Local anesthetic levobupivacaine promotes hip-fracture healing by targeting HIF/Ca²⁺signaling

Bone fractures, characterized by structural discontinuities in bone tissue, are a leading cause of functional impairment and reduced quality of life. Levobupivacaine, a long-acting local anesthetic, is routinely employed in perioperative settings for fracture management, including surgical anesthesia and postoperative analgesia. However, its potential influence on bone fracture healing remains underexplored. This study aims to evaluate the effects of levobupivacaine on the molecular and cellular mechanisms underlying bone fracture repair.

A rat model with a bone fracture was established and treated with levobupivacaine. The images of the bone site were scanned by micro-CT and bone parameters were calculated. The tissue structure and healing were detected by Hematoxylin/Eosin (HE) staining. Expression of VEGF, CD90, and HIF-1α in bone tissues was measured by Immunohistochemistry (IHC) analysis. Bone Marrow-derived Mesenchymal Stem Cells (BMSCs) were isolated from the bones of rats. Cell migration was assessed using by Transwell system. The content of calcium in rat blood samples and cells was detected. The protein level of HIF-1α was detected by western blotting.

Levobupivacaine facilitated the bone fracture healing, manifested by increased formation of callus and elevated Total Volume (TV), Bone Volume (BV), Bone Mineral Density (BMD) to BMD/BV, TV ratio, and BV/TV. Further, Levobupivacaine promoted the CD90, HIF-1α, and VEGF expression in bone tissues during healing. The proliferation, migration, and calcium production were elevated by levobupivacaine treatment, and HIF-1α depletion suppressed these effects.

Levobupivacaine facilitates bone healing by promoting migration and proliferation of BMSCs through activating HIF-1α/Ca²⁺ signaling. These findings identify the clinical potential of levobupivacaine in the treatment of bone fractures.