title: 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.
  
  
  BACKGROUND
  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.
  
  
  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 < 0.01). Regenerate bone mineral content was higher in ZOL and Redosed ZOL versus Saline groups at 4 and 6 weeks (p < 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 < 0.01). ZOL and Redosed ZOL tibias were 29% and 89% stronger by four-point bending than the Saline group (p < 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 < 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.
authors.affiliation: Orthopaedic Research and Biotechnology, Children's Hospital at Westmead, Sydney, NSW, Australia. david13@chw.edu.au
authors.forename: David G
authors.initials: DG
authors.lastname: Little
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Smith
authors.forename: Paul R
authors.initials: PR
authors.lastname: Williams
authors.forename: Julie N
authors.initials: JN
authors.lastname: Briody
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Bilston
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Smith
authors.forename: Edith M
authors.initials: EM
authors.lastname: Gardiner
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Cowell
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000517:prevention & control*; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology / Q000601:surgery*; D004164:Diphosphonates / Q000494:pharmacology*; D004548:Elasticity / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D019857:Osteogenesis, Distraction / Q000009:adverse effects*; D011817:Rabbits; D013314:Stress, Mechanical; D013718:Tensile Strength / Q000187:drug effects; D013977:Tibia / Q000033:anatomy & histology / Q000187:drug effects / Q000254:growth & development / Q000601:surgery; D013997:Time Factors; D016474:Weight-Bearing; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid