Teriparatide alleviates limb ischemia-associated posttraumatic bone loss: potential involvement of the AKT/HIF-1α/VEGFA signaling axis

Posttraumatic bone loss is a common clinical complication characterized by localized osteopenia and microstructural degradation after traumatic injury. However, its precise pathogenesis remains unclear. Teriparatide (TPTD), administered intermittently, exerts potent pro-osteogenic and pro-angiogenic effects, and is widely used in the treatment of primary osteoporosis. This study aimed to investigate the therapeutic efficacy of TPTD in mitigating ischemia-associated posttraumatic bone loss, as well as to investigate the underlying molecular mechanisms. In vivo, models of simple femoral fracture and fracture with ipsilateral femoral artery ligation were established to evaluate secondary bone loss associated with arterial ligation, and the therapeutic efficacy of intermittent TPTD was subsequently assessed. In vitro, chemical hypoxia was induced in MC3T3-E1 cells using CoCl 2 . Intermittent TPTD was applied to both models. Furthermore, the inhibitor LY294002 was used in vitro to assess the involvement of the AKT/HIF-1α/VEGFA pathway. In vivo, compared with femoral fracture alone, concurrent femoral artery ligation markedly exacerbated bone loss and microarchitectural deterioration in the ipsilateral tibial metaphysis, characterized by decreased BMD and BV/TV, as well as increased osteoclast numbers. In this composite model, intermittent TPTD (40 µg/kg) not only promoted fracture healing but also attenuated secondary bone loss, restoring bone microarchitecture and angiogenesis-related markers. In vitro, intermittent TPTD (1 nM) significantly alleviated CoCl 2 -induced suppression of osteogenic differentiation in MC3T3-E1 cells. Mechanistically, TPTD promoted AKT phosphorylation, enhanced HIF-1α nuclear accumulation, and upregulated VEGFA, thereby enhancing pro-angiogenic paracrine activity. Notably, these osteogenic and pro-angiogenic effects were markedly attenuated by the PI3K/AKT inhibitor LY294002. In vivo and in vitro studies suggest that TPTD may have therapeutic potential for ischemia-associated posttraumatic bone loss. Mechanistically, the AKT/HIF-1α/VEGFA signaling axis may contribute, at least in part, to the osteogenic and pro-angiogenic effects of TPTD.