Sept. 23, 2016
Nearly 6 million people in the United States have post-traumatic osteoarthritis (OA) — chronic degradation of articular cartilage caused by injuries that damage the joint surface, such as osteochondral fractures and ligament or meniscus tears. This trauma initiates a cascade of events in joint tissues, including disruption of the cartilage matrix, the release of proinflammatory cytokines into synovial fluid, suppression of proteoglycan and collagen synthesis, and apoptosis. Although this is followed by a long, asymptomatic period, metabolic changes in articular cartilage eventually can progress to a symptomatic phase of joint pain and dysfunction.
Treatment may include surgical interventions to prevent progressive joint damage, such as reduction of intra-articular fractures, ligament repair and reconstruction, and joint stabilization. Yet even when joint biomechanics are successfully restored, the risk of post-traumatic OA is high, ranging from 20 to 50 percent. In the ankle joint, the risk may be even higher.
Although many medical therapies have been proposed to halt or reverse the progression of post-traumatic osteoarthritis, none has proved particularly useful. Now, however, investigators in the Rehabilitation Medicine Research Center at Mayo Clinic's campus in Rochester, Minnesota, are evaluating a particularly promising preventive therapy.
Christopher H. Evans, Ph.D., who directs the Rehabilitation Medicine Research Center, explains that the science originates from a collaboration with Massachusetts Institute of Technology professor Alan J. Grodzinsky, Sc.D. In 2011, they published a study in Arthritis Research & Therapy evaluating the effect of the glucocorticoid dexamethasone on cartilage subjected to mechanical injury and proinflammatory cytokines. That study built on previous research from Grodzinsky's group showing that mechanical injury combined with tumor necrosis factor-a and interleukin-6 (IL-6) induced severe matrix degradation in bovine and human knee cartilage explants.
The 2011 study demonstrated that the glucocorticoid dexamethasone prevented matrix degradation, sustained matrix synthesis and prevented cell death after cartilage explants were exposed to injury and inflammatory cytokines. In one series of experiments, dexamethasone was added at the time of injury, and in another, it was added two days before or up to four days after injury to determine if it could protect or rescue cartilage matrix metabolism.
Effects of dexamethasone on cell death
Effects of dexamethasone on cell death in bovine cartilage with mechanical injury and IL-1a compared with treated cartilage without the addition of dexamethasone and control.
Effects of dexamethasone on collagen loss
Effects of dexamethasone on collagen loss in bovine cartilage with mechanical injury and IL-1a.
In both instances, dexamethasone reduced glycosaminoglycan (GAG) loss and increased proteoglycan biosynthesis in bovine cartilage and suppressed GAG loss in human cartilage explants, leading researchers to conclude that the drug may have long-term protective effects.
Based on these studies, Dr. Evans, Sanjeev (Sanj) Kakar, M.D., a hand and upper extremity surgeon at Mayo Clinic's campus in Minnesota, and colleagues have initiated a human clinical trial testing intra-articular dexamethasone as a preventive treatment for early-onset post-traumatic OA after distal radius fracture.
Dr. Evans says one major obstacle to in vivo trials of glucocorticoids in joint disease is the perception that they damage cartilage. "Glucocorticoids have commonly been used to treat joint problems, but the rule of thumb is that you shouldn't inject an inflamed joint more than three times, so that has limited investigations," he says. "But although that is the case with existing disease, we argue the effects are different if you are trying to prevent disease. Moreover, we are advocating a single injection at a very low dose to block inflammation mediators so that joint recovery can proceed normally. At this dose, the drug will benefit cartilage structure and cell metabolism without unwanted side effects."
Another obstacle to human testing is the long latency period before arthritis symptoms appear. "Although injury accelerates the onset of arthritis, it typically takes five to 10 years for it to develop, which is a lifetime for a controlled interventional study. We chose to study wrist fracture because the literature suggests a high incidence and rapid development of post-traumatic osteoarthritis after injury, so it seemed an encouraging place to start for a clinical intervention," Dr. Evans explains.
The investigators are hoping to enroll 40 patients in the trial. Half will be randomized to receive an injection of 4 milligrams of dexamethasone in the radiocarpal joint within two weeks of injury. The rest will receive a saline placebo. The primary outcome is the incidence of post-traumatic OA at two years, as measured by arthritis pain and joint space narrowing using serial X-rays; the secondary outcome measure is a functional assessment of grip and pinch strength.
To date, about half the patients have been enrolled. "Dr. Kakar wanted to do a large study that would have strong statistical power, but we didn't have the data on which to base the power analysis. We will build on the data from this study for a larger clinical trial," Dr. Evans says. "We want to focus on patients who have just had surgery; the logic is that if you wait too long, the arthritic process will already have started, and we would be using dexamethasone as a therapeutic rather than a preventive." A further discussion of the current trial is in press in the Journal of Orthopaedic Research.
Dr. Evans stresses that if dexamethasone proves safe and effective in future trials, the potential is enormous. "The drug is inexpensive and readily available — it could be administered on the sidelines by a team doctor or in the emergency department immediately after an injury," he says, noting that dexamethasone has historic ties to Mayo Clinic. "The discovery of cortisone began at Mayo Clinic, where it was first used to treat rheumatoid arthritis. It's quite poetic that it might be rediscovered here, 60 years later, for preventing arthritic disease in the first place."
For more information
Lu YCS, et al. Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines. Arthritis Research & Therapy. 2011;13:R142.
Mayo Clinic. Intra-articular dexamethasone to prevent post-traumatic osteoarthritis: A pilot study. ClinicalTrials.gov.
Grodzinsky AJ, et al. Intra-articular dexamethasone to inhibit the development of post-traumatic osteoarthritis. Journal of Orthopaedic Research. In press.