Estrogen deficiency leads to rapid bone loss and skeletal fragility. Sclerostin, 
encoded by the sost gene, and a product of the osteocyte, is a negative 
regulator of bone formation. Blocking sclerostin increases bone mass and 
strength in animals and humans. Sirtuin1 (Sirt1), a player in aging and 
metabolism, regulates bone mass and inhibits sost expression by deacetylating 
histone 3 at its promoter. We asked whether a Sirt1-activating compound could 
rescue ovariectomy (OVX)-induced bone loss and biomechanical deterioration in 
9-week-old C57BL/6 mice. OVX resulted in a substantial decrease in skeletal 
Sirt1 expression accompanied by an increase in sclerostin. Oral administration 
of SRT3025, a Sirt1 activator, at 50 and 100 mg/kg·d for 6 weeks starting 6 
weeks after OVX fully reversed the deleterious effects of OVX on vertebral bone 
mass, microarchitecture, and femoral biomechanical properties. Treatment with 
SRT3025 decreased bone sclerostin expression and increased cortical periosteal 
mineralizing surface and serum propeptide of type I procollagen, a bone 
formation marker. In vitro, in the murine long bone osteocyte-Y4 osteocyte-like 
cell line SRT3025 down-regulated sclerostin and inactive β-catenin, whereas a 
reciprocal effect was observed with EX-527, a Sirt1 inhibitor. Sirt1 activation 
by Sirt1-activating compounds is a potential novel pathway to down-regulate 
sclerostin and design anabolic therapies for osteoporosis concurrently 
ameliorating other metabolic and age-associated conditions.