The first meta-analysis of long-term pharmacologic treatments for knee osteoarthritis (OA) found little evidence that most currently prescribed medications improve pain control or preserve joint structure after 12 months of treatment. There was a small but statistically and clinically significant benefit from prescription-grade glucosamine sulfate.

The study, by Dario Gregori, PhD, from the Unit of Biostatistics, Epidemiology, and Public Health, Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova, Italy, and colleagues, was published online December 25 in JAMA.

The analysis may have more implications for clinical trial design than for clinical practice. David S. Jevsevar, MD, vice-chairman, Department of Orthopaedics, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, told Medscape Medical News that these treatments are not generally recommended with the expectation that they will produce long-term relief.

“All of the conservative interventions for knee OA are generally intended to address relatively acute exacerbations of knee OA or the chronic ache component. By its nature, knee OA is generally a slowly progressive disease. The authors also appropriately highlight that it is challenging to measure the effect of these treatments, and that may also help to explain the small effect sizes. I don’t think there is anything new here,” Jevsevar explained.

Senior author Lucio C. Rovati, MD, CEO, and chief scientific officer of Rottapharm Biotech, which partly funded the study, told Medscape Medical News the authors were gratified to find that the systematic review produced 33 randomized controlled trials (RCTs) of knee OA drug therapy with follow-ups of at least 12 months but that they were disappointed that only 13 of the 33 interventions had been studied in two or more trials.

“The question is, therefore, why, in a chronic and progressive disease, medications are studied mainly over short-term period, and most guidelines are unclear on this. This is a major limitation, and regulators should convince sponsors to run long-term studies or to clearly label drugs for short-term use only. In parallel, clinical practice guidelines should clearly advise what to do for the long-term management of the disease, based on the available evidence,” Rovati said.

Rovati added, “Physicians should be aware that the clinical trial evidence to support long-term pharmacological management of knee OA is scarce.”

The researchers extracted data from the RCTs and performed a Bayesian random-effects network meta-analysis to assess the mean change from baseline in knee pain (the primary outcome, measured using the Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] or a visual analogue scale). Secondary outcomes were changes in physical function (measured using the WOMAC physical function scale) and in joint structure (measured as radiologic joint space narrowing).

The authors explain, “Network meta-analyses synthesize direct and indirect evidence in a network of trials that compare multiple interventions. This method allows comparison of all available knee osteoarthritis medications against placebo and between pharmacological agents despite the paucity of head-to-head comparisons of therapies in RCTs.”

The trials included more than 20,000 patients with knee OA (70% women); the mean age ranged from 55 to 70 years. The interventions included analgesics; antioxidants; bone-acting agents, such as bisphosphonates and strontium ranelate; nonsteroidal anti-inflammatory drugs; intra-articular injection medications, such as hyaluronic acid and corticosteroids; symptomatic slow-acting drugs for osteoarthritis, such as glucosamine and chondroitin sulfate; and putative disease-modifying agents, such as cindunistat and sprifermin. The RCTs tested 31 interventions for pain, 13 for physical function, and 16 for joint structure.

The analysis showed no significant association with pain improvement (the primary outcome) for 29 of the 31 treatments. Celecoxib and glucosamine sulfate were initially associated with reduced pain, but about 30% of the RCTs were judged to have high risk for bias. Once these trials were eliminated, celecoxib was no longer significantly effective. Glucosamine sulfate remained associated with a small but significant standardized mean difference (SMD) in pain of -0.29 (95% credibility interval [CrI], −0.49 to −0.09), as well as with a significant improvement in physical function (SMD, -0.32; 95% CrI, −0.52 to −0.12) and on joint space narrowing (SMD, -0.42; 95% CrI, −0.65 to −0.19).

The authors warn that, owing to the paucity of interventions tested in more than two RCTs, “there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo.”

Rovati explained that the glucosamine sulfate included in this analysis is a prescription drug available in Europe and in several countries in Asia. Other formulations, such as those sold in the United States, and which were not effective in this analysis, may be labeled “glucosamine sulfate” because they contain glucosamine hydrochloride, with or without sodium sulfate.

Although it is not the ideal drug, Rovati advised use of glucosamine sulfate as a background treatment until more effective medications are developed.

Rovati said, “The future in OA clinical research is the identification of the different OA phenotypes and the performance of trials specifically addressing the effects of the different medications in these different subsets. These are being identified by the scientific community, and they may include metabolic OA (linked to obesity and other characteristics), inflammatory OA, bone-remodeling OA, neuropathic component OA, etc.”

Rovati advised that physicians make full use of aerobic and strengthening exercise programs and physical therapy and encourage weight loss for patients who are overweight. Then long-term background pharmacologic treatment with prescription glucosamine sulfate should be used, with pain medications used to control breakthrough pain episodes over the short term.

The study was partly funded by Rottapharm Biotech. Dr Giacovelli and Dr Rovati have participated in clinical trials of glucosamine sulfate and hyaluronic acid as scientists and employees of Rottapharm prior to that company’s merger with Mylan. They are now scientists at Rottapharm Biotech, the research and development spin-off of the former Rottapharm. Rottapharm Biotech is engaged in new drug development but has no commercial or other interest in glucosamine sulfate, hyaluronic acid, or any other marketed or experimental pharmaceutical agents considered in the present study. Three coauthors of the article are also scientists and employees of Rottapharm Biotech. Dr Jevsevar has disclosed no relevant financial relationships.

JAMA. Published online December 25, 2018. Abstract

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