NEW YORK, NY—This month CIAOMed assembled a panel of osteoarthritis (OA) experts for a "virtual roundtable" discussion of current hot topics in OA research and treatment. They agreed that the inflammatory component of OA deserves (and is getting) more research attention, that OA joint damage might be somewhat preventable if approached early enough, and that clinically useful disease-modifying osteoarthritis drugs (DMOADs) are still far down the development pipeline.

"It is probable that the opportunity to prevent structural damage is inversely related to the stage of disease—that at early stages which are often not symptomatic, structure modification is feasible, but that at later stages, too many pathologic changes have occurred in too many joint structures to make structure modification a reachable target."—David Felson, MD.
The roundtable participants were:

  • David Felson, MD, professor of medicine and epidemiology and chief of the clinical epidemiology unit at Boston University School of Medicine, Massachusetts
  • Stephen B. Trippel, MD, professor of orthopaedic surgery at Indiana University School of Medicine, Indiana

  • Steven B. Abramson, MD, professor of medicine and pathology and chairman of rheumatology at New York University (NYU) School of Medicine and NYU Hospital for Joint Diseases, New York City

Is osteoarthritis an inflammatory disease?

Whether OA should be considered a form of inflammatory arthritis has sparked rabid discussion.

"This question has been debated for decades and remains contested," Dr. Trippel said. "The question may be a bit simplistic because it implies that OA is a single disease, and that OA is either inflammatory or not. Perhaps OA would be better viewed as a spectrum of disorders with a similar final outcome. And perhaps these disorders could be viewed as having distinct underlying mechanisms that may include an inflammatory component. We could then ask: to what degree does inflammation play a role in the various disorders?"

Dr. Felson agreed. "We know that inflammatory cytokines affect chondrocyte function and their products. We know less about synovitis in OA—whether it is affecting pain and cartilage loss," he said.

According to both Dr. Abramson and traditional classification, OA is not an inflammatory disorder because typically there are fewer than 2000 WBC/mm3 in OA synovial fluid. However, he pointed out that key pathogenic processes within cartilage and synovium are driven by pro-inflammatory cytokines, such as interleukin-a (IL-1), and inflammatory mediators such as nitric oxide and prostaglandins.

"In OA these classical molecules of inflammation, ordinarily associated with the inflammatory arthritides, promote the production of metalloproteinases that degrade collagen and proteoglycan and promote chondrocyte cell death. These processes lead to progressive joint destruction. Since cartilage is avascular and aneural, and [these molecules in situ act] in a paracrine/autocrine fashion, the classical signs of inflammation [heat, redness, swelling] are not usually present. Nevertheless, these inflammatory molecules may be targets for future disease-modifying treatments in OA ," Dr. Abramson said.

Can structural damage be prevented in OA?

The ideal OA treatment would both relieve pain and prevent structural damage. The panel thought that OA joint damage might be preventable through a combination of pharmacologic and nonpharmacologic approaches, but perhaps only if intervention begins very early.

Dr. Abramson explained, "Based on animal models and our understanding of pathogenesis, the answer must be ‘yes.' The drug development to show structure modifying effect is, however, daunting and has slowed progress in the field."

"It is probable that the opportunity to prevent structural damage is inversely related to the stage of disease—that at early stages, which are often not symptomatic, structure modification is feasible, but that at later stages, too many pathologic changes have occurred in too many joint structures to make structure modification a reachable target," Dr. Felson said. "It also depends on how structural damage is defined. Focusing on loss of hyaline cartilage alone probably does not provide enough of the big picture of disease damage to be useful."

Dr. Trippel agreed that OA damage is theoretically preventable. "If we view the common pathway in OA as an imbalance in articular cartilage homeostasis from some mechanism that leads to tissue loss, then all that is needed are agents capable of augmenting the reparative activities, reducing the degradative activities, or both, within joints. Pharmaceutical interventions in the pipeline may prove to be safe and efficacious in accomplishing this."

He added that current epidemiologic data suggest that if you are a young female, structural damage can be prevented by not becoming obese.

What is the role for DMOADs in OA? What might those drugs target?

DMOADs are still a distant hope, however.

Dr. Felson said, "There is no role in the current therapy for so-called DMOADs because we have no treatments that have any proven structure-modifying effects."

Dr. Abramson is cautiously optimistic. "Currently there are no proven DMOADs. However, since OA, while biomechanically initiated, is biochemically mediated, there is the potential to slow disease progression via pharmacologic strategies. In vivo, for example, animal models of OA have been effectively treated by a variety of therapies including nitric oxide synthase inhibitors, IL-1 antagonists, caspase inhibitors, and metalloproteinase inhibitors [including doxycycline]."

"From the standpoint of an orthopaedic surgeon, it could be argued that pharmaceutical approaches to OA, at least of the hip and the knee, are becoming less essential as the biomaterials being developed for total joint arthroplasty become more successful," Dr. Trippel commented. "That said, there is little question that prevention of OA would be superior to surgical treatment of any kind. Therefore, DMOADs will, in my view, play a critical role in the management of OA, when safe, efficacious ones are developed."