Knee transforming into seed for new cartilage.

Is End-Stage Knee Osteoarthritis the Key to Faster Drug Approvals?

Avery Sinclair in Health & Wellness June 2025 • 4 min read.

"New research explores using end-stage knee osteoarthritis incidence as a proxy for knee replacement in clinical trials, potentially speeding up the evaluation of new treatments."

Osteoarthritis (OA) is a significant health challenge, especially as populations age. The quest for effective treatments, particularly disease-modifying osteoarthritis drugs (DMOADs), is ongoing. These drugs aim to not only alleviate symptoms but also alter the course of the disease, potentially regenerating cartilage and improving joint structure.

Regulatory agencies require extensive Phase 3 trials to demonstrate changes in joint space width on X-rays and improvements in patient symptoms before a DMOAD can be approved. However, the real-world value of these drugs also depends on their acceptance by healthcare systems, which prioritize treatments that save resources.

Since joint replacements are costly, a DMOAD that reduces the need for surgery could be highly valuable. However, using knee joint replacement (KJR) as a primary endpoint in clinical trials presents challenges. KJR indications vary widely, and KJR is not considered a fully validated endpoint. New research explores using the incidence of end-stage knee osteoarthritis (esKOA) as a more practical proxy for KJR in clinical trials, potentially leading to faster drug approvals.

Why End-Stage Knee Osteoarthritis Could Be the Answer

Knee transforming into seed for new cartilage.

Researchers have been exploring the idea of using esKOA as a clinical endpoint. In a study utilizing data from the Osteoarthritis Initiative (OAI), a multicenter cohort study in the United States, researchers analyzed various factors to determine the potential of esKOA as a more viable endpoint than KJR. The study looked at data from 4,796 adults with or at risk for symptomatic knee OA.

The researchers defined esKOA using a combination of clinical and radiographic criteria, including:

Knee pain and function (using the WOMAC scale)
Radiographic severity (Kellgren-Lawrence grade)
Number of compartments affected
Joint stability and range of motion

By analyzing the OAI data, the researchers estimated the sample sizes needed for hypothetical DMOAD trials using esKOA as the primary endpoint and compared these with sample sizes required when using KJR as the endpoint. They considered factors like age, gender, and Kellgren-Lawrence grades to create different sub-cohorts within the OAI data.

The Future of Osteoarthritis Drug Development

The research indicates that using esKOA as an endpoint could significantly reduce the sample sizes needed for clinical trials, making them more feasible. The study found that the incidence of both esKOA and KJR increased with age, OA severity, and in female patients. However, detecting DMOAD efficacy was considerably easier when focusing on reducing esKOA incidence rather than KJR incidence.

While generating health-economic data is increasingly vital for securing drug reimbursement, this study suggests that clinical trials in the OA field can be more practical. By selecting esKOA as an endpoint, studies can potentially involve a few hundred participants per study arm. Future research will need to validate esKOA as a clinical outcome, particularly for regulatory purposes.

Ultimately, this work, combined with other studies, highlights new aspects in DMOAD research, emphasizing clinically meaningful outcomes beyond just structural and symptomatic improvements. By demonstrating the potential for more manageable trial sizes, it paves the way for trials with health-economic aspects that do not require insurmountable budgets.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1016/j.semarthrit.2018.12.002, Alternate LINK

Title: Sample Size Calculations For Detecting Disease-Modifying Osteoarthritis Drug Effects On The Incidence Of End-Stage Knee Osteoarthritis In Clinical Trials: Data From The Osteoarthritis Initiative

Subject: Anesthesiology and Pain Medicine

Journal: Seminars in Arthritis and Rheumatism

Publisher: Elsevier BV

Authors: Klaus Flechsenhar, Janina S Ried, Jeffrey B Driban, Lori Lyn Price, Timothy Mcalindon

Published: 2019-08-01

Everything You Need To Know

What is the significance of End-Stage Knee Osteoarthritis (esKOA) in the context of drug approvals?

Osteoarthritis (OA) is a widespread health issue, particularly affecting aging populations. End-stage knee osteoarthritis (esKOA) is a severe form of OA. Regulatory bodies require extensive trials, like Phase 3 trials, to approve drugs. These trials often use endpoints like joint space width on X-rays and patient symptom improvements. Using esKOA as a proxy for knee joint replacement (KJR) could speed up the drug approval process.

Why are researchers considering using End-Stage Knee Osteoarthritis (esKOA) as a clinical endpoint?

Researchers are exploring the use of esKOA as a clinical endpoint because it could offer a more practical and efficient way to assess new drug effectiveness. Compared to knee joint replacement (KJR), esKOA might be a more clearly defined and validated endpoint. The study used data from the Osteoarthritis Initiative (OAI), a multicenter cohort study, to analyze various factors and determine the potential of esKOA as a viable endpoint. This could lead to faster evaluation of new treatments for Osteoarthritis.

What criteria define End-Stage Knee Osteoarthritis (esKOA)?

The definition includes Knee pain and function, Radiographic severity using the Kellgren-Lawrence grade, Number of compartments affected, and Joint stability and range of motion. The definition uses a combination of clinical and radiographic criteria to accurately identify patients with esKOA. This comprehensive approach aims to provide a reliable and consistent method for identifying the endpoint in clinical trials. The more accurate the definition, the better the chances of success in clinical trials.

How might using End-Stage Knee Osteoarthritis (esKOA) impact the design of clinical trials?

Using esKOA as an endpoint could potentially reduce the number of participants needed in clinical trials. This is because detecting the effectiveness of Disease-Modifying Osteoarthritis Drugs (DMOADs) may be easier when focusing on reducing esKOA incidence rather than KJR incidence. Smaller trial sizes can make studies more feasible and less expensive. The study suggests that factors like age, gender, and Kellgren-Lawrence grades are considered when designing these trials.

What patient characteristics are associated with End-Stage Knee Osteoarthritis (esKOA) and Knee Joint Replacement (KJR)?

The incidence of esKOA and KJR increases with age, OA severity, and is more prevalent in female patients. The research indicates that esKOA incidence may be a more sensitive measure for detecting the efficacy of new treatments, specifically DMOADs. This could help in the development of drugs that reduce the need for knee joint replacement and improve the quality of life for individuals suffering from knee osteoarthritis.