SERMs have substance-specific effects on bone, and these effects are mediated via ERαAF-1 in female mice

Abstract

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-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 had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ERαAF-10 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.

Estrogen Regulates the Satellite Cell Compartment in Females

“…However, pharmacological progress has been made and there now exists FDA approved selective estrogen receptor modulators (SERMs) (Börjesson et al, 2016). Because SERMs function by inducing conformational changes in ER resulting in tissue-specific agonistic or antagonistic effects, largely depending on which cofactors are present, it was not clear whether the SERM, BZA, would present as an agonist or antagonist in skeletal muscle (Beck et al, 2015;Börjesson et al, 2016). Our results suggest that BZA is an ER agonist in skeletal muscle, or at least in muscle stem cells, as it restored the satellite cell pool in estradiol-deficient mice.…”

Estrogen Regulates the Satellite Cell Compartment in Females

“…The etiology of this disease is thought to be related to estradiol stimulation or mutations in the gene ERa (Dall et al, 2018;Gelsomino et al, 2018;Severson et al, 2018), which is known to exert proliferation of the normal breast tissue (Dall et al, 2018). However, pharmacological progress has been made, and there now exists US Food and Drug Administration (FDA)-approved selective ER modulators (SERMs) (Bö rjesson et al, 2016). Because SERMs function by inducing conformational changes in ER resulting in tissue-specific agonistic or antagonistic effects, largely depending on which cofactors are present, it was not clear whether the SERM, BZA, would present as an agonist or antagonist in skeletal muscle (Beck et al, 2015;Bö rjesson et al, 2016).…”

“…However, pharmacological progress has been made, and there now exists US Food and Drug Administration (FDA)-approved selective ER modulators (SERMs) (Bö rjesson et al, 2016). Because SERMs function by inducing conformational changes in ER resulting in tissue-specific agonistic or antagonistic effects, largely depending on which cofactors are present, it was not clear whether the SERM, BZA, would present as an agonist or antagonist in skeletal muscle (Beck et al, 2015;Bö rjesson et al, 2016). Our results suggest that BZA is an ER agonist in skeletal muscle, or at least in muscle stem cells, as it restored the satellite cell pool in estradiol-deficient mice.…”

Recent advances in the pharmaceutical manipulation of bone remodelling: the quest for a healthy skeleton

“…Both raloxifene and lasofoxifene increase cortical bone thickness and strength. 28 Complications reported with long-term SERM treatment include increased vaginal discharge, slightly elevated incidence of endometrial cancer (with some SERMs), venous thromboembolism and hot flushes. Indications for the use of SERMs therefore are post-menopausal females (particularly post-hysterectomy patients) and males with osteoporosis.…”