An Exploration of Outlier Patients in Systemic Biomarkers of Chondral Metabolism After Anterior Cruciate Ligament Reconstruction

Abstract

Background:

Changes in systemic biomarkers of chondral metabolism have been identified after anterior cruciate ligament (ACL) reconstruction. Patients with extremely high biomarker concentrations (outlier patients) are often observed and may represent a group at high risk for posttraumatic arthritis. It is unclear if outlier status changes over time, and if it can be explained by patient, injury, and surgical factors.

Purpose:

To evaluate outlier status changes over time for 3 biomarkers of chondral metabolism after ACL injury and reconstruction and describe factors associated with outlier status.

Study Design:

Cohort study; Level of evidence, 2.

Methods:

Patients from a prospective longitudinal study were included. Urine and serum samples were taken immediately before primary ACL reconstruction and at 6 and 12 months postoperatively. A total of 666 patients provided samples (mean age, 24.9 years; 60.5% male). Concentrations of urinary C-terminal cross-linked telopeptide of type 2 collagen (u-CTX-II), serum N-propeptide of collagen 2A (s-PIIANP), and serum matrix metalloproteinase 3 (s-MMP-3) were measured using immunoassays. Outlier status was defined as values above quartile 3 plus 1.5 times the interquartile range for each biomarker. Multivariable logistic regression models were developed with biomarker outlier status as the dependent variable and patient, injury, and surgical factors as explanatory variables.

Results:

At the baseline time point, the proportion of outliers was 9.29% for u-CTX-II, 1.97% for s-PIIANP, and 12.42% for s-MMP-3. Outlier patients at baseline were commonly also outliers at one or both of the future time points in terms of u-CTX-II (88.3%) and s-MMP-3 (82.93%). In contrast, for s-PIIANP outlier patients at baseline, only 15.38% were outliers at a future time point. It was uncommon for nonoutlier patients at baseline to become an outlier at either of the future time points (u-CTX-II: 6.83%; s-PIIANP: 2.32%; s-MMP-3: 2.08%). Patient and surgical factors had poor ability to discriminate between outlier and nonoutlier patients for s-PIIANP (Tjur R² = 0.056) and s-MMP-3 (Tjur R² = 0.013). However, for u-CTX-II (Tjur R² = 0.598), younger age, shorter time from injury to surgery, lower body mass index, and male sex were independently associated with outlier u-CTX-II concentrations at baseline.

Conclusion:

Outlier patients were observed when measuring all 3 systemic biomarkers of chondral metabolism after ACL reconstruction. For s-PIIANP and sMMP-3, outlier status was poorly explained by patient or surgical factors, but for u-CTX-II, outlier status could, in part, be explained by patient and surgical factors. These results support longitudinal biomarker analyses, given that outlier status can change over time, and this may not be identified in cross-sectional study designs.