Osteoarthritis (OA) is the most common specific arthritis condition, affecting 27 million people in the United States in 20051
. Knee and hip OA are generally considered to have the greatest impact due to effects on ambulation2
. OA of these joints accounted for 97% of the total knee replacements and 8% of the total hip replacements for arthritis in 20043
. OA, however, is frequently a generalized condition, involving multiple joint sites, including the hand, knee, hip, great toe, and spine, all of which can be associated with significant symptoms and disability4–6
In 2007, the Osteoarthritis Research Society International (OARSI) was awarded a contract from the Federal Drug Administration (FDA) to review issues related to the design and conduct of clinical trials for OA, particularly pertaining to agents purporting to effect disease modification (See Introduction to Issue). Several categories of inquiries, and Working Groups to examine them, were established, including Imaging, Biomarkers, Definition of Disease State, Safety, and Prevention and Risk Reduction. This paper will discuss the outcome of deliberations by the Working Group for Prevention and Risk Reduction. This Working Group was composed of individuals from academia and the pharmaceutical industry. The remit of this group was to examine potential outcome measures, the desirable duration of, and population for, an OA prevention trial, and the safety database and acceptable risk that would be required for prevention. Lastly, a research agenda to inform these issues was requested. Through a series of face-to-face meetings, telephone conferences, and electronic mail exchanges over almost 2 years, the members of the Working Group discussed these relevant questions, reviewed literature as required to inform answers, and presented the final product to a public forum attended by representatives from the FDA, the OARSI, and the National Institutes of Health (NIH), and academic and industry/private foundation communities.
Generally, clinical trials in OA have addressed three major types of outcomes: (1) symptoms of pain, function, and stiffness; (2) structural disease progression; and (3) replacement of affected joints. The clinical trials in OA to relieve symptoms of pain or stiffness and to improve function may involve pharmaceutical or nutraceutical agents7
, devices (i.e., braces, shoe orthotics), or behavioral interventions, such as weight-reduction, exercise, or increased physical activity8–12
. The less common disease-modifying trials aim to demonstrate slowing of the rate of structural progression, (frequently measured by change in joint space narrowing on radiographs of the knee or hip13–15
) and have employed pharmaceuticals or neutraceutical with, for example, putative anti-oxidant properties, the ability to inhibit cartilage degradative enzymes, impact bone turnover, modulate inflammation, or enhance or induce cartilage repair and/or lubrication16,17
. The goal of these trials is to prevent structural progression of established disease
, or to prevent disability or the need for total joint replacement, an indicator of total joint failure, in those with established disease, ie tertiary prevention. A third major type of OA trial involves evaluation of actions intended to assure the safety, efficiency, and efficacy of joint replacement.
This report will address the primary and secondary prevention and risk reduction of structural and symptomatic indicators of OA. These types of trials face specific hurdles because the onset of OA can be insidious and progression slow, with consequently, the need for trials of long duration, or the use of proxy measures with imperfect sensitivity and specificity for development of OA clinical outcomes, to allow the trial to be feasible. This report will discuss definitions, eligible populations and high-risk groups to whom initial prevention efforts might be directed for proof of concept, and possible outcome/surrogate outcome measures for primary and secondary prevention and risk reduction (). Then, an example of a prevention and a risk reduction trial for knee OA, directed at the high-risk group of those who are overweight or obese, and young athletes at risk of knee injury, respectively, will be proposed. These example trial designs are directed at knee OA with the understanding that OA in other joint sites (i.e., hands and hip) may have different prevalences, different risk factor profiles, different natural history of development and unique measures to define the disease state. Therefore, the approaches in these examples may not be generalizable to OA affecting joints other than the knee. In these examples, the recommended duration of a trial and appropriate database for safety will be outlined. Finally, ethical issues surrounding the conduct of clinical trials for OA prevention will be introduced.
Structural abn’l = structural abnormality.