Femoral Head Growth Plate Dysplasia and Fracture in Juvenile Rabbits Induced by Off-target Antiangiogenic Treatment

Area of Science:

• Oncology
• Pharmacology
• Orthopedics

Background:

• Epiphyseal growth plate dysplasia (chondrodysplasia) is a known side effect of antiangiogenic treatments in preclinical models.
• Inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor (FGF) receptors are common antiangiogenic agents.

Purpose of the Study:

• To investigate epiphyseal growth plate dysplasia induced by an oral spleen tyrosine kinase inhibitor in juvenile rabbits.
• To assess the potential for off-target antiangiogenic inhibition of VEGF and FGF family kinase receptors.

Main Methods:

• Juvenile rabbits were treated with an oral spleen tyrosine kinase inhibitor.
• Histopathological examination of epiphyseal growth plates and femoral heads was performed.
• Fracture lines and dysplasia in the femoral head physis and articular cartilage were analyzed.

Main Results:

• Epiphyseal growth plate dysplasia was observed, leading to femoral head physis weakening and fracturing in 6/10 males and 1/10 females.
• Microfracturing and dysplasia of the distal femoral articular cartilage occurred in one male rabbit.
• Fractures involved the hypertrophic cartilage zone, were parallel to the physeal plane, and often displaced the femoral head.

Conclusions:

• Spleen tyrosine kinase inhibitors can induce epiphyseal growth plate dysplasia through off-target antiangiogenic mechanisms.
• The high prevalence of growth plate fractures in rabbits suggests a potential adverse risk for pediatric patients undergoing antiangiogenic therapy.