NLR: a warning signal for vertebral fracture?

By Ana Espino | Published on March 16, 2026 | 3 min read


Osteoporosis is a systemic disease characterized by reduced bone mineral density and deterioration of bone microarchitecture. Vertebral fractures account for approximately 40% of osteoporotic fractures and are frequently asymptomatic, with underdiagnosis rates reaching up to 60%. Their occurrence increases the risk of subsequent fractures by nearly fivefold.  

Current risk assessment tools, such as FRAX, show limited sensitivity for predicting vertebral fractures specifically, particularly at early stages. These tools mainly incorporate static clinical risk factors and include few dynamic biological markers.  

Chronic low-grade inflammation plays a central role in the pathophysiology of osteoporosis. The neutrophil-to-lymphocyte ratio (NLR), a simple and accessible marker of systemic inflammation, has been proposed as a potential predictive biomarker. However, results from observational studies remain heterogeneous.  

This systematic review and meta-analysis, published in 2026 in Frontiers in Endocrinology, aimed to quantitatively assess the association between NLR and the risk of vertebral fracture in patients with osteoporosis.  

Does a high NLR increase fracture risk?  

This meta-analysis, conducted according to PRISMA guidelines and registered in PROSPERO (CRD420251023391), included six observational studies involving a total of 938 patients. Analyses distinguished between categorical data (high vs low NLR) and continuous data (absolute NLR values).  

Analysis of categorical variables, derived from five studies, showed that patients with elevated NLR had a significantly increased risk of vertebral fracture. However, substantial heterogeneity was observed, suggesting important methodological differences across studies.  

Conversely, analysis of continuous variables based on four studies did not show a statistically significant difference between fracture and non-fracture groups, with similarly high heterogeneity.  

Sensitivity analysis provided important insight. Excluding one study (Li et al., 2023) changed the results of the continuous-data analysis, which then became statistically significant with disappearance of heterogeneity. This instability highlights the statistical fragility of conclusions based on continuous data.  

Publication bias analyses revealed a significant bias for categorical data (Egger test p = 0.04), but not for continuous data.  

From a pathophysiological perspective, NLR reflects the balance between pro-inflammatory neutrophil activation and lymphocyte-mediated immune regulation. Inflammation stimulates osteoclastogenesis via the RANKL pathway, promoting bone resorption and vertebral fragility.  

A promising biomarker, but evidence remains limited  

Osteoporotic vertebral fractures represent a major clinical challenge due to their high frequency and often silent presentation. Identifying simple and accessible biomarkers is therefore an important objective.  

This meta-analysis suggests that elevated NLR is associated with a significantly increased risk of vertebral fracture when data are analyzed categorically. However, the absence of consistent confirmation in continuous analyses and the instability of results limit the strength of the current evidence.  

Key limitations include small sample sizes, the predominance of Asian populations, heterogeneity in NLR thresholds, variability in fracture diagnostic criteria, and insufficient adjustment for confounding factors.   Large prospective multicenter studies with standardized NLR thresholds and rigorous multivariable analyses will be required to determine the true incremental value of NLR in fracture risk stratification. With robust validation, NLR could become a complementary biomarker alongside existing risk assessment tools.  

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