Bone cell-independent benefits of raloxifene on the skeleton: A novel mechanism for improving bone material properties

Maxime A. Gallant, Drew M. Brown, Max Hammond, Joseph M. Wallace, Jiang Du, Alix C. Deymier-Black, Jonathan D. Almer, Stuart R. Stock, Matthew R. Allen, David B. Burr

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Raloxifene is an FDA approved agent used to treat bone loss and decrease fracture risk. In clinical trials and animal studies, raloxifene reduces fracture risk and improves bone mechanical properties, but the mechanisms of action remain unclear because these benefits occur largely independent of changes to bone mass. Using a novel experimental approach, machined bone beams, both from mature male canine and human male donors, were depleted of living cells and then exposed to raloxifene ex vivo. Our data show that ex vivo exposure of non-viable bone to raloxifene improves intrinsic toughness, both in canine and human cortical bone beams tested by 4-point bending. These effects are cell-independent and appear to be mediated by an increase in matrix bound water, assessed using basic gravimetric weighing and sophisticated ultrashort echo time magnetic resonance imaging. The hydroxyl groups (OH) on raloxifene were shown to be important in both the water and toughness increases. Wide and small angle X-ray scattering patterns during 4-pt bending show that raloxifene alters the transfer of load between the collagen matrix and the mineral crystals, placing lower strains on the mineral, and allowing greater overall deformation prior to failure. Collectively, these findings provide a possible mechanistic explanation for the therapeutic effect of raloxifene and more importantly identify a cell-independent mechanism that can be utilized for novel pharmacological approaches for enhancing bone strength.

Original languageEnglish (US)
Pages (from-to)191-200
Number of pages10
JournalBone
Volume61
DOIs
StatePublished - Apr 1 2014

Keywords

  • Mechanical testing
  • Raloxifene
  • Toughness
  • Water

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

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    Gallant, M. A., Brown, D. M., Hammond, M., Wallace, J. M., Du, J., Deymier-Black, A. C., Almer, J. D., Stock, S. R., Allen, M. R., & Burr, D. B. (2014). Bone cell-independent benefits of raloxifene on the skeleton: A novel mechanism for improving bone material properties. Bone, 61, 191-200. https://doi.org/10.1016/j.bone.2014.01.009