If all osteoarthritis experts considered the joint an organ, like a heart or kidney, would the process of developing novel treatments come sooner? Would more people be diagnosed with OA if there were standardized measures of the disease? What if all people who had ACL injuries were expected to register in a database of outcomes and tracked over time? 

These topics and others were discussed in depth at the recent Segal North American Osteoarthritis Workshop V, or SNOW V conference, hosted by the Arthritis Foundation and held in late October 2012 in Chicago. The Arthritis Foundation brings together distinguished scientists and researchers from more than 30 global institutions to discuss the problem of osteoarthritis (OA) for this annual event.

The conference was originally sponsored by Gordon and Carole Segal, founders of the home furnishings store Crate and Barrel.

An overriding theme to SNOW V was the concept of treating the ‘joint as an organ.’ In a recent review article in Arthritis & Rheumatism, Richard Loeser, MD, a former Arthritis Foundation-funded researcher from Wake Forest University and a speaker at SNOW V, explains that OA is not just a disease of wear and tear, but rather a collective disease of active multisystem processes deteriorating simultaneously. Thus, to fully understand OA it is necessary to integrate structural and molecular data and analyze it as one working unit.

The initial session included three speakers with OA describing the impact OA has had in their lives – from chronic pain to missing out in playing with grandchildren. As one invited OA patient put it, “Osteoarthritis is not a life-threatening disease, but a ‘quality of life’-threatening disease.” With those words fresh in their minds, researchers probed areas such as bone adaptations, synovium, age and weight, trauma to joints, and novel stem cell treatments.

When the FDA Talks…

One of the primary concerns addressed at the onset of SNOW was the standstill of drug development to treat OA. Since the Food and Drug Administration (FDA) ultimately approves all prescription and biologic drugs, attendees were interested to hear the presentation from Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER) of the FDA. She summarized the current drugs available to treat OA – they limit pain but not stop disease progression. Any new drugs in the pipeline have big shoes to fill: They cannot aggravate other illnesses; they must demonstrate little to no toxicity; and they must show measureable improvements over time, since treatment may be required at length before progress is seen.

On the issue of progression, Dr. Woodcock confirmed that radiographic measures of disease are limited, so objective standardized criteria are needed, such as one or more biomarkers specific to a joint. A biomarker is defined as a measurable physical or biological trait that can be used to evaluate disease onset, activity and progression. A biomarker, for example, could be a standard measurement of reduced joint space between the bones (called joint space narrowing) or the presence of a site-specific cytokine. The CDER established the Biomarker Qualification Program to provide a formal process to guide scientists in the regulatory process as they investigate biomarkers for drug development.

A related project, presented by Michael Nevitt, PhD, MPH, and representing more than 20 organizations including the Arthritis Foundation and spearheaded by the Foundation for the National Institutes of Health (http://fnih.org) Biomarkers Consortium, is called the Osteoarthritis Biomarkers Project. This important research study aims to identify and classify biological markers of progression in knee OA using biosamples and images from 400 knees already available from the Osteoarthritis Initiative (OAI). If the most responsive biomarker of progression can be pinpointed, then individuals at risk of developing severe OA can be identified and treated early in the disease.
 

The ‘Wonder Tissue’

“The diagnosis of OA is related to cartilage, the ‘wonder tissue,’” began Linda Sandell, PhD, professor and director of research at the Center for Musculoskeletal Research at the Washington University School of Medicine in St. Louis, “but not all cartilage is the same.”

Sandell’s lab wondered if some people have the ability to repair cartilage and whether it is inherited. Using large- and small-inbred mice strains, healing from mouse ear wounds and knee joint injuries were observed over time. It was determined that cartilage regeneration is inherited (large mice strains healed, while small did not), and this visible characteristic is related to ear wound healing.

Going a step further, Sandell – who is also the president of the Osteoarthritis Research Society International (OARSI) – wondered if OA in mice can be predicted by the ability to repair cartilage. Studies in her lab showed that healers appeared to have protection from OA (i.e., they did not get severe cartilage degeneration) versus the non-healers who developed OA. In one strain, subchondral bone became thinner early but regenerated in late stages post-surgery. “This shows that bone changes occur in response to injury and cartilage degeneration,” she concluded.

Conditions that Lead to OA

Studies have shown that ACL injury leads to OA 10 to 15 years later in 50 percent of cases. The negative effects of obesity, abnormal physiology and age on the development of OA were also addressed in “Disease Mechanisms that Impact the Joint.” “Overweight adults exert greater loads while walking because they must stabilize a greater mass,” said Steve Messier, PhD, professor at Wake Forest University in Winston-Salem, N.C., “and abnormal stress can cause mechanical failure and disability in joints.”

More than 450 adults older than 55 years old with a body mass index greater than 27 took part in the Intensive Diet and Exercise for Arthritis (IDEA) study for 18 months. Messier wanted to determine if there is a non-drug, noninvasive solution to reduce loads and relieve pain.

Participants were divided into three intervention groups: exercise only (walking and weight training), diet (800 to 1,000 kilocalories per day) combined with group counseling, and a combination of exercise and diet. Not surprisingly, all groups experienced reduced pain and improved function, but those who lost more than 10 percent of their body weight experienced even less pain and more function. Measurements of systemic inflammatory biomarker IL-6 were reduced in both diet groups, indicating a decreased risk of disability.

John Hardin, MD, vice president of research for the Arthritis Foundation, summed it up by saying, “Most importantly we learned that exercise is not just a mechanism to use up more calories, but actually adds an additional factor to symptom improvement beyond reduction in mechanical stress.”

Future of OA Research

An exciting area of research that will continue to develop is stem cell and regenerative medicine. Chondrogenesis is a process that uses unspecialized stem cells to grow cartilage tissue via nanotechnology. Rocky Tuan, PhD, professor at the University of Pittsburgh Medical Center, presented his recent research involving growing cartilage on a microscopic tissue-based structure to use directly on a femoral bone in a live animal model. The long-term goal is to grow tissue and other biomaterials to rebuild or replace cartilage.

Mother Nature had different plans for the conclusion of the SNOW V conference, as many attendees needed to leave early due to Hurricane Sandy. It precluded the call for applications for the ACL Intervention Initiative, a multicenter feasibility study sponsored by the Arthritis Foundation that uses ACL injury as a model for investigating chemical and imaging biomarkers as they relate to predicting OA. This is an important step in showing that images and data from several different locations can be standardized. The Arthritis Foundation will work with the partnering institutions to carry out this two-year project, estimated to cost $1 million.