The effect of anti-resorptive therapies on bone graft healing in an ovariectomized rat spinal arthrodesis model

Abstract

Bone grafting is commonly used to treat skeletal disorders associated with a large bone defect or unstable joint. Spinal arthrodesis surgery, which is the most common application of bone graft, is performed in the elderly and anti-resorptive therapy is sometimes started postoperatively in patients with bone fragility due to osteoporosis, despite insufficient knowledge about the effects of these drugs on bone graft healing. Therefore, we studied the effect of bisphosphonates (BP) and selective estrogen receptor modulators (SERM) on bone graft healing in an ovariectomized rat spinal arthrodesis model. Female Sprague–Dawley rats ( n = 100) were ovariectomized or sham-operated, and randomized into four groups: Sham (sham-operated + vehicle), Ovx (ovariectomy + vehicle), Ovx-Rlx (ovariectomy + raloxifene, 1 mg/kg/day), and Ovx-Aln (ovariectomy + alendronate, 0.01 mg/kg/day). Four weeks after ovariectomy, lumbar spinal arthrodesis surgery was performed using an autologous bone graft. Animals were killed 2, 4, and 8 weeks after surgery, and fusion assessment, three-dimensional micro-computed tomography, histomorphometry, mRNA expression analysis, and serum bone metabolic marker analysis were performed. The results indicated that neither BP nor SERM significantly altered the fusion rate, but the bone graft healing process was differentially affected. BP inhibited endochondral ossification and graft bone resorption, but induced the growth of a larger, denser fusion mass compared to Ovx by strongly suppressing osteoclastic activity. SERM mildly suppressed bone remodeling, but did not significantly inhibit the ossification process, leading to a fusion mass comparable with that of Sham animals. These findings suggested that spinal fusion surgery outcome is not likely to be altered by BP or SERM treatment started immediately after spinal arthrodesis surgery; however, to avoid adverse effects of BP on bone graft healing, BP treatment should be delayed during the immediate postoperative period.