title: Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone.
abstract: Bisphosphonates are widely used to treat osteoporosis, but have been associated with atypical femoral fractures (AFFs) in the long term, which raises a critical health problem for the aging population. Several clinical studies have suggested that the occurrence of AFFs may be related to the bisphosphonate-induced changes of bone turnover, but large discrepancies in the results of these studies indicate that the salient mechanisms responsible for any loss in fracture resistance are still unclear. Here the role of bisphosphonates is examined in terms of the potential deterioration in fracture resistance resulting from both intrinsic (plasticity) and extrinsic (shielding) toughening mechanisms, which operate over a wide range of length-scales. Specifically, we compare the mechanical properties of two groups of humeri from healthy beagles, one control group comprising eight females (oral doses of saline vehicle, 1 mL/kg/day, 3 years) and one treated group comprising nine females (oral doses of alendronate used to treat osteoporosis, 0.2mg/kg/day, 3 years). Our data demonstrate treatment-specific reorganization of bone tissue identified at multiple length-scales mainly through advanced synchrotron x-ray experiments. We confirm that bisphosphonate treatments can increase non-enzymatic collagen cross-linking at molecular scales, which critically restricts plasticity associated with fibrillar sliding, and hence intrinsic toughening, at nanoscales. We also observe changes in the intracortical architecture of treated bone at microscales, with partial filling of the Haversian canals and reduction of osteon number. We hypothesize that the reduced plasticity associated with BP treatments may induce an increase in microcrack accumulation and growth under cyclic daily loadings, and potentially increase the susceptibility of cortical bone to atypical (fatigue-like) fractures.
authors.affiliation: Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Materials Science and Engineering, University of California Berkeley, CA 94720, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Acevedo
authors.affiliation: Department of Materials Science and Engineering, University of California Berkeley, CA 94720, USA.
authors.forename: Hrishikesh
authors.initials: H
authors.lastname: Bale
authors.affiliation: Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gludovatz
authors.affiliation: Department of Materials Science and Engineering, University of California Berkeley, CA 94720, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Wat
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Simon Y
authors.initials: SY
authors.lastname: Tang
authors.affiliation: International Research Center for Advanced Structural and Bio-Materials, Beihang University, Beijing 100083, China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg, D-22529 Hamburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Busse
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg, D-22529 Hamburg, Germany.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Zimmermann
authors.affiliation: Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Schaible
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biomedical Engineering, Indiana University-Purdue University, Indianapolis (IUPUI), Indianapolis, IN 46202, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Burr
authors.affiliation: Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Materials Science and Engineering, University of California Berkeley, CA 94720, USA. Electronic address: roritchie@lbl.gov.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ritchie
mesh_terms: D000284:Administration, Oral; D019386:Alendronate / Q000627:therapeutic use*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology; D003094:Collagen / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D004285:Dogs; D055119:Elastic Modulus; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006811:Humerus / Q000502:physiology; D010024:Osteoporosis / Q000517:prevention & control; D017550:Spectroscopy, Fourier Transform Infrared; D013314:Stress, Mechanical; D013718:Tensile Strength
chemical_list: D050071:Bone Density Conservation Agents; D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced; D003094:Collagen; D019386:Alendronate
keywords: Anti-resorptives; Bisphosphonates; Fracture prevention; Fracture toughness; Osteoporosis