Skeletal accumulation of fluorescently tagged zoledronate is higher in animals with early stage chronic kidney disease

Abstract

These results provide new data regarding how reduced kidney function affects drug accumulation in rat bone.

Skeletal levels of bisphosphonate in the setting of chronic kidney disease are independent of remodeling rate and lower with fractionated dosing

“…supports this concern, as rats with CKD displayed significantly higher accumulation within the skeleton after an acute dose of fluorescently-labelled zoledronate [17]. However, there is still an absence of data assessing the impact of skeletal bisphosphonate accumulation over time in conditions of varying turnover rates and with different dosing regimens [18].…”

“…weeks of age (7 days before FAM-ZOL dose) and continuing throughout the experiment)) to suppress bone remodeling throughout the study [21,24]. This FAM-ZOL has been previously used in our work and others to allow for assessment of accumulation within the bone [17,25]. In order to evaluate the remodeling suppression activity of FAM-ZOL animals were administered a single subcutaneous dose (180 µg/kg).…”

“…All animals were administered a subcutaneous calcein injection (30µg/kg) thirteen and six days before the 30-week endpoint enabling the assessment of dynamic bone formation. As previously described in our work, calcein blue was used to avoid spectral overlap with FAM-ZOL [17,26]. At 30 weeks of age animals were anaesthetized with isoflurane before euthanasia by exsanguination.…”

“…Serum, tibia, ulna, radius, L3 vertebra, femora, and mandible were collected. Tissues were stored in 10% NBF for 24 hours before switching to 70% EtOH for long term storage [17]. CKD -weekly SQ doses of 18 µg/kg FAM-ZOL and supplemental with 3% calcium gluconate in drinking water (starting at 24 weeks of age (7 days before FAM-ZOL dose) and continuing throughout the experiment)).…”

“…Mandible, radius, ulna, vertebra (3 rd lumbar, L3), distal femur, and proximal tibia were assessed for whole bone fluorescence using reflectance epi-fluorescence imaging (IVIS SpectralCT, PerkinElmer). Our lab and others have previously used this method as an assay to measure fluorescently-tagged bisphosphonate levels in tissues [17,25,27,28]. Mandible, radius, and ulna were scanned whole whereas, vertebrae processes were removed, and distal femur and proximal tibiae were cut to 10 mm standard length sections.…”