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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR062002-02S1
Application #
8581777
Study Section
Special Emphasis Panel (ZAR1-KM (M1))
Program Officer
Sharrock, William J
Project Start
2011-09-01
Project End
2014-06-30
Budget Start
2013-07-04
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$154,928
Indirect Cost
$55,615
Name
Indiana University-Purdue University at Indianapolis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Allen, Matthew R; McNerny, Erin Mb; Organ, Jason M et al. (2015) True Gold or Pyrite: A Review of Reference Point Indentation for Assessing Bone Mechanical Properties In Vivo. J Bone Miner Res 30:1539-50
Allen, Matthew R; Territo, Paul R; Lin, Chen et al. (2015) In Vivo UTE-MRI Reveals Positive Effects of Raloxifene on Skeletal-Bound Water in Skeletally Mature Beagle Dogs. J Bone Miner Res 30:1441-4
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Bajaj, Devendra; Geissler, Joseph R; Allen, Matthew R et al. (2014) The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate. Bone 64:57-64
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Allen, Matthew R; Newman, Christopher L; Smith, Eric et al. (2014) Variability of in vivo reference point indentation in skeletally mature inbred rats. J Biomech 47:2504-7
Smith, Eric R; Allen, Matthew R (2013) Bisphosphonate-induced reductions in rat femoral bone energy absorption and toughness are testing rate-dependent. J Orthop Res 31:1317-22

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