Bone cell-independent benefits of raloxifene on the skeleton: a novel mechanism for improving bone material properties.
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.
Department of Anatomy & Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr, MS-5035, Indianapolis, IN 46202, USA.
Maxime A
MA
Gallant
Department of Anatomy & Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr, MS-5035, Indianapolis, IN 46202, USA.
Drew M
DM
Brown
Weldon School of Biomedical Engineering, Purdue University, 206 S. Martin Jischke Drive, West Lafayette, IN 47907, USA.
Max
M
Hammond
Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, 723 West Michigan Street, SL 220, Indianapolis, IN 46202, USA.
Joseph M
JM
Wallace
Department of Radiology, University of California, 200 West Arbor Drive, MC 0834 San Diego, CA 92103, USA.
Jiang
J
Du
Department of Materials Science and Engineering, Northwestern University, 2220 Campus Drive, Cook Hall Room 2036, Evanston, IL 60208, USA.
Alix C
AC
Deymier-Black
Advanced Photon Source, Argonne National Laboratory, Building 401, 9700 S. Cass Avenue, Argonne, IL 60439, USA.
Jonathan D
JD
Almer
Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Abbott Hall Suite 810, 710 N Lake Shore Drive, Chicago, IL 60611, USA.
Stuart R
SR
Stock
Department of Anatomy & Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr, MS-5035, Indianapolis, IN 46202, USA.
Matthew R
MR
Allen
Department of Anatomy & Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr, MS-5035, Indianapolis, IN 46202, USA; Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, 723 West Michigan Street, SL 220, Indianapolis, IN 46202, USA. Electronic address: dburr@iupui.edu.
David B
DB
Burr
D000818:Animals; D001696:Biomechanical Phenomena; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects*; D004285:Dogs; D005109:Extracellular Matrix / Q000187:drug effects*; D006801:Humans; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D012863:Skeleton
D050071:Bone Density Conservation Agents; D020849:Raloxifene Hydrochloride
Mechanical testing; Raloxifene; Toughness; Water