Statins promote bone anabolism in estrogen deficiency by inducing osteogenic differentiation of skeletal stem/progenitor cells

Abstract Menopause-associated estrogen deficiency drives age-related bone loss in women. Statin use has been associated with higher bone mineral density in postmenopausal women, but whether menopause alters skeletal responses to statins remains unclear. Here, we show that statin use was associated with a slower annual decline in bone mineral density in postmenopausal women and that atorvastatin promotes bone anabolism specifically under estrogen-deficient conditions by inducing osteogenic differentiation of leptin receptor-expressing (LEPR + ) bone marrow stromal cells, which include skeletal stem/progenitor cells. Atorvastatin increases osteoblast formation by restricting RAC1 prenylation and enabling nuclear factor kappa B-mediated Oln transcription. Estrogen acts on the same LEPR + cells through estradiol–estrogen receptor-α signaling to promote Oln transcription. Thus, statins compensate for reduced estradiol–estrogen receptor-α signaling through a mechanistically distinct pathway. These findings reposition a major component of estrogen action to an earlier osteogenic stage and suggest broader implications for how statins influence stem/progenitor cell responsiveness beyond cholesterol management.