Center of Research Translation on Osteoporosis Bone Anabolic Therapies

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Project Summary – Overall Osteoporosis is a major problem in our aging population. While the pharmacological treatment of osteoporosis has advanced substantially over the past 2 decades, treatment that can truly reduce the risks of fracture to youthful levels remains elusive. Bone anabolic therapies (parathyroid hormone receptor agonists teriparatide/abaloparatide and the anti-sclerostin antibody romosozumab) represent an important component of our therapeutic armamentarium for this common, costly, serious, and debilitating disease. Without an optimized ability to stimulate bone formation, cure of osteoporosis for many patients with severe disease will not be achieved. Notably, the anabolic efficacy of our currently-used agents wanes over time for unknown reasons. The goal of the CORT is to elucidate mechanisms of action of osteoporosis anabolic therapies, and to understand why they stop working. In doing so, the CORT will accelerate translation of knowledge to improve our understanding of osteoporosis pathobiology. To achieve this goal, the overall focus of the CORT is to define the cellular and molecular mechanisms of action of currently-used osteoporosis anabolic agents in humans. A highly-collaborative, multi-disciplinary, international network of investigators based at several Harvard Medical School-based institutions and Imperial College London have come together to tackle this challenge. In Project 1, investigators will define the effects of romosozumab and teriparatide on skeletal stem cells including osteoblast progenitors using flow cytometry, single cell RNA sequencing, and histopathology. Studies will be performed using samples from patients receiving anabolic therapy and in complementary genetically-modified mouse models where lineage tracing and single cell RNA sequencing can be combined. In Project 2, investigators will define the effects of romosozumab and teriparatide on osteocytes. Based on preliminary data, osteocytes can directly regulate bone matrix formation and remodeling, leading to the exciting hypothesis, tested here in human and mouse samples that anabolic agents impact cortical bone via direct effects on osteocytic perilacunar remodeling. Projects 1 and 2 will be supported by a highly innovative Bioinformatics Core that will incorporate cross-species transcriptomics datasets with available human and mouse genetics in order to develop novel hypotheses, also tested here, regarding genes and gene network that mediate bone anabolic responses. CORT efforts will be further enhanced by the complementary experience of investigators in osteoporosis clinical research, bone biomechanics, bone stem cell biology, osteocyte biology, bone marrow microenvironment investigation, statistical genetics, osteoporosis epidemiology, and genetic origins of bone disease.