Cellular Mechanisms of Age-Associated Cortical Bone Remodeling

Abstract
In the United States, 8.2 million women and 2.0 million men age 50 and above have osteoporosis. Moreover,
half of all women and one quarter of men are projected to suffer an age-related low bone mass fracture within
these populations. Importantly, an estimated 25% of individuals die within one year of a hip fracture. Cortical
bone comprises the majority of skeletal bone mass (80%) and diminished cortical bone mass accounts for 70%
of all bone lost with age. Although bone anabolic agents enhance vertebral cortical bone mass, efficacy of these
agents is lower at the hip as compared to the spine (+12.3% spine, +3.9% hip); therefore, additional therapeutics
improving cortical bone mass are desperately needed. Recent evidence shows that EMP-derived osteoclasts
support balanced bone remodeling. In contrast, HSC-derived osteoclasts facilitate bone resorption in perturbed
states. These observations suggest that osteoclasts of alternate developmental origins impact bone remodeling
differentially, but we lack an understanding of how bone remodeling may differ within specific bone compartments
(e.g., cortical versus trabecular bone). The two-year deliverables of the proposed study are: 1) identification of
myeloid progenitors that aid in maintenance of cortical bone with age and 2) characterization of putative
cells/molecules that promote coupling within cortical bone. If successful, this work could spur the development
of new therapeutics that specifically limit age-associated cortical bone loss.

Grant Number: 1R21AR084530-01
NIH Institute/Center: NIH
Principal Investigator: Elizabeth Bradley