Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model

Matthew R. Allen, Erin McNerny, Mohammad Aref, Jason M. Organ, Christopher L. Newman, Brian McGowan, Tim Jang, David B. Burr, Drew M. Brown, Max Hammond, Paul R. Territo, Chen Lin, Scott Persohn, Lei Jiang, Amanda A. Riley, Brian P. McCarthy, Gary D. Hutchins, Joseph M. Wallace

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1 Scopus citations

Abstract

A growing number of studies have investigated combination treatment as an approach to treat bone disease. The goal of this study was to investigate the combination of alendronate and raloxifene with a particular focus on mechanical properties. To achieve this goal we utilized a large animal model, the beagle dog, used previously by our laboratory to study both alendronate and raloxifene monotherapies. Forty-eight skeletally mature female beagles (1-2 years old) received daily oral treatment: saline vehicle (VEH), alendronate (ALN), raloxifene (RAL) or both ALN and RAL. After 6 and 12 months of treatment, all animals underwent assessment of bone material properties using in vivo reference point indentation (RPI) and skeletal hydration using ultra-short echo magnetic resonance imaging (UTE-MRI). End point measures include imaging, histomorphometry, and mechanical properties. Bone formation rate was significantly lower in iliac crest trabecular bone of animals treated with ALN (-71%) and ALN+RAL (-81%) compared to VEH. In vivo assessment of properties by RPI yielded minimal differences between groups while UTE-MRI showed a RAL and RAL+ALN treatment regimens resulted in significantly higher bound water compared to VEH (+23 and +18%, respectively). There was no significant difference among groups for DXA- or CTbased measures lumbar vertebra, or femoral diaphysis. Ribs of RAL-treated animals were smaller and less dense compared to VEH and although mechanical properties were lower the material-level properties were equivalent to normal. In conclusion, we present a suite of data in a beagle dog model treated for one year with clinically-relevant doses of alendronate and raloxifene monotherapies or combination treatment with both agents. Despite the expected effects on bone remodeling, our study did not find the expected benefit of ALN to BMD or structural mechanical properties, and thus the viability of the combination therapy remains unclear.

Original languageEnglish (US)
Article numbere0181750
JournalPloS one
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Allen, M. R., McNerny, E., Aref, M., Organ, J. M., Newman, C. L., McGowan, B., Jang, T., Burr, D. B., Brown, D. M., Hammond, M., Territo, P. R., Lin, C., Persohn, S., Jiang, L., Riley, A. A., McCarthy, B. P., Hutchins, G. D., & Wallace, J. M. (2017). Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model. PloS one, 12(8), [e0181750]. https://doi.org/10.1371/journal.pone.0181750