BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism

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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 and insights of disease models and complementary technical expertise, to synergistically attack a major clinical problem. i.e., a bone fracture, that leads to high morbidity and mortality among Veterans. The overall research strategy of each integrated project is to use pre-clinical models of diseases that either weaken bone or delay 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 the 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 specific proposal is based on a large body of investigations that demonstrate a central role of the Ca2+- sensing receptor (CaSR) in mediating systemic mineral homeostasis by counteracting the calciotropic activities of PTH and in synergizing the anabolic effects of PTH on bone as well as the recent studies that show robust anabolic actions of a long-acting PTH1-34/PTHrP hybrid analog, namely, LAPTH. We will test the hypothesis that co-injections of calcimimetics with LAPTH produce much more robust osteoanabolism than the current PTH1-34 therapy without producing hypercalcemia to accelerate rehabilitation of aging- or estrogen deficiency- induced osteoporotic skeletons by activating CaSRs in mature OBs, OCYs, and OCLs through 3 highly integrated specific Aims. Aim 1 will first establish the clinical relevance of the combined LAPTH/calcimimetic regimen by (a) optimizing the drug doses needed to produce maximal skeletal anabolism without producing hypercalcemia and the related complications in aging male mice and ovariectomized mice; and (b) determining whether an antiresorptive treatment is required to retain the newly formed bone and ultimately resist bone fracture following the combined treatment. Aim 2 will (a) define the role of CaSR in mature OB/osteocytes in mediating the anabolic actions of the combined LAPTH/NPS-R568 treatment by assessing changes in mineral and skeletal parameters and perilacunar remodeling (PLR) activities in mice with their Casr genes ablated in those cells; (b) delineate the underlying cell-autonomous mechanisms by comparing the effects of the compounds individually and in combination on the proliferation, survival, differentiation, and mineralizing functions of primary OBs and osteocytic MLO-Y4 cells with or without CaSR overexpression or knockdown in culture; and (c) elucidate signaling cross-talk between CaSR and PTH1R in mature OBs and MLO-Y4 cells by single live cell imaging technology. Aim 3 will (a) define the role of OCL CaSR in preventing the development of hypercalcemia and in mediating osteoanabolic effects of the combined LAPTH/NPS-R568 treatment by assessing changes in mineral and skeletal homeostasis in mice with their Casr genes knocked-out in OCLs; and (b) define the underlying mechanisms by examining the effects of the compounds on the growth, survival, differentiation, and bone- resorbing functions of cultured OCLs overexpressing or lacking CaSR. Successful completion of the study will provide essential information for designs of “first-in-man” trials for more effective treatments of osteoporosis.