WASHINGTON, D.C.—Will we witness dramatic breakthroughs in treating osteoarthritis (OA) in the coming decade? That’s the question three experts sought to address at a presentation titled, “Osteoarthritis Therapeutics: Will This be the Decade for Breakthroughs?” at the 2012 ACR/ARHP Annual Meeting, held here November 9–14. [Editor’s Note: This session was recorded and is available via ACR SessionSelect at www.rheumatology.org.]
Novel treatment strategies for OA aim to relieve symptoms like pain, to rebuild or replenish deteriorated cartilage and bone, or to replace the damaged joint altogether through surgery. Every treatment comes with potential adverse effects, and some lack measurable efficacy, the panelists noted. Most importantly, they stressed that rheumatologists use nonpharmacologic strategies first and that future strategies should slow disease progression through early detection and intervention efforts.
A number of currently available pharmacologic options enable rheumatologists to treat OA pain and other symptoms, said Marc Hochberg, MD, MPH, professor of medicine at the University of Maryland School of Medicine in Baltimore. He stressed to the audience that when treating their OA patients, rheumatologists should first offer guidance on nondrug approaches like exercise and weight reduction, then add layers of drugs as necessary. Treating OA pain effectively often helps patients achieve better physical function and, in turn, achieve better sleep and other positive outcomes, he said.
Acetaminophen is no longer strongly recommended as the first option to treat OA due to its minimal efficacy on pain and lack of efficacy on function and stiffness, Dr. Hochberg noted. Although it is safer for the upper gastrointestinal tract than traditional nonsteroidal antiinflammatory drugs (NSAIDs), there is evidence for liver-related side effects with its long-term use, he said. The U.S. Food and Drug Administration recommends no more than 3,000 milligrams of acetaminophen per day, and rheumatologists should warn OA patients about taking over-the-counter drugs for colds that contain acetaminophen in addition to their regular daily dose for pain, he added.
Effective treatments incurring minimal adverse effects are topical analgesics, including 1% diclofenac gel for pain and 1.5% diclofenac solution for the signs and symptoms of OA, said Dr. Hochberg. The main adverse effect is dry skin at the application site; this is seen less with the gel preparation. Among injectable treatments, intraarticular corticosteroids are efficacious at reducing pain, but viscosupplementation shows mild efficacy at best, he said.
Oral NSAIDS and Other Oral Drugs
Oral NSAIDs cause many adverse events that discourage their use for treating chronic OA pain, especially in patients 75 years and up, Dr. Hochberg said. When used in younger patients, the upper gastrointestinal adverse effects may be attenuated with misoprostol or proton pump inhibitors, Dr. Hochberg said. Although numerous NSAIDs are available, “there is no substantial evidence that one [nonselective] NSAID is more efficacious than another,” he said. He also stressed recent label changes on ibuprofen that state it can interfere with the antiplatelet effect of low-dose aspirin, reducing protection against heart attacks and strokes. “This is something our residents know nothing about,” Dr. Hochberg said.
Also effective for use in treating chronic OA pain are oral drugs like duloxetine, Dr. Hochberg said, and among opioids, tramadol. Tramadol carries the risk of both minor and major adverse effects, including dependence, he said. “If you’re going to use tramadol, you start low and increase the dose slowly to ensure your patient tolerates the therapy,” he noted. Opioids other than tramadol should be avoided in OA due to adverse effects, except in patients who are either unwilling to undergo total joint arthroplasty or have contraindications to the procedures, Dr. Hochberg said.
Stem Cell Therapy
Stem cell therapy may be one potential way to restore damaged cartilage and even bone lesions in OA-affected joints, said Rocky Tuan, PhD, director of the Center for Cellular and Molecular Engineering at the University of Pittsburgh Medical Center. Stem cell research in the U.S. has focused on animals, he said. “Unfortunately, there are no specific, longitudinal studies of the efficacy of stem cell therapy in animals, so it’s tough to make that transition to humans,” he said. There are ethical concerns about using embryonic stem cells, so researchers now focus on applications of multipotent stromal cells, or MSCs, autologous cells that may be harvested from sources like bone marrow or umbilical cord blood.
Active MSCs are potentially very useful for OA, said Dr. Tuan. “A stem cell cannot just sit around and be a stem cell. They have to get up and do something!” he joked. MSCs differentiate into other cells like osteoblasts and chondrocytes that may be used to replace OA-damaged tissues, said Dr. Tuan.
MSCs are effective at making new cartilage, but only in 1-mm strands, so Dr. Tuan and his colleagues designed a scaffold to hold stem cells around the joint, he explained. They modified electrospinning, a technique originally designed for the textile industry, to create a scaffold of polymer nanofibers that resembles the cartilage structures within knees. “The cells love this. The cells are sprayed in and are quite happy to latch onto the fibers,” he said. They tested the technique on a miniature pig’s deteriorated knee joint. “It looks promising. We were able to grow cartilage, put it in the knee, and repair the defect,” he said. Dr. Tuan also described the fabrication of an MSC-based osteochondral construct to repair a damaged knee joint in a miniature pig. The joint had an 8-mm lesion in the femoral head, which the researchers filled with a gelatin-based hydrogel that was then illuminated using a dentist’s light. Dr. Tuan showed stained images of the construct after three days that illustrated the viability of MSCs in this application.
Stem cells may be used one day to mend or treat OA-damaged joints, or to create models that help test potential disease-modifying drugs or figure out how OA occurs, Dr. Tuan said. “The cells are really the true tissue engineers. We are just the coaches and cheerleaders,” he concluded.
OA Starting at an Earlier Age
People are getting OA earlier in many developed countries, said David Hunter, MD, PhD, a rheumatologist at Royal North Shore Hospital in Sydney, Australia. The median age of diagnosis is now around 56 years of age, he said. OA diagnoses will likely increase due to several factors. “We are all getting bigger!” he said. “Similarly, joint injury is also one of the biggest drivers for people getting this disease, along with obesity. We are not doing anything about these problems and we need to.”
Most of his OA patients want to delay or avoid surgery, Dr. Hunter said. Weight reduction to reduce load on joints, preventing OA, or slowing progression should be the first line of defense. Later, palliative strategies like analgesia or, if necessary, arthroplasty can be implemented, Dr. Hunter said.
Drugs now in development that are attracting attention for OA include antinerve growth factor antibodies like tanezumab (although phase III trials to treat OA pain were halted when some participants required joint replacements due to rapidly progressing disease despite symptom relief); bisphosphonates like zoledronic acid; calcitonin; and strontium ranelate. In the future, researchers will focus more on biomarkers that may reveal what patients are most at risk for OA, Dr. Hunter said. These genetic clues, the subject of research efforts by groups like the Biomarkers Consortium of the Foundation of the National Institutes of Health, may indicate signs of OA years before symptoms develop or radiographic evidence is detectable, Dr. Hunter said.
Most of all, rheumatologists must focus on the whole patient in OA, as well as the whole joint, Dr. Hunter concluded. “We are not just interested in cartilage, but OA’s effects on bone, muscle, synovium, and also cartilage. If we do, we are likely to have much more meaningful results,” he said.
Susan Bernstein is a freelance medical journalist based in Atlanta.