The bone-sparing effect of estrogens is mediated primarily via estrogen receptor 
(ER)α, which stimulates gene transcription through activation function (AF)-1 
and AF-2. The role of ERαAF-1 for the estradiol (E2) effects is tissue specific. 
The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and 
bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all 
reduce the risk for vertebral fractures, whereas Las and partly Bza, but not 
Ral, reduce the risk for nonvertebral fractures. Here, we have compared the 
tissue specificity of Ral, Las, and Bza and evaluated the role of ERαAF-1 for 
the effects of these SERMs, with an emphasis on bone parameters. We treated 
ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ERαAF-1 
(ERαAF-1(0)) with E2, Ral, Las, or Bza. All three SERMs increased trabecular 
bone mass in the axial skeleton. In the appendicular skeleton, only Las 
increased the trabecular bone volume/tissue volume and trabecular number, 
whereas both Ral and Las increased the cortical bone thickness and strength. 
However, Ral also increased cortical porosity. The three SERMs had only a minor 
effect on uterine weight. Notably, all evaluated effects of these SERMs were 
absent in ovx ERαAF-1(0) mice. In conclusion, all SERMs had similar effects on 
axial bone mass. However, the SERMs had slightly different effects on the 
appendicular skeleton since only Las increased the trabecular bone mass and only 
Ral increased the cortical porosity. Importantly, all SERM effects require a 
functional ERαAF-1 in female mice. These results could lead to development of 
more specific treatments for osteoporosis.