Transformative approaches for effective clinical trials to reduce the disease burden of osteoarthritis

Abstract

Osteoarthritis (OA) is a leading cause of disability and morbidity that has eluded development of effective disease modifying drugs and therapies. While established OA in the form of symptomatic radiographic disease is a recognizable final common pathway, OA development encompasses a broad spectrum of pathological changes, susceptibilities, and etiological pathways that cannot be considered a single disease process. Beginning with preclinical disease where radiographs are normal, the concept of pre-osteoarthritis (pre-OA) offers a systems-based approach to OA prevention by targeting reduction of OA risk prior to the onset of definable OA. Early OA ensues when cellular, molecular, and joint tissue changes begin to overlap that of OA, a process that can begin before the onset of definitive symptoms or radiographic changes. A myriad of pathways and crossroads of pre-OA and early OA eventually leads to poorly irreversible symptomatic radiographic OA. With increasing recognition of pre-OA and early OA markers, pathways and subtypes, opportunities arise to address these new therapeutic targets. The current status of clinical trials in OA was identified as a critical barrier to progress by the 2022 National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIAMS) Roundtable on "Cartilage Preservation and Restoration in Knee Osteoarthritis: Challenges, Gaps, and Opportunities". This manuscript summarizes the recommendations of the work group established from the Roundtable to address this issue. The work group recommends that clinical trial design and endpoints evolve to effectively evaluate new treatment approaches suitable for pre-osteoarthritis and early OA by different criteria than what has been set for symptomatic radiographic OA. While symptomatic improvement is the primary goal for palliation of irreversible established OA, important goals for treating earlier disease states include disease modification and prevention, with the potential to alter the natural history of progressive OA. Because symptoms may not correlate with structural changes in pre-OA and early OA, the primary outcomes in these trials need to match the intended mechanistic target and the therapeutic goal for the disease state being treated. The purpose of this manuscript is to transform the approach to clinical trials in OA by establishing a new benchmark of identifying critical outcomes that are appropriate for the joint disease states and subtypes of the target patient population, and the therapeutic or mechanistic target of the intervention being tested. By shifting the approach from using standardized outcomes based on established OA towards customizing clinical trials according to these principles, new precision medicine strategies to address the full spectrum of disease from pre-OA to OA can be more readily advanced into clinical practice.

Keywords: Biologics; Cartilage; Clinical trials; Early OA; MRI; Precision medicine; Preosteoarthritis.

Fig. 1.

Radiographic Knee Osteoarthritis signifies late-stage disease for which cartilage preservation and strategies for disease modification are less likely to show positive effect than in pre-osteoarthritis and early osteoarthritis.

Fig. 2.

Pre-osteoarthritis to established osteoarthritis. radiographs have been paired with arthroscopic images of the medial knee in (A) Radiographs are normal in Pre-Osteoarthritis where (B) arthroscopy shows a smooth and intact articular surface. The probe shows the cartilage is indentable consistent with softening and swelling seen in early degeneration. (C) Radiographs in Early Osteoarthritis can show small osteophytes and possible joint space narrowing where (D) arthroscopy can show a chronic full thickness chondral defect (blue arrows), as in this example. (E) Radiographs in Established Osteoarthritis show definite joint space narrowing where (c) arthroscopy shows generalized full thickness cartilage loss with exposed bone (blue arrows) and a displaced medial meniscus tear, as in this example.

Fig. 3.

Radiographs can underestimate structural Knee Osteoarthritis. These images consisting of (A) weight bearing radiograph; (B) The coronal T1 image shows subtle cartilage changes (blue arrow) and a degenerative meniscus (yellow arrow). (C) cartilage loss (blue arrows) and the medial meniscus tear (yellow arrow) appear more apparent on the T2 weighted image. (D) The arthroscopic image shows generalized medial compartment full thickness cartilage loss (blue arrows) with exposed bone (beige areas) to the femoral condyle and a displaced degenerative medial meniscus tear (yellow arrow) consistent with osteoarthritis.

Fig. 4.

Femoral bone shape models corresponding to the mean femur B-scores measured in ACLR and uninjured contralateral knees 18,20. Compared to a spectrum of femur shapes ranging from no OA (B-score = 0) to extreme OA (B-score = 5), the mean femur B-scores of knees from ACLR participants illustrate the pre-osteoarthritic status of most patients 2 years after ACLR where none met radiographic criteria for established knee OA and only 12.5 % met B-score criteria for knee OA. These models also highlight the sensitivity of femur B-score to subtle bone shape differences that relate to knee symptoms. Red and blue colorations illustrate local shape changes for various B-scores by percentage change in area where red indicates an increase in size and blue indicates a decrease in size. From Williams et al, American Journal of Sports Medicine (Vol. 51, Is. 14) pp.3677-3686. © 2023 by the Authors. Reprinted by Permission of Sage Publications.