By David Kiefer, MD

Clinical Assistant Professor, Department of Family Medicine, University of Wisconsin; Clinical Assistant Professor of Medicine, Arizona Center for Integrative Medicine, University of Arizona, Tucson

Dr. Kiefer reports no financial relationships relevant to this field of study.

SYNOPSIS: Six months of 800 mg of pharmaceutical-grade chondroitin sulfate daily relieved knee pain as much as 400 mg of celecoxib.

SOURCE: Reginster JY, Dudler J, Blicharski T, Pavelka K. Pharmaceutical-grade chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: The ChONdroitin versus Celecoxib versus Placebo Trial (CONCEPT). Ann Rheum Dis 2017; May 22. doi: 10.1136/annrheumdis-2016-210860.

The search continues for even partial solutions to symptomatic knee osteoarthritis. Near the top of the dietary supplement list for this is glucosamine hydrochloride (or sulfate), which is usually paired with chondroitin sulfate. Rarely is chondroitin mentioned in its own sentence. That is, until this clinical trial. In this double-blind trial, 604 people with knee osteoarthritis were randomized to 800 mg of chondroitin sulfate (and a placebo celecoxib capsule; n = 199), 200 mg of celecoxib (and a placebo chondroitin capsule; n = 199), or two placebo capsules (n = 205) for six months. The patients were selected from several European countries, and needed to be > 50 years of age and with medial or lateral femorotibial compartment arthritis as per the American College of Rheumatology clinical and radiologic criteria.

The “target” knee was the side with a greater score on a 0-100 visual analog scale (VAS) for pain. Exclusion criteria were referenced from a prior trial (but not detailed in this study), or presenting with grade 4 knee osteoarthritis, receiving intra-articular injections in the last six months, taking any dietary supplements for knee pain in the last three months, taking nonsteroidal anti-inflammatory drugs (NSAIDs) in the last five days, or taking paracetamol in the 10 hours before study enrollment.

The primary endpoints were patient VAS pain rating and the Lequesne Index (LI), a pain and function score from 0-24. Also, several secondary endpoints were recorded, as were adverse events and abnormal laboratory values. Paracetamol 500 mg tablets were allowed up to a maximum of 3 grams daily for breakthrough pain control.

The authors made a point to draw a stark contrast between pharmaceutical-grade chondroitin, and what is available as a nutraceutical, the latter less reliable with respect to label claims and product content. They cited more favorable research for pharmaceutical-grade chondroitin, hence the reason for including the form in this trial. They described pharmaceutical-grade chondroitin as the 4&6 sulfate form, in no less than a 95% purity.

Investigators completed an intention-to-treat analysis on the 603 patients who actually took the study medication. The demographics between the three groups were similar at baseline, and there were not any significant differences between the dropouts in any of the three groups. For the VAS, all three groups improved compared to baseline at day 30, 91, and 182.

Compared to the placebo group, the chondroitin and celecoxib groups improved more than the placebo group, but were similar to each other at six months. A similar general trend was observed for the LI score, although the celecoxib group reached significance earlier (day 30) than the chondroitin group (day 91) when compared to placebo. All three groups exhibited the same rate of adverse reactions, most commonly abdominal pain and discomfort. The rate of adverse effects was 2.5% in the chondroitin group, 4.5% in the celecoxib group, and 2.9% in the placebo group.

COMMENTARY

This is a favorable study for a dietary supplement for knee osteoarthritis, not always a common outcome in this field. The authors studied chondroitin sulfate, as they described, “… a sulfated glycosaminoglycan composed of chains of alternating D-glucuronic acid and N-acetyl-D-galactosamine.” But, this wasn’t garden-variety chondroitin; this was pharmaceutical-grade chondroitin sulfate of at least 95% purity.

When clinicians send patients to the pharmacy to purchase a dietary supplement, unless the clinician (or the patient) have checked a third-party certifier’s database for accuracy of product content and label claims, patients may or may not receive the necessary bang for their buck. The authors aligned themselves with past research on this pure form of chondroitin to maximize the effect on symptoms of knee osteoarthritis. It appears that their strategy worked.

This study was focused on symptomatic improvement, as documented by the VAS and LI scoring systems, the latter involving both pain and function parameters. The study was considered too short to capture structural change, so the decision was made not to analyze for bone nor cartilage markers. Therefore, it is unknown whether chondroitin is “building up cartilage” or simply serving as an anti-inflammatory, two of the proposed mechanisms of action.

At the end of the day, it may or may not matter, as long as patients notice some benefit to their symptoms. Does chondroitin sulfate lead to symptomatic improvement immediately, as NSAIDs of choice might? It is unlikely. In fact, the pharmaceutical in this study, celecoxib, led to benefits in the LI scale a full two months before chondroitin. Not unlike other subtly acting dietary supplements, when nudging them down the chondroitin trail, clinicians encourage patients to commit to that treatment in the medium-to-long term, not expecting short-term benefit.

Perhaps this study is the beginning of clinicians considering chondroitin in its own right. Many prior studies examined chondroitin in combination with its more well-known “cousin,” glucosamine. Now that clinicians know that a very pure form of chondroitin sulfate also may be efficacious, which one do clinicians choose? Perhaps both. Perhaps what patients’ budget would allow. Perhaps what will be safe with their pharmaceutical list after clinicians consult their resources for supplement-pharmaceutical interactions (which clinicians always should do).

Such personalized decision-making should lead, hopefully, to optimal outcomes. For patients with symptomatic knee osteoarthritis, there is little reason not to steer them toward a pharmaceutical-grade chondroitin sulfate for at least a three-month trial.