Spine Journal - 2026-07-17 - Journal Article
TNF-α Modulation in Spinal Fusion: High-Dose TNF-α Is Associated With Failed Arthrodesis, While Etanercept Is Associated With Successful Fusion in a Rat Model.
Koerner JD, Ng MK, Dalton J, Eichbaum YK, Banko SJ, Vaccaro AR, Markova DZ, Kepler CK
Topics
Key Takeaway
High-dose TNF-α resulted in 0/5 fusion rate versus 4/5 controls, while systemic Etanercept achieved 5/5 bilateral fusion by microCT at 4 weeks in a rat posterolateral fusion model.
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Summary
This study examined whether TNF-α dose and pharmacologic inhibition with Etanercept alter L4-L5 posterolateral fusion outcomes in rats using demineralized bone matrix. High-dose TNF-α produced early spikes in local IGF-1 (22.1 vs 6.2 ng/mg) and VEGF (539 vs 112 pg/mg) at day 2 but resulted in 0/5 fusion by palpation and 0/5 bilateral fusion by microCT at 4 weeks. Systemic Etanercept achieved the highest bilateral fusion rate (5/5 by microCT) compared to 2/5 controls, suggesting TNF-α inhibition does not impair and may enhance arthrodesis.
Key Limitation
The 4-week rat model with n=5 per group at the fusion endpoint is underpowered and does not replicate the chronic inflammatory milieu, bone quality, or biomechanical environment of human spinal fusion, making direct clinical translation premature.
Original Abstract
BACKGROUND CONTEXT
TNF-α has been studied in fracture healing; modulation of its activity, either by supraphysiologic exposure or pharmacologic inhibition, may alter the likelihood of pseudarthrosis in spinal fusion.
PURPOSE
Our main objective is to determine the effects of high- and low-dose tumor necrosis factor-α (TNF-α) and the TNF-α inhibitor Etanercept on spinal fusion outcomes.
STUDY DESIGN
Laboratory Study
METHODS
Seventy-five Wistar rats underwent L4-L5 posterolateral fusion with demineralized bone matrix and received either high-dose TNF-α, low-dose TNF-α, local Etanercept, systemic Etanercept, or carrier alone. At 2, 4, and 28 days, serum and local fusion masses were analyzed with ELISA for IGF-1 and VEGF. Fusion was assessed at 4 weeks by manual palpation and microCT. The study was funded by the ***, no study specific conflicts of interest to report.
RESULTS
In vivo, high-dose TNF-α significantly elevated local IGF-1 (22.1 ± 2.1 ng/mg) and VEGF (539 ± 177 pg/mg) at day 2 compared with controls (IGF-1: 6.2 ± 1.2;
VEGF
112 ± 12; P < 0.001). By day 28, only VEGF was reduced in all treatment groups compared with controls (P < 0.001). At 4 weeks, fusion was present in 4/5 controls, 0/5 high-dose TNF-α animals (P = 0.048), 5/5 low-dose TNF-α, 3/5 local Etanercept, and 4/5 systemic Etanercept. MicroCT demonstrated bilateral fusion in 5/5 systemic Etanercept animals, 2/5 controls, and 0/5 high-dose TNF-α (P = 0.016).
CONCLUSION
High-dose TNF-α impaired fusion and was consistently associated with pseudarthrosis despite early increases in growth factor expression. Low-dose TNF-α and Etanercept, administered locally or systemically, did not compromise fusion, with systemic Etanercept showing the highest bilateral fusion rate. These findings indicate that TNF-α modulation significantly influences spinal fusion, and that TNF-α inhibition does not adversely affect arthrodesis.
CLINICAL SIGNIFICANCE
Modulating TNF-α appears to affect fusion success and implementing anti-TNF-α could decrease pseudoarthrosis rates among patients who have elevated TNF-α disease states.