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TNF-α modulation in spinal fusion: high-dose TNF-α is associated with failed arthrodesis, while etanercept is
John D Koerner1, Mitchell K Ng2, Jonathan Dalton2
1Department of Orthopaedic Surgery, Hackensack University Medical Center, Hackensack, NJ, USA; Department of Orthopaedic Surgery, Rothman Orthopaedic Institute, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
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 Rothman Orthopaedic Institute , 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<.001). By day 28, only VEGF was reduced in all treatment groups compared with controls (p<.001). At 4 weeks, fusion was present in 4/5 controls, 0/5 high-dose TNF-α animals (p=.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=.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.
