Osteoporosis selective estrogen receptor modulators

Goldstein SR, Nanavati N (2002) Adverse events that are associated with the selective estrogen receptor modulator levormeloxifene in an aborted phase III osteoporosis treatment study. Am J Obstet Gynecol 187 521-527... 

Arshad M, Sengupta S, Sharma S, Ghosh R, Sawlani V, Singh MM (2004) In vitro anti-resorptive activity and prevention of ovariectomy-induced osteoporosis in female Sprague-Dawley rats by ormeloxifene, a selective estrogen receptor modulator. J Steroid Biochem Mol Biol 91(l-2) 67-78... 

Estrogen replacement (see p. 264) is the most effective therapy for the prevention of postmenopausal bone loss. When initiated in the immediate postmenopausal period, estrogen prevents osteoporosis and reduces the risk of hip fracture. Raloxifene, a second-generation selective estrogen receptor modulator (see p. xxx), increases women s bone density without increasing the risk for endometrial cancer. In addition, raloxifene has recently been reported to decrease the risk of estrogen receptor-positive breast cancer. 

The benzothiophene derivative raloxifene (Evista /Lilly) is a selective estrogen receptor modulator (SERM). Raloxifene produces its biological actions via modulation (both activation and blockade) of estrogen receptors that ultimately results in decreased resorption of bone. The bisphosphonate derivative alendronate (Fosamax /Merck), an inhibitor of osteoclast-mediated bone resorption, is also useful in the treatment of osteoporosis. Both raloxifene and alendronate are useful in the treatment of osteoporosis in postmenopausal women. 

Rosenfeld JA. Can the prophylactic use of raloxifene, a selective estrogen-receptor modulator, prevent bone mineral loss and fractures in women with diagnosed osteoporosis or vertebral fractures West J Med 2000 173(3) 186-8. 

Treatment of osteoporosis depends on the cause. In secondary osteoporosis, treatment is directed at the underlying condition. Most therapies for the treatment of postmenopausal osteoporosis are directed at decreasing osteoclastic bone resorption. Antiresorptive therapies include bisphosphoiiates (alendronate and risedronate), estrogen replacement, selective estrogen receptor modulators (raloxifene), and calcitonin (nasal spray or injection). The FDA has recently approved recombinant hPTH(l-34) (injection), the first approved therapy for stimulating bone formation. 

Drugs currently used to treat osteoporosis are classified into those that inhibit osteoclastic bone resorption (including bisphos-phonates, denosumab, and selective estrogen receptor modulators) and those that stimulate bone formation by osteoblasts (parathyroid hormone and derivatives, such as teriparatide). Strontium ranelate may have a dual effect. Other drugs being tested in clinical trials include inhibitors of cathepsin K (an osteoclastic enzyme critical for bone resorption) and of sclerostin (a negative modulator of the Wnt pathway) [21],... 

Calcitonin therapy results in decreased bone resorption. Osteoclasts have calcitonin receptors and calcitonin inhibits their activity. Sodium fluoride stimulates bone formation by unknown mechanisms. In women with osteoporosis, fluoride therapy produced an increased bone mineral density but no reduction in the rate of vertebral fractures. Other drugs known as selective estrogen receptor modulators (raloxifene, droloxifene, idoxifene, and levormeloxifene) may provide an alternative to estrogen replacement therapy (Chapter 34). Administration of low doses of PTH [or recombinant PTH( 1 -34)] does not affect serum calcium concentration, promotes bone formation, and increases mineral density. This anabolic action of PTH is probably mediated by decreasing osteoblast apoptosis. 

Their ligands are well known and widely used. The more recent advances in this field concern the so-called selective estrogen receptor modulators (SERMs) like tamoxifen and raloxifene. SERMs are used for the prevention and treatment of diseases such as osteoporosis and breast cancer. Ideally, it is presumed that SERMs should selectively act as an agonist in the bone and brain while simultaneously acting as an antagoiust in the breast and uterus. " ... 

Fontana A, Delmas PD. Selective estrogen receptors modulators in the prevention and treatment of postmenopausal osteoporosis. Endocrinol Metab Clin North Am 2003 32 219-232. 

Stump, A.L., Kelley, K.W. and Wensel, T.M. (2007) Bazedoxifene a third-generation selective estrogen receptor modulator for treatment of postmenopausal osteoporosis. Annals of Pharmacotherapy, 41, 833-839. 

The second drug is the selective estrogen receptor modulating drug, raloxifene (Figure 7.5) , which is used for the treatment of postmenopausal osteoporosis. The in vitro bioactivation of raloxifene by human liver microsomal CYP3A4 results in mechanism-based inactivation of this enzyme. The inactivation is attenuated by the CYP3A4-selective inhibitor ketoconazole (10 xM), is quenched minimally ( 15%) by GSH (5 mM), and is characterized by K, and partition... 

Selective Estrogen Receptor Modulators Raloxifene (EVISTa) acts as an estrogen agonist on bone and liver, is inactive on the uterus, and acts as an estrogen antagonist on the breast. In postmenopausal women, raloxifene modestly increases bone mineral density and has been shown to reduce the risk of vertebral compression fractures in this setting, it is approved for both the prevention and treatment of osteoporosis. The major adverse effect is worsened vasomotor symptoms the drug also increases the incidence of deep venous thrombosis. 

Selective estrogen receptor modulator (SERM) agonist at bone receptors (used in osteoporosis), antagonist at breast receptors (used in cancCT) but does not stimulate endometrial receptors. 

Jordan, V.C., Gapstur, S., and Morrow, M., Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis, and coronary heart disease, J. Natl Cancer Inst, 93,... 

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