Fig. 1 (A) Patients with ACL injuries typically have intact articular surfaces at arthroscopy. (B) Optical coherence tomography shows subsurface changes to articular cartilage in ACL-injured knees. (C) Novel ultrashort echo time enhanced T2* mapping is sensitive to matrix changes to deep articular cartilage and menisci. Courtesy Constance R. Chu, MD

AAOS Now

Published 9/1/2012
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Constance R. Chu, MD

New Treatments to Prevent, Delay Osteoarthritis

Transforming OA into a modifiable disease process

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide. The disease has traditionally been associated with aging and described using clinical and radiographic criteria reflective of advanced biologic and structural changes of joint destruction. Consequently, disease-modifying treatments are lacking and clinical treatment of OA is palliative until joint replacement.

Methods to directly visualize and image intra-articular structures support a paradigm shift toward viewing OA as a continuum of disease. This redefinition of OA permits diagnosis and staging of pre-osteoarthritic conditions. Combined with personalized medicine, these methods will help make it possible to develop prevention strategies to reduce OA risk in patients with pre-osteoarthritic disease states.

The role of imaging
To properly treat a condition, it is first necessary to obtain a diagnosis. With the advent of radiographs more than a century ago, physicians and surgeons gained the means to subcategorize bone and joint conditions involving changes to bone or the relationships between bones.

Based on radiographic criteria, the classic signs of OA include osteophytes, joint space narrowing, subchondral bone thickening, and cyst formation. These represent advanced biologic and structural changes of OA disease states that have not been shown to be reversible. The ability to visualize the bone changes underlying symptoms of joint pain, deformity, and functional disability, however, supported development of treatments such as osteotomy that can address progressive angular deformity and joint space loss. Observation of radiographic changes reflective of total joint destruction led to total joint replacement, one of the most significant medical developments of the past century.

Through arthrotomy and open joint surgery, orthopaedic surgeons have long treated injuries such as traumatic meniscus tears, large chondral defects, and intra-articular fractures that have later been shown to increase OA risk in affected patients. In the past 30 years, the increased clinical use of arthroscopy has given orthopaedic surgeons the ability to routinely visualize (Fig. 1A), describe, and treat pre-osteoarthritic conditions ranging from chondrosis and chondromalacia to full thickness chondral defects, ligament and intra-articular tendon tears, labral tears, meniscal pathologies, and capsular deficiencies.

The ability to see and describe intra-articular soft-tissue conditions led to new treatments for the observed pathologies. These treatments range from repair to reconstruction and regeneration. Efforts to repair, regenerate, and replace damaged articular cartilage using scaffolds, cells, and osteochondral transplantation have intensified as the ability to diagnose and image full-thickness chondral defects has improved.

A few clinical studies suggest that restoring damaged articular surfaces may delay the onset of OA. Long-term randomized controlled studies with larger cohorts are needed to determine if cartilage restoration delays the onset of radiographic OA. Validation of more refined imaging assessments may show reduction of OA risk in shorter term studies.

The evolution of noninvasive methods such as magnetic resonance imaging (MRI), which directly image intra-articular soft tissues, enable improved understanding of the prevalence of pre-osteoarthritic changes. Among these are chondrosis, bone marrow edema, and soft-tissue attrition such as degenerative meniscal tears in the symptomatic joint. This has led to a new awareness of the continuum of pre-osteoarthritic conditions. Longitudinal evaluations using MRI permit development of new staging criteria and identification of candidate disease states potentially amenable to early intervention strategies.

For example, identification of meniscal root tears by MRI has led to efforts to treat the condition and to understand the clinical sequelae. Laboratory, arthroscopic, and MRI evaluations have now shown evidence for acute and substantial stress concentration to the central weight-bearing region of the medial femoral condyle following posterior root tears of the medial meniscus. MRI clinical data additionally implicate the meniscal root tear as an etiology of both spontaneous osteonecrosis of the knee (SPONK) and rapidly progressive medial compartment OA.

In response to this information, new techniques to repair meniscal root tears have evolved. Continued clinical study is needed to determine if early diagnosis and early repair of meniscal root tears will prevent SPONK or reduce OA risk.

Compromise of the articular surface results in acute structural changes that are considered progressive, given that partial-thickness injuries to articular cartilage do not heal. Animal and laboratory studies show that the earliest changes to articular cartilage associated with progressive joint degeneration occur prior to breakdown of the articular surface. It is at these earliest stages, where the articular surface remains intact, that pathologic processes are likely the most readily reversible.

New quantitative MRI (qMRI) techniques such as delayed gadolinium enhanced MRI of cartilage (dGEMRIC), T2 mapping, ultra-short echo time enhanced (UTE) T2* mapping, T1 rho and sodium MRI are being used to evaluate subsurface changes to the biochemistry and matrix properties of still intact articular cartilage. These techniques show promise in diagnosis and staging of the earliest changes that may be indicative of heightened OA risk.

Other nondestructive imaging modalities such as optical coherence tomography have been important in early diagnosis of subsurface cartilage damage following impact injury (Fig. 1B) and in early degeneration. This new technology has been used clinically to assist in clinical validation of MRI T2 mapping of articular cartilage.

Joint injury accelerates OA development in both animal models and in humans from a known point (time of injury). Therefore, human joint injury cohorts provide a unique opportunity to study the earliest stages of disease. One such cohort comprises young, healthy individuals with anterior cruciate ligament (ACL) tears. Interest in validating imaging and biochemical markers of early disease and for evaluating early intervention strategies in ACL-injured cohorts is increasing because these individuals are less likely to have pre-existing OA than elderly cohorts.

Newer quantitative MRI techniques—such as UTE T2* mapping (Fig. 1C)—show evidence of subsurface matrix changes to both articular cartilage and the meniscus acutely after ACL injury. Continued longitudinal studies in human joint injury cohorts to validate the predictive potential of qMRI for assessment of OA risk are important in the eventual development of preventive strategies.

Prevention and risk reduction
Identification of molecular, biologic, and biomechanic targets for therapeutic intervention depends on improved understanding of OA risk and OA pathogenesis. The pathogenesis of OA has remained elusive in part because OA development in humans occurs over years to decades and is largely asymptomatic until advanced biologic and structural changes have already occurred. Consequently, the clinical and clinical research focus in OA has been on end-stage radiographically apparent disease involving elderly cohorts.

Viewing OA as a continuum of disease and involving younger pre-osteoarthritic joint injury and early degeneration cohorts in the development of new imaging and biochemical biomarkers of joint degeneration and OA risk will be critical to understanding OA pathogenesis in humans. This new direction in OA research will lead to new biologic and biomechanic treatments to transform the clinical care of osteoarthritis from palliation to prevention.

Constance R. Chu, MD, is the Albert Ferguson Professor of Orthopedic Surgery at the University of Pittsburgh. She reports no conflicts.

Bench to Bedside
“Bench to Bedside” is a quarterly column sponsored by the AAOS Research Development Committee (RDC) highlighting new translational research. The RDC—under the auspices of the Council on Research and Quality—serves as the primary liaison to the National Institutes of Health on issues in musculoskeletal research and oversees research advocacy events, the clinician scientist development programs, and the Kappa Delta Research Awards.

Bottom Line

  • Recent advances in imaging techniques have changed researchers’ understanding of how OA develops, resulting in a paradigm shift toward viewing it as a continuum of disease.
  • Early identification and repair of damaged tissues may be able to delay the onset of OA.
  • Cohort studies of young individuals with joint injuries, such as ACL tears, may be useful in identifying imaging and biochemical markers of early OA and for evaluating early intervention strategies.

References

  1. U.S.Bone & Joint Decade, The Burden of Musculoskeletal Diseases in the United States, 2008, www.usbjd.org.
  2. Chu CR, Williams AA, Coyle CH, Bowers M.: Early diagnosis to enable early treatment of pre-osteoarthritis. Arth Research & Therapy 2012, 14:212 doi: 10.1186/ar3845
  3. Chu CR, Williams A, Tolliver D, Kwoh K, Bruno S, Irrgang J:. Clinical optical coherence tomography of early cartilage degeneration in persons with degenerative meniscal tears. Arthr Rheum. 2010 May; 62(5):1412-20. PMID: 20213801. PMC2972585
  4. Chu CR, Beynnon BD, Buckwalter JA, Garrett WE, Katz JN, Rodeo SA, et al: Closing the Gap Between Bench to Bedside Research for Early Arthritis Therapies (EARTH): Report from the AOSSM/NIH U-13 Post-joint Injury Osteoarthritis Conference II. Am J Sports Med. 2011 Jul;39(7):1569-78. PMID: 21730208.
  5. Williams AA, Qian Y, Chu CR: UTE-T2* mapping detects sub-clinical meniscus injury after anterior cruciate ligament tear. In press. E-pub February 21, 2012. Reference: YJOCA2569.