Once-weekly parathyroid hormone combined with ongoing long-term alendronate treatment promotes osteoporotic fracture healing in ovariectomized rats

Abstract

This study examined the effect of once-weekly parathyroid hormone (PTH) combined with alendronate upon osteoporotic fracture healing after long-term alendronate anti-osteoporosis therapy. Seventy-six 12-week-old female Sprague-Dawley rats were either sham operated or bilaterally ovariectomized (OVX). Following confirmation of osteoporosis 3 months after OVX, the remaining 64 animals received alendronate therapy. After 3 months of alendronate treatment, all rats underwent unilateral transverse tibial osteotomy. Animals were immediately randomly assigned to one of four groups: (1) alendronate followed by vehicle (ALN-VEH), (2) continuation of alendronate (ALN-ALN), (3) alendronate followed by once-weekly PTH alone (ALN-PTH), (4) continuation of alendronate combined with once-weekly PTH (ALN-ALN + PTH) until collection at 4 or 8 weeks after osteotomy. The fractured tibia was assessed using x-ray, dual-energy x-ray absorptiometry, microcomputed tomography, biomechanical testing, histology, and sequential fluorescence labeling. The ALN-ALN + PTH treatment significantly increased total callus volume, mineralized callus volume, mineralized callus volume/total callus volume, and biomechanical strength of the callus relative to ALN-VEH and ALN-PTH treatments at both 4 and 8 weeks and produced more mature trabecular bone compared with ALN-ALN treatment at 8 weeks. RANKL/osteoprotegerin (OPG) are osteoclastogenesis markers, while cluster of differentiation 31 (CD31) is an important marker of angiogenesis. Qualitative immunohistochemical analysis revealed that CD31 and OPG expression was was strong after ALN-ALN + PTH compared with ALN-ALN treatment, whereas RANKL expression was weak after ALN-ALN + PTH versus ALN-PTH treatment. Our study showed that once-weekly PTH combined with alendronate was beneficial in promoting the healing of fractures acquired after long-term alendronate therapy in OVX-induced osteoporotic rats.

Keywords: alendronate; combination therapy; long-term alendronate therapy; osteoporotic fracture healing; parathyroid hormone (PTH).