Shockwave-driven activation of endoplasmic reticulum stress in osteoblasts to enhance bone formation under osteoporotic conditions

Extracorporeal shockwave (ESW) therapy is a noninvasive physical intervention widely applied in orthopedics for the treatment of musculoskeletal disorders such as plantar fasciitis, osteoarthritis, delayed fracture healing and tendinopathies. In recent years, accumulating evidence has suggested that ESW may also have beneficial effects on bone regeneration and local bone mineral density, particularly under osteoporotic conditions. However, the precise biological mechanisms underlying these effects remain incompletely elucidated. In this study, we systematically investigated the effects of different radial extracorporeal shockwave (r-ESW) intensities on osteoblasts derived from osteoporotic bone (OPOB), with a specific focus on osteogenic activity and the involvement of endoplasmic reticulum (ER) stress. Our <i>in vitro</i> results demonstrated that moderate-intensity r-ESW (3 bar) significantly enhanced osteoblast proliferation, upregulated the expression of osteogenic markers including Runx2, Col I, OPN and OCN and promoted matrix mineralization. Mechanistically, this was accompanied by mild ER stress and activation of the PERK-eIF2α-ATF4 signaling pathway, which contributed to improved osteogenic differentiation and alleviated cellular senescence. In contrast, high-intensity stimulation (5 bar) induced excessive ER stress, calcium overload and subsequent apoptosis and necrosis, ultimately impairing osteogenesis. Furthermore, in an ovariectomy (OVX)-induced osteoporotic rat model, 3 bar r-ESW treatment effectively increased bone mass, stimulated new bone formation and decreased osteoclast activity and senescence-associated markers in vivo. These findings collectively highlight the potential of moderate-intensity r-ESW as a promising nonpharmacological strategy for osteoporosis management, providing novel insights into the modulation of ER stress as a therapeutic target in OPOB remodeling.