Drug repurposing of the anti-fibrinolytic drug tranexamic acid in orthopedic trauma surgery – preclinical and mechanistic studies in mouse models with osteoporosis, fractures, or their combination.

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Osteoporosis and impaired fracture healing have a high prevalence and are characterized by an alteration in the activity of bone cells and macrophages. In this regard, we previously showed that the plasminogen inhibitor tranexamic acid (TXA), an anti-fibrinolytic drug widely used in orthopedic surgery, stimulates osteoblast proliferation, inhibits osteoclast formation, and modulates macrophage immune responses in vitro. As several lines of evidence suggest a beneficial effect of TXA in musculoskeletal disease independent from its role in the coagulation system, the project is designed to evaluate a therapeutic potential in osteoporosis and fracture healing. WT mice with OVX-induced bone loss, with osteotomies stabilized with an external fixator, or with their combination will be treated with TXA. Additionally, mice lacking plasminogen globally will be subjected to the same procedures to identify plasminogen-independent effects of TXA. Bone turnover and fracture healing will be assessed using state-of-the-art radiological, histological, and biochemical outcome measures. In vivo experiments will be complemented by cell culture assays to test a potential involvement of alternative TXA receptors. In parallel, potential effects of systemic or local TXA treatment on bone healing will be assessed in a clinical cohort with patients receiving a high tibial osteotomy, a highly standardized surgical procedure for early and unilateral osteoarthritis of the knee in comparatively young and healthy patients. Through the combination of the proposed work packages, the project is expected to provide the necessary translational evidence to further estimate whether prospective trials studying novel treatment indications of TXA are warranted.