side effects.