“Our ultimate goal is to describe the disease well enough to fuel biomarker validation and clinical trials to develop interventions,” says Joan A. McGowan, PhD, director of the Musculoskeletal Diseases Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the NIH.

AAOS Now

Published 2/1/2009
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Annie Hayashi

NIH initiative seeks answers to OA questions

Osteoarthritis Initiative focuses on predictive biomarkers, natural history

Why do some people with radiographic evidence of osteoarthritis (OA) of the knee develop painful symptoms and others do not? Why does OA progress faster in some individuals? Which interventions are most effective in slowing the progress of OA? Can more effective interventions be developed?

These are among the issues that the National Institutes of Health (NIH) hopes to address through its Osteoarthritis Initiative (OAI), a multi­center, longitudinal, prospective, observational study of knee OA.

Joan A. McGowan, PhD

“This is one of the first public/private partnerships in the history of NIAMS,” she points out. “The OAI is certainly the largest study of this type that we have ever undertaken.”

A powerful partnership for innovation
“The OAI Consortium—comprised of private industry, academic institutions, government agencies, and the Foundation of the NIH—has provided extensive intellectual input into the design and planning of the study,” says Dr. McGowan (
Fig. 1).

“This has enabled us to develop a public research resource to assist in identifying and evaluating potential biomarkers that can be used as surrogate endpoints for OA of the knee,” she notes.

Under the leadership of NIAMS and the National Institute on Aging (NIA), several NIH agencies—as well as four pharmaceutical companies—have contributed to this ambitious project (Table 1).

According to Dr. McGowan, “One of the most exciting aspects of the OAI is the pooling of public and private funds to create a publicly available scientific and biomarker resource that would not have been possible by either sector alone.”

Due to its success and the abundance of available data, the project is being extended for 5 additional years to follow and report on the disease process of OAI participants. The clinical centers will continue to evaluate those in the study and collect all pertinent data.

OAI database drives quest for novel treatments
The
central repository for all OAI patient information is an online database developed by the University of California, San Francisco.

More than 17,000 individuals were screened for the OAI and 4,796 participants have been enrolled in the study since the project was initiated in 2002. In addition to clinical assessments of all participants, the database includes imaging studies and biologic specimens.

“The entire study population has been seen at baseline, at 12 months, and at 24 months,” reports Dr. McGowan. Imaging studies and biospecimens from these three visits are available for about 90 percent of the study population.

“Approximately 80 percent of the 36-month visits and 60 percent of the 48-month visits are also complete,” she says.

A substantial amount of clinical data is now available and can be downloaded; magnetic resonance images (MRI) are available on request and shipped on portable hard drives. Biologic samples will be released when all of the preliminary work has been completed, according to Dr. McGowan.

Since the OAI Web site went live in 2006, more than 1,000 users have registered to use the online data—747 from the United States and 316 from 51 other countries. More than 2,000 data sets have been downloaded and 126 image sets have been distributed.

According to Gayle Lester, PhD, project officer for OAI, great care has been taken in both collecting and storing the biomarkers. “All data collected are extensively reviewed and outcomes are validated by the clinical centers and the coordinating center.”

Two workshops for OAI data users have already been held; presentation materials from both are available on the Web site. Future workshops will be extensively advertised.

OAI study population
Because study participants have “risk factors that we think are associated with the development of the disease,” says Dr. McGowan, “we can determine the characteristics of those participants on a fast trajectory and others on a slower one.

These risk factors include, but are not limited to, the following: pain, aching, or stiffness in or around the knee; radiographic identification of tibiofemoral osteophytes; the use of medications to treat pain, aching, or stiffness; overweight; knee injury; knee surgery; family history; Heberden’s nodes; or repetitive knee bending as part of activities of daily life.

“Investigators will have the opportunity to evaluate biomarkers and risk factors for both the onset and progression of knee OA disease,” she adds.

The “progression” subgroup, comprising 29 percent of the study population, consists of individuals who exhibited symptomatic OA at baseline. The clinical centers are collecting data on changes in symptoms, function, and structure of OA in this group.

Individuals at increased risk of developing symptomatic knee OA during their participation in the study were assigned to the “incidence” subgroup, which makes up 68 percent of the study population (Fig 2).

The third group consists of those participants without any of the risk factors for OA. The “nonexposed” subgroup serves as the control group with 3 percent of the total study population.

“Most of the existing OA studies have been done with people who have osteoarthritis,” says Dr. McGowan. “But to evaluate biomarkers, we needed to include participants who have no evidence of the disease.”

Approximately the same per­centage of men and women are enrolled in the study; 21 percent of the study population are members of a racial or ethnic minority group.

Study participants range in age from 45 years old to 79 years old with the largest number—35 per­cent—in the 50-to-59 age group.

Extensive research opportunities

Dr. McGowan strongly encourages researchers and investigators to take advantage of this powerful and unique resource.

NIAMS, in collaboration with the Orthopaedic Research and Education Foundation (OREF), has established a fellowship program specifically for orthopaedic surgeons interested in clinical and health services research. “The OAI would be a terrific resource for individuals interested in these awards,” she says.

In addition, recognizing the need for orthopaedic surgeons to continue clinical activities, Career Development awards submitted by surgeons require only a 50 percent time commitment to research. View more information on these awards.

“We would like to see scientists from both the private sector and academic settings request this data, the images, or the biospecimens—particularly those who have developed a putative biomarker,” says Dr. McGowan.

She points out that R01 grants are also available, “to use this existing data as well as for ancillary projects.

“We would really like to see people interested in systems biology and bioinformatics pursue some of these awards. We’re also interested in having people from other fields who have a more sophisticated biomarker experience—from the cancer field, for example—who could look at this data and ask some standard biomarker questions,” she adds.

With the extension of this project, opportunities for novel research will increase. According to Dr. McGowan, “extended follow-up will provide increased statistical power for key analyses, including gains in power for subgroup analyses.

“The extension will also provide information to enable explorations of the relationship and interactions among OA of the knee, other co-morbidities, and health outcomes,” she concludes.

Annie Hayashi is the senior science writer for AAOS Now. She can be reached at hayashi@aaos.org

An invitation to investigate
A large, sophisticated database is available to orthopaedic clinician scientists and researchers interested in validating biomarkers and finding novel interventions for osteoarthritis.

Clinical data can be downloaded, archived images are available on demand, and biospecimens can be obtained by application.

  • Baseline and annual knee imaging data include:
  • Bilateral radiographs, posteroanterior fixed-flexion
  • Bilateral knee magnetic resonance images (MRIs)
  • Baseline and follow-up pelvis and hand radiographs
  • Full limb radiographs for knee alignment
  • Lateral knee radiographs in controls
  • MRIs of the thigh

For imaging schedules, go to www.oai.ucsf.edu/ExamMeasures.pdf.

  • Clinical data and biospecimens include:
  • Knee symptoms and function
  • Hip and other joint symptoms
  • General function, quality of life
  • Physical performance
  • Knee examination
  • Risk factors, health behaviors, psychosocial measures
  • Medications, supplements
  • Blood, urine, DNA, lymphocytes (archived)

For measurement schedules, go to www.oai.ucsf.edu/ExamMeasures.pdf and www.oai.ucsf.edu/MNACR2008.pdf