Bushen Huoxue Formula promotes osteoporotic fracture healing by CGRP-mediated dual regulation of BMSCs-osteoclasts balance through modulating mitochondrial energy metabolism.

Abstract

Osteoporotic fracture (OPF) is a serious complication that severely impairs the quality of life. Bushen Huoxue Formula (BHF), a clinically established prescription based on the TCM principle of "tonifying the kidney and activating blood circulation," has been widely used to treat osteoporosis. However, its efficacy in OPF and the underlying mechanisms remain unclear. In this study, using a rat OPF model, we found that BHF treatment significantly accelerated the fracture healing process and improved callus microstructure and mineralization. Multi-omics analysis revealed that its therapeutic effect was closely associated with the regulation of mitochondrial energy metabolism, identifying CGRP as a key differential target. Mechanistically, CGRP was upregulated in bone mesenchymal stem cells (BMSCs), where it enhanced mitochondrial energy metabolism and promoted osteogenic differentiation. Conversely, in osteoclast precursor RAW264.7 cells, CGRP was downregulated and inhibited osteoclast differentiation, demonstrating its dual regulatory role in bone remodeling via the same target. Further studies showed that taurine, a major component of BHF, could recapitulate the formula's effects by modulating CGRP to promote osteogenesis and suppress osteoclastogenesis. Importantly, corroborative clinical research demonstrated that BHF treatment effectively alleviated clinical symptoms and promoted fracture repair in OPF patients. In summary, BHF facilitates OPF healing through CGRP mediated mitochondrial energy metabolism, providing both mechanistic insight and clinical evidence for its repositioning from osteoporosis to fracture management.