BARCELONA – People with osteoarthritis who are going to need knee replacement have markedly more cartilage loss earlier in the course of their disease than do osteoarthritis patients who keep their knees, judging from an image biomarker validation study presented at the World Congress on Osteoarthritis.
The finding that early loss of cartilage thickness predicts the need for future knee replacement is clinically significant, because some of the disease-modifying osteoarthritis drugs (DMOADs) that are under development aim both to ease or eliminate pain and to provide structural benefit in order to stop or reverse the structural changes, said Dr. Felix Eckstein, chief of the institute of anatomy and musculoskeletal research at Paracelsus Medical University, Salzburg, Austria.
Dr. Felix Eckstein
"It’s unknown whether the modifying effect on joint structures will also provide clinical benefit for patients. The FDA would not approve a drug that improves structure without clinical benefit," said Dr. Eckstein, the lead investigator of the study.
The data presented were drawn from the U.S.-based Osteoarthritis Initiative (OAI), a multicenter, 4-year observational study of men and women that was designed to help improve treatment of knee osteoarthritis. Dr. Eckstein and his colleagues investigated structural changes that were detected using magnetic resonance imaging and observed their relationship to knee replacement in the year after measuring cartilage thickness.
In all, the study involved 109 knees from participants in the OAI who had received knee replacements between study years 1 and 4. A matched control knee was selected for each knee replacement case from OAI participants with the same Kellgren-Lawrence grade (KLG) at baseline.
The primary end point biomarker was loss of cartilage thickness after 1 year (taken as a time point prior to knee replacement and 1 year earlier) for the central medial compartment. The secondary end point was loss of cartilage thickness in the total medial compartment.
Segmentation of the cartilage using sagittal 3D dual-echo in steady state with water excitation (DESSwe) MRI sequence (3 Tesla) images provided measures of cartilage thickness. The investigators evaluated measurements of 16 subregions.
Dr. Eckstein and his associates matched participants according to their baseline radiographic disease stage, and looked within these strata for differentiation between those cases that progress to knee replacement and those that do not. "The new approach of this study was that we did not look at cases versus the rest of the cohort that may have been at a far earlier disease stage. We know that people at later radiographic disease stages have more cartilage loss than earlier disease stages."
They found that participants who had received knee replacement had lost three times as much cartilage as controls. "There was a lot variability, but it still discriminates with an area under the curve [AUC] of 0.59 (P = .007), so it is a significant differentiation," said Dr. Eckstein.
Breakdown by radiographic disease strata showed that the most marked differentiation occurred at the early disease stages. The AUC for KLG 2 was 0.67 (P = .009), versus an AUC of 0.55 (P = .16) for KLG 3, and an AUC of 0.53 (P = .65) for KLG 4. "At KLG 2, we see a relatively large difference in cartilage loss," he added.
Dr. Eckstein used ordered values as exploratory end points. "Rather than looking at the same region in every participant, we looked at the one region in each participant that changed the most over 1 year. Ordered values allow us look at the magnitude of change where it occurs with a specific risk factor set and then measure and compare this quantitatively between participants," he said.
The results showed that if magnitude of change is investigated wherever that change occurs, then the findings are greater in patients who progress to knee replacement, Dr. Eckstein said. "The differentiation for that particular order value is greater than a regional-based measure."
Looking ahead to the potential use of cartilage loss as a biomarker in trials, Dr. Eckstein said that "we think longitudinal, quantitative measures of cartilage loss predict knee replacement, particularly at the early radiographic stages. These MRI measures may be used in clinical trials to demonstrate the efficacy of DMOADs, with the large likelihood that these will translate into clinical benefits too."
The findings also lend support to the concept that treatments that slow cartilage loss may delay or prevent knee replacement. "We think that if a drug could reduce the cartilage loss, then this would also reduce the risk of knee replacement, because we’ve shown there is a link between cartilage loss and knee replacement," summarized Dr. Eckstein.