Optimal Timing of a Single Dose of Zoledronic Acid to Increase Strength in Rat Fracture Repair

Authors

  • Negin Amanat,

    1. Orthopaedic Research and Biotechnology, The Children's Hospital at Westmead, Westmead, Australia
    2. School of Aerospace, Mechanical and Mechatronic Engineering, University of Sydney, Sydney, Australia
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  • Michelle McDonald,

    1. Orthopaedic Research and Biotechnology, The Children's Hospital at Westmead, Westmead, Australia
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  • Craig Godfrey,

    1. Orthopaedic Research and Biotechnology, The Children's Hospital at Westmead, Westmead, Australia
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  • Lynne Bilston,

    1. The Prince of Wales Medical Research Institute, University of New South Wales, Randwick, Australia
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  • David Little MBBS, FRACS (Orth)

    Corresponding author
    1. Orthopaedic Research and Biotechnology, The Children's Hospital at Westmead, Westmead, Australia
    2. Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia
    • FAOrthA, PhD, Research Building, Locked Bag 4001, Westmead, New South Wales 2145, Australia
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  • Dr Little serves as a consultant for Novartis Pharma. All other authors state that they have no conflicts of interest.

  • Published online on March 19, 2007;

Abstract

We hypothesized that ZA treatment would bolster fracture repair. In a rat model for closed fracture healing, a single dose of ZA at 0, 1, or 2 wk after fracture significantly increased BMC and strength of the healed fracture. Delaying the dose (1 or 2 wk after fracture) displayed superior results compared with dosing at the time of fracture.

Introduction: Bisphosphonates are known to increase bone strength and thus the resistance to fracture by decreasing osteoclastic bone resorption. These properties may enable bisphosphonates to also increase the strength of fracture repair. Zoledronic acid (ZA) is a potent bisphosphonate with a high affinity for bone mineral, allowing bolus intraveous dosing in a range of indications. In this study, we examined the application of bolus dose ZA in endochondral fracture repair.

Materials and Methods: Carbon-14 labeled ZA was used in a closed rat fracture model. Rats were divided into five treatment groups (n = 25 per group): saline control, local ZA (0.01 mg/kg), and three systemic bolus ZA groups (0.1 mg/kg) with different administration times: at fracture, 1 wk after fracture, and 2 wk after fracture. Rats were killed 6 wk postoperatively. Postmortem analyses included radiography, QCT, μCT, biomechanical testing, scintillation counting, autoradiography, and histology.

Results: Single-dose systemic ZA administration significantly increased callus volume, callus BMC, and mechanical strength. Perioperative treatment increased mechanical strength by 30% compared with controls (p < 0.05). Administering the systemic dose at 1 or 2 wk after fracture further increased mechanical strength compared with controls by 44% and 50%, respectively (p < 0.05). No significant differences in mechanical parameters were seen with local injection at the dose studied. Autoradiographic analysis indicated that ZA binds significantly to bone that is present at the time of administration. ZA quantification indicated that delayed administration significantly increased the uptake efficiency in the callus. Histological and μCT analysis showed that ZA treated calluses had a distinctive internal structure consisting of an intricate network of retained trabecular bone.

Conclusions: The timing of a single systemic dose of ZA plays an important role in the modulation of callus properties in this rat fracture model; delaying the single dose produces a larger and stronger callus.

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