Peripheral blood neutrophil-to-lymphocyte ratio is associated with age but not with body mass index or radiographic severity in osteoarthritis: a translational study in mice and humans

The neutrophil-to-lymphocyte ratio (NLR) is a cost-effective indicator of systemic inflammation. This study aimed to evaluate the dynamics and translational relevance of NLR in osteoarthritis (OA), and to determine, with explicit adjustment for age, whether NLR is associated with the presence of OA, with body mass index (BMI, a surrogate of obesity-related mechanical load), and with radiographic severity. NLR dynamics were assessed in bone marrow and peripheral blood using destabilization of the medial meniscus (DMM) surgery and natural aging mouse models. Translational relevance was evaluated in large clinical datasets from healthy donors ( n = 3482) and patients with knee or hip OA ( n = 564), using age-stratified, multivariable age-adjusted, and 1:1 age-matched analyses. Findings were validated in an independent population-based cohort (NHANES 2007–2008, OA-specific; and 2011–2020, all-cause arthritis). Peripheral blood NLR was significantly elevated after DMM surgery and in naturally aged mice, whereas bone marrow NLR showed a muted response. In healthy donors, peripheral NLR increased significantly with age in both sexes, with a stronger association in males (β = 0.013 per year, R2 = 0.04) than in females (β = 0.007 per year, R2 = 0.01). Male OA patients had higher NLR than healthy donors in crude analysis, but this association was markedly attenuated after adjustment for age (adjusted OR per 1-SD increase in log-NLR = 1.03, 95% CI 0.90–1.19) and was not significant in 1:1 age-matched comparisons; no significant difference was observed in females. NLR did not correlate with BMI (crude or age-adjusted) and did not differ between KL grade 3 and grade 4 OA. These patterns were replicated in NHANES. Human bone marrow NLR was approximately 6 (exploratory estimate in the mononuclear-cell fraction), substantially higher than peripheral values. Peripheral blood NLR tracks age-related systemic inflammation, but it showed no association with BMI or with the moderate-to-severe radiographic grades represented in the present OA cohorts. The apparent elevation of NLR in OA patients is largely attributable to age, and NLR should be interpreted with age as a key confounder.