Deutscher Kongress für Orthopädie und Unfallchirurgie 2025 (DKOU 2025)
Exploring innovative strategies to enhance osteoporotic lumbar fusion: Efficacy of local delivery of prostaglandin EP4 receptor agonist KMN-159 and zoledronic acid in a rat model
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Objectives and questions: Spinal fusion in patients with osteoporosis is challenging [1]. rhBMP-2 is the only FDA-approved osteoinductive agent but has high costs and side effects [2]. KMN-159, a novel prostaglandin EP4 receptor agonist, promotes spinal fusion in healthy rats (Vater et al., 2024). Zoledronic acid (ZA) inhibits osteoclast activity and enhances fusion when locally administered with rhBMP-2 [3]. This study examined whether local co-administration of a minimal effective dose of KMN-159 with ZA could improve osteoporotic spinal fusion.
Material and methods: An osteoporotic spinal fusion model was created using 40–41-week-old female Wistar rats subjected to bilateral ovariectomy (OVX) for 18 weeks. A mineralized collagen matrix (MCM) scaffold was used for local drug delivery. Rats were divided into five groups: MCM, MCM + 20 µg rhBMP-2, MCM + 20 µg KMN-159, MCM + 10 µg ZA, and MCM + 20 µg KMN-159 + 10 µg ZA. At 3 and 6 weeks, 9 animals per group were euthanized for µCT and histological analysis. Statistical significance was set at p < 0.05.
Results: µCT analysis showed that rhBMP-2 enhanced spinal fusion but caused heterotopic ossification. MCM alone or with KMN-159 did not induce fusion, while ZA, with or without KMN-159, promoted fusion. Histology confirmed rhBMP-2-induced bone formation, whereas ZA ± KMN-159 enhanced scaffold mineralization. Biomechanical testing showed improved stability in the rhBMP-2 and ZA ± KMN-159 groups at 6 weeks (Figure 1 [Fig. 1]).
Figure 1: (A) micro-CT analysis at 3 and 6 weeks. (B-C) Histological staining and fluorescent labeling. (D) Biomechanical analysis at 6 weeks. Scale bar = 1,000 µm. *P < 0.05, **P < 0.01.
Discussion and conclusions: rhBMP-2 was associated with significant ectopic bone formation, suggesting the need to develop safe alternatives in spinal fusion surgery. Local delivery of ZA facilitated spinal fusion through scaffold mineralization, presenting a promising alternative. While KMN-159 alone has shown efficacy in promoting bone growth in healthy rat models, its reduced effectiveness as monotherapy in this osteoporotic rat highlights the challenges of fusion in compromised bone environments. Although the particular combination of KMN-159 and ZA doses used here did not appear to produce synergistic effects, it is reasonable that a higher dose of KMN-159 in combination with ZA might be efficacious in an osteoporotic spinal fusion model and warrants further investigation.
Literatur
[1] Park SB, Chung CK. Strategies of spinal fusion on osteoporotic spine. J Korean Neurosurg Soc. 2011 Jun;49(6):317-22. DOI: 10.3340/jkns.2011.49.6.317[2] Gillman CE, Jayasuriya AC. FDA-approved bone grafts and bone graft substitute devices in bone regeneration. Mater Sci Eng C Mater Biol Appl. 2021 Nov;130:112466. DOI: 10.1016/j.msec.2021.112466
[3] Tian X, Vater C, Raina DB, Findeisen L, Matuszewski LM, Tägil M, Lidgren L, Winkler A, Gottwald R, Modler N, Schaser KD, Disch AC, Zwingenberger S. Co-delivery of rhBMP-2 and zoledronic acid using calcium sulfate/hydroxyapatite carrier as a bioactive bone substitute to enhance and accelerate spinal fusion. Bioact Mater. 2024 Mar 6;36:256-71. DOI: 10.1016/j.bioactmat.2024.02.034
