Endometrial safety: A key hurdle for selective estrogen receptor modulators in development

Menopause

Volumn 17, Issue 3, 2010, Pages 642-653

  Pinkerton, Joann V ^a   Goldstein, Steven R ^b  

^a UNIVERSITY OF VIRGINIA   (United States)

^b NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Endometrium; Menopause; Postmenopausal; Safety; Selective estrogen receptor modulator; Uterus

Indexed keywords

ACOLBIFENE; ARZOXIFENE; BAZEDOXIFENE; CENTCHROMAN; DROLOXIFENE; ESTRADIOL; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; IDOXIFENE; LASOFOXIFENE; OSPEMIFENE; PIPENDOXIFENE; PLACEBO; RALOXIFENE; SELECTIVE ESTROGEN RECEPTOR MODULATOR; TAMOXIFEN; TOREMIFENE;

BONE DENSITY; BREAST CANCER; CANCER CONTROL; CANCER SURGERY; CANCER SURVIVAL; CLINICAL TRIAL; DEEP VEIN THROMBOSIS; DRUG EFFICACY; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG WITHDRAWAL; EDEMA; ENDOMETRIAL DISEASE; ENDOMETRIAL THICKNESS; ENDOMETRIUM; ENDOMETRIUM CANCER; ENDOMETRIUM CARCINOMA; ENDOMETRIUM HYPERPLASIA; ENDOMETRIUM POLYP; ESTROGEN THERAPY; FRACTURE; HOT FLUSH; HUMAN; LEUKORRHEA; LIPID ANALYSIS; LUNG EMBOLISM; NIGHT SWEAT; OVARY CANCER; OVARY CARCINOMA; OVARY CYST; PELVIC ORGAN PROLAPSE; POSTMENOPAUSE; POSTMENOPAUSE OSTEOPOROSIS; REVIEW; RISK ASSESSMENT; SIDE EFFECT; SURVIVAL RATE; TISSUE DISTRIBUTION; URINE INCONTINENCE; UTERINE CERVIX CANCER; UTERINE CERVIX TUMOR; UTERUS BLEEDING; UTERUS CANCER; UTERUS DISEASE; UTERUS MYOMA; UTERUS PROLAPSE; VAGINA BLEEDING; VASCULARIZATION; VASOMOTOR DISORDER;

ANTINEOPLASTIC AGENTS, HORMONAL; BREAST NEOPLASMS; CLINICAL TRIALS AS TOPIC; DRUG THERAPY, COMBINATION; ENDOMETRIUM; FEMALE; HUMANS; OSTEOPOROSIS, POSTMENOPAUSAL; POSTMENOPAUSE; PYRROLIDINES; RALOXIFENE; RECEPTORS, ESTROGEN; SELECTIVE ESTROGEN RECEPTOR MODULATORS; TAMOXIFEN; TETRAHYDRONAPHTHALENES; UROGENITAL SYSTEM; WOMEN'S HEALTH;

EID: 77952228433     PISSN: 10723714     EISSN: None     Source Type: Journal    
DOI: 10.1097/gme.0b013e3181c4f1d6     Document Type: Review

References (110)

1. Riggs BL, Hartmann LC. Selective estrogen-receptor modulatorsV mechanisms of action and application to clinical practice. N Engl J Med 2003;348:618-629.
2. Constantine GD, Pickar JH. Estrogens in postmenopausal women: recent insights. Curr Opin Pharmacol 2003;3:626-634.
3. Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004:CD002978.
4. Farquhar CM, Marjoribanks J, Lethaby A, Lamberts Q, Suckling JA. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2005:CD004143.
5. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998; 351:1451-1467.
6. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371-1388.
7. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992;326:852-856.
8. Christodoulakos GE, Lambrinoudaki IV, Botsis DC. The cardiovascular effects of selective estrogen receptor modulators. Ann N Y Acad Sci 2006;1092:374-384.
9. Rutqvist LE, Mattsson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 1993;85:1398-1406.
10. Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994;86:527-537. (Pubitemid 24111008)
11. Cosman F, Lindsay R. Selective estrogen receptor modulators: clinical spectrum. Endocr Rev 1999;20:418-434. (Pubitemid 30649813)
12. Goldstein SR. Not all SERMs are created equal. Menopause 2006;13: 325-327.
13. Henke BR, Heyer D. Recent advances in estrogen receptor modulators. Curr Opin Drug Discov Devel 2005;8:437-448.
14. Draper MW. The role of selective estrogen receptor modulators (SERMs) in postmenopausal health. Ann N Y Acad Sci 2003;997: 373-377.
15. McDonnell DP. Selective estrogen receptor modulators (SERMs): a first step in the development of perfect hormone replacement therapy regimen. J Soc Gynecol Investig 2000;7:S10-S15.
16. Goldstein SR. Controversy about uterine effects and safety of SERMs: the saga continues. Menopause 2002;9:381-384.
17. Miller CP. SERMs: evolutionary chemistry, revolutionary biology. Curr Pharm Des 2002;8:2089-2111.
18. McDonnell DP. The molecular determinants of estrogen receptor pharmacology. Maturitas 2004;48:S7-S12.
19. Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 1999;20:358-417.
20. Kuiper GG, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and A. Endocrinology 1997;138:863-870. (Pubitemid 27089735)
21. Palacios S. The future of the new selective estrogen receptor modulators. Menopause Int 2007;13:27-34.
22. Hammond CB, Jelovsek FR, Lee KL, Creasman WT, Parker RT. Effects of long-term estrogen replacement therapy. II. Neoplasia. Am J Obstet Gynecol 1979;133:537-547.
23. Smith DC, Prentice R, Thompson DJ, Herrmann WL. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 1975; 293:1164-1167.
24. The North American Menopause Society. Role of progestogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society. Menopause 2003;10:113-132.
25. Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 2001;75:1080-1087.
26. Lobo RA, Whitehead MI. Is low-dose hormone replacement therapy for postmenopausal women efficacious and desirable? Climacteric 2001; 4:110-119.
27. Goldstein SR. The case for less-than-monthly progestogen in women on HT: is transvaginal ultrasound the key? Menopause 2005;12:110-113.
28. Odmark IS, Bixo M, Englund D, Risberg B, Jonsson B, Olsson SE. Endometrial safety and bleeding pattern during a five-year treatment with long-cycle hormone therapy. Menopause 2005;12:699-707.
29. Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003;361:296-300.
30. Cohen I. Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol 2004;94:256-266
31. American College of Obstetricians and Gynecologists. ACOG committee opinion. Tamoxifen and endometrial cancer. Number 169
32. February 1996. Committee on Gynecologic Practice. Int J Gynaecol Obstet 1996;53:197-199.
33. O'Regan RM, Jordan VC. Tamoxifen to raloxifene and beyond. Semin Oncol 2001;28:260-273.
34. Mourits MJ, de Vries EG, Willemse PH, Ten Hoor KA, Hollema H, van der Zee AG. Tamoxifen treatment and gynecologic side effects: a review. Obstet Gynecol 2001;97:855-866.
35. Goldstein SR. The effect of SERMs on the endometrium. Ann N Y Acad Sci 2001;949:237-242.
36. Inoue M. Current molecular aspects of the carcinogenesis of the uterine endometrium. Int J Gynecol Cancer 2001;11:339-348.
37. Curtis RE, Freedman DM, Sherman ME, Fraumeni JF Jr. Risk of malignant mixed Müllerian tumors after tamoxifen therapy for breast cancer. J Natl Cancer Inst 2004;96:70-74.
38. Wickerham DL, Fisher B, Wolmark N, et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002;20:2758-2760.
39. Saadat M, Truong PT, Kader HA, et al. Outcomes in patients with primary breast cancer and a subsequent diagnosis of endometrial cancer: comparison of cohorts treated with and without tamoxifen. Cancer 2007;110:31-37.
40. Bland AE, Calingaert B, Secord AA, et al. Relationship between tamoxifen use and high risk endometrial cancer histologic types. Gynecol Oncol 2009;112:150-154.
41. Hoogendoorn WE, Hollema H, van Boven HH, et al. Prognosis of uterine corpus cancer after tamoxifen treatment for breast cancer. Breast Cancer Res Treat 2008;112:99-108.
42. Swerdlow AJ, Jones ME. Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study. J Natl Cancer Inst 2005; 97:375-384.
43. Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991;9:286-294.
44. Love RR, Cameron L, Connell BL, Leventhal H. Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 1991;151:1842-1847.
45. Dignam JJ, Fisher B. Occurrence of stroke with tamoxifen in NSABP B-24. Lancet 2000;355:848-849.
46. Cuzick J, Forbes JF, Sestak I, et al. Long-term results of tamoxifen prophylaxis for breast cancerV96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 2007;99:272-282.
47. Lindahl B, Andolf E, Ingvar C, Ranstam J, Willen R. Adjuvant tamoxifen in breast cancer patients affects the endometrium by time, an effect remaining years after end of treatment and results in an increased frequency of endometrial carcinoma. Anticancer Res 2008;28:1259-1262.
48. Harvey HA, Kimura M, Hajba A. Toremifene: an evaluation of its safety profile. Breast 2006;15:142-157.
49. Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmen J. A phase III comparison of two toremifene doses to tamoxifen in post-menopausal women with advanced breast cancer. Eastern European Study Group. Breast Cancer Res Treat 1997;45:251-262.
50. Hayes DF, Van Zyl JA, Hacking A, et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol 1995;13:2556-2566.
51. Pyrhönen S, Valavaara R, Modig H, et al. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the FNordic- phase III study. Br J Cancer 1997;76:270-277.
52. EVISTA (raloxifene hydrochloride) tablet for oral use [package insert]. Indianapolis, IN: Eli Lilly & Company. 2008.
53. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 1999;281:2189-2197.
54. Fugere P, Scheele WH, Shah A, Strack TR, Glant MD, Jolly E. Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in postmenopausal women. Am J Obstet Gynecol 2000;182:568-574.
55. Goldstein SR, Scheele WH, Rajagopalan SK, Wilkie JL, Walsh BW, Parsons AK. A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet Gynecol 2000;95:95-103.
56. Martino S, Disch D, Dowsett SA, Keech CA, Mershon JL. Safety assessment of raloxifene over eight years in a clinical trial setting. Curr Med Res Opin 2005;21:1441-1452.
57. Stovall DW, Utian WH, Gass ML, et al. The effects of combined raloxifene and oral estrogen on vasomotor symptoms and endometrial safety. Menopause 2007;14:510-517.
58. Lufkin EG, Whitaker MD, Nickelsen T, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 1998;13:1747-1754.
59. Jolly EE, Bjarnason NH, Neven P, et al. Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years. Menopause 2003;10:337-344.
60. Glusman JE, Huster WJ, Paul S. Raloxifene effects on vasomotor and other climacteric symptoms in postmenopausal women. Prim Care Update Ob Gyns 1998;5:166.
61. Davies GC, Huster WJ, Lu Y, Plouffe L Jr, Lakshmanan M. Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet Gynecol 1999;93:558-565.
62. Cohen FJ, Lu Y. Characterization of hot flashes reported by healthy postmenopausal women receiving raloxifene or placebo during osteoporosis prevention trials. Maturitas 2000;34:65-73.
63. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125-137. (Pubitemid 44050394)
64. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295:2727-2741.
65. DeMichele A, Troxel AB, Berlin JA, et al. Impact of raloxifene or tamoxifen use on endometrial cancer risk: a population-based case-control study. J Clin Oncol 2008;26:4151-4159.
66. Davis SR, O'Neill SM, Eden J, et al. Transition from estrogen therapy to raloxifene in postmenopausal women: effects on treatment satisfaction and the endometriumVa pilot study. Menopause 2004;11:167-175.
67. Pinkerton JV, Shifren JL, La Valleur J, Rosen A, Roesinger M, Siddhanti S. Influence of raloxifene on the efficacy of an estradiol-releasing ring for treating vaginal atrophy in postmenopausal women. Menopause 2003;10:45-52.
68. Fleischer AC, Wheeler JE, Yeh IT, Kravitz B, Jensen C, MacDonald B. Sonographic assessment of the endometrium in osteopenic post-menopausal women treated with idoxifene. J Ultrasound Med 1999; 18:503-512.
69. Smith Kline Beecham drops idoxifene for osteoporosis. SCRIP 1999; 2431:21.
70. Albertazzi P, Sharma S. Urogenital effects of selective estrogen receptor modulators: a systematic review. Climacteric 2005;8:214-220.
71. Goldstein SR, Nanavati N. Adverse events that are associated with the selective estrogen receptor modulator levormeloxifene in an aborted phase III osteoporosis treatment study. Am J Obstet Gynecol 2002;187: 521-527.
72. Ravn P, Nielsen TF, Christiansen C. What can be learned from the levormeloxifene experience? Acta Obstet Gynecol Scand 2006;85: 135-142.
73. Novo Nordisk drops levormeloxifene. SCRIP 1998;2374:18.
74. Bolognese M, Weiss S, Ettinger MP, Moffett AH, Lee A. Lasofox-ifene: a next generation selective estrogen receptor modulator (SERM) for the prevention of bone loss in postmenopausal women. Osteoporos Int 2004;15:S11. Abstract presented at: the Annual Meeting of the International Osteoporosis Foundation; 2004; Rio de Janeiro, Brazil. Abstract OC19.
75. McClung MR, Siris E, Cummings S, et al. Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with ral-oxifene. Menopause 2006;13:377-386.
76. Pfizer Inc. FABLYN (lasofoxifene tartrate) 0.5 mg tablets. NDA 22-242. Reproductive Health Drugs Advisory Committee briefing document. September 8, 2008. Available at: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4381b1- 02-Pfizer.pdf. Accessed April 19, 2009.
77. Rutanen EM, Heikkinen J, Halonen K, Komi J, Lammintausta R, Ylikorkala O. Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial. Menopause 2003;10:433-439.
78. Komi J, Lankinen KS, Harkonen P, et al. Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women. Menopause 2005;12:202-209.
79. Ronkin S, Northington R, Baracat E, et al. Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women. Obstet Gynecol 2005;105:1397-1404. (Pubitemid 40734275)
80. Pinkerton JV, Archer DF, Utian WH, et al. Bazedoxifene effects on the reproductive tract in postmenopausal women at risk for osteoporosis. Menopause. 2009;16:1102-1108.
81. Archer DF, Pinkerton JV, Utian WH, et al. 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.
82. Buzdar A, O'Shaughnessy JA, Booser DJ, et al. Phase II, randomized, double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer. J Clin Oncol 2003;21: 1007-1014.
83. Baselga J, Llombart-Cussac A, Bellet M, et al. Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients. Ann Oncol 2003;14:1383-1390.
84. Bolognese M, Krege JH, Utian WH, et al. Effects of arzoxifene on bone mineral density and endometrium in postmenopausal women with normal or low bone mass. J Clin Endocrinol Metab. 2009;94:2284-2289.
85. Postmenopausal Evaluation and Risk-Reduction With Lasofoxifene (PEARL). ClinicalTrials.gov identifier: NCT00141323. Available at: http://www. clinicaltrials.gov/ct2/show/NCT00141323?term= lasofoxifene&rank=1. Accessed May 14, 2008.
86. Cummings SR, Eastell R, Ensrud K, et al. The effects of lasofoxifene on fractures and breast cancer: 3-year results from the PEARL Trial. J Bone Miner Res 2008;23:S81. Abstract 1288.
87. Gennari L. Lasofoxifene, a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy. Expert Opin Pharmacother 2009;10:2209-2220.
88. Bachmann G, Gass M, Kagan R, Moffett A, Barcomb L, Symons J. Lasofoxifene (LASO), a next generation selective estrogen response modulator (SERM), improves dyspareunia in postmenopausal women with vaginal atrophy (VA). Menopause 2005;12:238. Abstract ED1.
89. Gass M, Portman D, Bachmann G, Moffett A, Symons J. Clinical signs of vaginal atrophy are improved by the SERM, lasofoxifene. Menopause 2004;11:670. Abstract P-68.
90. Simon J, Gass M, Kagan R, Spino C, Nemmeth MA. Lasofoxifene effectively treats dyspareunia in postmenopausal women with vaginal atrophy. Obstet Gynecol 2005;105:2S. Abstract A3423.
91. Voipio SK, Komi J, Kangas L, Halonen K, DeGregorio MW, Erkkola RU. Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmeno-pausal women. Maturitas 2002;43:207-214.
92. Gennari L. Ospemifene Hormos. Curr Opin Investig Drugs 2004;5: 448-455.
93. QuatRx Pharmaceuticals Company, Hormos Medical Ltd. A clinical study to evaluate the safety of ospemifene. ClinicalTrials.gov identifier: NCT00566982. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00566982. Accessed December 16, 2008.
94. QuatRx Pharmaceuticals Company. Efficacy and safety of ospemifene in the treatment of moderate to severe vaginal dryness and vaginal pain associated with sexual activity. ClinicalTrials.gov identifier: NCT00729469. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00729469. Accessed December 16, 2008.
95. QuatRx Pharmaceuticals Company, Hormos Medical Ltd. A clinical study to evaluate the safety of ospemifene. ClinicalTrials.gov identifier: NCT00630539. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00630539. Accessed December 16, 2008.
96. QuatRx Pharmaceuticals Company, Hormos Medical Ltd. A clinical study to evaluate ospemifene in the treatment of vulvar and vaginal atrophy in postmenopausal women. ClinicalTrials.gov identifier: NCT00276094. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00276094. Accessed December 16, 2008.
97. 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.
98. Komm BS, Miller CP, Lyttle CR. Preclinical profile of WAY-140424, a third-generation selective estrogen receptor modulator with an improved therapeutic potential. J Soc Gynecol Investig 2001;8:84a.
99. 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.
100. Miller PD, Chines AA, Christiansen C, et al. 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.
101. Silverman SL, Christiansen C, Genant HK, et al. 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.
102. Munster PN, Buzdar A, Dhingra K, et al. Phase I study of a third-generation selective estrogen receptor modulator, LY353381.HCL, in metastatic breast cancer. J Clin Oncol 2001;19:2002-2009.
103. Fabian CJ, Kimler BF, Anderson JR et al. Phase II breast cancer chemoprevention trial of the third generation selective estrogen receptor modulator arzoxifene. Proc Am Soc Clin Oncol 2006;24. Abstract 1001.
104. Burke TW, Walker CL. Arzoxifene as therapy for endometrial cancer. Gynecol Oncol 2003;90:S40-S46.
105. McMeekin DS, Gordon A, Fowler J, et al. A phase II trial of arzoxifene, a selective estrogen response modulator, in patients with recurrent or advanced endometrial cancer. Gynecol Oncol 2003;90:64-69.
106. US National Institute of Health, National Library of Medicine. Effects of arzoxifene on bone mass and the uterus. Available at: http://www. clinicaltrials.gov/ct2/show/NCT00085956. Accessed April 8, 2008.
107. US National Institute of Health, National Library of Medicine. Effects of arzoxifene on bone fractures and incidence of breast cancer. ClinicalTrials.gov [online]. Available at: http://www.clinicaltrials.gov/ct/show/NCT00088010. Accessed April 8, 2008.
108. Deshmane V, Krishnamurthy S, Melemed AS, Peterson P, Buzdar AU. Phase III double-blind trial of arzoxifene compared with tamoxifen for locally advanced or metastatic breast cancer. J Clin Oncol 2007;25: 4967-4973.
109. Munster PN. Arzoxifene: the development and clinical outcome of an ideal SERM. Expert Opin Investig Drugs 2006;15:317-326.
110. Eli Lilly & Company. Lilly reports on outcome of phase III study of arzoxifene. Based on preliminary phase III GJAD study results, Lilly concludes arzoxifene's clinical profile does not support regulatory submission [press release]. Available at: http://news.prnewswire.com/ViewContent.aspx?ACCT= 109&STORY=/www/story/08-18-2009/0005079632&EDATE=. Accessed August 20, 2009.