Pharmaceutical agents used to treat osteoporosis significantly reduce fracture risk via different mechanisms that ultimately enhance either structural or material biomechanical properties. Bisphosphonates such as Alendronate (ALN) increase structural bone strength almost entirely by promoting increased bone volume and density, but at the expense of impaired material properties. Raloxifene (RAL) minimally affects bone mass yet significantly improves material properties leading to an enhancement in overall bone strength. The goal of this BIRT revision is to test the hypothesis that pharmacological treatment with RAL enhances skeletal hydration and these changes correlate with enhanced biomechanical properties. Skeletal hydration has known effects on bone mechanical properties and preliminary data generated in our laboratory show enhanced skeletal bound water with RAL-treatment. Using longitudinal in vivo ultrashort echo time (UTE) magnetic resonance imaging (MRI) scans we aim to determine how ALN, RAL, and their combination affect skeletal hydration (bound and free water). To achieve this goal we have established a new collaboration with experts in medical physics/imaging who have experience with UTE-MRI. Specifically, the experiments in this BIRT will test the hypotheses that 1) Monotherapy with RAL, or combination treatment with RAL and ALN, will increase the total hydration and the bound water fraction in bone as measured by UTE-MRI compared to other treatment groups and 2) Increased total hydration and bound water fraction as measured by UTE-MRI will increase the energy required to fracture the bone, and will be positively correlated to improvements in bone toughness. The data generated in this project will provide the first evidence of how pharmacological agents modulate skeletal hydration in vivo and how this relates to the biomechanical properties of the bone. As UTE-MRI can be utilized in humans, these data have the potential to launch a new focus area for non- invasive methods of fracture risk assessment.

Public Health Relevance

Alterations in skeletal hydration have known effects on mechanical properties of bone and are a potential mechanism by which some anti-osteoporotic agents reduce fracture risk. The data generated in this project will determine how FDA approved anti- osteoporotic drugs alter skeletal hydration and the relationship of these changes to mechanical properties.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1-KM (M1))
Program Officer
Sharrock, William J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Allen, Matthew R (2018) Recent Advances in Understanding Bisphosphonate Effects on Bone Mechanical Properties. Curr Osteoporos Rep 16:198-204
Larsen, Rachel A; Peveler, Jessica L; Klutzke, Joshuah B et al. (2017) Effects of daily restraint with and without injections on skeletal properties in C57BL/6NHsd mice. Lab Anim (NY) 46:299-301
Allen, Matthew R; McNerny, Erin; Aref, Mohammad et al. (2017) Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model. PLoS One 12:e0181750
Shao, Yu; Hernandez-Buquer, Selene; Childress, Paul et al. (2017) Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism. Endocrinology 158:2722-2740
Meixner, Cory N; Aref, Mohammad W; Gupta, Aryaman et al. (2017) Raloxifene Improves Bone Mechanical Properties in Mice Previously Treated with Zoledronate. Calcif Tissue Int 101:75-81
Aref, M W; McNerny, E M B; Brown, D et al. (2016) Zoledronate treatment has different effects in mouse strains with contrasting baseline bone mechanical phenotypes. Osteoporos Int 27:3637-3643
Bajaj, Devendra; Geissler, Joseph R; Allen, Matthew R et al. (2016) Response to Courtney et al. Bone 89:77-79
Clinkenbeard, Erica L; Cass, Taryn A; Ni, Pu et al. (2016) Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia. J Bone Miner Res 31:1247-57
Krege, John B; Aref, Mohammad W; McNerny, Erin et al. (2016) Reference point indentation is insufficient for detecting alterations in traditional mechanical properties of bone under common experimental conditions. Bone 87:97-101
McNerny, Erin M B; Organ, Jason M; Wallace, Joseph M et al. (2016) Assessing the inter- and intra-animal variability of in vivo OsteoProbe skeletal measures in untreated dogs. Bone Rep 5:192-198

Showing the most recent 10 out of 19 publications