# Interpretation and Utility of Novel Composite Structural Endpoints of Cumulative Damage and Disease Activity in Knee Osteoarthritis

> **NIH NIH R01** · TUFTS MEDICAL CENTER · 2021 · $627,942

## Abstract

The United States Food and Drug Administration (FDA) recognizes osteoarthritis as a serious disease with an
unmet need for therapies that slow, stop, or reverse joint damage. A challenge to testing new therapies is the
lack of a comprehensive definition of disease progression that incorporates multiple structural changes.
Another challenge is not knowing how much change in a structural measure would reflect meaningful benefit or
worsening to a patient. Magnetic resonance (MR) imaging has great potential to address these critical gaps.
However, no-one has developed an MR-based composite outcome that reflects multiple structural aspects
(“whole-knee”) of knee osteoarthritis progression and is sensitive to change. This remains a critical
technological obstacle to testing and developing new therapies. We recently tackled these barriers and found
that structural measures of knee osteoarthritis progression can be summarized as: 1) cumulative damage
(quantitative articular cartilage damage throughout a knee; relates to radiographic progression), and 2) disease
activity (quantitative bone marrow lesions and effusion-synovitis volumes; relates to pain progression). The
critical next steps are to demonstrate these outcomes are valid and useful predictive biomarkers of KOA
progression by determining 1) how much change in each measure translates to indicators of clinically
meaningful improvement or worsening and 2) the discriminative performance of each composite measure. We
will accomplish this by assessing annual MR images in 3 nested case-control samples to determine the
magnitude of change in cumulative damage and disease activity that predict changes in patient-reported
outcomes (Aim 2) and walking speed (Aim 3), and knee replacement (Aim 4) across biological factors (e.g.,
sex). To achieve our goal, we will quantify 1- or 2-year change in articular cartilage as well as bone marrow
lesions and effusion-synovitis volume on MR images for 5,270 knee visits. We will then determine the amount
of change in cumulative damage or disease activity that relates to these outcomes during the same time
period. We will also test how much change in these measures differentiates adults who will receive a knee
replacement. Finally, we will test whether cumulative damage and disease activity will reliably predict changes
in patient-centered outcomes across sex, body mass index, radiographic severity, and duration of observation
period. This study will support an application for approval of these structural endpoints as predictive
biomarkers for KOA progression, which could greatly improve the chance of success for clinical trials testing
disease-modifying therapies for knee osteoarthritis.

## Key facts

- **NIH application ID:** 10120980
- **Project number:** 1R01AR076411-01A1
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** Jeffrey B Driban
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $627,942
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120980

## Citation

> US National Institutes of Health, RePORTER application 10120980, Interpretation and Utility of Novel Composite Structural Endpoints of Cumulative Damage and Disease Activity in Knee Osteoarthritis (1R01AR076411-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120980. Licensed CC0.

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