Chapter 15
Raloxifene: A Selective Estrogen Receptor Modulator (SERM)
Jeffrey A. Dodge,
Henry U. Bryant,
Jeffrey A. Dodge
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
Search for more papers by this authorHenry U. Bryant
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
Search for more papers by this authorJeffrey A. Dodge,
Henry U. Bryant,
Jeffrey A. Dodge
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
Search for more papers by this authorHenry U. Bryant
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
Search for more papers by this authorBook Editor(s):Xianhai Huang, Robert G. Aslanian,
Summary
This chapter contains sections titled:
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Introduction: SERMs
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The Benzothiophene Scaffold: A New Class of SERMs
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Assays for Biological Evaluation of Tissue Selectivity
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Benzothiophene Structure Activity
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The Synthesis of Raloxifene
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SERM Mechanism
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Raloxifene Pharmacology
-
Summary
-
References
REFERENCES
- KALU, D., SALERNO, E., LIU, C. C., ECHON, R., RAY, M., GAZA-ZEPATA, M., and HOLLIS, B.W. A comparative study of the actions of tamoxifen, estrogen and progesterone in the ovariectomized rat. Bone Miner. 1991, 15, 109–124.
- BRYANT, H. U., BLACK, L. J., ROWLEY, E. R., MAGEE, D. M., WILLIAMS, D. C., CULLINAN, G. J., KAUFFMAN, R. F., and SATO, M. Raloxifene (LY139481 HCl): bone, lipid and uterine effects in the ovariectomized rat model. J. Bone Mineral Res. 1993, 8 (suppl 1), S123.
- DRAPER, M. W., FLOWERS, D. E., HUSTER, W. J., and NEILD, J. A. Effects of raloxifene (LY139481 HCl) on biochemical markers of bone and lipid metabolism in healthy postmenopausal women. Proc. Fourth Int. Symp. Osteopor. 1993, 119–121.
- FELDMAN, S., MINNE, H. W., PARVIZI, S., PFEIFER, M., LEMPERT, U. G., BAUSS, F., and ZIEGLER, R. Antiestrogen and antiandrogen administration reduce bone mass in the rat. Bone Miner 1989, 7, 245–254.
- BLACK, L. J. and GOODE, R. L., Uterine bioassay of trioxifene, tamoxifen, and a new estrogen antagonist (LY117018) in rats and mice. Life Sci. 1980, 26, 1453.
- BLACK, L. J., JONES, C. D., and GOODE, R. L. Differential actions of antiestrogens with cytosol estrogen receptors. Mol. Cell. Endo. 1981, 22, 95.
- JONES, C. D., JEVNIKAR, M. G., PIKE, J., PETERS, M. K., BLACK, L. J., THOMPSON, A. R., FALCONE, J. F., and CLEMENS, J. A. Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl) benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl] methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity. J. Med Chem, 1984, 27, 1057.
- BLACK, L. J., ROWLEY, E., BEKELE, A., SATO, M., MAGEE, D. E., WILLIAMS, D. C., CULLINAN, G. J., BENDELE, R., KAUFFMAN, R. F., BENSCH, W., FROLIK, C. A., TERMINE, J. D., and BRYANT, H. U. Raloxifene (LY139482 HCl) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J. Clin. Invest. 1994, 93, 63–69.
- GRESE, T.A., SLUKA, J. P., BRYANT, H.U., CULLINAN, G.C., GLASEBROOK, A.L., JONES, C.D., MATSUMOTO, K., PALKOWITZ, A. D., SATO, M., TERMINE, J. D., WINTER, M. A., YANG, N.N., andDODGE, J. A. Molecular determinants of tissue selectivity in estrogen receptor modulators. Proc. Natl. Acad. Sci. 1997, 94, 14105–14110.
- BRZOZOWSKI, A. M., PIKE, A. C., DAUTER, Z., HUBBARD, R. E., BONN, T., ENGSTROM, O., OHMAN, L., GREEN, G. L., and GUSTAFSSON, J. A. Molecular basis of agonism and antagonism in the estrogen receptor. Nature 1997, 389, 753–768.
- (a) GRESE, T. A., CHO, S., FINLEY, D.R., GODFREY, A.G., JONES, C.D., LUGAR, C. W., MARTIN, M.J., MATSUMOTO, K., PENNINGTON, L.D., WINTER, M. A., ADRIAN, M.D., COLE, H. W., MAGEE D. E., PHILLIPS, D.L., ROWLEY, E.R., SHORT, L. L., GLASEBROOK, A.L., and BRYANT, H.U. Structure- activity relationships of selective-estrogen receptor modulators: modifications to the 2-arylbenzothiophene core of raloxifene. J. Med. Chem. 1997, 40, 146–167; (b) OBATA, T., and KUBOTA, S. Protective effect of tamoxifen on 1-methyl-4-phenylpyridine-induced hydroxyl radical generation in the rat striatum. Neurosci. Lett. 2001, 308, 87–90.
- (a) SHIAU, K., BARSTAD, D., LORIA, P. M., CHENG, L., KUSHNER, P. J., AGARD, A., and GREENE, G. L. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998, 95, 927–937; (b) SUN, J., MEYERS, M. J., FINK, B., RAJENDRAN, R., KATZENELLENBOGEN, J. A., and KATZENELLENBOGEN, B. S. Novelligands that function as selective estrogens or antiestrogens for estrogen receptor-α or estrogen receptor-β. Endocrinology 1999, 140, 800–804.
- DAI, S. Y., CHALMERS, M. J., BRUNING, J., BRAMLETT, K. S., OSBORNE, H. E., MONTROSE-RAFIZADEH, C., BARR, R. J., WANG, Y., WANG, M., BURRIS, T. P., DODGE, J. A., and GRIFFIN, P. R. Prediction of tissue-specificity of selective estrogen receptor modulators by using a single biochemical method. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 7171.
- (a) DAI, S. Y., BURRIS, T.P., DODGE, J. A., MONTROSERAFIZADEH, C., WANG, Y., CHALMERS, M. J., and GRIFFIN, P. R. Unique ligand binding patterns between estrogen receptor alpha and beta revealed by hydrogen-deuterium exchange. Biochemistry, 2009, 48, 9668; (b) HE, L., XIANG, H., LU-YONG, Z., WEI-SHENG, T., and HONG, H. H. Novel estrogen receptor ligands and their structure activity relationship evaluated by scintillation proximity assay for high throughput screening. Drug Discov. Res. 2005, 64, 203–212.
- GRESE, T.A., PENNINGTON, L. D., SLUKA, J. P., ADRIAN, M. D., COLE, H.W., FUSON, T.R., MAGEE, D.E., PHILLIPS, D. L., ROWLEY, E. R., SHETLER, P.K., SHORT, L. L., VENUGOPALAN, M., YANG, N.N., SATO, M., GLASEBROOK, A. L., and BRYANT, H. U. Synthesis and pharmacology of Conformationally Restricted Raloxifene Analogues: Highly Potent Selective Estrogen Receptor Modulators. J. Med. Chem. 1998, 41, 1272–1283.
- WALLACE, O. B., BRYANT, H. U., SHETLER, P.K., ADRIAN, M. D., and GEISER, A. G. Benzothiophene and naphthalene derived constrained SERMs. Bioorg. Med. Chem. Lett. 2004, 14, 5103.
- WALLACE, O.B., LAUWERS, K. S., DODGE, J. A., MAY, S. A., CALVIN, J.R., HINKLIN, R., BRYANT, H. U., SHETLER, P. K., ADRIAN, M.D., GEISER, A.G., SATO, M., andBURRIS, T. P. A selective estrogen receptor modulator for the treatment of hot flushes. J. Med. Chem. 2006, 49, 843–846.
- DODGE, J. A., BRYANT, H. U., GRESE, T. A., WANG, Y., SATO, M., and BURRIS, T. B. Pharmacological characterization, SAR, and X-ray crystal structure of an estrogen receptor alpha selective SERM. 227th ACS National Meeting, 2004, abstract MEDI-219.
- PALKOWITZ, A. L., GLASEBROOK, A. L., THRASHER, K. J., HAUSER, K. L., SHORT, L. L., PHILLIPS, D. L., MUEHL, B. S., SATO, M., SHETLER, P. K., CULLINAN, G. J., ZENG, G. Q., PELL, T. R., and BRYANT, H. U. Discovery and synthesis of 6-hydroxy-3-[4-(1-piperidinyl)-ethoxy-phenoxy]-2-(4-hydroxyphenyl)benzo[b]-thiophene: A novel, highly potent selective estrogen receptor modulator (SERM). J. Med. Chem. 1997, 40, 1407–1416.
- HUMMEL, C. W., GEISER, A. G., BRYANT, H. U., COHEN, I. R., DALLY, R. D., FONG, K. C., FRANK, S. A., HINKLIN, R., JONES, S. A., LEWIS, G., MCCANN, D. J., RUDMANN, D. G., SHEPHERD, T.A.TIAN, H., WALLACE, O. B., WANG, M., WANG, Y., and DODGE, J. A. A selective estrogen receptor modulator designed for the treatment of uterine leiomyoma with unique tissue specificity for uterus and ovaries in rats. J. Med. Chem. 2005, 48, 6772–6775.
- GEISER, A. G., HUMMEL, C. W., DRAPER, M. D., HENCK, J. W., COHEN, I. R., RUDMANN, D. G., DONNELLY, K. B., ADRIAN, M. D., SHEPHERD, T. A., WALLACE, O. B., MCCANN, D. J., OLDHAM, S. W., BRYANT, H. U., SATO, M., and DODGE, J. A. A new selective estrogen receptor modulator (SERM) with potent uterine antagonist activity, agonist activity in bone, and minimal ovarian stimulation. Endocrinology 2005, 146: 4524–4535.
- PIÑEIRO-NÚÑEZ, M. Raloxifene, Evista: A Selective Estrogen Receptor Modulator (SERM), in Modern Drug Synthesis (eds J. J. Li and D. S. Johnson), John Wiley & Sons, Inc., Hoboken, NJ. 2010, doi: Slc.
- NILSSON, S., MAKELA, S., TREUTER, E., TUJAGUE, M., THOMSEN, J., ANDERSSON, G., ENMARK, E., PETTERSSON, K., WARNER, M., and GUSTAFSSON, J. A. Mechanisms of estrogen action. Physiol. Rev. 2001, 81, 1535–1565.
- SIMONCINI, T., and GENAZZANI, A. R. Raloxifene acutely stimulates nitric oxide release from human endothelial cells via an activation of endothelial nitric oxide synthase. J. Clin. Endocrinol. Metab. 2000, 85, 2966–2969.
- MCDONNEL, D. P., CLEMM, D. L., HERMANN, T., GOLDMAN, M. E., and PIKE, J. W. Analysis of estrogen receptor function in vitro reveals three distinct classes of anti-estrogens. Mol. Endocrinol. 1995, 9, 659–669.
- (a) JORDAN, V., COLLINS, M. M., ROWSBY, L., and PRESTWICH, G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J. Endocrinol. 1977, 75, 305–316; (b) FURR, B. J. and JORDAN, V. C. The pharmacology and clinical uses of tamoxifen. Pharmacol. Ther. 1984, 25, 127–205.
- KUIPER, G. J. M., ENMARK, E., PELTO-HUIKKO, M., NILSSON, S., and GUSTAFSSON, J. A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. 1996, 93, 5925–5930.
- (a) SAUNDERS, P. T., MAGUIRE, S. M., GAUGHAN, J., and MILLAR, M. R. Expression of oestrogen receptor beta (ER beta) in multiple rat tissues visualised by immunohistochemistry. J. Endocrinol. 1997, 154, R13–R16; (b) DE BOER, T., OTJENS, D., MUNTENDAM, A., MEULMAN, E., VAN OOSTIJEN, M., and ENSING, K. Development and validation of fluorescent receptor assays based on the human recombinant estrogen receptor subtypes alpha and beta. J. Pharmaceutic. Biomed. Anal. 2004, 34, 671–679.
- REY, J. M., PUJOL, P., DECHAUD, H., EDOUARD, E., HEDON, B., and MAUDELONDE T. Expression of oestrogen receptor-alpha splicing variants and oestrogen receptor-beta in endometrium of intertile patients. Mol. Human Repro. 2002, 4, 641–647.
- MCINERNEY, E. M., ROSE, D. W., FLYNN, S. E., WESTIN, S. E., MULLEN, T. M., KRONES, A., INOSTROZA, J., TORCHIA, J., NOLTE, R. T., ASSA-MUNT, N., MILBURN, M.V., GLASS, C. K., and ROSENFELD, M. G. Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. Genes Dev. 1998, 12, 3357–68.
- ONATE, S. A., TSAI, S. Y., TSAI, M.-J., and O'MALLEY, B. W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995, 270, 1354–1357.
- CHEN, H., LIN, R. J., SCHILTZ, R. L., CHANKRAVARTI, D., NASH, A., PRIVALSKY, M. L., NAKATANI, Y., and EVANS, R. M. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 1997, 90, 569–80.
- VOEGEL, J.J., HEINE, M. J., ZECHEL, C., CHAMBON, P., and GRONEMEYER, H. TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J. 1996, 15, 3667–75.
- LANZ, R. B., MCKENNA, N.J., ONATE, S. A., ALBRECHT, U., WONG, J., TSAI, S. Y., TSAI, M.-J., and O'MALLEY, B.W. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 1999, 97, 17–27.
- SMITH, C. L., NAWAZ, Z., and O'MALLEY, B.W. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol. Endocrinol. 1997, 11, 657–66.
- MONTANO, M. M., EKENA, K., DELAGE-MOURROUX, R., CHANG, W., MARTINI, P., and KATZENELLENBOGEN, B.S. An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. Proc. Natl. Acad. Sci. 1999, 96, 6947–52.
- XU, J., LIAO, L., NING, G., YOSHIDA-KOMIYA, H., DENG, C., and O'MALLEY, B. W. The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc. Natl. Acad. Sci. 2000, 97, 6379–6384.
- SMITH, C. L., DEVERA, D. G., LAMB, D. J., ZAFAR, N., YONG-HIU, J., BEAUDET, A. L., and O'MALLEY, B.W. Genetic ablation of the steroid receptor co-activator ubiquitin ligase, E6-AP, results in tissue selective steroid hormone resistance and defects in reproduction. Mol. Cell. Biol. 2002, 22, 525–535.
- BAUTISTA, S., VALLES, H., WALKER, R. L., ANZICK, S., ZELLINGER, R., MELTZER, P., and THEILLET, C. In breast cancer, amplification of the steroid receptor coactivator gene AIB1 is correlated with estrogen and progesterone receptor positivity. Clin. Cancer Res. 1998, 4, 2925–9.
- SHANG, Y. and BROWN, M. Molecular determinants for the tissue specificity of SERMs. Science 2002, 295, 2465–2468.
- KLEIN-HITPASS, L., SCHORPP, M., WAGNER, U., and RYFFEL, G. U. An estrogen-responsive element derived from the 5′ flanking region of the Xenopus vitellogenin A2 gene functions in transfected human cells. Cell 1986, 46, 1053–61.
- VANACKER, J., PETTERSSON, K., GUSTAFSSON, J. A., and LADET, V. Transcriptional targets shared by ERRs and ER alpha but not ER beta. EMBO J 1999, 18, 4270–4279.
- (a) YANG, N. N., HARDIKAR, S., SATO, M., GALVIN, R. J. S., GLASEBROOK, A. L., BRYANT, H. U., and TERMINE, J.D. Estrogen and raloxifene stimulate transforming growth Factor-β3 expression in rat bone: a potential mechanism for estrogen or raloxifene-mediated bone maintenance. Endocrinology 1996, 137, 2075–2084; (b) YANG, N. N., VENUGOPALAN, M., HARDIKAR, S., and GLASEBROOK, A.L. Identification of an estrogen response element activated by a metabolite of 17β-estradiol and raloxifene. Science 1996, 273, 1222–1225.
- TURNER, C. H., SATO, M., and BRYANT, H. U. Raloxifene preserves bone strength and bone mass in ovariectomized rats. Endocrinology 1994, 135, 2001–2005.
- CANO, A., DAPIA, S., NOGUERA, I., PINEDA, B., HERMENEGILDO, C., DEL VAL, R., CAEIRO, J. R., and GARCIA-PEREZ, M. A. Comparative effects of 17β-estradiol, raloxifene and genistein on bone 3D microarchitecture and volumetric bone mineral density in the ovariectomized mice. Osteoporos. Int. 2008, 19, 793–800.
- BASHIR, A., MAK, Y.T., SANKARALINGAM, S., CHEUNG, J., MCGOWAN, N. W. A., GRIGORIADIS, A. E., FOGELMAN, I., and HAMPSON, G. Changes in RANKL/OPG/RANK gene expression in peripheral mononuclear cells following treatment with estrogen or raloxifene. Steroids 2005, 70, 847–855.
- VIERECK, V., GRUNDKER, C., BLASCHKE, S., NIEDERKLEINE, B., SIGGELKOW, H., FROSCK, K.-H., RADDATZ, D., EMONS, G., and HOFBAUER, L. C. Raloxifene concurrently stimulates osteoprotogerin and inhibits interleukin-6 production by human trabecular osteoblasts. J. Clin. Endocrinol. Metab. 2003, 88, 4206–4213.
- MIYAURA, C., ONOE, Y., INADA, M., MAKI, K., IKUTA, K., ITO, M., and SUDA, T. Increased B-lymphopoeisis by interleukin-7 induces bone loss in mice with intact ovarian function: similarity to estrogen deficiency. Proc. Natl. Acad. Sci. 1997, 94, 9360–9365.
- FROLIK, C. A., BRYANT, H. U., BLACK, E. C., MAGEE, D. E., and CHANDRASEKHAR, S. Time dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: Effects of raloxifene HCI, tamoxifen, estrogen and alendronate. Bone 1996, 18, 621–627.
- EVANS, G., BRYANT, H., MAGEE, D., SATO, M., and TURNER, R. T. The effects of raloxifene on tibia histomorphometry in ovariectomized rats. Endocrinology 1994, 134, 2283–2288.
- (a) HELVERING, L. M., ADRIAN, M. D., GEISER, A. G., ESTREM, S. T., WEI, T., HUANG, S., CHEN, P., DOW, E. R., CALLEY, J. N., DODGE, J. A., GRESE, T. A., JONES, S. A., HALLADAY, D. L., MILES, R. R., ONYIA, J. E., MA, Y.L., SATO, M., and BRYANT, H. U. Differential effects of estrogen and raloxifene on messenger RNA and matrix metalloproteinase 2 activity in the rat uterus. Biol. Reproduct. 2005, 72, 830–841; (b) HELVERING, L. M., LIU, R., KULKARNI, N. H., WEI, T., CHEN, P., HUANG, S., LAWRENCE, F., HALLADAY, D. L., MILES, R. R., AMBROSE, E. M., SATO, M., MA, Y. L., FROLIK, C. A., DOW, E. R., BRYANT, H. U., and ONYIA, J. E. Expression profiling of rat femur revealed suppression of bone formation genes by treatment with alendronate and estrogen but not raloxifene. Mol. Pharmacol. 2005, 68, 1225–1238.
- SATO, M., BRYANT, H. U., IVERSEN, P., HELTERBRAND, J., SMIETANA, F., BEMIS, K., HIGGS, R., TURNER, C., OWAN, I., TAKANO, Y., and BURR D. B. Advantages of raloxifene over alendronate or estrogen on non-reproductive and reproductive tissues in the long-term dosing of ovariectomized rats. J. Pharmacol. Exp. Ther. 1996, 279, 298–305.
- ETTINGER, B., BLACK, D. M., MITLAK, B. M., KNICKERBOCKER, R. K., NICKELSEN, T., GENANT, H. K., CHRISTIANSEN, C., DELMAS, P. D., ZANCHETTA, J. R., STAKKESTAD, J., GLUER, C. C., KRUEGER, K., COHEN, F. J., ECKERT, S., ENSRUD, K. E., AVIOLI, L. V., LIPS, P., and CUMMINGS, S. R. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. J. Am. Med. Assoc. 1999, 282, 637–645.
- HEANY, R. P. and DRAPER, M. W. Raloxifene and estrogen: Comparative bone-remodelling kinetics. J. Clin. Endocrinol. Metab. 1997, 8, 3425–3429.
- OTT, S. M., OLEKSIK, A., LU, Y., HARPER, K. D., and LIPS, P. Bone histomorphometric and biochemical marker results of a two year placebo controlled trial of raloxifene in postmenopausal women. J. Bone Miner. Res. 2002, 17, 341–348.
- WEINSTEIN, R. S., PARFITT, A. M., MARCUS, R., GREENWALD, M., CRANS, G., and MUCHMORE, D. B. Effects of raloxifene, hormone replacement therapy, and placebo on bone turnover in postmenopausal women. Osteoporos Intl. 2003, 14, 814–822.
- JOHNELL, O., SCHEELE, W. M., LU, Y., REGINSTER, J.-Y., NEED, A. G., and SEEMAN, E. Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J. Clin. Endocrinol. Metab. 2002, 87, 985–002.
- ALLEN, M. R., IWATA, K., SATO, M., and BURR, D. B. Raloxifene enhances vertebral mechanical properties independent of bone density. Bone 2006, 39, 1130–1135.
- LI, J., SATO, M., JEROME, C., TURNER, C. H., FAN, Z., and BURR, D. B. Microdamage accumulation in the monkey vertebrae does not occur when bone turnover is suppressed by 50% or less with estrogen or raloxifene. J. Bone Miner. Res. 2005, 23, 48–54.
- UUSI-RASI, K., BECK, T. J., SEMANICK, L. M., DAPHTARY, M. M., CRANS, G. G., DESAIAH, D., and HARPER, K.D. Structural effects of raloxifene on the proximal femur: results from the multiple outcomes of raloxifene evaluation trial. Osteoporosis Intl. 2006, 17, 575–586.
- KANIS, J. A., JOHNELL, O., BLACK, D. M., DOWNS, R.W. JR., SARKAR, S., FUERST, T., SECREST, R. J., and PAVO, I. Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial. Bone 2003, 33, 293–300.
- DELMAS, P. D., GENANT, H. K., CRANS, G. G., STOCK, J. L., WONG, M., SIRIS, E., and ADACHI, J. C. Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone 2003, 33, 522–532.
- SAKAMOTO, T., EGUCHI, H., OMOTO, Y., AYABE, T., MORI, H., and HAYASHI, S. Estrogen receptor-mediated effects of tamoxifen on human endometrial cancer cells. Mol. Cell Endocrinol. 2002, 192, 93–104.
- KODA, M., JARZABEK, K., HACZYNSKI, J., KNAPP, P., SULKOWSKI, S., and WOCZYNSKI, S. Differential effects of raloxifene and tamoxifen on the expression of estrogen receptors and antigen Ki-67 in human endometrial adenocarcinoma cell line. Oncology Rep. 2004, 12, 517–521.
- BRAMLETT, K. S. and BURRIS. T. P. Target specificity of selective estrogen receptor modulators within human endometrial cancer cells. Steroid Biochem. Mol. Biol. 2003, 86, 27–34.
- LEES, C. J., REGISTER, T. C., TURNER, C., H. WANG, T., STANCILL, M., and JEROME, C. P. Effects of raloxifene on bone density, biomarkers, and histomorphometric and biomechanical measures in ovariectomized cynomolgus monkeys. Menopause. 2002, 9, 320–328.
- ADRIAN, M. D., COLE, H. W., SHETLER, P. K., ROWLEY, E. R., MAGEE, D. E., PELL, T., ZENG, G., SATO, M., and BRYANT, H. U. Comparative pharmacology of a series of selective estrogen receptor modulators. J. Bone Mineral Res. 1996, 11 (Suppl. 1), S447.
- SILFEN, S. L., CIACCIA, A. V., and BRYANT, H. U. Selective estrogen receptor modulators: tissue specificity and differential uterine effects. Climacteric 1999, 2, 268–283.
- FUCHS-YOUNG, R., MAGEE, D., COLE, H. W., SHORT, L., GLASEBROOK, A. L., RIPPY, M. K., TERMINE, J. D., and BRYANT, H. U. Raloxifene is a tissues specific anti-estrogen that blocks tamoxifen or estrogen stimulated uterotropic effects. Endocrinology 1995, 136 (Suppl), 57.
- WAKELING, A. E. and VALCACCIA, B. Antiestrogenic and antitumor activities of a series of non-steroidal antiestrogens. J. Endocrinol. 1987, 99, 455–464.
- Writing Group for Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. J. Am. Med. Assoc. 2002, 288, 321–333.
- (a) STEFANICK, M. L., ANDERSON, G. L., MARGOLIS, K. L., HENDRIZ, S. L., RODABOUGH, R. J., PASKETT, E. D., LANE, D. S., HUBBELL, F. A., ASSAF, A. R., SARTO, G. E., SCHENKEN, R. S., YASMEEN, S., LESSIN, L., and SHLEBOWSKI, R.T. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. J. Am. Med. Assoc. 2006, 295, 1647–1657; (b) LEBLANC, K., SEXTON, E., PARENT, S., BELANGER, G., DERY, M.-C., BOUCEHR, V., and ASSELIN, E. Effects of 4-hydroxytamoxifen, raloxifene and ICI-182, 780 on survival of uterine cancer cell lines in the presence and absence of exogenous estrogens. Intl. J. Oncol. 2007, 30, 477–487; (c) BOYD, N. F., BYNG, J. W., JONG, R. A., FISHELL, E. K., LITTLE, L. E., MILLER, A. B., LOCKWOOD, G. A., TRITCHLER, D. L., and YAFFE, M. J. Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J. Natl. Cancer Inst. 1995, 87, 670–675.
- MARTINO, S., CAULEY, J. A., BARRETT-CONNOR, E., POWLES, T. J., MERSHON, J., DISCH, D., SECREST, R. J., and CUMMINGS, S. R. 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.
- VOGEL, V. G., COSTANTINO, J. P., WICKERHAM, D. L., CRONIN, W. M., CECCHINI, R. S., ATKINS, J. N., BEVERS, T. B., FEHRENBACHER, L., PAJON, E. R., WADE, J. L., ROBIDOUX, A., MARGOLESE, R. G., JAMES, J., LIPPMAN, S. M., RUNOWICZ, C. D., GANZ, P. A., REIS, S. E., MCCASKILL-STEVENS, W., FORD, L. G., JORDAN, V.C., and WOLMARK, N. 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. J. Am. Med. Assoc. 2006, 295, 2727–2741.
- BARRETT-CONNOR, E., MOSCA, L., COLLINS, P., GEIGER, M. J., GRADY, D., KORNITZER, M., MCNABB, M., and WENGER, N. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N. Engl. J. Med. 2006, 335, 125–137.
- REINDOLLAR, R., KOLTUN, W., PARSONS, A., ROSEN, A., SIDDHANTI, S., and PLOUFFE, L. Effects of oral raloxifene on serum estradiol levels and other markers of estrogenicity. Fertil. Steril. 2002, 78, 469–472.
- MANDLEKAR, S. and KONG, A. N. Mechanisms of tamoxifen-induced apoptosis. Apoptosis 2001, 6, 469–477.
- DIEL, P., OLFF, S., SCHMIDT, S., and MICHNA, H. Effects of the environmental estrogens bisphenol A, o, p′-DDT, ptert-octylphenol and coumestrol on apoptosis induction, cell proliferation and the expression of estrogen sensitive molecular parameters in the human breast cancer cell line MCF-7. J. Steroid Biochem. Mol. Biol. 2002, 80, 61–70.
- HOUVINEN, R., WARRI, A., and COLLAN, Y. Mitotic activity, apoptosis and TRPM-2 mRNA expression in DMBA-induced rat mammary carcinoma treated with anitestrogen toremifene. Intl. J. Cancer 1993, 55, 685–691.
- FITZPATRICK, L. A. and SANTEN, R. J. Hot flashes: the old and the new, what is really true? Mayo. Clin. Proc. 2002, 77, 1155–1158.
- BARNABEI, V. M., COCHRANE, B. B., ARAGAKI, A. K., NYGAARD, I.WILLIAMS, R. S., MCGOVERN, P.G., YOUNG, R. L., WELLS, E. C., O'SULLIVAN, M. J., CHEN, B., SCHENKEN, R., and JOHNSON, S. R. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet. Gynecol. 2005, 105, 1063–1073.
- COHEN, F.J. and LU, Y. M. Characterization of hot flashes reported by healthy postmenopausal women receiving raloxifene or placebo during osteoporosis prevention trials. Maturitas 2000, 34, 65–73.
- DAVIES, G. C., HUSTER, W. J., LU, Y., PLOUFFE, L., and LAKSHMANAN, M. Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet. Gynecol. 1999, 93, 558–565.
- HERINGA, M. Review on raloxifene: profile of a selective estrogen receptor modulator. Int. J. Clin. Pharmacol. Ther. 2003, 41, 331–345.
- SNYDER, K. R., SPARANO, N., MALINOWKSI, and J. M. Raloxifene hydrochloride. Am. J. Health Sys. Pharmacy. 2000, 57, 1669–1678.
- KNADLER, M. P., LANTZ, R. J., and GILLESPIE, T.A. The disposition and metabolism of 14C-labelled raloxifene in humans. Pharm. Res. 1995, 12 (suppl), 372.