Reducing age-related fragility fractures remains a major objective of musculoskeletal research. Currently, increased fracture risk is diagnosed after an individual loses bone mass and strength. This strategy is not optimal as a long-term fracture reduction strategy because it leads to a transient loss in strength that unnecessarily increases fracture risk prior to treatment. An ideal fracture-reduction strategy would aim to maintain bone strength over time rather than attempt to replace bone after significant loss. However, we lack crucial information about inter-individual differences in skeletal aging that limits existing technologies from accurately predicting a person's future bone strength prior to age-related bone loss. Our research examining the complex adaptive nature of bone identified a common morphological trait, robustness, that may serve as a new biomarker for predicting fracture risk earlier in life and for providing insight into fragility-related biological activitie. Robustness (a measure of transverse size relative to length) is established early postnatally and varies widely among individuals. Our key finding was that the natural variation in robustness was accompanied by highly coordinated changes in cortical area and tissue mineral density. Our work in human bone established these functional interactions in the context of whole bone stiffness (mechanical homeostasis), and the traits examined were largely limited to those that could be measured non-invasively. The extent to which other matrix variables (e.g., collagen crosslinking) are coordinately adjusted to accommodate the natural variation in robustness, how the functional interactions among these extended traits affect fracture resistance properties (e.g., strength, ductility, toughness, fatigability), and how these relationships change with aging remain unclear. To address these questions, we propose to study bone as a complex adaptive system using the natural variation in robustness as an experimental model to predict inter-individual differences in BMU-based remodeling (Aim 1), fracture resistance (Aim 2), and skeletal aging (Aim 3). Successful completion of these Aims will provide fundamental new knowledge about the functional adaptation process in bone, and will establish the complex adaptive nature of the skeletal system as a biomechanical mechanism contributing to differential aging and fracture resistance among individuals. Our long term goal is to use this knowledge to develop preventative personalized technologies aimed at maintaining bone strength with aging to reduce fracture incidence.

Public Health Relevance

We propose to generate new information about how skeletal aging differs predictably among individuals by identifying a new biomarker of bone strength, fragility, and the biology of aging. Establishing robustness as a biomarker of age-related changes in structure and tissue-level properties may fill an unmet clinical need for non-invasively assessing a broader range of fracture resistance properties on a personalized basis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR065424-03S1
Application #
9225662
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Lester, Gayle E
Project Start
2014-07-15
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Orthopedics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Xin, Frances; Smith, Lauren M; Susiarjo, Martha et al. (2018) Endocrine-disrupting chemicals, epigenetics, and skeletal system dysfunction: exploration of links using bisphenol A as a model system. Environ Epigenet 4:dvy002
Patton, Daniella M; Bigelow, Erin M R; Schlecht, Stephen H et al. (2018) The relationship between whole bone stiffness and strength is age and sex dependent. J Biomech :
Ramcharan, M A; Faillace, M E; Guengerich, Z et al. (2017) The development of inter-strain variation in cortical and trabecular traits during growth of the mouse lumbar vertebral body. Osteoporos Int 28:1133-1143
Jepsen, Karl J; Kozminski, Andrew; Bigelow, Erin Mr et al. (2017) Femoral Neck External Size but not aBMD Predicts Structural and Mass Changes for Women Transitioning Through Menopause. J Bone Miner Res 32:1218-1228
Jepsen, Karl J; Bigelow, Erin M R; Ramcharan, Melissa et al. (2016) Moving toward a prevention strategy for osteoporosis by giving a voice to a silent disease. Womens Midlife Health 2:
Khoury, Basma M; Bigelow, Erin M R; Smith, Lauren M et al. (2015) The use of nano-computed tomography to enhance musculoskeletal research. Connect Tissue Res 56:106-19
Jepsen, Karl J; Bigelow, Erin M R; Schlecht, Stephen H (2015) Women Build Long Bones With Less Cortical Mass Relative to Body Size and Bone Size Compared With Men. Clin Orthop Relat Res 473:2530-9
Jepsen, Karl J; Silva, Matthew J; Vashishth, Deepak et al. (2015) Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. J Bone Miner Res 30:951-66
Schlecht, Stephen H; Bigelow, Erin M R; Jepsen, Karl J (2015) How Does Bone Strength Compare Across Sex, Site, and Ethnicity? Clin Orthop Relat Res 473:2540-7
Goldman, Haviva M; Hampson, Naomi A; Guth, J Jared et al. (2014) Intracortical remodeling parameters are associated with measures of bone robustness. Anat Rec (Hoboken) 297:1817-28

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