Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone

Claire Acevedo, Hrishikesh Bale, Bernd Gludovatz, Amy Wat, Simon Y. Tang, Mingyue Wang, Björn Busse, Elizabeth A. Zimmermann, Eric Schaible, Matthew R. Allen, David B. Burr, Robert O. Ritchie

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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, 0.2. mg/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.

Original languageEnglish
Pages (from-to)352-363
Number of pages12
StatePublished - Dec 1 2015


  • Anti-resorptives
  • Bisphosphonates
  • Fracture prevention
  • Fracture toughness
  • Osteoporosis


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