There is an increase in the risk of bone fracture with aging and the onset of diabetes, and this increase cannot be solely explained by changes in bone mineral density (BMD). As such, clinical assessment of fracture resistance should also include quantitative characteristics of collagen. Moreover, lowering fracture risk for the elderly and those individuals with diabetes requires a complete understanding of the biophysical basis for the changes in bone that decrease fracture resistance. Addressing these needs, the proposal aims to determine the extent to which water that is bound to the bone matrix and water residing in bone pores, as determined by Nuclear Magnetic Resonance (NMR), explain bone's resistance to fracture with respect to aging and disease. NMR underlies clinical Magnetic Resonance Imaging (MRI), and the proposed mechanical tests characterize the ability of bone to resist fracture, not just bone strength.
Aim 1 will determine whether NMR-measurable attributes - including those quantifiable by clinical MRI - contribute to the age-related decreases in the post-yield toughness, fatigue life, crack initiation toughness, and crack growth toughness of human cortical and trabecular bone, and do so in relation to other explanatory factors.
Aim 2 will examine potential determinants of bound water through series of manipulations experiments that will affect matrix-water interactions and the fracture properties of bone. Specimens for Aims 1 and 2 will be extracted from cadaveric femurs that are acquired from donors of varying age (23 to 100 years of age). Then, using pre-clinical, rat models of disease, Aim 3 will determine whether NMR properties can explain 1) the deleterious effect of type-2 diabetes on the fracture resistance of bone and 2) the protective effect of bisphosphonate treatment on ovariectomy-induced decrease in fracture resistance. In addition, it will be determined if the NMR attributes can explain whole bone strength and brittleness in relation to bone structure. To explore the biophysical basis for the changes in the NMR and fracture properties in each aim, a number of characteristics of bone will be measured. Micro-Computed Tomography will quantify volumetric BMD and structure and architecture;high performance liquid chromatography will quantify the concentration of mature crosslinks and collagen content as well as fraction of denatured collagen;thermal gravimetric analysis will quantify the collagen, mineral, and water fractions;Raman spectroscopy will quantify mineral structure;microscopy (light and electron) will quantify osteonal architecture and collagen fibril orientation. Statistical models will determine the relatie contribution of the NMR-derived properties to the fracture properties of bone. This will address the relevance of measuring matrix-bound water and porosity by NMR to improving bone health. The long-term goal is to identify the factors affecting the important determinants of fracture resistance and developing accurate, MRI-based diagnostic assessments of fracture risk.

Public Health Relevance

Current clinical diagnosis of osteoporosis is only sensitive to changes in mineral density and content as well as structure, ignoring important factors such as collagen and porosity to fracture risk. The proposed research therefore uses clinically translatable NMR techniques to elucidate the changes in bone tissue that determine the fracture resistance of bone. In doing so, this research will potentially reveal new targets for improving fracture resistance as well as properly diagnosing a loss in fracture resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR063157-02
Application #
8532824
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Lester, Gayle E
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$328,566
Indirect Cost
$114,816
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Nyman, Jeffry S; Granke, Mathilde; Singleton, Robert C et al. (2016) Tissue-Level Mechanical Properties of Bone Contributing to Fracture Risk. Curr Osteoporos Rep 14:138-50
Granke, Mathilde; Makowski, Alexander J; Uppuganti, Sasidhar et al. (2016) Prevalent role of porosity and osteonal area over mineralization heterogeneity in the fracture toughness of human cortical bone. J Biomech 49:2748-2755
Manhard, Mary Kate; Nyman, Jeffry S; Does, Mark D (2016) Advances in imaging approaches to fracture risk evaluation. Transl Res :
Uppuganti, Sasidhar; Granke, Mathilde; Makowski, Alexander J et al. (2016) Age-related changes in the fracture resistance of male Fischer F344 rat bone. Bone 83:220-32
Creecy, Amy; Uppuganti, Sasidhar; Merkel, Alyssa R et al. (2016) Changes in the Fracture Resistance of Bone with the Progression of Type 2 Diabetes in the ZDSD Rat. Calcif Tissue Int 99:289-301
Newman, Christopher L; Creecy, Amy; Granke, Mathilde et al. (2016) Raloxifene improves skeletal properties in an animal model of cystic chronic kidney disease. Kidney Int 89:95-104
Nyman, Jeffry S; Uppuganti, Sasidhar; Makowski, Alexander J et al. (2015) Predicting mouse vertebra strength with micro-computed tomography-derived finite element analysis. Bonekey Rep 4:664
Harmata, Andrew J; Uppuganti, Sasidhar; Granke, Mathilde et al. (2015) Compressive fatigue and fracture toughness behavior of injectable, settable bone cements. J Mech Behav Biomed Mater 51:345-55
Allen, M R; Newman, C L; Chen, N et al. (2015) Changes in skeletal collagen cross-links and matrix hydration in high- and low-turnover chronic kidney disease. Osteoporos Int 26:977-85
Granke, Mathilde; Does, Mark D; Nyman, Jeffry S (2015) The Role of Water Compartments in the Material Properties of Cortical Bone. Calcif Tissue Int 97:292-307

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