BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Role of Hypertension in Favoring Osteoporosis

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To ensure aging Veterans remain active and mobile with as little musculoskeletal pain as possible, new approaches to the prevention of osteoporosis and promotion of timely bone regeneration following a fracture are necessary. This collaborative research study brings together a group of VA investigators with diverse perspectives, insights, models, and techniques, to synergistically attack a major clinical problem that leads to high morbidity and mortality among Veterans, a bone fracture. The overall research strategy of each integrated project is to use pre-clinical models of a disease that either weakens bone or delays bone repair, to investigate novel ways to enhance the ability of parathyroid hormone (PTH) to promote bone formation, and to assess disease and treatment effects on bone in a unified, stringent manner. Already under-diagnosed and under- treated, osteoporosis is likely to increase the number of fragility fractures being treated at VA hospitals without novel tools for early detection and novel treatment strategies that circumvent the rare but devastating side effects of current therapies that inhibit bone loss. Addressing this unmet clinical need, the overall aims are to identify therapeutic strategies to improve bone health among Veterans and to enhance the bone anabolism of PTH signaling. The collaboration will address this overarching hypothesis: health problems disproportionately affecting Veterans activate signaling pathways that increase bone resorption, suppress bone formation, or impede the transition of cartilage to bone in a fracture callus such that improvements in the clinical management of osteoporosis lie in understanding how these health problems hurt bone health. This project recognizes that hypertension and osteoporosis often develop together as patients grow older beyond 50 years of age and that female and male Veterans are susceptible to both chronic diseases. Based on our preliminary studies of what happens to bone in standard pre-clinical mouse models of hypertension, we will investigate a mechanism by which hypertension weakens bone with the ultimate goal of identifying a new therapeutic strategy in the prevention of osteoporosis. Specifically, the first aim of the project will be to test the hypothesis that sex steroids, namely estrogen and testosterone, influence the decline in bone mass and bone quality that occurs with the onset of hypertension. Achieving this goal involves assessing the relative effect of estrogen deficiency (or testosterone deficiency) and hypertension on the fracture resistance of mouse bone. Furthermore, by investigating treatment and surgery effects on gene and protein expression in bone and bone marrow, on markers of bone resorption and bone formation, and on the number and activity of bone cells, the project will provide insight into how rising blood pressure and rising sympathetic tone negatively affects bone. In the second aim, we will ascertain whether an inflammatory factor known as colony stimulating factor 1 (CSF1) is a major mediator of bone loss in hypertension and do so with respect to the cellular source of this cytokine. Doing so requires the induction of hypertension in 2 different mouse strains engineered to either prevent bone forming (mature osteoblasts) and bone sensing cells (osteocytes) from producing CSF1 or preventing cells lining blood vessels (endothelial cells) from producing CSF1. Transitioning from mechanic studies to translational studies, we will determine whether inhibiting CSF1 signaling in combination with intermittent parathyroid hormone treatment, an approved therapy for osteoporosis, and/or with a calcium channel blocker, an approved therapy for hypertension, improves the fracture resistance of bone in aged, hypertensive mice. In all these aims, the assessment of fracture resistance is comprehensive going beyond bone mass and bone volume to include the matrix. By understanding how hypertension affects bone and by working as a collaborative research team, new therapeutic strategies will be sought to prevent the age-related increase in fracture risk. This is needed because osteoporotic fractures lead to many complications in Veteran population and because osteoporosis is underdiagnosed and undertreated.