Estrogens protect bone mass by inhibiting NAD ⁺ metabolism in osteoclasts

Estrogens protect against bone loss by reducing osteoclast number and bone resorption, primarily via direct actions on osteoclast precursors. In these cells, estrogens attenuate RANKL-induced stimulation of mitochondrial complex I, which is crucial for ATP generation through NADH oxidation. NAD ⁺ promotes redox reactions and activates NAD ⁺ -dependent enzymes, including the mitochondrial deacetylase SIRT3. However, the contribution of NAD ⁺ to the skeletal effects of estrogens remains unknown. We show that NAD ⁺ levels and SIRT3 activity are upregulated by RANKL and inhibited by 17β-estradiol (E ₂ ) in mouse and human osteoclast precursors. Increasing NAD ⁺ or the mitochondrial NAD ⁺ /NADH ratio reverses the inhibitory effects of E ₂ on SIRT3 activity and osteoclastogenesis in vitro . Deletion of Nampt , a key NAD salvage enzyme, reduces NAD ⁺ and prevents bone loss in ovariectomized mice. Similarly, deletion of Sirt3 in osteoclast precursors mitigates estrogen deficiency–induced bone resorption. These findings indicate that suppression of NAD ⁺ levels and mitochondrial redox metabolism by estrogens contributes to their anti-resorptive effects via inhibition of SIRT3.