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However, the effect of these changes on the fracture response of bone is not well understood. As a result, the goal of the current study is to evaluate the individual and combined effects of microcracks and tissue compositional heterogeneity on fracture resistance of cortical bone using finite element modeling (FEM) of compact tension (CT) specimen tests with varying microcrack density, location, and clustering, and material heterogeneity in three different bone samples. The simulation results showed that an increase in microcrack density improved the fracture resistance irrespective of the local material property heterogeneity and microcrack distribution. A reduction in material property heterogeneity adversely affected the fracture resistance in models both with and without microcracks. When the combined changes in microcrack density and tissue material property heterogeneity representing BP treatment were evaluated, the models corresponding to BP-treated bone demonstrated reduced fracture resistance. The simulation results also showed that although microcrack location and clustering, and microstructure significantly influenced fracture resistance, the trends observed on the effect of microcrack density and tissue material property heterogeneity did not change. In summary, these results provide new information on the interaction of microcracks, tissue material property heterogeneity, and fracture resistance and may improve the understanding of the influence of mechanical changes due to prolonged BP use on the fracture behavior of cortical bone.<\/jats:p>","DOI":"10.1115\/1.4040123","type":"journal-article","created":{"date-parts":[[2018,5,25]],"date-time":"2018-05-25T22:31:39Z","timestamp":1527287499000},"update-policy":"https:\/\/doi.org\/10.1115\/crossmarkpolicy-asme","source":"Crossref","is-referenced-by-count":8,"title":["Interaction of Microcracks and Tissue Compositional Heterogeneity in Determining Fracture Resistance of Human Cortical Bone"],"prefix":"10.1115","volume":"140","author":[{"given":"Ahmet","family":"Demirtas","sequence":"first","affiliation":[{"name":"Department of Mechanical Engineering, Villanova University, 800 Lancaster Avenue, Villanova, PA 19085 e-mail:"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ani","family":"Ural","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, Villanova University, 800 Lancaster Avenue, Villanova, PA 19085 e-mail:"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"33","published-online":{"date-parts":[[2018,5,24]]},"reference":[{"issue":"26","key":"2019100513221133300_bib1","doi-asserted-by":"publisher","first-page":"E1769","DOI":"10.1097\/BRS.0b013e3182174d0a","article-title":"Atypical Bilateral Pedicle Fracture in Long-Term Bisphosphonate Therapy","volume":"36","year":"2011","journal-title":"Spine (Phila Pa 1976)"},{"issue":"12","key":"2019100513221133300_bib2","doi-asserted-by":"publisher","first-page":"2544","DOI":"10.1002\/jbmr.1719","article-title":"Incidence of Atypical Nontraumatic Diaphyseal Fractures of the Femur","volume":"27","year":"2012","journal-title":"J. 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