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

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Abstract

Summary

This work examines the skeletal accumulation of fluorescently tagged zoledronate in an animal model of chronic kidney disease. The results show higher accumulation in 24-h post-dose animals with lower kidney function due to greater amounts of binding at individual surfaces.

Introduction

Chronic kidney disease (CKD) patients suffer from increased rates of skeletal-related mortality from changes driven by biochemical abnormalities. Bisphosphonates are commonly used in reducing fracture risk in a variety of diseases, yet their use is not recommended in advanced stages of CKD. This study aimed to characterize the accumulation of a single dose of fluorescently tagged zoledronate (FAM-ZOL) in the setting of reduced kidney function.

Methods

At 25 weeks of age, FAM-ZOL was administered to normal and CKD rats. Twenty-four hours later, multiple bones were collected and assessed using bulk fluorescence imaging, two-photon imaging, and dynamic histomorphometry.

Results

CKD animals had significantly higher levels of FAM-ZOL accumulation in the proximal tibia, radius, and ulna, but not in lumbar vertebral body or mandible, based on multiple measurement modalities. Although a majority of trabecular bone surfaces were covered with FAM-ZOL in both normal and CKD animals, the latter had significantly higher levels of fluorescence per unit bone surface in the proximal tibia.

Conclusions

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

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Acknowledgments

Two-photon microscopy was performed in the O’Brien Center for Advanced Renal Microscopy (NIH P30 DK 079312).

Funding

This work was supported by a United States (U.S.) Department of Veterans Affairs grant (BX003025) to MRA. MWA was supported by NIH F30 DK115162 and NIH T32 AR065971 during separate portions of this work.

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr, Indianapolis, IN, 46202, USA

    E. A. Swallow, M. W. Aref, I. Byiringiro, M. A. Hammond & M. R. Allen

  2. Department of Medicine – Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA

    N. Chen, M. M. Kamocka, S. Winfree, K. W. Dunn, S. M. Moe & M. R. Allen

  3. School of Mechanical Engineering, Purdue University, West Lafayette, IN, USA

    M. A. Hammond

  4. Department of Radiology, Indiana University School of Medicine, Indianapolis, IN, USA

    B. P. McCarthy & P. R. Territo

  5. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA

    S. M. Moe & M. R. Allen

  6. Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, USA

    M. R. Allen

Authors
  1. E. A. Swallow
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  2. M. W. Aref
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  3. N. Chen
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  11. S. M. Moe
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  12. M. R. Allen
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Corresponding author

Correspondence to M. R. Allen.

Ethics declarations

All procedures conducted in this study were reviewed and approved by the Indiana University School of Medicine Institutional Animal Care and Use Committee.

Conflicts of interest

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Electronic supplementary material

Supplementary Figure 1

Analysis of two photon images. A) Raw image of green channel detector. B) MATLAB Input image with bone area as white and black for bone marrow. C) Analysis region with non-analyzed regions shown in grayscale. D) Pixels above FAM-ZOL threshold. (PNG 1616 kb)

High Resolution Image (TIFF 3420 kb)

Supplementary Figure 2

Bulk fluorescence assessment of whole radius and tibia from normal animals administered FAM-ZOL by either intravenous (IV) or subcutaneous (SC) injection (n = 4 per dose route). There was no significant difference in the mean group values between the two routes for either the radius or tibia sites (p > 0.60). (PNG 336 kb)

High Resolution Image (TIFF 3420 kb)

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Swallow, E.A., Aref, M.W., Chen, N. et al. Skeletal accumulation of fluorescently tagged zoledronate is higher in animals with early stage chronic kidney disease. Osteoporos Int 29, 2139–2146 (2018). https://doi.org/10.1007/s00198-018-4589-3

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