BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): A stitch in time saves nine!

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Overall Research Strategy: 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 utilize or 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. Project Research Strategy: The traditional clinical standard of care for fracture prevention, is to screen for osteoporosis late in the course of the disease, after bone has been denuded and fracture is imminent, before resorting to anti-osteoporotic pharmacotherapies. Such therapies however, are inefficient at regenerating lost bone, and bone quality, an important aspect of load bearing strength, often remains deficient. Thus, the clinical standard of care is frequently inadequate and many patients ultimately go on to sustain a fracture, irrespective of therapy. Compounding the problem, anti-resorptives (especially bisphosphonates) have significant immediate, as well as rare, but serious long-term side-effects, making for poor compliance and refusal to initiate therapy. Given this array of issues associated with late drug intervention, this project will investigate whether “a stich in time, saves nine”, by examining if early prophylaxis using anti-catabolic drugs, anabolic drugs and a non- pharmacological nutritional supplement, to prevent bone loss from occurring early in the etiology of the disease, is more effective at preventing bone fracture than late therapy after bone has already been denuded and regeneration is more difficult. We will study two maladies associated with increased fracture incidence and that disproportionally affect Veterans. 1. Postmenopausal Osteoporosis, the archetypal bone disease of women and an escalating problem in the VA healthcare system given women are the most rapidly increasing demographic. 2. Immune reconstitution bone loss (IRBL) which is caused by antiretroviral therapy (ART) used to treat HIV infection. We will test in mouse models, the hypothesis that short-term intervention to preserve bone mass during the early course of the disease, is superior to the traditional standard of care approach of withholding interventions until the skeleton has been seriously denuded, before intervening with pharmacologic approaches that are inherently inefficient at rejuvenating lost bone, and at best delay rather than prevent fractures. We will leverage our VA collaborative partners to synergistically expand the depth and scope of our studies and allow us to perform extensive state-of-the-art bone phenotyping to assess bone structure, quality and fracture resistance in the two-model system. Should our studies reveal a significant advantage for early therapy, this would support studies future studies in humans towards a change in the standard of care for fracture prevention.