Breast-related effects of selective estrogen receptor modulators and tissue-selective estrogen complexes

Breast Cancer Research

Volumn 16, Issue 3, 2014, Pages

  Smith, Carolyn L ^a   Santen, Richard J ^b   Komm, Barry ^c   Mirkin, Sebastian ^c  

^a BAYLOR COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF VIRGINIA   (United States)

^c PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BAZEDOXIFENE; CONJUGATED ESTROGEN; ESTROGEN; LASOFOXIFENE; RALOXIFENE; SELECTIVE ESTROGEN RECEPTOR MODULATOR; TAMOXIFEN; TISSUE SELECTIVE ESTROGEN COMPLEX; UNCLASSIFIED DRUG; INDOLE DERIVATIVE;

BONE DENSITY; BREAST CANCER; BREAST DISEASE; BREAST TENDERNESS; COMPARATIVE STUDY; ESTROGEN THERAPY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MASTALGIA; MENOPAUSE; MULTICENTER STUDY (TOPIC); OUTCOME ASSESSMENT; PATIENT SAFETY; PHASE 3 CLINICAL TRIAL (TOPIC); POSTMENOPAUSE; POSTMENOPAUSE OSTEOPOROSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; BREAST; DRUG EFFECTS; FEMALE; MIDDLE AGED; OSTEOPOROSIS, POSTMENOPAUSAL; PATHOLOGY; PROCEDURES;

BONE DENSITY; BREAST; ESTROGEN REPLACEMENT THERAPY; ESTROGENS, CONJUGATED (USP); FEMALE; HUMANS; INDOLES; MIDDLE AGED; OSTEOPOROSIS, POSTMENOPAUSAL; SELECTIVE ESTROGEN RECEPTOR MODULATORS;

EID: 84902466995     PISSN: 14655411     EISSN: 1465542X     Source Type: Journal    
DOI: 10.1186/bcr3677     Document Type: Review

References (104)

1. Williams RE, Kalilani L, DiBenedetti DB, Zhou X, Granger AL, Fehnel SE, Levine KB, Jordan J, Clark RV. Frequency and severity of vasomotor symptoms among peri- and postmenopausal women in the United States. Climacteric 2008, 11:32-43. 10.1080/13697130701744696, 18202963.
2. Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc 2010, 85:87-94. 10.4065/mcp.2009.0413, 2800285, 20042564.
3. Riggs BL, Khosla S, Melton LJ. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998, 13:763-773. 10.1359/jbmr.1998.13.5.763, 9610739.
4. National Osteoporosis Foundation What women need to know. http://www.nof.org/articles/235, National Osteoporosis Foundation.
5. The 2012 hormone therapy position statement of The North American Menopause Society. Menopause 2012, 19:257-271. 3443956, 22367731.
6. Chen WY, Manson JE, Hankinson SE, Rosner B, Holmes MD, Willett WC, Colditz GA. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006, 166:1027-1032. 10.1001/archinte.166.9.1027, 16682578.
7. Barnabei VM, Cochrane BB, Aragaki AK, Nygaard I, Williams RS, McGovern PG, Young RL, Wells EC, O'Sullivan MJ, Chen B, Schenken R, Johnson SR. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet Gynecol 2005, 105:1063-1073. 10.1097/01.AOG.0000158120.47542.18, 15863546.
8. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 2003, 289:3243-3253. 10.1001/jama.289.24.3243, 12824205.
9. Pickar JH, Yeh IT, Bachmann G, Speroff L. Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril 2009, 92:1018-1024. 10.1016/j.fertnstert.2009.05.094, 19635613.
10. Lobo RA, Pinkerton JV, Gass ML, Dorin MH, Ronkin S, Pickar JH, Constantine G. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril 2009, 92:1025-1038. 10.1016/j.fertnstert.2009.03.113, 19635615.
11. Archer DF, Lewis V, Carr BR, Olivier S, Pickar JH. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril 2009, 92:1039-1044. 10.1016/j.fertnstert.2009.05.093, 19635614.
12. Lindsay R, Gallagher JC, Kagan R, Pickar JH, Constantine G. Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril 2009, 92:1045-1052. 10.1016/j.fertnstert.2009.02.093, 19635616.
13. Pinkerton JV, Utian WH, Constantine GD, Olivier S, Pickar JH. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial. Menopause 2009, 16:1116-1124. 10.1097/gme.0b013e3181a7df0d, 19546826.
14. Utian W, Yu H, Bobula J, Mirkin S, Olivier S, Pickar JH. Bazedoxifene/conjugated estrogens and quality of life in postmenopausal women. Maturitas 2009, 63:329-335. 10.1016/j.maturitas.2009.06.006, 19647382.
15. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause 2010, 17:281-289. 10.1097/gme.0b013e3181b7c65f, 19779382.
16. Bachmann G, Bobula J, Mirkin S. Effects of bazedoxifene/conjugated estrogens on quality of life in postmenopausal women with symptoms of vulvar/vaginal atrophy. Climacteric 2010, 13:132-140. 10.3109/13697130903305627, 19863455.
17. Mirkin S, Komm BS, Pan K, Chines AA. Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women. Climacteric 2013, 16:338-346. 10.3109/13697137.2012.717994, 23038989.
18. Pinkerton JV, Harvey JA, Pan K, Thompson JR, Ryan KA, Chines AA, Mirkin S. Breast effects of bazedoxifene-conjugated estrogens: a randomized controlled trial. Obstet Gynecol 2013, 121:959-968. 10.1097/AOG.0b013e31828c5974, 23635731.
19. Pinkerton JV, Pan K, Abraham L, Racketa J, Ryan KA, Chines AA, Mirkin S. Sleep parameters and health-related quality of life with bazedoxifene/conjugated estrogens: a randomized trial. Menopause 2014, 21:252-259. 10.1097/GME.0b013e31829f0433, 23942245.
20. Pinkerton JV, Harvey JA, Lindsay R, Pan K, Chines AA, Mirkin S, Archer DF. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab 2014, 99:E189-E198. 10.1210/jc.2013-1707, 24438370.
21. Crandall CJ, Aragaki AK, Cauley JA, McTiernan A, Manson JE, Anderson GL, Wactawski-Wende J, Chlebowski RT. Breast tenderness after initiation of conjugated equine estrogens and mammographic density change. Breast Cancer Res Treat 2012, 131:969-979. 10.1007/s10549-011-1803-9, 3685488, 21979747.
22. McTiernan A, Martin CF, Peck JD, Aragaki AK, Chlebowski RT, Pisano ED, Wang CY, Brunner RL, Johnson KC, Manson JE, Lewis CE, Kotchen JM, Hulka BS. Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women's Health Initiative randomized trial. J Natl Cancer Inst 2005, 97:1366-1376. 10.1093/jnci/dji279, 16174858.
23. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004, 291:1701-1712.
24. Anderson GL, Chlebowski RT, Aragaki AK, Kuller LH, Manson JE, Gass M, Bluhm E, Connelly S, Hubbell FA, Lane D, Martin L, Ockene J, Rohan T, Schenken R, Wactawski-Wende J. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012, 13:476-486. 10.1016/S1470-2045(12)70075-X, 3412626, 22401913.
25. Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, Manson JE, Stefanick ML, Ockene J, Sarto GE, Johnson KC, Wactawski-Wende J, Ravdin PM, Schenken R, Hendrix SL, Rajkovic A, Rohan TE, Yasmeen S, Prentice RL. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010, 304:1684-1692. 10.1001/jama.2010.1500, 20959578.
26. Kenemans P, Bosman A. Breast cancer and post-menopausal hormone therapy. Best Pract Res Clin Endocrinol Metab 2003, 17:123-137. 10.1016/S1521-690X(02)00084-2, 12763516.
27. Santen RJ, Yue W, Heitjan DF. Modeling of the growth kinetics of occult breast tumors: role in interpretation of studies of prevention and menopausal hormone therapy. Cancer Epidemiol Biomarkers Prev 2012, 21:1038-1048. 10.1158/1055-9965.EPI-12-0043, 22586072.
28. Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I, Higginbotham S, Johansson SL, Patil KD, Gross ML, Gooden JK, Ramanathan R, Cerny RL, Rogan EG. Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci U S A 1997, 94:10937-10942. 10.1073/pnas.94.20.10937, 23537, 9380738.
29. Song Y, Santen RJ, Wang JP, Yue W. Inhibitory effects of a bazedoxifene/conjugated equine estrogen combination on human breast cancer cells in vitro. Endocrinology 2013, 154:656-665. 10.1210/en.2012-2038, 23254198.
30. Song Y, Santen RJ, Wang JP, Yue W. Effects of the conjugated equine estrogen/bazedoxifene tissue-selective estrogen complex (TSEC) on mammary gland and breast cancer in mice. Endocrinology 2012, 153:5706-5715. 10.1210/en.2012-1583, 23070546.
31. Obr AE, Edwards DP. The biology of progesterone receptor in the normal mammary gland and in breast cancer. Mol Cell Endocrinol 2012, 357:4-17. 10.1016/j.mce.2011.10.030, 3318965, 22193050.
32. Axlund SD, Sartorius CA. Progesterone regulation of stem and progenitor cells in normal and malignant breast. Mol Cell Endocrinol 2012, 357:71-79. 10.1016/j.mce.2011.09.021, 3288619, 21945473.
33. Liang Y, Benakanakere I, Besch-Williford C, Hyder RS, Ellersieck MR, Hyder SM. Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice. Menopause 2010, 17:1040-1047. 10.1097/gme.0b013e3181d3dd0c, 2923240, 20461021.
34. Tkach M, Rosemblit C, Rivas MA, Proietti CJ, Diaz Flaque MC, Mercogliano MF, Beguelin W, Maronna E, Guzman P, Gercovich FG, Deza EG, Elizalde PV, Schillaci R. p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth. Endocr Relat Cancer 2013, 20:197-212. 10.1530/ERC-12-0194, 23329648.
35. Brisken C. Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer 2013, 13:385-396. 10.1038/nrc3518, 23702927.
36. Rivas MA, Venturutti L, Huang YW, Schillaci R, Huang TH, Elizalde PV. Downregulation of the tumor-suppressor miR-16 via progestin-mediated oncogenic signaling contributes to breast cancer development. Breast Cancer Res 2012, 14:R77. 10.1186/bcr3187, 3446340, 22583478.
37. Lopez Perez FR, Liang Y, Besch-Williford CL, Mafuvadze B, Hyder SM. Differential expression of FGF family members in a progestin-dependent BT-474 human breast cancer xenograft model. Histol Histopathol 2012, 27:337-345.
38. Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ, Paterson AD. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 2005, 6:798-808. 10.1016/S1470-2045(05)70390-9, 16198986.
39. McCormack VA, dos Santos SI. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006, 15:1159-1169. 10.1158/1055-9965.EPI-06-0034, 16775176.
40. Carney PA, Miglioretti DL, Yankaskas BC, Kerlikowske K, Rosenberg R, Rutter CM, Geller BM, Abraham LA, Taplin SH, Dignan M, Cutter G, Ballard-Barbash R. Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography. Ann Intern Med 2003, 138:168-175. 10.7326/0003-4819-138-3-200302040-00008, 12558355.
41. Crandall CJ, Aragaki AK, Cauley JA, McTiernan A, Manson JE, Anderson G, Chlebowski RT. Breast tenderness and breast cancer risk in the estrogen plus progestin and estrogen-alone women's health initiative clinical trials. Breast Cancer Res Treat 2012, 132:275-285. 10.1007/s10549-011-1848-9, 3697872, 22042371.
42. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators - mechanisms of action and application to clinical practice. N Engl J Med 2003, 348:618-629. 10.1056/NEJMra022219, 12584371.
43. Pickar JH, MacNeil T, Ohleth K. SERMs: progress and future perspectives. Maturitas 2010, 67:129-138. 10.1016/j.maturitas.2010.05.009, 20580502.
44. Jordan VC, Morrow M. Tamoxifen, raloxifene, and the prevention of breast cancer. Endocr Rev 1999, 20:253-278.
45. Jordan VC, Phelps E, Lindgren JU. Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 1987, 10:31-35. 10.1007/BF01806132, 3689979.
46. Turner CH, Sato M, Bryant HU. Raloxifene preserves bone strength and bone mass in ovariectomized rats. Endocrinology 1994, 135:2001-2005.
47. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, Carbone PP, DeMets DL. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992, 326:852-856. 10.1056/NEJM199203263261302, 1542321.
48. Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE, Cosgrove DO, Campbell S. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 1994, 343:1318-1321. 10.1016/S0140-6736(94)92466-X, 7910323.
49. Maximov PY, Lee TM, Jordan VC. The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Curr Clin Pharmacol 2013, 8:135-155. 10.2174/1574884711308020006, 3624793, 23062036.
50. Goldstein SR, Bhattoa HP, Neven P, Cox DA, Dowsett SA, Alam J, Sipos A, Muram D. Gynecologic effects of arzoxifene in postmenopausal women with osteoporosis or low bone mass. Menopause 2012, 19:41-47. 10.1097/gme.0b013e318223bbf4, 21993078.
51. Cummings SR, McClung M, Reginster JY, Cox D, Mitlak B, Stock J, Amewou-Atisso M, Powles T, Miller P, Zanchetta J, Christiansen C. Arzoxifene for prevention of fractures and invasive breast cancer in postmenopausal women. J Bone Miner Res 2011, 26:397-404. 10.1002/jbmr.191, 20658564.
52. Powles TJ, Diem SJ, Fabian CJ, Neven P, Wickerham DL, Cox DA, Muram D, Agnusdei D, Dowsett SA, Amewou-Atisso M, Cummings SR. Breast cancer incidence in postmenopausal women with osteoporosis or low bone mass using arzoxifene. Breast Cancer Res Treat 2012, 134:299-306. 10.1007/s10549-012-2041-5, 22484799.
53. Osphena [package insert] 2013, Florham Park, NJ: Shionogi Inc.
54. Nolvadex [package insert] 2005, Wilmington, DE: AstraZeneca Pharmaceuticals LP.
55. Jordan VC. Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 1976, 12:419-424. 10.1016/0014-2964(76)90030-X, 821733.
56. Shafie SM, Grantham FH. Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst 1981, 67:51-56.
57. Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB. Selective estrogen receptor modulators: an update on recent clinical findings. Obstet Gynecol Surv 2008, 63:163-181.
58. Chow CK, Venzon D, Jones EC, Premkumar A, O'Shaughnessy J, Zujewski J. Effect of tamoxifen on mammographic density. Cancer Epidemiol Biomarkers Prev 2000, 9:917-921.
59. Cuzick J, Warwick J, Pinney E, Duffy SW, Cawthorn S, Howell A, Forbes JF, Warren RM. Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: a nested case-control study. J Natl Cancer Inst 2011, 103:744-752. 10.1093/jnci/djr079, 21483019.
60. Evista [package insert] 2011, Indianapolis, IN: Eli Lilly and Company.
61. Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology 2005, 146:3999-4008. 10.1210/en.2005-0030, 15961563.
62. Chang KC, Wang Y, Bodine PV, Nagpal S, Komm BS. Gene expression profiling studies of three SERMs and their conjugated estrogen combinations in human breast cancer cells: insights into the unique antagonistic effects of bazedoxifene on conjugated estrogens. J Steroid Biochem Mol Biol 2010, 118:117-124. 10.1016/j.jsbmb.2009.11.003, 19914376.
63. Lewis-Wambi JS, Kim H, Curpan R, Grigg R, Sarker MA, Jordan VC. The selective estrogen receptor modulator bazedoxifene inhibits hormone-independent breast cancer cell growth and down-regulates estrogen receptor alpha and cyclin D1. Mol Pharmacol 2011, 80:610-620. 10.1124/mol.111.072249, 3187528, 21737572.
64. Crabtree JS, Peano BJ, Zhang X, Komm BS, Winneker RC, Harris HA. Activity of three selective estrogen receptor modulators on hormone-dependent responses in the mouse uterus and mammary gland. Mol Cell Endocrinol 2008, 287:40-46. 10.1016/j.mce.2008.01.027, 18367319.
65. Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, Farrerons J, Karasik A, Mellstrom D, Ng KW, Stepan JJ, Powles TJ, Morrow M, Costa A, Silfen SL, Walls EL, Schmitt H, Muchmore DB, Jordan VC, Ste-Marie LG. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat 2001, 65:125-134. 10.1023/A:1006478317173, 11261828.
66. Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, Secrest RJ, Cummings SR. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004, 96:1751-1761. 10.1093/jnci/djh319, 15572757.
67. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, McNabb MA, Wenger NK. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006, 355:125-137. 10.1056/NEJMoa062462, 16837676.
68. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER, Wade JL, Robidoux A, Margolese RG, James J, Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res (Phila) 2010, 3:696-706.
69. Voss S, Quail D, Dawson A, Backstrom T, Aguas F, Erenus M, The HS, Bonnar J, De GC, Hunter M, Nickelsen T. A randomised, double-blind trial comparing raloxifene HCl and continuous combined hormone replacement therapy in postmenopausal women: effects on compliance and quality of life. BJOG 2002, 109:874-885. 10.1111/j.1471-0528.2002.01510.x, 12197366.
70. Pearman L, Kagan R, Arsenault J, Muram D. The effects of raloxifene on mammographic breast density: a review of clinical trials. Menopause 2010, 17:654-659.
71. Freedman M, San MJ, O'Gorman J, Eckert S, Lippman ME, Lo SC, Walls EL, Zeng J. Digitized mammography: a clinical trial of postmenopausal women randomly assigned to receive raloxifene, estrogen, or placebo. J Natl Cancer Inst 2001, 93:51-56. 10.1093/jnci/93.1.51, 11136842.
72. Jackson VP, San Martin JA, Secrest RJ, McNabb M, Carranza-Lira S, Figueroa-Casas P, Fernandes CE, Romaguera J. Comparison of the effect of raloxifene and continuous-combined hormone therapy on mammographic breast density and breast tenderness in postmenopausal women. Am J Obstet Gynecol 2003, 188:389-394. 10.1067/mob.2003.21, 12592245.
73. Eilertsen AL, Karssemeijer N, Skaane P, Qvigstad E, Sandset PM. Differential impact of conventional and low-dose oral hormone therapy, tibolone and raloxifene on mammographic breast density, assessed by an automated quantitative method. BJOG 2008, 115:773-779. 10.1111/j.1471-0528.2008.01690.x, 18355366.
74. Gennari L. Lasofoxifene, a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy. Expert Opin Pharmacother 2009, 10:2209-2220. 10.1517/14656560903127241, 19640205.
75. Rosati RL, Da Silva JP, Cameron KO, Thompson DD, Ke HZ, Toler SM, Brown TA, Pan LC, Ebbinghaus CF, Reinhold AR, Elliott NC, Newhouse BN, Tjoa CM, Sweetnam PM, Cole MJ, Arriola MW, Gauthier JW, Crawford DT, Nickerson DF, Pirie CM, Qi H, Simmons HA, Tkalcevic GT. Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J Med Chem 1998, 41:2928-2931. 10.1021/jm980048b, 9685230.
76. Cline JM, Botts S, Lees CJ, Brommage R. Effects of lasofoxifene on the uterus, vagina, and breast in ovariectomized cynomolgus monkeys (Macaca fascicularis). Am J Obstet Gynecol 2008, 199:158.
77. LaCroix AZ, Powles T, Osborne CK, Wolter K, Thompson JR, Thompson DD, Allred DC, Armstrong R, Cummings SR, Eastell R, Ensrud KE, Goss P, Lee A, Neven P, Reid DM, Curto M, Vukicevic S. Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women. J Natl Cancer Inst 2010, 102:1706-1715. 10.1093/jnci/djq415, 21051656.
78. Davidson M, Moffett A, Welty F, Simon J, Bolognese M, de Melo N, Wolter K, Proulx J, Radecki D. Extraskeletal effects of lasofoxifene on postmenopausal women [abstract SA428]. J Bone Miner Res 2005, 20(suppl 1):S173.
79. Fablyn®. Ligand. http://www.ligand.com/fablyn.
80. Ligand inks week's second lasofoxifene licensing deal. Genet Eng Biotechnol News http://www.genengnews.com/gen-news-highlights/ligand-inks-week-s-second-lasofoxifene-licensing-deal/81248637/.
81. Miller PD, Chines AA, Christiansen C, Hoeck HC, Kendler DL, Lewiecki EM, Woodson G, Levine AB, Constantine G, Delmas PD. Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res 2008, 23:525-535.
82. Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, de Villiers TJ, Constantine GD, Chines AA. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 2008, 23:1923-1934. 10.1359/jbmr.080710, 18665787.
83. Komm BS, Lyttle CR. Developing a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation. Ann N Y Acad Sci 2001, 949:317-326.
84. Santen RJ, Kagan R, Altomare CJ, Komm B, Mirkin S, Taylor HS. Current and evolving approaches to individualizing estrogen receptor-based therapy approaches for menopausal women. J Clin Endocrinol Metab 2014, 99:733-747.
85. Mirkin S, Archer DF, Taylor HS, Pickar JH, Komm BS. Differential effects of menopausal therapies on the endometrium. Menopause 2014, [Epub ahead of print].
86. Wardell SE, Nelson ER, Chao CA, McDonnell DP. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res 2013, 19:2420-2431. 10.1158/1078-0432.CCR-12-3771, 3643989, 23536434.
87. Pinkerton JV, Archer DF, Utian WH, Menegoci JC, Levine AB, Chines AA, Constantine GD. Bazedoxifene effects on the reproductive tract in postmenopausal women at risk for osteoporosis. Menopause 2009, 16:1102-1108. 10.1097/gme.0b013e3181a816be, 19546825.
88. Archer DF, Pinkerton JV, Utian WH, Menegoci JC, de Villiers TJ, Yuen CK, Levine AB, Chines AA, Constantine GD. Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause 2009, 16:1109-1115. 10.1097/gme.0b013e3181a818db, 19543129.
89. Christiansen C, Chesnut CH, Adachi JD, Brown JP, Fernandes CE, Kung AW, Palacios S, Levine AB, Chines AA, Constantine GD. Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis. BMC Musculoskelet Disord 2010, 11:130. 10.1186/1471-2474-11-130, 2908075, 20569451.
90. Harvey JA, Holm MK, Ranganath R, Guse PA, Trott EA, Helzner E. The effects of bazedoxifene on mammographic breast density in postmenopausal women with osteoporosis. Menopause 2009, 16:1193-1196. 10.1097/gme.0b013e3181a7fb1e, 19503006.
91. de Villiers TJ, Chines AA, Palacios S, Lips P, Sawicki AZ, Levine AB, Codreanu C, Kelepouris N, Brown JP. Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial. Osteoporos Int 2011, 22:567-576. 10.1007/s00198-010-1302-6, 20535606.
92. Palacios S, de Villiers TJ, Nardone FC, Levine AB, Williams R, Hines T, Mirkin S, Chines AA. Assessment of the safety of long-term bazedoxifene treatment on the reproductive tract in postmenopausal women with osteoporosis: results of a 7-year, randomized, placebo-controlled, phase 3 study. Maturitas 2013, 76:81-87. 10.1016/j.maturitas.2013.06.008, 23871271.
93. Kharode Y, Bodine PV, Miller CP, Lyttle CR, Komm BS. The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology 2008, 149:6084-6091. 10.1210/en.2008-0817, 18703623.
94. de Villiers TJ, Pines A, Panay N, Gambacciani M, Archer DF, Baber RJ, Davis SR, Gompel AA, Henderson VW, Langer R, Lobo RA, Plu-Bureau, Sturdee DW. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric 2013, 16:316-337. 10.3109/13697137.2013.795683, 23672656.
95. Liu S, Han SJ, Smith CL. Cooperative activation of gene expression by agonists and antagonists mediated by estrogen receptor heteroligand dimer complexes. Mol Pharmacol 2013, 83:1066-1077. 10.1124/mol.112.084228, 3629828, 23462505.
96. Wardell SE, Kazmin D, McDonnell DP. Research resource: transcriptional profiling in a cellular model of breast cancer reveals functional and mechanistic differences between clinically relevant SERM and between SERM/estrogen complexes. Mol Endocrinol 2012, 26:1235-1248. 10.1210/me.2012-1031, 3385791, 22570330.
97. Berrodin TJ, Chang KC, Komm BS, Freedman LP, Nagpal S. Differential biochemical and cellular actions of Premarin estrogens: distinct pharmacology of bazedoxifene-conjugated estrogens combination. Mol Endocrinol 2009, 23:74-85. 10.1210/me.2008-0366, 19036900.
98. Peano BJ, Crabtree JS, Komm BS, Winneker RC, Harris HA. Effects of various selective estrogen receptor modulators with or without conjugated estrogens on mouse mammary gland. Endocrinology 2009, 150:1897-1903. 10.1210/en.2008-1210, 19022889.
99. Ethun KF, Wood CE, Register TC, Cline JM, Appt SE, Clarkson TB. Effects of bazedoxifene acetate with and without conjugated equine estrogens on the breast of postmenopausal monkeys. Menopause 2012, 19:1242-1252. 3762946, 23103754.
100. Harvey JA, Pinkerton JV, Baracat EC, Shi H, Chines AA, Mirkin S. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause 2013, 20:138-145.
101. Gallagher JC, Lindsay R, Pan K, Mirkin S, Chines A. Effects of bazedoxifene/conjugated estrogens on bone mineral density and bone turnover markers in postmenopausal women: a double-blind, randomized, placebo- and active-controlled phase 3 study [abstract 1133]. J Bone Miner Res 2011, 26(suppl 1):S46.
102. Archer DF, Lobo RA, Pan K, Chines AA, Mirkin S. Safety and tolerability of bazedoxifene/conjugated estrogens in postmenopausal women: findings from a 1-year, randomized, placebo- and active-controlled, phase 3 trial [abstract P-25]. Menopause 2011, 18:1355-1356.
103. Duavee [package insert] 2013, Philadelphia, PA: Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.
104. Pinkerton JV, Taylor H, Pan K, Chines A. Breast parameters with bazedoxifene/conjugated estrogens in randomized, controlled trials of postmenopausal women [abstract]. Menopause 2010, 17:1221-1222.