By David Fiore, MD

Professor of Family Medicine, University of Nevada, Reno

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

SYNOPSIS: The authors of a European study found a statistically significant and clinically marginally significant reduction in pain at three and six months in patients taking pharmaceutical-grade chondroitin sulfate for knee osteoarthritis.

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. pii: annrheumdis-2016-210860. doi: 10.1136/annrheumdis-2016-210860. [Epub ahead of print].

Symptomatic osteoarthritis (OA) of the knee affects approximately 4.3 million adults in the United States.1 This can lead to decreased activity, with its concomitant effect of comorbidities such as depression, obesity, and cardiovascular disease. Pharmacologic treatment of knee OA typically starts with acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). Unfortunately, acetaminophen has limited efficacy, and NSAIDs may cause renal compromise and gastric bleeding. Patients who have failed first-line treatment may progress to opiate therapy, but there are no data demonstrating a benefit of opiates for chronic pain, and, as we are all aware, there are many problems associated with long-term opiate use.

Current guidelines outline disparate recommendations about treatment, especially regarding what are termed symptomatic slow-acting drugs for osteoarthritis (SYSADOAs).2,3 In 2012, the American College of Rheumatology conditionally recommended against the use of chondroitin for knee OA.2 On the other hand, the 2016 consensus statement by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases (ESCEO) recommended pharmaceutical-grade chondroitin as part of first-step therapy for knee OA, along with paracetamol (acetaminophen).3 A 2015 Cochrane Review on chondroitin for OA (primarily of the knee) found a likely small benefit compared to placebo, but the authors qualified their endorsement based on low quality and heterogeneity of studies.4

In their introduction, the authors of the current study, which was funded by IBSA Institut Biochimique, a manufacturer of pharmaceutical-grade chondroitin, questioned the benefit vs. harm of acetaminophen and NSAIDs, and stressed the inclusion of pharmaceutical-grade chondroitin in the new European guidelines as the basis for their study. The authors randomized 604 patients with symptomatic knee OA into three groups: 800 mg pharmaceutical-grade chondroitin sulfate daily, 200 mg celecoxib daily, and placebo once daily. Baseline characteristics and dropout rates were similar across groups. Subjects were evaluated at baseline and days 30, 91, and 182. The two primary endpoints were well-defined and well-validated: a 100 mm Visual Analog Scale (VAS) and the Lequesne Index.

All three groups demonstrated significant improvement in all measured outcomes at 30, 91, and 182 days. The two active treatment arms demonstrated benefit over placebo in all measures at the end of the study (six months), with both active arms demonstrating a statistically significant improvement in the Lequesne Index at 91 days.

Although the authors stressed the statistically significant difference between both chondroitin and celecoxib when compared to placebo, the magnitude of the difference is small and barely meets criteria for clinical significance according to the 2015 ESCEO guideline on study protocols.6 To put the benefit in perspective, the chondroitin group exhibited a 9.2 mm greater reduction in pain on the VAS scale compared to placebo, with a minimal clinically significant difference of 5-10 mm,5,6 but the total reduction in VAS scores were 42.6 mm and 33.4 mm for chondroitin and placebo, respectively. Similar improvements were seen with the other outcome measures.

COMMENTARY

As a primary care physician with many patients suffering from knee osteoarthritis, I am disappointed that this study doesn’t show a greater benefit of pharmaceutical-grade chondroitin compared to placebo. However, I am encouraged that so many patients benefit from placebo, and that there seems to be little harm from chondroitin. I don’t believe the minimally positive results from this study are enough to offset the negative results of the GAIT study, which failed to show a benefit of 1,200 mg chondroitin daily compared to placebo.7 Perhaps there were differences in the quality of the chondroitin, but since we do not have pharmaceutical-grade chondroitin in the United States, we should be cautious before expecting much benefit from chondroitin compared to placebo for knee OA. Therefore, I will continue to recommend non-pharmacologic approaches to first-line knee OA treatment, followed by acetaminophen and/or NSAIDs based on the patient’s profile. If I’m asked about using chondroitin and/or glucosamine, I will continue to tell my patients that some patients seem to benefit significantly from these supplements, but that the studies on them are equivocal.

REFERENCES

  1. Dillon CF, Rasch EK, Gu Q, Hirsch R. Prevalence of knee osteoarthritis in the United States: Arthritis data from the Third National Health and Nutrition Examination Survey 1991-94. J Rheumatol 2006;33:2271-2279.
  2. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;64:465-474.
  3. Reginster JY, Reiter-Niesert S, Bruyère O, et al. Recommendations for an update of the 2010 European regulatory guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis and reflections about related clinically relevant outcomes: Expert consensus statement. Osteoarthritis Cartilage 2015;23:2086-2093.
  4. Singh JA, Noorbaloochi S, MacDonald R, Maxwell LJ. Chondroitin for osteoarthritis. Cochrane Database of Syst Rev 2015 Jan 28;1:CD005614. doi: 10.1002/14651858.CD005614.pub2.
  5. Bruyère O, Cooper C, Pelletier JP, et al. A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis-From evidence-based medicine to the real-life setting. Semin Arthritis Rheum 2016;45(4 Suppl):S3-11.
  6. Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) 2011;63(Suppl 11):S240-252.
  7. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808.