Zoledronic Acid Prevents Osteopenia and Increases Bone Strength in a Rabbit Model of Distraction Osteogenesis

Abstract

Prolonged healing times and stress-shielding osteopenia remain problematic in distraction osteogenesis. In this study of 30 rabbits, zoledronic acid increased regenerate volume, mineralization, and tibial strength and prevented osteopenia over a 6-week period. Translation to the clinical setting, if safe, could improve outcomes in distraction osteogenesis in children.Introduction: Because the external fixators for limb lengthening and reconstruction are designed to control the positions of bone fragments accurately, they also produce stress-shielding effects on the forming regenerate and surrounding bone. Osteopenia, leading to refracture and limitations on rehabilitation, are common consequences, potentially increasing morbidity and detracting from final clinical outcome. Materials and Methods:We examined the effect of zoledronic acid on distraction osteogenesis in 42 immature male NZW rabbits. The model chosen results in reliable regenerate formation and stress-shielding osteopenia. Fourteen animals received either Saline, zoledronic acid 0.1 mg/kg at surgery (ZOL), or another dose 2 weeks postoperatively (Redosed ZOL). Rabbits underwent DXA for bone mineral content and bone mineral density in regenerate and surrounding segments of operated and contralateral tibias. After death at 6 weeks, 30 pairs of tibias underwent quantitative computerized tomography (QCT) and four-point bend testing, and 12 were examined by histomorphometry. The study was powered at 0.8 to show differences of 1.3 SDs for mineral and mechanical parameters. Results: Osteopenia observed in tibias of the Saline group was absent in ZOL and Redosed ZOL tibias, the latter exhibiting higher bone mineral density and bone mineral content over contralateral regions (p Ͻ 0.01). Regenerate bone mineral content was higher in ZOL and Redosed ZOL versus Saline groups at 4 and 6 weeks (p Ͻ 0.01). Cross-sectional area was 49% and 59% greater at 6 weeks in ZOL and Redosed ZOL regenerates compared with the Saline group (p Ͻ 0.01). ZOL and Redosed ZOL tibias were 29% and 89% stronger by four-point bending than the Saline group (p Ͻ 0.01). Histomorphometry in the regenerate of ZOL and Redosed ZOL groups revealed higher trabecular bone volume and trabecular number compared with the Saline group (p Ͻ 0.001). Conclusions: Zoledronic acid administration led to significantly greater bone area, mineral content, strength, and trabecular number with reduced stress-shielding osteopenia in this model of distraction osteogenesis. These data suggest that intraoperative and postoperative zoledronic acid administration could improve outcomes in children undergoing limb lengthening.

Calcium phosphate drug delivery system: influence of local zoledronate release on bone implant osteointegration

“…In most in vivo studies, the effect of bisphosphonates on the histomorphometry of bone was an increase in trabecular number and thickness and a decrease of trabecular separation [18,24,30]. In our study, none of those parameters seems to be altered by the presence of zoledronate.…”

Bisphosphonates: Mode of Action and Pharmacology

“…142 In studies of the osseointegration of metal implants in ovariectomized rats, treatment with ibandronate resulted in improved osseointegration rather than impairment of the healing process. 143 Potential applications of bisphosphonates in orthopedics include protection against loosening of prostheses, 144 better integration of biomaterials and implants, improved healing in distraction osteogenesis, 145 and conserving bone architecture after osteonecrosis 146,147 and in Perthes disease. 148 There are potentially important differences between clinically useful bisphosphonates regarding their potency and duration of action.…”

Avaliação do efeito do ibandronato na consolidação de fratura: estudo experimental em coelhos

“…Estudos semelhantes com outras drogas correlacionam estes resultados com melhora das propriedades estruturais do calo ósseo, como aumento da densidade mineral óssea, do volume e da resistência do calo ósseo formado (24)(25) . Com base na literatura e nos resultados deste estudo, podese inferir que o ibandronato de sódio tem efeito benéfico no processo de consolidação das fraturas, porém ainda existem controvérsias sobre o período ideal para iniciar sua administração e quanto à duração do tratamento, já que vários autores demonstraram haver inibição da consolidação óssea em pacientes em uso de bisfosfonatos a longo prazo (26) .…”