Long term bone uptake of 14C-ZA and effectiveness of PTH in redistributing it to the areas of new bone formation

  • Mr Divesh Kumar, PETNET Solutions, The The Children's Hospital and Westmead Hospital (Dept of Nuclear Medicine and PET), University of Sydney, Australia
  • A/Prof Vijay Kumar, Westmead Hospital (Dept of Nuclear Medicine and PET), University of Sydney, Australia
  • A/Prof David Little, The Children's Hospital at Westmead, Orthopaedic and Biotechnology Research, University of Sydney, Australia
  • Prof Robert Howman-Giles, The Children's Hospital at Westmead (Dept of Nuclear Medicine and PET), University of Sydney, Australia

    • Introduction: Bisphosphonates are established compounds that bind to the hydroxyapatite with useful therapeutic and diagnostic options in bone diseases. The first generation bisphosphonate (medronate) is used as bone imaging agent. The second-generation bisphosphonate (pamidronate) is currently the standard treatment for hypercalcemia of malignancy and bone metastases. Zoledronic acid (ZA), a third generation bisphosphonate has highly potent therapeutic effect due to inhibition of osteoclast-mediated bone resorption.Minimal data is available on the biodistribution of ZA. In this study we evaluated the long-term biodistribution of carbon (14)-ZA in rats and test the effectiveness of parathyroid hormone to redistribute 14C-ZA to areas of new bone formation.

    Method: 14C-ZA (0.01mg/kg) was injected in rats (4-5wks) to determine the biodistribution at different time points:(1,2,8,24 & 48 h) and (1,2,6,12 & 24 wk). Liquid scintillation counting was used to estimate the percentage bone uptake of 14C-ZA. Autoradiography images were obtained to determine qualitative localisation.

    Results: The uptake was greatest in bone between 1 and 24h period, with gradual increases over time. After the initial plateau at 48h, the uptake was stable between 1 and 24 wk with no measurable redistribution. This was also evidenced by the autoradioragraphy. Animals daily injected with PTH showed substantial redistribution from old bone to areas of new bone.

    Conclusion: We determined the short and long term biodistribution of 14C-ZA in rats with and without PTH. Extrapolating these results to human pharmacokinetic opens an opportunity for innovative therapeutic options which would improve patient amenity without compromising the therapeutic outcome.