title: Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling.
abstract: BACKGROUND
  It has been widely assumed that osteoclasts play a pivotal role during the entire process of fracture healing. Bisphosphonates (BPs) are anti-catabolic agents commonly used to treat metabolic bone diseases including osteoporosis, minimizing fracture incidence. Yet, fractures do occur in these patients and the potential for negative effects of BPs on healing has been suggested. We aimed to examine the effect of different dosing regimes of the potent BP zoledronic acid (ZA) on early endochondral fracture repair and later callus remodeling in a normal bone healing environment.
  
  
  METHODS
  Saline, a Bolus dose of 0.1 degrees mg/kg ZA or 5 weekly divided doses of 0.02 degrees mg/kg of ZA commenced 1 week post operatively in a rat closed fracture model. Samples at 1, 2, 4 and 6 weeks post fracture were used to analyze initial fracture union, and 12 and 26 weeks post fracture to investigate the progress of remodeling.
  
  
  RESULTS
  ZA did not alter the rate of endochondral fracture union. All fractures united by 6 weeks, with no difference in the progressive reduction of cartilaginous soft callus between control and treatment groups over time. ZA treatment increased hard callus bone mineral content (BMC), volume and increased callus strength at 6 and 26 weeks post fracture. Hard callus remodeling commenced at 4 weeks post fracture with Bolus ZA treatment but was delayed until after 6 weeks in the Weekly ZA group. By 12 and 26 weeks, Bolus ZA had equivalent callus content of remodeled neo-cortical bone to the Saline controls, whereas Weekly ZA remained reduced compared to Saline controls at these times (P<0.01). Callus material properties such as peak stress were significantly reduced in both ZA groups at 6 weeks. At 26 weeks, Bolus ZA-treated calluses generated peak stress equivalent to control values, whereas Weekly ZA callus peak stress remained significantly reduced, indicating remodeling delay.
  
  
  CONCLUSIONS
  Osteoclast inhibition with ZA does not delay endochondral fracture repair in healthy rats. Bolus ZA treatment increased net callus size and strength at 6 weeks while allowing hard callus remodeling to proceed in the long term, albeit more slowly than control. Prolonged bisphosphonate dosing during repair does not delay endochondral ossification but can significantly affect remodeling long after the drug is ceased.
authors.affiliation: Orthopaedic Research and Biotechnology, The Children's Hospital at Westmead, Westmead, Australia. MichelM9@chw.edu.au
authors.forename: Michelle M
authors.initials: MM
authors.lastname: McDonald
authors.forename: Sukhdeep
authors.initials: S
authors.lastname: Dulai
authors.forename: Craig
authors.initials: C
authors.lastname: Godfrey
authors.forename: Negin
authors.initials: N
authors.lastname: Amanat
authors.forename: Tamara
authors.initials: T
authors.lastname: Sztynda
authors.forename: David G
authors.initials: DG
authors.lastname: Little
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology; D002146:Bony Callus / Q000737:chemistry / Q000187:drug effects*; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D005269:Femur / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D017102:Fracture Healing / Q000187:drug effects*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014057:Tomography, X-Ray Computed; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid