The bone-sparing effect of estrogens is primarily mediated 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, partly Bza, but not Ral, reduce the risk for non-vertebral 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-10) 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 only had a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ERαAF-10mice. 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.