Effects of the Selective Estrogen Receptor Modulator Ospemifene on Bone in Rats

Abstract

Ospemifene is a non-estrogen agent that exerts tissue-specific estrogen agonistic and weak antagonistic effects (i. e., is a selective estrogen receptor modulator [SERM]). The effects of various once-daily oral doses of ospemifene on bone are examined across 3 studies for 4 or 52 weeks after surgery in the ovariectomized (OVX) rat model of postmenopausal bone loss. Ospemifene treatment reduced the loss of bone mineral content and density observed in untreated OVX rats, significantly increased distal femur bone mineral content at 51 weeks at 25 mg/kg dose compared with untreated OVX rats (p<0.01), and significantly increased trabecular bone mineral density of the distal femur and proximal tibia with 1, 5, or 25 mg/kg doses after 52 weeks. Ospemifene 5 and 25 mg/kg preserved distal femur trabecular structure; trabecular number was significantly increased, whereas trabecular separation and eroded surface values were significantly decreased (all p<0.01). Structural changes associated with ospemifene were accompanied by increased mechanical strength of femurs and 4^th lumbar vertebra compared with untreated OVX rats. Ospemifene 10 mg/kg prevented OVX-induced bone loss; trabecular bone volume of distal femurs was increased after 4 weeks. Further, histomorphometric measures revealed decreased bone resorption after 4 weeks of ospemifene treatment, with effects similar to other SERMs (raloxifene and droloxifene). Ospemifene 3 and 10 mg/kg significantly inhibited OVX-induced increases in osteoclast number, and doses ≥0.3 mg/kg dose-dependently reversed the OVX-induced increase in the double-labeled volume:bone volume ratio. These results demonstrate antiresorptive, selective agonist effects of ospemifene on bone that appear similar to raloxifene in this in vivo animal model of estrogen deficiency.

Key words

tissue-selective estrogen agonist - ovariectomized rat - bone mineral content - bone mineral density - osteoporosis - estrogen deficiency

• References

• 1 Clarke BL, Khosla S. Female reproductive system and bone. Arch Biochem Biophys 2010; 503: 118-128
• 2 McNamara LM. Perspective on post-menopausal osteoporosis: establishing an interdisciplinary understanding of the sequence of events from the molecular level to whole bone fractures. J R Soc Interface 2010; 7: 353-372
• 3 Teede HJ. Hormone replacement therapy and the prevention of cardiovascular disease. Hum Reprod Update 2002; 8: 201-215
• 4 Barrett-Connor E, Laughlin GA. Endogenous and exogenous estrogen, cognitive function, and dementia in postmenopausal women: evidence from epidemiologic studies and clinical trials. Semin Reprod Med 2009; 27: 275-282
• 5 Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332: 1589-1593
• 6 Dardes RC, Jordan VC. Novel agents to modulate oestrogen action. Br Med Bull 2000; 56: 773-786
• 7 Lewiecki EM. Current and emerging pharmacologic therapies for the management of postmenopausal osteoporosis. J Womens Health (Larchmt) 2009; 18: 1615-1626
• 8 Evista (raloxifene hydrochloride) . Full Prescribing Information. Eli Lilly & Company; Indianapolis, IN: 2011
• 9 OsphenaTM (ospemifene) . Full Prescribing Information. Shionogi Inc; Florham Park, NJ: 2013
• 10 Qu Q, Zheng H, Dahllund J, Laine A, Cockcroft N, Peng Z, Koskinen M, Hemminki K, Kangas L, Väänänen K, Härkönen P. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology 2000; 141: 809-820
• 11 Qu Q, Härkönen PL, Väänänen HK. Comparative effects of estrogen and antiestrogens on differentiation of osteoblasts in mouse bone marrow culture. J Cell Biochem 1999; 73: 500-507
• 12 Komi J, Heikkinen J, Rutanen EM, Halonen K, Lammintausta R, Ylikorkala O. Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. Gynecol Endocrinol 2004; 18: 152-158
• 13 Komi J, Lankinen KS, DeGregorio M, Heikkinen J, Saarikoski S, Tuppurainen M, Halonen K, Lammintausta R, Väänänen K, Ylikorkala O, Erkkola R. Effects of ospemifene and raloxifene on biochemical markers of bone turnover in postmenopausal women. J Bone Miner Metab 2006; 24: 314-318
• 14 Lelovas PP, Xanthos TT, Thoma SE, Lyritis GP, Dontas IA. The laboratory rat as an animal model for osteoporosis research. Comp Med 2008; 58: 424-430
• 15 Takano-Yamamoto T, Rodan GA. Direct effects of 17 beta-estradiol on trabecular bone in ovariectomized rats. Proc Natl Acad Sci USA 1990; 87: 2172-2176
• 16 Chow J, Tobias JH, Colston KW, Chambers TJ. Estrogen maintains trabecular bone volume in rats not only by suppression of bone resorption but also by stimulation of bone formation. J Clin Invest 1992; 89: 74-78
• 17 Turner RT, Vandersteenhoven JJ, Bell NH. The effects of ovariectomy and 17 beta-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res 1987; 2: 115-122
• 18 Sato M, Rippy MK, Bryant HU. Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J 1996; 10: 905-912
• 19 Michael H, Härkönen PL, Kangas L, Väänänen HK, Hentunen TA. Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro. Br J Pharmacol 2007; 151: 384-395
• 20 Osella G, Ventura M, Ardito A, Allasino B, Termine A, Saba L, Vitetta R, Terzolo M, Angeli A. Cortisol secretion, bone health, and bone loss: a cross-sectional and prospective study in normal non-osteoporotic women in the early postmenopausal period. Eur J Endocrinol 2012; 166: 855-860
• 21 Gaete L, Tchernitchin AN, Bustamante R, Villena J, Ferrada K, Erazo S, Garcia R, Lemus I. Biological activity of genistein and soy extracts: selective induction of some but not all estrogenic responses in the prepubertal rat uterus. Bol Latinoam Caribe Plant Med Aromat 2010; 9: 302-311
• 22 Gaete L, Tchernitchin AN, Bustamante R, Villena J, Lemus I, Gidekel M, Cabrera G, Astorga P. Daidzein-estrogen interaction in the rat uterus and its effect on human breast cancer cell growth. J Med Food 2012; 15: 1081-1090
• 23 Galand P, Tchernitchin N, Tchernitchin AN. Time-course of the effects of nafoxidine and oestradiol on separate groups of responses in the uterus of the immature rat. J Steroid Biochem 1984; 21: 43-47
• 24 Galand P, Tchernitchin N, Tchernitchin AN. Dissociation of uterine eosinophilia and water imbibition from other estrogen-induced responses by nafoxidine pretreatment. Mol Cell Endocrinol 1985; 42: 227-233
• 25 Grunert G, Neumann G, Porcia M, Tchernitchin AN. The estrogenic responses to clomiphene in the different cell types of the rat uterus: morphometrical evaluation. Biol Reprod 1987; 37: 527-538
• 26 Tchernitchin AN, Mena MA, Soto J, Unda C. The role of eosinophils in the action of estrogens and other hormones. Med Sci Res 1989; 17: 5-10
• 27 Wang H, Masironi B, Eriksson H, Sahlin L. A comparative study of estrogen receptors alpha and beta in the rat uterus. Biol Reprod 1999; 61: 955-964
• 28 Nenci I, Fabris G, Marzola A, Marchetti E. The plasma membrane as an additional level of steroid-cell interaction. J Steroid Biochem 1981; 15: 231-234
• 29 Markaverich BM, Upchurch S, Clark JH. Progesterone and dexamethasone antagonism of uterine growth: a role for a second nuclear binding site for estradiol in estrogen action. J Steroid Biochem 1981; 14: 125-132
• 30 Tchernitchin A, Tchernitchin X, Robel P, Baulieu EE. The binding of estradiol to human polynuclear eosinophilic leukocytes. C R Acad Sci Hebd Seances Acad Sci D 1975; 280: 1477-1480
• 31 Damdimopoulos AE, Spyrou G, Gustafsson JA. Ligands differentially modify the nuclear mobility of estrogen receptors alpha and beta. Endocrinology 2008; 149: 339-345
• 32 Charlier TD. Importance of steroid receptor coactivators in the modulation of steroid action on brain and behavior. Psychoneuroendocrinology 2009; 34 (Suppl. 01) S20-S29
• 33 McKeen HD, Byrne C, Jithesh PV, Donley C, Valentine A, Yakkundi A, O’Rourke M, Swanton C, McCarthy HO, Hirst DG, Robson T. FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy. Cancer Res 2010; 70: 1090-1100
• 34 Gaete L, Tchernitchin AN, Bustamante R, Villena J, Lemus I, Gidekel M, Cabrera G, Carrillo O. Genistein selectively inhibits estrogen-induced cell proliferation and other responses to hormone stimulation in the prepubertal rat uterus. J Med Food 2011; 14: 1597-1603