1Alpha,25-dihydroxy-2beta(3-hydroxypropoxy)vitamin D3 (ED-71) suppressed callus remodeling but did not interfere with fracture healing in rat femora

Abstract

Introduction: Because osteoporotic patients are prone to fractures, it must be considered whether or not patients undergoing drug therapies should discontinue treatment after sustaining a non-vertebral fracture. This study has tested the effect of novel active vitamin D3 analog, 1alpha,25-dihydroxy-2beta(3-hydroxypropoxy)vitamin D3 (ED-71), on the fracture healing comparing with a powerful anti-resorptive agent, alendronate, using a rat femoral fracture model.

Materials and methods: Female SD rats (n=201) allocated into 6 groups were treated with MCT-vehicle and ED-71 at 0.025 and 0.05 microg/kg/day (EDL and EDH groups), and with saline-vehicle and alendronate at 5 and 10 microg/kg/day (ALL and ALH groups). After 4 weeks of pretreatment, osteotomy of the femur was performed. Treatment was continued until sacrifice at 6 and 16 weeks post-fracture. Fracture callus was evaluated by soft X-ray radiography, pQCT, biomechanical testing and histomorphometry.

Results: At 16 weeks post-fracture, new cortical shell appeared in 100% of Control (MCT and saline-vehicle), EDL and EHL, and in 67% and 56% of ALL and ALH, respectively. ED-71 treatment showed insignificantly large callus area only at 6 weeks, while alendronate treatment induced bigger callus at both 6 and 16 weeks post-fracture. The lamellar/callus area was decreased only at 6 weeks by ED-71 treatment, but both at 6 and 16 weeks by alendronate treatment. Osteoclast number in callus surface was decreased in both ED-71 and alendronate treatment groups at 6 weeks and in EDH, ALL and ALH at 16 weeks, indicating that ED-71 inhibits osteoclastic bone resorption, but its effect is less prominent than alendronate. Almost complete callus remodeling was observed in ED-71-treated groups at 16 weeks without any significant change in structural and material properties of fractured bone.

Conclusions: ED-71 suppression of callus remodeling by inhibiting osteoclastic bone resorption was mild and dose-dependent and did not interfere with natural fracture healing process at 16 weeks post-fracture.