Veterans are at high risk for skeletal fragility and fracture. In particular, conditions that limit mobility-and consequently decrease physiologic loading of the skeleton-concomitantly increase fracture risk. Inbred mouse strains are known to differ in their responsiveness to experimentally imposed loading, bone mineral density, and long bone diaphyseal geometry. Loading-induced modeling is known to be enhanced by the action of parathyroid hormone (PTH). However, the uniformity of this effect across genetic backgrounds has not been studied. While recombinant human PTH 1-34 (teriparatide, TPT) leads to dramatic increases in vertebral trabecular bone volume fraction and bone mineral density (BMD), this may occur at the expense of increased cortical porosity and reduced trabecular bone volume fraction at unloaded sites. Finally, animal studies of the interaction of mechanical loading and PTH have focused exclusively on the modeling response, and have largely ignored the potential for increased cortical porosity. There is therefore a lack of data addressing the interaction of PTH and mechanical loading on osteoclastic activity across diverse genetic backgrounds. The objective of this proposal is to compare the effects of TPT, mechanical loading, and their interaction in C57BL/6J (B6) and A/J (A) male mice. The central hypothesis of this project is that genetic background affects not only the response to mechanical loading, but the response to TPT and the interaction between loading and TPT as well, at both experimentally loaded sites and at remote sites. We will subject male A and B6 mice to intermittent cyclic loading of the right tibia over a 3-week period, treating half the mice of each strain with TPT. Using these mice, we will undertake the following specific aims: 1) Measure the mouse strain-specific response to TPT and mechanical loading on cortical modeling, 2) Determine the impact of loading and TPT on cortical bone at unloaded sites, 3) Determine the impact of loading and TPT treatment on trabecular bone. We will use defined loading of the tibia in compression as the experimental approach to accomplish the specific aims. At the conclusion of the proposed studies, we will have determined the interaction of TPT and mechanical loading on cortical bone modeling in A and B6 mice. We will have determined the effects of mechanical loading and TPT on cortical and trabecular bone at sites not subjected to experimental loading in A and B6 mice. These data will provide a comprehensive comparison of the response to TPT, mechanical loading, and their interaction in a pair of mouse strains used in constructing the collaborative cross. They will leave us poised to develop a research program aimed at optimizing the combination of bone anabolic drugs and physical therapy in immobilized patients to prevent low trauma fractures. We expect that this line of investigation will lead to better-informed medication and exercise prescriptions for patients at risk for low trauma fracture, particularly those with limited mobility.
Veterans, as a population, have a high risk of low trauma fractures. Advanced age per se places World War II and Korean War era veterans at high risk, independently of any other contributors to skeletal fragility or fall risk. Vietnam-era veterans are now predominantly in their 60's and as this large cohort ages, the risk of fracture will increase as well. The younger veterans include individuals include many with limited mobility and decreased weight bearing. Recent data in a veteran population show that spinal cord injury more than doubles fracture risk. Bones grow stronger with weight bearing, and their capacity to do so depends on genetics. There are also drugs that can help to strengthen bones, and the combination of drugs and weight bearing may be particularly beneficial. We will study the combination of one of these drugs and experimental weight bearing in mice to study the interaction of drug, weight bearing, and genetics systematically. In follow-up studies, we will use this knowledge to optimize drug and physical therapy for immobilized veterans.
