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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Depending on regulatory approval in different world regions, raloxifene is used for the treatment and prevention of osteoporosis in postmenopausal women, for the reduction of risk and treatment of invasive breast cancer, or to reduce breast density. It was first approved by the FDA to prevent and treat osteoporosis (bone thinning) in postmenopausal women based on its estrogenic effect in bone tissue. Unlike some other hormone replacement therapies, raloxifene does not reduce menopausal vasomotor symptoms. Later clinical studies showed that, taken once a day, it works almost as well as tamoxifen in lowering the relative risk of breast cancer by up to approximately 40%. It was shown to reduce breast density in postmenopausal women, a known risk factor for breast cancer. However, in comparative clinical trials it was shown to cause fewer cases of uterine cancer than tamoxifen (due to the negligible estrogenic activity in the uterus), and did not increase the risk of cataracts, a common tamoxifen side effect. Furthermore, although both groups of patients developed more blood clots in the veins and lungs compared to a control group, this side effect was more common with tamoxifen than raloxifene.
Role of Aromatase Inhibitors (AIs) and Selective Estrogen Receptor Modulators (SERMs) in the Treatment of Uterine Leiomyoma
Published in John C. Petrozza, Uterine Fibroids, 2020
In postmenopausal women, Palomba et al. conducted a pilot study in 2002 that included 90 asymptomatic postmenopausal patients with uterine leiomyoma and divided them into three different arms: one group was treated with 60 mg of raloxifene daily, a second group used 180 mg daily and the third groups was a placebo group. They were treated for a total of six 28-day cycles, without any significant statistical difference in leiomyoma size among the three groups [24]. In 2005, this same group conducted a prospective, randomized, double-blinded, placebo-controlled study that included 40 postmenopausal women selected for hysterectomy. They were randomized into two groups: one treated with raloxifene for a total of three cycles of 28 days each using a dose of 180 mg/day versus a placebo group. They concluded that after treatment, there was a statistically significant decrease in both uterine volume and leiomyoma size in the raloxifene group compared with baseline and placebo groups. After treatment, decrease in uterine and leiomyoma volumes were −11.8 ± 6.3 cm3 and −17.4 ± 6.1 cm3, respectively, in the raloxifene group, and 1.6 ± 0.9 cm3 and 1.9 ± 1.1 cm3, respectively, in the placebo group. In addition, after hysterectomy, they studied the proliferation and apoptotic indexes for the raloxifene and placebo groups. Leiomyoma cells and adjacent myometrial cells revealed evidence of antiproliferative and apoptotic effects in the raloxifene-treated group [22]. These studies summarize the limited experience in treating postmenopausal women with SERMs.
Hormonal therapy of breast cancer
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
There are currently no prospective clinical data to support the use of raloxifene as a chemopreventive agent for breast cancer, although an unplanned analysis of the randomized trial that led to its registration for the treatment of osteoporosis showed that women receiving the drug had a lower incidence of breast cancer than those who received placebo (72% risk reduction)57. A prospective trial comparing raloxifene and tamoxifen as chemopreventive agents in postmenopausal women at high risk of invasive breast cancer is now being conducted (NSABP P-2; Study of Tamoxifen and Raloxifene (STAR)) by the National Surgical Adjuvant Breast and Bowel Project in the USA.
Human serum albumin-based nanoparticles alter raloxifene administration and improve bioavailability
Published in Drug Delivery, 2022
Shu-Jyuan Yang, Chih-Hao Chang, Tai-Horng Young, Chung-Hao Wang, Tzu-Hao Tseng, Man-Ling Wang
Raloxifene hydrochloride is a popular second-generation SERM that was approved by the US Food and Drug Administration in 1997 for the treatment and prevention of bone absorption caused by postmenopausal osteoporosis (Riggs & Hartmann, 2003; Saini et al., 2015). Raloxifene at the dosage of 60 mg must be taken once a day continuously for more than two years to significantly increase bone density and reduce the occurrence of fractures (Cooper et al., 2012). Raloxifene also lowers total and low-density lipoprotein cholesterol without increasing triglycerides or altering high-density lipoprotein cholesterol. Furthermore, preclinical data show that raloxifene also can display as an estrogen antagonist to reduce the risk of breast cancer incidence in postmenopausal women (Delmas et al., 2002; Waters et al., 2012). Because raloxifene is hydrophobic molecule and has a low aqueous solubility, it is primarily administered orally as tablets. However, the oral administration of raloxifene undergoes extensive intestinal glucuronidation and phase II metabolism in the liver (the first-pass effect), which reduce its bioavailability to 2% (Jagadish et al., 2010; Ahmed & Badr-Eldin, 2018). Additionally, the long-term, high-dose administration of raloxifene can cause several side effects, such as hot flashes, nausea, deep vein thrombosis, stroke, leg cramps, swelling, and cold-like symptoms, which results in poor patient compliance (Modi et al., 2016).
Pharmacological Management of Postmenopausal Osteoporosis: a Level I Evidence Based - Expert Opinion
Published in Expert Review of Clinical Pharmacology, 2021
Filippo Migliorini, Giorgia Colarossi, Alice Baroncini, Jörg Eschweiler, Markus Tingart, Nicola Maffulli
The decline in estrogen plays a role in the pathogenesis of postmenopausal osteoporosis [110], reducing the activity of osteoblasts and osteocytes and promoting apoptosis in osteoblasts [2]. Raloxifene works as an estrogen agonist in bone and on lipid metabolism, and as an antagonist on estrogen receptors in breast and endometrial tissue [111]. The effectiveness of Raloxifene in reducing fractures is uncertain [112], but this drug did reduce vertebral and non-vertebral fractures and showed good tolerability with an improvement in the quality of life in Japanese postmenopausal women [113]. In the present meta-analysis, although it resulted in less effective in reducing fractures, Raloxifene showed low rates of serious adverse events. Of note, serious adverse events were those declared as such in the RCTs included; however, we acknowledge that the definition of serious adverse events was not always clear.
Estrogen and estrogen receptors in kidney diseases
Published in Renal Failure, 2021
Hao-Yang Ma, Shuang Chen, Yang Du
Selective estrogen receptor modulators (SERMs) are antiestrogens designed to compete with estrogen and modulate ER activity in a tissue-specific manner [70,71]. For instance, tamoxifen can exhibit antagonistic effect on mammary tissue, whereas it can have agonistic effects on other tissues such as the uterus, bone, and heart [72]. Raloxifene acts as an estrogen agonist in bone and an estrogen antagonist in uterine and breast tissues [73]. Similarly, bazedoxifene functions as a pure antagonist in the breast and an agonist in the bone [74]. Since ERs are nuclear transcription factors involved in the regulation of a variety of physiological and pathological processes in humans, modulation of the receptors either by SERMs or by agonists/antagonists might be beneficial for the prevention and treatment of various diseases [27].