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Bisphosphonate Binding Affinity Affects Drug Distribution in Both Intracortical and Trabecular Bone of Rabbits

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Abstract

Differences in the binding affinities of bisphosphonates for bone mineral have been proposed to determine their localizations and duration of action within bone. The main objective of this study was to test the hypothesis that mineral binding affinity affects bisphosphonate distribution at the basic multicellular unit (BMU) level within both cortical and cancellous bone. To accomplish this objective, skeletally mature female rabbits (n = 8) were injected simultaneously with both low- and high-affinity bisphosphonate analogs bound to different fluorophores. Skeletal distribution was assessed in the rib, tibia, and vertebra using confocal microscopy. The staining intensity ratio between osteocytes contained within the cement line of newly formed rib osteons or within the reversal line of hemiosteons in vertebral trabeculae compared to osteocytes outside the cement/reversal line was greater for the high-affinity compared to the low-affinity compound. This indicates that the low-affinity compound distributes more equally across the cement/reversal line compared to a high-affinity compound, which concentrates mostly near surfaces. These data, from an animal model that undergoes intracortical remodeling similar to humans, demonstrate that the affinity of bisphosphonates for the bone determines the reach of the drugs in both cortical and cancellous bone.

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Acknowledgement

The authors thank the following individuals for their technical contributions to the project: Dr. Keith Condon (tissue processing), Drs. Malgorzata Kamocka and Ken Dunn (technical assistance with confocal microscopy set-up), and Carrie Pell and staff (animal care/dosing). The confocal microscopy was performed within the Indiana Center for Biological Microscopy Resources. Funding for this study was provided by a grant from Warner Chilcott.

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Authors and Affiliations

  1. Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, USA

    John Turek

  2. Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS 5035, Indianapolis, IN, 46202, USA

    John Turek, Mark W. Lundy, Maxime A. Gallant, Lilian I. Plotkin, Teresita Bellido, David B. Burr & Matthew R. Allen

  3. Warner-Chilcott, Dundalk, Co Louth, Ireland

    F. Hal Ebetino

  4. Department of Chemistry, University of Southern California, Los Angeles, CA, USA

    Shuting Sun, Boris A. Kashemirov & Charles E. McKenna

  5. Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Oxford University Institute of Musculoskeletal Sciences, Headington, Oxford, OX3 7LD, UK

    Xuchen Duan, James T. Triffitt & R. Graham G. Russell

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  1. John Turek
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  2. F. Hal Ebetino
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  3. Mark W. Lundy
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  4. Shuting Sun
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  5. Boris A. Kashemirov
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  6. Charles E. McKenna
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  7. Maxime A. Gallant
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  8. Lilian I. Plotkin
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  9. Teresita Bellido
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  10. Xuchen Duan
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  11. James T. Triffitt
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  12. R. Graham G. Russell
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  13. David B. Burr
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  14. Matthew R. Allen
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Corresponding author

Correspondence to Matthew R. Allen.

Additional information

M. Allen has received funding from Warner Chilcott. D. Burr has received remuneration from Eli Lilly and Amgen; serves as consultant for Eli Lilly, Procter and Gamble, Amgen, and PharmaLegacy; and has received funding from Eli Lilly, Procter and Gamble, Pfizer, NephroGenex, The Alliance for Better Bone Health, and Amgen. C. Mckenna, M. Lundy, and G. Russell have had consultant/advisory roles to Warner Chilcott. F. Ebetino is an employee of Warner Chilcott. All other authors have stated that they have no conflict of interest.

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Turek, J., Ebetino, F.H., Lundy, M.W. et al. Bisphosphonate Binding Affinity Affects Drug Distribution in Both Intracortical and Trabecular Bone of Rabbits. Calcif Tissue Int 90, 202–210 (2012). https://doi.org/10.1007/s00223-012-9570-0

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  • DOI: https://doi.org/10.1007/s00223-012-9570-0

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