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Clinical use of selective estrogen receptor modulators
Bone Vol. 25, No. 1 July 1999:115–118
Clinical Use of Selective Estrogen Receptor Modulators P. D. DELMAS INSERM Research Unit 403 and Claude Bernard University of Lyon, Lyon, France
a major advance for the management of postmenopausal women. There are several synthetic compounds, most of them nonsteroidal, that have both estrogen agonist and estrogen antagonist activities in vitro and in animal models. They can be classified as triphenylethylenes (tamoxifen, toremifene, droloxifene, and idoxifene), chroman (levormeloxifene) benzothiophenes (raloxifene and LY 35 3381), and others. We will only review the clinical effects of newly developed SERMs on major tissue targets, with reference to the effects of tamoxifene.
Introduction The concept of selective estrogen receptor modulators (SERMs) is derived from the observation that tamoxifen, an effective adjuvant therapy of breast cancer that has an antiestrogenic effect on breast tissue, has estrogen-like effects on the skeleton and on lipoproteins. Thus, an estrogen-like compound that binds with high affinity to the estrogen receptor (ER) could have either estrogen agonist or antagonist activity according to the type of estrogen-responsive tissue. Although the molecular basis for tissue-specific actions of SERMs is not yet fully understood, recent advances in the field of ER biology has led to new insights in their mechanism of action. The ER ligand-binding domain has been recently cristallized and its structure has been studied without bound ligand and, after binding to either 17b estradiol or to raloxifene,1 a SERM that has undergone extensive clinical investigation. Although both compounds bind the same site of the ER, raloxifene induces conformational changes of surrounding sites that differ from those induced by 17b estradiol, resulting in an inability of the activating function-2 (AF-2) to activate the ER element-driven gene transcription.1 The recent discovery of a second ER isoform, ERb, that has a tissue distribution distinct from ER probably also contributes to the tissue specificity of SERM’s action2,3 as well as the potential role of tissue-specific transcription factors interacting with the ER-ligand complex.4 Finally, there might be gene-specific pathways for ER-mediated gene transcription that do not depend upon the classical estrogen receptor element (ERE) sequence.5 The clinical interest in SERMs is linked to the limitations of hormone replacement therapy (HRT). Long-term HRT is associated with an increase in bone mineral density and a decrease in skeletal fragility,6 and with an improvement of the plasma lipoprotein profile that may result in a reduced incidence of coronary heart disease, although this is still controversial.7 The long-term compliance to HRT, however, is limited by side effects such as uterine bleeding and by the fear of breast cancer, the risk of which appears to increase after prolonged treatment. Although tamoxifen has an excellent benefit/risk ratio as an adjuvant treatment of breast cancer, its use in healthy postmenopausal women is questionable because of its associated increased risk of endometrial cancer. A SERM that would have an estrogen agonist activity on the skeleton and the cardiovascular system, without having some of the undesirable estrogen actions on tissues such as the endometrium and the breast, would represent
Effects of SERMs on the Skeleton Tamoxifen has a protective effect on bone in postmenopausal women.8 In women with breast cancer who were on average 10 years postmenopausal, tamoxifen 20 mg/day prevented bone loss at the lumbar spine over 2 years, while the rate of bone loss at the radius was not different from the placebo group.9 In younger women who had menopause induced from chemotherapy for breast cancer, we found that tamoxifen only halved the rate of bone loss at the spine and hip, contrasting with no bone loss in those receiving a new bisphosphonate (risedronate) with or without tamoxifen.10 These data suggest that tamoxifen acts as a partial estrogen agonist on bone. Its effects on osteoporotic fractures are not adequately documented. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 Study, involving over 13,000 women with increased risk of breast cancer randomized to tamoxifen or placebo for up to 5 years, there was a nonsignificant decrease of hip, vertebral and wrist Colle’s fractures.11 Because the population was not selected on the basis of a low bone mineral density (BMD), the number of fracture events was quite low, and therefore the study was underpowered to show a reduction of osteoporotic fractures. Raloxifene is the first SERM to be available for prevention of osteoporosis in the U.S. and in several other countries. In a multicentric European study, 600 early postmenopausal women were randomized to raloxifene 30, 60, or 120 mg/day or to placebo.12 Raloxifene prevented bone loss at all skeletal sites and at all doses, with a 2.4% increase in BMD at the lumbar spine and total hip over placebo at 2 years, and 2% in the total body with the daily dose of 60 mg (Figure 1). Bone turnover decreased to premenopausal levels, with a reduction of the markers of bone formation serum osteocalcin and bone-specific alkaline phosphatase of 23% and 15%, respectively, and a reduction of 34% of the urinary excretion of type I collagen c-telopeptide (CTX), a sensitive index of bone resorption12 (Figure 2). The effect of raloxifene (60 and 120 mg/day) on fracture risk has been evaluated in a large placebo-controlled study (the MORE Study) including 7700 postmenopausal women with osteoporosis with or without vertebral fractures at baseline.13 All
Key Words: Osteoporosis; Breast cancer; Estrogen; Lipids Address for correspondence and reprints: Pierre D. Delmas, M.D., Ph.D., Hopital E. Herriot, Pavillon F, 69437 Lyon Cedex 03, Lyon, France. © 1999 by Elsevier Science Inc. All rights reserved.
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Figure 1. Median percentage change in serum total and LDL cholesterol concentrations, serum osteocalcin concentrations, and urinary type I collagen fragment C-telopeptide/creatinine in postmenopausal women treated with raloxifene or placebo for 2 years. Standard errors for median change were estimated using the d-delete jackknife method. Treatment: (•2•2•2) placebo, (- - - - -) 30 mg raloxifene, ( ) 60 mg raloxifene, (2 2 2) 150 mg raloxifene. Reproduced with permission from Delmas et al.12
patients were supplemented daily with calcium (500 mg) and vitamin D (400 iu). After 24 months, the incidence of new vertebral fractures defined by vertebral morphometry was twice as low in raloxifene-treated women than in women treated with placebo (RR 0.52, 0.43– 0.64) with a similar reduction in those with or without prevalent vertebral fractures. Overall, there was a lower incidence of fractures in the 120-mg raloxifene group than in the 60-mg group (3.3% vs. 4.6%, respectively, p , 0.03). The difference between doses was significant in women with, but
Figure 2. Mean percentage change in bone mineral density in postmenopausal women treated with raloxifene or placebo for 2 years. Treatment: (•2•2•2) placebo, (- - - - -) 30 mg raloxifene, ( ) 60 mg raloxifene, (2 2 2) 150 mg raloxifene. Reproduced with permission from Delmas 12 et al.
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not in women without, prevalent vertebral fractures. There was a 50% reduction in the occurrence of clinical vertebral fracture with raloxifene, contrasting with no significant decrease in the rate of any nonvertebral fracture. The increase in BMD at various skeletal sites and the reduction of bone turnover was of a magnitude comparable with that observed in the prevention study.12 The discrepancy between the modest increase in BMD and the substantial decrease in fracture rate raises the intriguing hypothesis that the antifracture efficacy of raloxifene (and possibly of other SERMs) may only be partly related to its effect on BMD. When the change in hip BMD during treatment is plotted against vertebral fracture incidence using a logistic regression model, it appears that fracture reduction is greater than predicted by changes in BMD. Interestingly, the same statistical modeling approach shows that fracture reduction is also related to decreased bone turnover assessed by changes in serum osteocalcium during treatment (unpublished data). The effects on bone turnover of two other SERMs, idoxifene and levormeloxifene, have been documented in large phase II studies. Idoxifene (4-iodopyrrolidinotamoxifen) induces a dosedependent decrease of bone markers that reaches, after 3 months of treatment with 10 mg, 25% and 22% for urinary and serum CTX, respectively, and 18% for serum osteocalcin.14 Levormeloxifene, the b-enanthiomer of racemic centchroman, induces a marked reduction of bone turnover at 3 and 12 months, even at the lowest dose tested. The minimum effective dose to reduce adequately bone turnover has not been established.15 Effects of SERMs on Lipoproteins and Cardiovascular Diseases Tamoxifen reduces the serum levels of total and LDL cholesterol,16 and may reduce the risk of coronary heart disease in postmenopausal women with breast cancer.17 In the NSABP P-1 Study, however, there was no difference between tamoxifeneand placebo-treated women in the incidence of myocardial infarction and of events related to ischemic heart disease regardless of age.11 There was a trend for an increase in the risk of stroke. In all osteoporosis prevention and treatment studies,12,13 raloxifene induced a dose-dependent decrease of serum total and LDL cholesterol (averaging 11% with 60 mg) without significant change in HDL cholesterol or triglycerides. In a 6-month randomized, placebo- and hormone replacement therapy (HRT)controlled trial with cardiovascular markers as a primary end point, raloxifene was also found to increase the HDL2 subfraction of cholesterol and to decrease plasma fibrinogen without significantly changing plasminogen activator inhibitor-1 (PAI-1) levels.18 A 3-month treatment with idoxifene, 10 mg/day, induced a significant decrease of serum total cholesterol (210%), LDL cholesterol (216%), plasma fibrinogen (222%), and factor VII (217%), a small decrease of lipoprotein (a) (212%) with no change of LDL cholesterol and triglycerides. Phase II data indicate that levormeloxifene might reduce markedly serum LDL cholesterol and plasma fibrinogene, but again at high doses that do not appear to have an adequate safety profile. Although the overall effect of SERMs on plasma lipoproteins is consistent with a beneficial effect, plasma lipids and coagulation factors are not reliable surrogate markers of cardiovascular disease. Experimental models of atherogenesis in monkeys and rabbits fed with a high-cholesterol diet suggest a protective effect of 17b estradiol and phytoestrogens against the development of the atherosclerotic plaque that is independent, at least in part, of their effects on plasma lipids.19 The effect of raloxifene in these models is controversial.20,21 The effects of various SERMs on in vitro models of vascular functions have also been studied with reference to 17b estradiol. Eventually, the potentially beneficial
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effects of SERMs will have to be documented in clinical trials with adequate clinical end points. The effects of raloxifene on coronary heart disease morbidity and mortality will be assessed in 10,000 postmenopausal women at increased risk of cardiovascular disease (Raloxifene Use in the Heart [RUTH] Study). Effects of SERMs on the Breast Tamoxifen is an effective adjuvant therapy in advanced breast cancer and in reducing tumor recurrence and prolonging survival when administered after surgery in stage I and II disease. It also reduces the incidence of controlateral breast cancer.22,23 Recently, the NSABP P-1 Study showed that tamoxifene given at 20 mg/day for 5 years reduces the risk of breast cancer by 49% in women considered to be at high risk because of their age (60 years or more), of a history of lobular carcinoma in situ, or because of combined clinical risk factors, including first-degree relatives with breast cancer, nulliparity, or age at first child birth, age of menarche, number of breast biopsies, and pathologic diagnosis of atypical hyperplasia. The reduction was more pronounced for women 60 years or older (255%) than 49 years or younger (244%) and was significant only for estrogen receptorpositive tumors (269%).11 Although two European studies were published that did not find such a reduction,24,25 probably for methodological reasons such as the size and type of population studied, the NSABP P-1 Trial clearly opens the way for primary prevention of breast cancer in high-risk patients with tamoxifene or eventually with another SERMs that would have the same antiproliferative effect on the breast with a better safety profile. The interim analysis of the safety data base of all placebocontrolled phase III studies conducted with raloxifene and included annual mammograms indicates that raloxifene decreases the risk of breast cancer in postmenopausal women.26 The analyses of integrated studies of over 10,000 women followed for up to 3.5 years showed a relative risk of 0.46 (95% confidence interval 0.28 – 0.75) in raloxifene-treated women, with a total number of 58 breast cancers. Seventy-five percent of cases occurred in osteoporotic women (in the MORE Study), and the magnitude of the reduction may not be the same in a population of women at high risk of breast cancer. A head-to-head comparison of raloxifene with tamoxifen for prevention of breast cancer (STAR Study) that will enroll 22,000 women has been announced. Effects of SERMs on the Uterus Tamoxifen increases the endometrial thickness evaluated by transvaginal ultrasonography (TVU)27 and significantly increases the risk of endometrial adenocarcinoma.28 In the NSABP Trial, the relative risk in tamoxifen users was 2.5, and reached 4 in women over the age of 50 years. Thus, a careful evaluation of new SERMs on the genital tract is critical to determine their safety profile. The overall analysis of all phase III trials of raloxifene shows no increase of endometrial thickness (but a small increase in the number of patients with endometrial cavity fluid) by TVU, no increased incidence of proliferative or hyperplastic endometrium on biopsies, and a nonsignificant decrease of the risk of endometrial cancer, although the total number of cases is still low. Clinically, there is no increase in vaginal bleeding and spotting with raloxifene compared with placebo.29 Thus, in contrast to tamoxifen, raloxifene has no estrogen agonist activity on the endometrium and its clinical use does not require a specific gynecologic surveillance. Phase II data obtained after 3 months of idoxifene show a dose-related increase in apparent endometrial thickness but without increased endometrial hyperplasia or cancer on histology. Clearly, uterine data obtained after
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longer treatment are necessary to understand the significance of the TVU observations and therefore the uterine safety of idoxifene. Levormeloxifene induces a marked increase in endometrial thickness and a significant increase of urinary incontinence and prolapsus that has led to the discontinuation of its clinical development. The effects of SERMs on the genital tract appear to differ significantly from one compound to the other and require extensive investigation. Overall Safety of SERMs Because of its size, the NSABP P-1 Trial provides useful information on the safety profile of tamoxifen.11 There was an age-related increase of deep veinous thrombosis (RR 1.60, 95% CI 0.91–2.86) and pulmonary embolism (RR 3.01, 95% CI 1.15–9.27). In addition to the increased risk of endometrial cancer, tamoxifen use was associated with a significant increase of vaginal discharge, of hot flushes, and, unexpectedly, of cataracts (RR 1.14) and of surgery for cataracts (RR 1.57). Conversely, there was no increased risk of colon, ovarian, and liver cancer, nor of mental depression. The safety profile of raloxifene is well documented in the MORE Study.13 The magnitude of the increased risk of venous thrombosis and pulmonary embolism (RR 3.0, 1.4 – 6.7) is of comparable magnitude with that observed with tamoxifen and with hormone replacement therapy, suggesting similar mechanisms. The risk appears to be highest in the first 6 months of therapy. This vascular event is quite uncommon in postmenopausal women, so that the absolute attributable risk under raloxifene is low, approximately 28 per 100,000 patientyears for all raloxifene studies. Other adverse events were uncommon and benign, and did not lead to treatment discontinuation, including flu syndrome (involving 2% more of patients on raloxifene 60 mg than on placebo), hot flushes (approximately 3.3% more on raloxifene), and leg cramps (an excess of less than 2% with raloxifene over placebo). Thus, data available today indicate a favorable safety profile of raloxifene with only one serious, but uncommon, side effect, i.e., venous thromboembolism, with a relative risk similar to that of hormone replacement therapy. Conclusion and Perspectives Raloxifene, the first of the second generation of SERMs to be widely available, represents a significant improvement over tamoxifen. It prevents postmenopausal bone loss and reduces the incidence of vertebral fractures and of new breast cancer cases in osteoporotic patients, without stimulating the endometrium. The extension of the MORE Study up to 5 years will tell whether or not raloxifene also decreases the incidence of nonvertebral fractures. In early postmenopausal women, raloxifene is not an alternative to hormone replacement in those that have severe hot flushes. It remains to be demonstrated if the decrease of LDL cholesterol and fibrinogen, two independent risk factors for coronary heart disease, results in a reduction of clinical events, a pattern that would extend markedly its clinical use if demonstrated in the ongoing RUTH Study. Because of the multiplicity of the potential target organs (i.e., all estrogen receptor responsive tissues), the development of long-term use of SERMs in postmenopausal women is challenging; of particular concern is the effect on cognitive functions, as hormone replacement therapy has been suggested to be associated with a reduced risk of Alzeimer disease,30 an intriguing hypothesis that awaits confirmation in prospective controlled studies. There are some preclinical data suggesting that raloxifene acts as an estrogen agonist on the brain, and it is reassuring that no deterioration of cognitive functions assessed by a battery of tests has been detected so far
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in the MORE Study, which includes a large number of elderly women. One fundamental question is to know if the doseresponse curve of new SERMs on the estrogen receptor is the same or differs in various estrogen-responsive tissues (in which it may act as an estrogen agonist or antagonist), as this will determine the choice of the dose providing the best benefit/risk profile. In conclusion, SERMs represent a new and promising class of agents for the management of postmenopausal women, with a scope that goes far beyond the prevention and treatment of osteoporosis. Finally, the recent observation that estrogens may play a crucial role in bone metabolism of men, and that SERMs prevent bone loss and induce prostatic atrophy in orchidectonized male rats,31 raises the possibility that they also may be of interest for the treatment of elderly men. References 1. Brzozowski, A. M., Pike, A. C. W., Dauter, Z., et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758; 1997. 2. Giguere, V., Tremblay, A., and Tremblay, G. B. Estrogen receptor b: reevaluation of estrogen and antiestrogen signaling. Steroids 63:335–339; 1998. 3. Paech, K., Webb, P., Kuiper, G. G. J. M., et al. Differential ligand activation of estrogen receptors ER alpha and ER beta at AP1 sites. Science 277:1508 –1510; 1997. 4. White, R. and Parker, M. G. Molecular mechanisms of steroid hormone action. Endocrine-Related Cancer 5:1–14; 1998. 5. Elgort, M. G., Zou, A., Marschke, K. B., et al. Estrogen and estrogen receptor antagonists stimulate transcription from the human retinoic acid receptor-a-1 promoter via a novel sequence. Mol Endocrinol 10:477– 487; 1996. 6. Delmas, P. D. Hormone replacement therapy in the prevention and treatment of osteoporosis. Osteoporosis Int 1(Suppl.):3–7; 1997. 7. Mulley, S., Grady, D., Bush, T., et al, for the Heart and Estrogen (Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progesting for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc 250:605– 613; 1998. 8. Turken, S., Siris, E., Seldin, D., et al. Effects of Tamoxifen on spinal bone density in women with breast cancer. J Natl Cancer Inst 81:1086 –1088; 1989. 9. Love, R. R., Mazess, R. B., Barden, H. S., et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852– 856; 1992. 10. Delmas, P. D., Balena, R., Confavreux, E., Hardouin, C., Hardy, P., and Bremond, A. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double blind placebo controlled study. J. Clin Oncol 15:955–962; 1997. 11. Fisher, B., Costantino, J. P., Wickerham, D. L., 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 90:1371–1388; 1998. 12. Delmas, P. D., Bjarnason, N. H., Mitlak, B. H., et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641–1647; 1997. 13. Ettinger, B., Black, D. M., Mitlak, B. M., et al. The effect of raloxifene on the risk of fracture in postmenopausal women with osteoporosis. (submitted). 14. Delmas, P. D., Garnero, P., and McDonald, B. Idoxifene reduces bone turnover in osteopenic postmenopausal women. Bone 23(Suppl.)494; 1998.
Bone Vol. 25, No. 1 July 1999:115–118 15. Bjarnason, K., Skrumsager, B. K., and Kiehr, B. Levormeloxifene, a new partial estrogen receptor agonist demonstrates antiresorptive and antiatherogenic properties in postmenopausal women (abstract). J Bone Miner Res 12(Suppl.):346; 1997. 16. Chang, J., Powles, T. J., Ashley, S. E., et al. The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study. Ann Oncol 7:671– 675; 1996. 17. McDonald, C. C., Alexander, F. E., Whyte, B. W., et al. Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. Br Med J 311:977– 980; 1995. 18. Wash, B. W., Kuller, L. H., Wild, R. A., et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. J Am Med Assoc 279:1445–1551; 1998. 19. Clarkson, T. B., Cline, J. M., Williams, J. K., and Anthony, M. S. Gonadal hormone substitutes: effects on the cardiovascular system. Osteoporosis Int 1(Suppl.)43–51; 1997. 20. Bjarnasson, N. H., Haarbo, J., Byrjalsen, I., Kauffman, R. F., and Christiansen, C. Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits. Circulation 96:1964 –1969; 1997. 21. Clarkson, T. B., Anthony, M. S., and Jerome, C. P. Lack of effect of Raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab 83:721–726; 1998. 22. Early Breast Cancer Trialist’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351:1451–1467; 1998. 23. Osborne, C. K. Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609 –1618; 1998. 24. Veronesi, U., Maisonneuve, P., Costa, A., et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomized trial among hysterectomized women. Italian Tamoxifen Prevention Study. Lancet 352:93– 97; 1998. 25. Powles, T., Eeles, R., Ashley, S., et al. Interim analysis of the incidence of breast cancer in Royal Marsden Hospital tamoxifen randomized chemoprevention trial. Lancet 352:98 –101; 1998. 26. Jordan, V. C., Glusman, J., Eckert, S., et al. Incident primary breast cancers are reduced by raloxifene: integrated data from multicenter, double-blind, randomized trials in 12,000 postmenopausal women (abstract). In: American Society of Clinical Oncology, 34th Annual Meeting, 1998, Los Angeles, CA. 446. 27. Kedar, R. P., Bourne, T. H., Powles, T. J., et al. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomized breast cancer prevention trial. Lancet 343:1318 –1321; 1994. 28. Sasco, A. J. Tamoxifen and menopausal status: risks and benefits. Lancet 347:761; 1996. 29. Cummings, S. R., Norton, I., Eckert, S., et al. Raloxifene reduces the risk of breast cancer and may decrease the risk of endometrial cancer in postmenopausal women. Two year findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. (Abstract). Proc Am Soc Clin Oncol 17:2(Abstr.); 1998. 30. Paganini-Hill, A. Does estrogen replacement therapy protect against alzheimer’s disease? Osteoporosis Int 1(Suppl.):512–517; 1997. 31. Ke, H. Z., Oi, H., Crawford, D. T., et al. A new selective estrogen receptor modulator (SERM), CP 336,156, preserves bone mass and bone strength, decreases total serum cholesterol without causing prostate hyperthrophy in a model of male osteoporosis. Bone 23(Suppl.):183; 1998.
Clinical Use of Selective Estrogen Receptor Modulators P. D. DELMAS INSERM Research Unit 403 and Claude Bernard University of Lyon, Lyon, France
a major advance for the management of postmenopausal women. There are several synthetic compounds, most of them nonsteroidal, that have both estrogen agonist and estrogen antagonist activities in vitro and in animal models. They can be classified as triphenylethylenes (tamoxifen, toremifene, droloxifene, and idoxifene), chroman (levormeloxifene) benzothiophenes (raloxifene and LY 35 3381), and others. We will only review the clinical effects of newly developed SERMs on major tissue targets, with reference to the effects of tamoxifene.
Introduction The concept of selective estrogen receptor modulators (SERMs) is derived from the observation that tamoxifen, an effective adjuvant therapy of breast cancer that has an antiestrogenic effect on breast tissue, has estrogen-like effects on the skeleton and on lipoproteins. Thus, an estrogen-like compound that binds with high affinity to the estrogen receptor (ER) could have either estrogen agonist or antagonist activity according to the type of estrogen-responsive tissue. Although the molecular basis for tissue-specific actions of SERMs is not yet fully understood, recent advances in the field of ER biology has led to new insights in their mechanism of action. The ER ligand-binding domain has been recently cristallized and its structure has been studied without bound ligand and, after binding to either 17b estradiol or to raloxifene,1 a SERM that has undergone extensive clinical investigation. Although both compounds bind the same site of the ER, raloxifene induces conformational changes of surrounding sites that differ from those induced by 17b estradiol, resulting in an inability of the activating function-2 (AF-2) to activate the ER element-driven gene transcription.1 The recent discovery of a second ER isoform, ERb, that has a tissue distribution distinct from ER probably also contributes to the tissue specificity of SERM’s action2,3 as well as the potential role of tissue-specific transcription factors interacting with the ER-ligand complex.4 Finally, there might be gene-specific pathways for ER-mediated gene transcription that do not depend upon the classical estrogen receptor element (ERE) sequence.5 The clinical interest in SERMs is linked to the limitations of hormone replacement therapy (HRT). Long-term HRT is associated with an increase in bone mineral density and a decrease in skeletal fragility,6 and with an improvement of the plasma lipoprotein profile that may result in a reduced incidence of coronary heart disease, although this is still controversial.7 The long-term compliance to HRT, however, is limited by side effects such as uterine bleeding and by the fear of breast cancer, the risk of which appears to increase after prolonged treatment. Although tamoxifen has an excellent benefit/risk ratio as an adjuvant treatment of breast cancer, its use in healthy postmenopausal women is questionable because of its associated increased risk of endometrial cancer. A SERM that would have an estrogen agonist activity on the skeleton and the cardiovascular system, without having some of the undesirable estrogen actions on tissues such as the endometrium and the breast, would represent
Effects of SERMs on the Skeleton Tamoxifen has a protective effect on bone in postmenopausal women.8 In women with breast cancer who were on average 10 years postmenopausal, tamoxifen 20 mg/day prevented bone loss at the lumbar spine over 2 years, while the rate of bone loss at the radius was not different from the placebo group.9 In younger women who had menopause induced from chemotherapy for breast cancer, we found that tamoxifen only halved the rate of bone loss at the spine and hip, contrasting with no bone loss in those receiving a new bisphosphonate (risedronate) with or without tamoxifen.10 These data suggest that tamoxifen acts as a partial estrogen agonist on bone. Its effects on osteoporotic fractures are not adequately documented. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 Study, involving over 13,000 women with increased risk of breast cancer randomized to tamoxifen or placebo for up to 5 years, there was a nonsignificant decrease of hip, vertebral and wrist Colle’s fractures.11 Because the population was not selected on the basis of a low bone mineral density (BMD), the number of fracture events was quite low, and therefore the study was underpowered to show a reduction of osteoporotic fractures. Raloxifene is the first SERM to be available for prevention of osteoporosis in the U.S. and in several other countries. In a multicentric European study, 600 early postmenopausal women were randomized to raloxifene 30, 60, or 120 mg/day or to placebo.12 Raloxifene prevented bone loss at all skeletal sites and at all doses, with a 2.4% increase in BMD at the lumbar spine and total hip over placebo at 2 years, and 2% in the total body with the daily dose of 60 mg (Figure 1). Bone turnover decreased to premenopausal levels, with a reduction of the markers of bone formation serum osteocalcin and bone-specific alkaline phosphatase of 23% and 15%, respectively, and a reduction of 34% of the urinary excretion of type I collagen c-telopeptide (CTX), a sensitive index of bone resorption12 (Figure 2). The effect of raloxifene (60 and 120 mg/day) on fracture risk has been evaluated in a large placebo-controlled study (the MORE Study) including 7700 postmenopausal women with osteoporosis with or without vertebral fractures at baseline.13 All
Key Words: Osteoporosis; Breast cancer; Estrogen; Lipids Address for correspondence and reprints: Pierre D. Delmas, M.D., Ph.D., Hopital E. Herriot, Pavillon F, 69437 Lyon Cedex 03, Lyon, France. © 1999 by Elsevier Science Inc. All rights reserved.
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Figure 1. Median percentage change in serum total and LDL cholesterol concentrations, serum osteocalcin concentrations, and urinary type I collagen fragment C-telopeptide/creatinine in postmenopausal women treated with raloxifene or placebo for 2 years. Standard errors for median change were estimated using the d-delete jackknife method. Treatment: (•2•2•2) placebo, (- - - - -) 30 mg raloxifene, ( ) 60 mg raloxifene, (2 2 2) 150 mg raloxifene. Reproduced with permission from Delmas et al.12
patients were supplemented daily with calcium (500 mg) and vitamin D (400 iu). After 24 months, the incidence of new vertebral fractures defined by vertebral morphometry was twice as low in raloxifene-treated women than in women treated with placebo (RR 0.52, 0.43– 0.64) with a similar reduction in those with or without prevalent vertebral fractures. Overall, there was a lower incidence of fractures in the 120-mg raloxifene group than in the 60-mg group (3.3% vs. 4.6%, respectively, p , 0.03). The difference between doses was significant in women with, but
Figure 2. Mean percentage change in bone mineral density in postmenopausal women treated with raloxifene or placebo for 2 years. Treatment: (•2•2•2) placebo, (- - - - -) 30 mg raloxifene, ( ) 60 mg raloxifene, (2 2 2) 150 mg raloxifene. Reproduced with permission from Delmas 12 et al.
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not in women without, prevalent vertebral fractures. There was a 50% reduction in the occurrence of clinical vertebral fracture with raloxifene, contrasting with no significant decrease in the rate of any nonvertebral fracture. The increase in BMD at various skeletal sites and the reduction of bone turnover was of a magnitude comparable with that observed in the prevention study.12 The discrepancy between the modest increase in BMD and the substantial decrease in fracture rate raises the intriguing hypothesis that the antifracture efficacy of raloxifene (and possibly of other SERMs) may only be partly related to its effect on BMD. When the change in hip BMD during treatment is plotted against vertebral fracture incidence using a logistic regression model, it appears that fracture reduction is greater than predicted by changes in BMD. Interestingly, the same statistical modeling approach shows that fracture reduction is also related to decreased bone turnover assessed by changes in serum osteocalcium during treatment (unpublished data). The effects on bone turnover of two other SERMs, idoxifene and levormeloxifene, have been documented in large phase II studies. Idoxifene (4-iodopyrrolidinotamoxifen) induces a dosedependent decrease of bone markers that reaches, after 3 months of treatment with 10 mg, 25% and 22% for urinary and serum CTX, respectively, and 18% for serum osteocalcin.14 Levormeloxifene, the b-enanthiomer of racemic centchroman, induces a marked reduction of bone turnover at 3 and 12 months, even at the lowest dose tested. The minimum effective dose to reduce adequately bone turnover has not been established.15 Effects of SERMs on Lipoproteins and Cardiovascular Diseases Tamoxifen reduces the serum levels of total and LDL cholesterol,16 and may reduce the risk of coronary heart disease in postmenopausal women with breast cancer.17 In the NSABP P-1 Study, however, there was no difference between tamoxifeneand placebo-treated women in the incidence of myocardial infarction and of events related to ischemic heart disease regardless of age.11 There was a trend for an increase in the risk of stroke. In all osteoporosis prevention and treatment studies,12,13 raloxifene induced a dose-dependent decrease of serum total and LDL cholesterol (averaging 11% with 60 mg) without significant change in HDL cholesterol or triglycerides. In a 6-month randomized, placebo- and hormone replacement therapy (HRT)controlled trial with cardiovascular markers as a primary end point, raloxifene was also found to increase the HDL2 subfraction of cholesterol and to decrease plasma fibrinogen without significantly changing plasminogen activator inhibitor-1 (PAI-1) levels.18 A 3-month treatment with idoxifene, 10 mg/day, induced a significant decrease of serum total cholesterol (210%), LDL cholesterol (216%), plasma fibrinogen (222%), and factor VII (217%), a small decrease of lipoprotein (a) (212%) with no change of LDL cholesterol and triglycerides. Phase II data indicate that levormeloxifene might reduce markedly serum LDL cholesterol and plasma fibrinogene, but again at high doses that do not appear to have an adequate safety profile. Although the overall effect of SERMs on plasma lipoproteins is consistent with a beneficial effect, plasma lipids and coagulation factors are not reliable surrogate markers of cardiovascular disease. Experimental models of atherogenesis in monkeys and rabbits fed with a high-cholesterol diet suggest a protective effect of 17b estradiol and phytoestrogens against the development of the atherosclerotic plaque that is independent, at least in part, of their effects on plasma lipids.19 The effect of raloxifene in these models is controversial.20,21 The effects of various SERMs on in vitro models of vascular functions have also been studied with reference to 17b estradiol. Eventually, the potentially beneficial
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effects of SERMs will have to be documented in clinical trials with adequate clinical end points. The effects of raloxifene on coronary heart disease morbidity and mortality will be assessed in 10,000 postmenopausal women at increased risk of cardiovascular disease (Raloxifene Use in the Heart [RUTH] Study). Effects of SERMs on the Breast Tamoxifen is an effective adjuvant therapy in advanced breast cancer and in reducing tumor recurrence and prolonging survival when administered after surgery in stage I and II disease. It also reduces the incidence of controlateral breast cancer.22,23 Recently, the NSABP P-1 Study showed that tamoxifene given at 20 mg/day for 5 years reduces the risk of breast cancer by 49% in women considered to be at high risk because of their age (60 years or more), of a history of lobular carcinoma in situ, or because of combined clinical risk factors, including first-degree relatives with breast cancer, nulliparity, or age at first child birth, age of menarche, number of breast biopsies, and pathologic diagnosis of atypical hyperplasia. The reduction was more pronounced for women 60 years or older (255%) than 49 years or younger (244%) and was significant only for estrogen receptorpositive tumors (269%).11 Although two European studies were published that did not find such a reduction,24,25 probably for methodological reasons such as the size and type of population studied, the NSABP P-1 Trial clearly opens the way for primary prevention of breast cancer in high-risk patients with tamoxifene or eventually with another SERMs that would have the same antiproliferative effect on the breast with a better safety profile. The interim analysis of the safety data base of all placebocontrolled phase III studies conducted with raloxifene and included annual mammograms indicates that raloxifene decreases the risk of breast cancer in postmenopausal women.26 The analyses of integrated studies of over 10,000 women followed for up to 3.5 years showed a relative risk of 0.46 (95% confidence interval 0.28 – 0.75) in raloxifene-treated women, with a total number of 58 breast cancers. Seventy-five percent of cases occurred in osteoporotic women (in the MORE Study), and the magnitude of the reduction may not be the same in a population of women at high risk of breast cancer. A head-to-head comparison of raloxifene with tamoxifen for prevention of breast cancer (STAR Study) that will enroll 22,000 women has been announced. Effects of SERMs on the Uterus Tamoxifen increases the endometrial thickness evaluated by transvaginal ultrasonography (TVU)27 and significantly increases the risk of endometrial adenocarcinoma.28 In the NSABP Trial, the relative risk in tamoxifen users was 2.5, and reached 4 in women over the age of 50 years. Thus, a careful evaluation of new SERMs on the genital tract is critical to determine their safety profile. The overall analysis of all phase III trials of raloxifene shows no increase of endometrial thickness (but a small increase in the number of patients with endometrial cavity fluid) by TVU, no increased incidence of proliferative or hyperplastic endometrium on biopsies, and a nonsignificant decrease of the risk of endometrial cancer, although the total number of cases is still low. Clinically, there is no increase in vaginal bleeding and spotting with raloxifene compared with placebo.29 Thus, in contrast to tamoxifen, raloxifene has no estrogen agonist activity on the endometrium and its clinical use does not require a specific gynecologic surveillance. Phase II data obtained after 3 months of idoxifene show a dose-related increase in apparent endometrial thickness but without increased endometrial hyperplasia or cancer on histology. Clearly, uterine data obtained after
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longer treatment are necessary to understand the significance of the TVU observations and therefore the uterine safety of idoxifene. Levormeloxifene induces a marked increase in endometrial thickness and a significant increase of urinary incontinence and prolapsus that has led to the discontinuation of its clinical development. The effects of SERMs on the genital tract appear to differ significantly from one compound to the other and require extensive investigation. Overall Safety of SERMs Because of its size, the NSABP P-1 Trial provides useful information on the safety profile of tamoxifen.11 There was an age-related increase of deep veinous thrombosis (RR 1.60, 95% CI 0.91–2.86) and pulmonary embolism (RR 3.01, 95% CI 1.15–9.27). In addition to the increased risk of endometrial cancer, tamoxifen use was associated with a significant increase of vaginal discharge, of hot flushes, and, unexpectedly, of cataracts (RR 1.14) and of surgery for cataracts (RR 1.57). Conversely, there was no increased risk of colon, ovarian, and liver cancer, nor of mental depression. The safety profile of raloxifene is well documented in the MORE Study.13 The magnitude of the increased risk of venous thrombosis and pulmonary embolism (RR 3.0, 1.4 – 6.7) is of comparable magnitude with that observed with tamoxifen and with hormone replacement therapy, suggesting similar mechanisms. The risk appears to be highest in the first 6 months of therapy. This vascular event is quite uncommon in postmenopausal women, so that the absolute attributable risk under raloxifene is low, approximately 28 per 100,000 patientyears for all raloxifene studies. Other adverse events were uncommon and benign, and did not lead to treatment discontinuation, including flu syndrome (involving 2% more of patients on raloxifene 60 mg than on placebo), hot flushes (approximately 3.3% more on raloxifene), and leg cramps (an excess of less than 2% with raloxifene over placebo). Thus, data available today indicate a favorable safety profile of raloxifene with only one serious, but uncommon, side effect, i.e., venous thromboembolism, with a relative risk similar to that of hormone replacement therapy. Conclusion and Perspectives Raloxifene, the first of the second generation of SERMs to be widely available, represents a significant improvement over tamoxifen. It prevents postmenopausal bone loss and reduces the incidence of vertebral fractures and of new breast cancer cases in osteoporotic patients, without stimulating the endometrium. The extension of the MORE Study up to 5 years will tell whether or not raloxifene also decreases the incidence of nonvertebral fractures. In early postmenopausal women, raloxifene is not an alternative to hormone replacement in those that have severe hot flushes. It remains to be demonstrated if the decrease of LDL cholesterol and fibrinogen, two independent risk factors for coronary heart disease, results in a reduction of clinical events, a pattern that would extend markedly its clinical use if demonstrated in the ongoing RUTH Study. Because of the multiplicity of the potential target organs (i.e., all estrogen receptor responsive tissues), the development of long-term use of SERMs in postmenopausal women is challenging; of particular concern is the effect on cognitive functions, as hormone replacement therapy has been suggested to be associated with a reduced risk of Alzeimer disease,30 an intriguing hypothesis that awaits confirmation in prospective controlled studies. There are some preclinical data suggesting that raloxifene acts as an estrogen agonist on the brain, and it is reassuring that no deterioration of cognitive functions assessed by a battery of tests has been detected so far
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in the MORE Study, which includes a large number of elderly women. One fundamental question is to know if the doseresponse curve of new SERMs on the estrogen receptor is the same or differs in various estrogen-responsive tissues (in which it may act as an estrogen agonist or antagonist), as this will determine the choice of the dose providing the best benefit/risk profile. In conclusion, SERMs represent a new and promising class of agents for the management of postmenopausal women, with a scope that goes far beyond the prevention and treatment of osteoporosis. Finally, the recent observation that estrogens may play a crucial role in bone metabolism of men, and that SERMs prevent bone loss and induce prostatic atrophy in orchidectonized male rats,31 raises the possibility that they also may be of interest for the treatment of elderly men. References 1. Brzozowski, A. M., Pike, A. C. W., Dauter, Z., et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758; 1997. 2. Giguere, V., Tremblay, A., and Tremblay, G. B. Estrogen receptor b: reevaluation of estrogen and antiestrogen signaling. Steroids 63:335–339; 1998. 3. Paech, K., Webb, P., Kuiper, G. G. J. M., et al. Differential ligand activation of estrogen receptors ER alpha and ER beta at AP1 sites. Science 277:1508 –1510; 1997. 4. White, R. and Parker, M. G. Molecular mechanisms of steroid hormone action. Endocrine-Related Cancer 5:1–14; 1998. 5. Elgort, M. G., Zou, A., Marschke, K. B., et al. Estrogen and estrogen receptor antagonists stimulate transcription from the human retinoic acid receptor-a-1 promoter via a novel sequence. Mol Endocrinol 10:477– 487; 1996. 6. Delmas, P. D. Hormone replacement therapy in the prevention and treatment of osteoporosis. Osteoporosis Int 1(Suppl.):3–7; 1997. 7. Mulley, S., Grady, D., Bush, T., et al, for the Heart and Estrogen (Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progesting for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc 250:605– 613; 1998. 8. Turken, S., Siris, E., Seldin, D., et al. Effects of Tamoxifen on spinal bone density in women with breast cancer. J Natl Cancer Inst 81:1086 –1088; 1989. 9. Love, R. R., Mazess, R. B., Barden, H. S., et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852– 856; 1992. 10. Delmas, P. D., Balena, R., Confavreux, E., Hardouin, C., Hardy, P., and Bremond, A. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double blind placebo controlled study. J. Clin Oncol 15:955–962; 1997. 11. Fisher, B., Costantino, J. P., Wickerham, D. L., 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 90:1371–1388; 1998. 12. Delmas, P. D., Bjarnason, N. H., Mitlak, B. H., et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641–1647; 1997. 13. Ettinger, B., Black, D. M., Mitlak, B. M., et al. The effect of raloxifene on the risk of fracture in postmenopausal women with osteoporosis. (submitted). 14. Delmas, P. D., Garnero, P., and McDonald, B. Idoxifene reduces bone turnover in osteopenic postmenopausal women. Bone 23(Suppl.)494; 1998.
Bone Vol. 25, No. 1 July 1999:115–118 15. Bjarnason, K., Skrumsager, B. K., and Kiehr, B. Levormeloxifene, a new partial estrogen receptor agonist demonstrates antiresorptive and antiatherogenic properties in postmenopausal women (abstract). J Bone Miner Res 12(Suppl.):346; 1997. 16. Chang, J., Powles, T. J., Ashley, S. E., et al. The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study. Ann Oncol 7:671– 675; 1996. 17. McDonald, C. C., Alexander, F. E., Whyte, B. W., et al. Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. Br Med J 311:977– 980; 1995. 18. Wash, B. W., Kuller, L. H., Wild, R. A., et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. J Am Med Assoc 279:1445–1551; 1998. 19. Clarkson, T. B., Cline, J. M., Williams, J. K., and Anthony, M. S. Gonadal hormone substitutes: effects on the cardiovascular system. Osteoporosis Int 1(Suppl.)43–51; 1997. 20. Bjarnasson, N. H., Haarbo, J., Byrjalsen, I., Kauffman, R. F., and Christiansen, C. Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits. Circulation 96:1964 –1969; 1997. 21. Clarkson, T. B., Anthony, M. S., and Jerome, C. P. Lack of effect of Raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab 83:721–726; 1998. 22. Early Breast Cancer Trialist’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351:1451–1467; 1998. 23. Osborne, C. K. Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609 –1618; 1998. 24. Veronesi, U., Maisonneuve, P., Costa, A., et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomized trial among hysterectomized women. Italian Tamoxifen Prevention Study. Lancet 352:93– 97; 1998. 25. Powles, T., Eeles, R., Ashley, S., et al. Interim analysis of the incidence of breast cancer in Royal Marsden Hospital tamoxifen randomized chemoprevention trial. Lancet 352:98 –101; 1998. 26. Jordan, V. C., Glusman, J., Eckert, S., et al. Incident primary breast cancers are reduced by raloxifene: integrated data from multicenter, double-blind, randomized trials in 12,000 postmenopausal women (abstract). In: American Society of Clinical Oncology, 34th Annual Meeting, 1998, Los Angeles, CA. 446. 27. Kedar, R. P., Bourne, T. H., Powles, T. J., et al. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomized breast cancer prevention trial. Lancet 343:1318 –1321; 1994. 28. Sasco, A. J. Tamoxifen and menopausal status: risks and benefits. Lancet 347:761; 1996. 29. Cummings, S. R., Norton, I., Eckert, S., et al. Raloxifene reduces the risk of breast cancer and may decrease the risk of endometrial cancer in postmenopausal women. Two year findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. (Abstract). Proc Am Soc Clin Oncol 17:2(Abstr.); 1998. 30. Paganini-Hill, A. Does estrogen replacement therapy protect against alzheimer’s disease? Osteoporosis Int 1(Suppl.):512–517; 1997. 31. Ke, H. Z., Oi, H., Crawford, D. T., et al. A new selective estrogen receptor modulator (SERM), CP 336,156, preserves bone mass and bone strength, decreases total serum cholesterol without causing prostate hyperthrophy in a model of male osteoporosis. Bone 23(Suppl.):183; 1998.