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. These two distinct pathways for improving bone strength suggest that combination treatment could significantly reduce fracture risk more than either ALN or RAL monotherapy. The goal of this proposal is to determine if the combination of ALN and RAL will have a greater positive effect on bone structural mechanical properties compared to either agent alone by combining their positive effects on BMD (from ALN) and material properties (from RAL). A second goal of this project is to determine if a lower dose of ALN can be used when given in combination with RAL, to achieve at least equivalent BMD and bone strength as ALN alone at higher doses. Demonstrating efficacy for enhancing bone strength with a reduced dose of ALN could improve safety by reducing negative side effects that accompany treatment with oral BPs. The third goal is to determine if combination treatment with RAL is effective as a combination therapy with non-bisphosphonate anti- resorptives such as Denosumab, the newest FDA-approved anti-remodeling agent. The human antibody denosumab cannot be given to animals, yet other mechanisms of inhibiting the RANK-L pathway such as by using osteoprotogerin fusion compound (OPG-Fc) have been shown in pre-clinical studies to mimic the skeletal effects of denosumab. Specifically, the experiments in this project will test the hypotheses that 1) the combination of ALN and RAL at current clinical doses will improve bone's mechanical properties more than each drug alone, 2) lower doses of ALN used in combination with the clinical dose of RAL will produce at least equivalent effects on bone strength as mono-therapy with ALN at the current therapeutic dose, and 3) The combination of a OPG-Fc and RAL will improve bone's mechanical properties more than each drug alone. We will test these hypotheses using both traditional outcome measures (ex vivo bone density, histology, mechanics) as well as a novel in vivo assessment tool (BioDent) to longitudinally track changes in bone material properties in animals. The data generated in this proposal will be highly translatable as our analyses will establish the relationship between changes in mechanical properties assessed in vivo to more traditional measures that can only be only made on excised bone. Additionally, as all drugs in these studies are already FDA approved for treatment of osteoporosis, combination treatment could be rapidly translated to the clinic.

Public Health Relevance

Pharmaceutical agents used to treat osteoporosis significantly reduce fracture risk via different mechanisms that ultimately enhance either structural or material biomechanical properties. The data generated in this proposal will determine if FDA approved anti- osteoporotic drugs can be used in combination to enhance bone mechanical properties more than treatment with either drug alone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR062002-03
Application #
8605855
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2012-03-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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
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
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
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
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
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
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
Burr, David B; Liu, Ziyue; Allen, Matthew R (2015) Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs. Bone 71:58-62
Burr, David B; Allen, Matthew R (2015) Foreword: Calcified Tissue International and Musculoskeletal Research Special Issue: Bone Material Properties and Skeletal Fragility. Calcif Tissue Int 97:199-200

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