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Clinical Research and Regional Bone Centers, Helen Hayes Hospital, New York State Department of Health, West Haverstraw, New York 10993
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Abstract |
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 Top Abstract I. IntroductionII. Breast EffectsIII. Reproductive System EffectsIV. Skeletal Effects: Bone...V. Vascular System Effects:...VI. Central Nervous System...VII. Hepatic EffectsVIII. Miscellaneous EffectsIX. ConclusionReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. Breast EffectsIII. Reproductive System EffectsIV. Skeletal Effects: Bone...V. Vascular System Effects:...VI. Central Nervous System...VII. Hepatic EffectsVIII. Miscellaneous EffectsIX. ConclusionReferences |
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The majority of data concerning long-term outcomes of exogenous estrogen administration are based on epidemiological observations where estrogen users are compared with nonusers either in prospective cohorts or in retrospective case/control studies. Not all confounders can be identified and controlled for in studies of this design. The recent publication of results from the Heart and Estrogen/Progestin Replacement Study [HERS (11)], a controlled clinical trial of continuous combined hormone replacement therapy (HRT) in patients with established heart disease, showing an increase in cardiovascular events in the first year and only a modest effect on cardiovascular outcomes thereafter, highlights the difficulty in drawing conclusions from epidemiological data (12, 13). The results of this major clinical trial also questioned whether symptomatic fracture occurrence is reduced with estrogen use, but this study was designed and powered to examine cardiac end points, not fracture end points. Furthermore, spinal deformity was not assessed radiographically.
Even if the majority of the benefits documented by observational data concerning estrogen replacement therapy or HRT are true, several meta-analyses have also shown an increase in the risk of breast cancer, particularly after long-term estrogen treatment (14, 15). Therefore, the use of estrogens is often restricted to a small group of women and is often used for insufficient time to provide significant positive effects on chronic disease outcomes. Long-term compliance is often estimated to be no more than 15–40% (16). The fear of breast cancer is so profound that many women mistakenly view it as the most common cause of death among women (17). In addition, the stimulatory action of estrogen on the uterine endometrium, although easily controlled with progestins, also remains an issue, since for many regimens, regular vaginal bleeding is necessary to protect the endometrium. Furthermore, the risk of uterine cancer may be increased with some hormone replacement regimens even when progestins are given (18, 19). The increased risk of deep venous thrombosis (11, 20, 21, 22), breast tenderness, and engorgement, increased risk of gallbladder disease, as well as the perception that hormone replacement is associated with weight gain, are other reasons that limit long-term use of this therapy.
Agents that can maintain the benefits of estrogens but avoid the risks
are therefore needed to provide additional choices for women who are at
increased risk of diseases associated with chronic estrogen deficiency
or those who are interested in using medication for overall health
maintenance after menopause. Medications in the class now called
Selective Estrogen Receptor Modulators (SERMS) or estrogen analogs,
previously called ‘antiestrogens’ (Fig. 1
), hold thispromise. A large body of
research in animal models beginning in the l960s suggested that these
compounds could have partial estrogenic activity in some tissues while
inhibiting mammary tumor growth. The historical perspective and the
interplay between animal experiments and clinical investigation are
reviewed by Jordan and Morrow in an accompanying article in this
journal. Some of these agents act as antagonists in human reproductive
tissues, but partial agonists on the skeletal system and on serum
lipoproteins. They might, therefore, be alternatives for prevention of
osteoporosis, particularly in women with an increased risk of breast or
uterine cancer, or in those women who are not willing to take estrogen
because of the fear of breast or uterine cancer. Each agent has its own
unique spectrum of activities, with qualitative and quantitative
variability in its agonist and antagonist properties at different
target tissues. A discussion of the mechanisms of variable actions of
these estrogen analogs is beyond the scope of this review but clearly,
mechanisms involve differential binding to different estrogen receptor
subtypes, different conformations produced with each agent when bound
to the estrogen receptor, availability of different coactivator and
corepressor proteins in different tissues, as well as differential
binding of these proteins to different estrogen analog-receptor
complexes.
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Other estrogen analogs are also in clinical development. One triphenylethylene tamoxifen derivative, droloxifene, is in Phase III trial for osteoporosis prevention and treatment. Both idoxifene and levormeloxifene were in clinical development for osteoporosis, but programs were aborted, apparently because of adverse uterine effects. Two agents that were previously thought to be purely antiestrogenic, ICI 164,384 and 182,780, are analogs of 17ß-estradiol with a long alkylamine side chain, which are being tested for breast cancer treatment potential. Recent studies indicate that both of these agents have some tissue-selective estrogenic activity, on nonreproductive estrogen target tissues.
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II. Breast Effects |
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TopAbstractI. IntroductionII. Breast EffectsIII. Reproductive System EffectsIV. Skeletal Effects: Bone...V. Vascular System Effects:...VI. Central Nervous System...VII. Hepatic EffectsVIII. Miscellaneous EffectsIX. ConclusionReferences |
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Tamoxifen has been shown conclusively in an abundance of clinical trials to decrease the risk of recurrent breast cancer, contralateral breast cancer, and death, and increase disease-free survival in patients with breast cancer at multiple stages of the disease (26, 27, 28, 29), including small primary, node-negative disease as well as metastatic disease.
A. Women with primary breast cancer without metastases
Overall, of more than 37,000 women with operable breast cancer in
55 randomized clinical trials of adjuvant tamoxifen therapy, after 10
yr of follow-up, annual breast cancer recurrence
was reduced by 26% and death by 14%
(27, 28). Recurrence and mortality data are shown separately for
node-negative and node-positive disease in Fig. 2. The benefit of
tamoxifen is greatest when administered for 5 yr, rather than for a
shorter duration (27, 28, 29); however, treatment for longer than 5 yr does
not appear to be more effective than 5 (30, 31).
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The benefits of tamoxifen on breast cancer occur in both premenopausal and postmenopausal women at all ages (27). Furthermore, when treating women with ER-positive tumors, the combination of tamoxifen with standard cytotoxic chemotherapy shows an advantage over cytotoxic chemotherapy alone in all age groups (27). What is somewhat less clear is whether combining standard chemotherapy with tamoxifen should be routinely recommended (26, 32, 33, 34, 35, 36, 37, 38, 39, 40). In general, it seems that for postmenopausal women with high-risk breast cancer, combination chemotherapy plus tamoxifen is warranted.
B. Women with metastatic disease
Tamoxifen is also beneficial to women with metastatic disease.
Overall, 30% of women with metastatic breast cancer responded to
tamoxifen for an average of 1 yr and, in an additional 20%, the
disease did not progress for 6 months. ER status is an important
prognostic indicator, and menopausal status may vary responsivity as
well, with postmenopausal women showing greater response rates than
premenopausal women (28, 41, 42, 43, 44).
Toremifene has also been shown to be effective in the treatment of advanced breast cancer, with overall treatment responses, including complete or partial remissions of 48–63% (45, 46, 47). Higher doses of toremifene appear more effective than lower doses (48). In a relatively large international trial of 648 women with metastatic breast cancer (previously untreated) randomly assigned to one of two toremifene doses vs. tamoxifen, there were no statistically significant differences in response rates or response durations among any of the treatment arms (49). Tamoxifen response rate was 19%, with median survival 32 months. Toremifene, 60 mg, resulted in a response rate of 21% with median survival 38 months. Toremifene, 200 mg, resulted in a 23% response rate with median survival of 30 months. All end points were superior in those patients with ER-positive tumors. These data support the use of toremifene as an alternative to tamoxifen for metastatic breast cancer.
Droloxifene has also been used in several small trials of women with metastatic breast cancer with variable success (50, 51, 52, 53, 54). The largest is a series of 369 women where three doses of droloxifene were compared (53). Response rates varied from 30–47%, without a clear dose-response relationship. Raloxifene, originally called Keoxifene, was also studied as an anti-breast cancer agent (54A ), but development for this indication was dropped when no superior effect of keoxifene over tamoxifen was found in tamoxifen-resistant breast cancer patients.
C. Breast cancer prevention
Because of the substantial effect of tamoxifen to reduce the
risk of contralateral breast cancer in women with primary breast cancer
(27, 28), investigations were initiated almost 10 yr ago to determine
whether tamoxifen could reduce the risk of breast cancer occurrence in
women at high risk. The largest of the three studies was the National
Cancer Institute (NCI) Breast Cancer Prevention Trial or National
Surgical Adjuvant Breast and Bowel (NSABP) P-1 Study (55). High risk
was considered age 60 or older (without additional risk factors),
between age 35–59 with a 5-yr predicted risk for breast cancer of at
least 1.66% [based on the Gail model for breast cancer risk (56)] or
a history of lobular carcinoma in situ. Of the 13,388 women
entered into the trial, approximately 40% were premenopausal and 96%
were Caucasian. Because of a dramatic overall breast cancer incidence
reduction of approximately 50%, the NCI Breast Cancer Prevention Trial
was terminated early, at just under 4 yr instead of the planned 5 yr
(55). The breast cancer reduction was for both invasive and noninvasive
types (Table 1) and occurred in both
premenopausal and postmenopausal women. For invasive breast cancer,
risk reduction was 44% in women under 49 yr of age and 55% for those
60 yr of age or older. For noninvasive breast cancer, reduction in
incidence was approximately 49% in the tamoxifen-treated group.
Reduction in breast cancer incidence was limited to those with
ER-positive tumors (see Section II). The annual rate
of ER-positive breast cancers was reduced by 69% in tamoxifen-treated
women, whereas there was no difference in the rate of appearance of
ER-negative tumors.
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26%). In contrast to the NCI investigation, in neither
of these studies was an overall difference in breast cancer incidence
found between the tamoxifen and placebo groups (57, 58). Differences
between the NCI study and the other studies may be related to
differences in the populations, including age (more younger women in
the British study) and genetic factors (more with positive family
history in British study), compliance, length of follow-up period, and
study power (57, 58, 59). Another breast cancer prevention trial, the
International Breast Cancer Intervention Trial, might help resolve some
of these issues (59). Raloxifene has been used in healthy women to test for efficacy in osteoporosis prevention and in women with osteoporosis to test for prevention of fracture. Although the main outcomes of these trials were maintenance of bone mass and osteoporotic fracture occurrence, breast cancer and uterine cancer were monitored for safety. The largest study is the MORE trial (Multiple Outcomes of Raloxifene Evaluation), involving 7,704 postmenopausal women up to age 80, mean age 66.5 yr, with osteoporosis defined by prevalent vertebral deformity and/or bone mass in the osteoporotic range at the spine or hip. Volunteers were randomly assigned to placebo or one of two doses of raloxifene. After 28.9 months median follow-up, overall breast cancer risk was reduced by 74%, with no significant difference between results from the two doses of raloxifene (60). If one looks at integrated risk of breast cancer from all of the raloxifene osteoporosis studies (prevention and treatment), which includes 14,800 patient-years cumulative exposure to raloxifene and 6,750 patient-years exposure to placebo, relative risk of breast cancer is reduced by 58% in raloxifene-treated volunteers (61). These studies suggest a preliminary conclusion that raloxifene produces a profound reduction in the risk of development of breast cancer in postmenopausal women who were not selected for high risk of this disease. Further confirmatory data are expected as safety monitoring from these osteoporosis studies continues. Furthermore, a large prevention study (STAR, Study of Tamoxifen and Raloxifene) in 22,000 postmenopausal women, comparing the effects of tamoxifen vs. raloxifene on prevention of breast cancer, has now been started. This study will confirm the efficacy of both drugs (using expected frequency of breast cancer from the literature, but no actual control group) and provide relative potency data in prevention of breast cancer, while also providing information on relative toxicities.
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III. Reproductive System Effects |
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TopAbstractI. IntroductionII. Breast EffectsIII. Reproductive System EffectsIV. Skeletal Effects: Bone...V. Vascular System Effects:...VI. Central Nervous System...VII. Hepatic EffectsVIII. Miscellaneous EffectsIX. ConclusionReferences |
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Rats treated with very high doses of raloxifene over 2 yr exhibited an increased incidence of benign ovarian tumors of the granulosa/theca cell type, but no increase in incidence of any ovarian cancer (72). In mice also, increased frequency of benign ovarian tumors was seen after 21 months of exposure to raloxifene. At the highest doses, malignant ovarian tumors were also seen in mice, but these were of the granulosa/theca cell type, not of epithelial origin (73, 74). Similar ovarian tumors in mice have been associated with the administration of both tamoxifen and toremifene (75, 76). These mouse malignancies were associated with substantial increments in LH, a hormonal change known to produce these tumors in the mouse. This LH surge does not occur in humans (see Section III.D below) and the mouse tumor cell type is extremely rare in humans. Furthermore, in women, there has been no increase in ovarian cancer frequency or in benign ovarian disease associated with use of raloxifene (77).
B. Uterus
Tamoxifen increases the risk of benign uterine disease, including
fibroid tumors, adenomyosis, and endometrial hyperplasia, as well as
uterine cancer (55, 66, 67, 68, 69, 70, 71, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88). In the breast cancer treatment
trial NSABP B-14 (68), tamoxifen increased the relative risk of
endometrial cancer up to 7.5. Importantly, however, there were no data
in this study to indicate that uterine tumors in women receiving
tamoxifen were of a higher malignancy grade than those in women
receiving no medication or on estrogen replacement therapy. In the
British breast cancer prevention study, a subgroup of the original
cohort of women (n = 111) was investigated for effects on the
uterus (83). Women receiving tamoxifen had a larger uterus and greater
uterine blood flow than those on placebo. Thirty-nine percent of women
on tamoxifen had tissue evidence of abnormal endometrium compared with
10% in the placebo group. In the tamoxifen-treated group, 16% of
women had atypical hyperplasia and an additional 8% had an endometrial
polyp. In the NCI Breast Cancer Prevention Study (55),
tamoxifen-treated women had a 2.53 times greater risk of developing
invasive endometrial cancer than placebo-treated women. In women aged
50 or older, the relative risk was higher at 4.01 (95% CI,
1.7–10.90). All endometrial tumors that developed in this study were
Stage I, localized tumors. Thus, as also shown in the NSABP B-14
treatment trial, there was no evidence to suggest that uterine tumors
were of higher malignancy grade or aggressiveness than tumors
associated with estrogen or no hormonal therapy (55). Studies suggest
that toremifene has stimulatory effects on the uterus similar to those
of tamoxifen (89).
One of the major distinctions between tamoxifen and raloxifene is the effect on the uterus. Unlike tamoxifen, raloxifene does not appear to stimulate uterine tissue (77, 90). There have been no reports of any increase in uterine or vaginal bleeding associated with raloxifene use (90). In a short-term (8 week) study, no change in endometrial tissue assessed by endometrial biopsies before and after treatment with raloxifene was documented (91). Furthermore, approximately 400 women had serial transvaginal ultrasonography over 2 yr in the multicenter European osteoporosis prevention study (90). There was no significant difference in endometrial thickness at any time during the study between raloxifene and placebo-treated patients. More importantly, preliminary analyses from the MORE study of raloxifene use in postmenopausal women with osteoporosis suggest that raloxifene might be associated with an actual reduction in the risk of uterine cancer (60). Relative risk of endometrial cancer in a 2-yr analysis of 7,704 women was 0.38 (P = 0.2). If two cases of endometrial cancer that were diagnosed within 1 month of entry into the investigation were excluded, relative risk was decreased to 0.13, P = 0.045.
Recently, clinical trials involving both levormeloxifene and idoxifene were discontinued due to effects on the uterus, particularly uterine prolapse.
C. Vagina
In the NCI Breast Cancer Prevention Trial (55), tamoxifen was
associated with an increase in the development of vaginal discharge
that was moderately bothersome (or worse) in 29% of the tamoxifen
group, in contrast to only 13% in the placebo group. In a small study
of postmenopausal women with breast cancer on tamoxifen compared with
healthy postmenopausal controls, vaginal pH was closer to premenopausal
levels in tamoxifen-treated women, and vaginal smears were well
estrogenized in most of the tamoxifen-treated women while all of the
controls showed atrophic changes (92).
Raloxifene was not associated with any vaginal complaints related to atrophic vaginitis or dyspareunia in a study of 619 postmenopausal women over a 3-yr period (93). In premenopausal women, however, raloxifene produced a reduction in the vaginal maturation index, suggesting a mild estrogen antagonist effect (94).
D. Neuroendocrine
Although clomiphene is effective at reducing fertility in rodents,
it actually increases fertility in humans and is currently used most
frequently as an ovulation inducer in women trying to conceive. This
fertility-enhancing effect appears to be mediated by
estrogen-antagonist effects on the neuroendocrine axis with a
subsequent stimulation of gonadotropin secretion (95). Tamoxifen was
first studied in rodent models as a possible postcoital contraceptive,
like clomiphene, but in women, was later found to induce ovulation.
Similarly to clomiphene, this agent exerts estrogen-antagonist effects
on the neuroendocrine axis in premenopausal women, and thereby boosts
gonadotropin production (96, 97, 98). In contrast, in postmenopausal women,
tamoxifen suppresses gonadotropin levels (96, 97, 99, 100, 101, 102, 103, 104, 105). Toremifene
also suppresses gonadotropin levels and increases sex hormone-binding
globulin levels slightly (106).
In both premenopausal and postmenopausal women, however, tamoxifen increases hot flashes (30, 107, 108, 109, 110, 111, 112). In the Breast Cancer Prevention Trial (55), hot flashes that were "quite a bit or extremely bothersome" occurred in 46% of women in the tamoxifen group and 29% of the placebo group. Similarly to tamoxifen, raloxifene increases the incidence of hot flashes (77, 90, 91). Of 1,165 postmenopausal women enrolled in osteoporosis prevention trials, 24.6% in the raloxifene group complained of hot flashes compared with 18.3% in the placebo group (77). In premenopausal women (94), similar to tamoxifen, raloxifene increases serum FSH levels slightly (30% increase for the 100 mg raloxifene group), but no significant changes in serum levels of LH were seen.
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IV. Skeletal Effects: Bone Mass, Bone Metabolism, and Fracture Occurrence |
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TopAbstractI. IntroductionII. Breast EffectsIII. Reproductive System EffectsIV. Skeletal Effects: Bone...V. Vascular System Effects:...VI. Central Nervous System...VII. Hepatic EffectsVIII. Miscellaneous EffectsIX. ConclusionReferences |
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A. Tamoxifen
1. Bone metabolism. Histomorphometric studies and bone
turnover assessments corroborate tamoxifen’s estrogen-like actions on
the skeleton in postmenopausal women (116, 117, 118, 119, 120, 121, 122). Bone biopsies were
obtained in 41 women with breast cancer, 22 of whom were treated with
tamoxifen for a mean of 33 months (minimum of 15 months) and 19
untreated controls (121). Tamoxifen reduced activation frequency of
remodeling by approximately 46% (but this difference was not
statistically significant). Tamoxifen reduced bone formation rate by
43% (P < 0.05)), and the remodeling period was
extended accordingly. Resorption cavity dimensions were also reduced in
tamoxifen-treated patients (all P < 0.03). In multiple
studies, tamoxifen has been shown to reduce biochemical indices of bone
turnover by 20–40%, with variability dependent upon the specific
assay and the duration of treatment (116, 117, 118, 119, 121, 122). Tamoxifen has
also been associated with a reduction in serum calcium (116, 119, 122),
serum phosphorus (116, 119, 123), and urinary calcium (119), in
addition to an increase in serum PTH (119, 122), although this is not
consistent across all studies (118, 121, 124).
2. Bone mass. Tamoxifen was initially expected to show negative effects on the skeleton because it was assumed that antiestrogen action would dominate there, just as it did in the breast. Early cross-sectional, retrospective, and finally prospective studies in patients with breast cancer given tamoxifen, however, did not demonstrate these negative effects, and in fact showed neutral or even positive effects on the skeleton (116, 117, 123, 125, 126, 127, 128, 129, 130, 131). Love et al. (118) subsequently studied 140 breast cancer patients randomized to receive tamoxifen vs. placebo for 2 yr. Lumbar spine mass in the tamoxifen-treated group increased significantly (0.61%/yr) compared with placebo losses (1%/year), and radius losses were steeper in placebo-treated vs. tamoxifen-treated patients. Five year follow-up data of 62 of these original subjects who were still on the no-tamoxifen or tamoxifen regimen to which they had been originally assigned was published subsequently (132). At the 5-yr point, bone mass of the lumbar spine was elevated by 0.8% above baseline in the tamoxifen group and reduced by 0.7% in the placebo group (group difference, P = 0.06).
Two prospective studies have also been performed in normal
postmenopausal women without history of breast cancer. In late
postmenopausal women (average time from menopause 11 yr, n
= 57), spine mass increased over 2 yr in tamoxifen-treated patients
(1.4% vs. loss of 0.7% in placebo group), but there was
only a minimal effect on total body bone mineral (group difference
0.5% at 2 yr) and no effect on hip bone mass (119). In the other
study, a subgroup of the British breast cancer prevention study (133),
bone loss occurred in premenopausal patients (n = 125) treated
with tamoxifen, but small bone gains occurred in the postmenopausal
group (n = 54) in both spine and hip (Fig. 3). These investigations demonstrated
that tamoxifen could exert a net antiestrogenic effect in the presence
of normal premenopausal estrogen levels but a net estrogenic effect
when estrogen levels are low as seen in postmenopausal women.
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The occurrence of symptomatic fracture of the spine, hip, nonspecific lower radius, and Colles’ fracture were recorded as primary end points in the Breast Cancer Prevention Trial (55). A total of 955 women experienced a fracture of any type, with 483 in the placebo group and 472 in the tamoxifen group, an inconsequential difference of 2.5%. When evaluating occurrence of the classic osteoporotic fractures (hip, wrist, and symptomatic spine only), 137 events occurred in the placebo group, compared with 111 events in the tamoxifen group (relative risk 0.81; 95% CI, 0.63–1.05). These fracture data do not include osteoporotic vertebral deformity incidence since routine spine radiographs were not performed in this study. More importantly, the data combine premenopausal and postmenopausal women. Since tamoxifen might be deleterious to bone in premenopausal women (133), to include the two groups together might underestimate any potential benefit to the skeleton of postmenopausal women. Estimates of the incidence of fracture relative to menopausal status can be gleaned from the breakdown of fracture occurrence by age less than or greater than 50. In those women less than 50 yr of age, 23 events occurred in the placebo group and 20 in the tamoxifen group (relative risk 0.88; 95% CI, 0.46–1.68), suggesting no beneficial or detrimental effect. In those women 50 yr of age or greater, 114 events occurred in the placebo group and 91 in the tamoxifen group (RR 0.79; 95% CI, 0.60–1.05). From the available published data, one has to assume that tamoxifen-treated patients had more fractures that were not labeled as symptomatic spine, hip, or wrist fractures, since the overall number of women having fractures was almost identical in the two groups (55). Hopefully, more data to resolve these questions about tamoxifen’s ability to reduce osteoporotic fracture will be available in the future, from the NCI trial, as well as from the British, Italian, and International Prevention trials still underway, and the recently initiated STAR study.
B. Raloxifene
1. Bone metabolism. In a short-term, 8-week preliminary trial
of raloxifene in 251 healthy, postmenopausal women, two doses of
raloxifene (200 mg and 600 mg/day) were tested against conjugated
estrogen (0.625 mg/day) and placebo (91). These doses of raloxifene
were higher than the doses used in subsequent studies but active
bioavailable raloxifene is limited by the enterohepatic circulation and
probably does not substantially exceed that seen with the 60 mg
raloxifene dose. In this study, bone turnover variables, including
serum alkaline phosphatase, serum osteocalcin, urine pyridinoline, and
urine hydroxyproline, were measured and reductions occurred for all
markers except urinary hydroxyproline. Furthermore, reductions were
similar to those seen with estrogen for all markers except osteocalcin
in the lower dose raloxifene group. Likewise, urinary calcium was
reduced similarly to reductions seen with estrogen.
Bone turnover changes were also monitored in the European multicenter osteoporosis prevention study of 601 normal postmenopausal women randomly assigned to receive 30, 60, or 150 mg raloxifene/day or placebo (90). After 24 months of treatment, median reductions of serum bone-specific alkaline phosphatase and serum osteocalcin (markers of bone formation), and urinary type I collagen C-telopeptide (a marker of bone resorption) were 23.1%, 15%, and 34%, respectively, in the 60 mg raloxifene group. Reductions were significant for all three markers at all raloxifene doses.
Raloxifene also decreased bone turnover in a small treatment study of 143 postmenopausal women with established osteoporosis. Subjects were investigated after 1 yr of therapy with raloxifene, 60 or 120 mg/day, compared with a calcium and vitamin D control group (135). Reductions for the 60-mg dose were of similar magnitude to those above (15% for serum bone alkaline phosphatase, 21% for serum osteocalcin, and 25% for urinary C-telopeptide).
In an ongoing study of 65 postmenopausal women randomized to receive raloxifene (60 or 120 mg/day) vs. placebo, bone biopsies were obtained before and after 2 yr of drug therapy. Results showed that bone quality was normal with both doses of raloxifene, with no evidence of osteomalacia, osteocyte damage, woven bone, marrow fibrosis, or other abnormality. Bone formation rate and activation frequency were reduced in both raloxifene groups (76A ). Another small histomorphometric study comparing the influence of 6 months of treatment with raloxifene, 60 mg/day, vs. conjugated estrogen, 0.625 mg/day, showed activation frequency and bone formation to be reduced in both groups, although reductions were slightly greater in the estrogen-treated patients (77).
Calcium metabolism studies have also compared raloxifene to estrogen in 33 early postmenopausal women (136). Both raloxifene and estrogen induced positive calcium balance changes at both 1 month and 7 month analyses. Urinary calcium declined in response to both medications, and calcium absorption efficiency improved marginally. At the early time point, remodeling change was the same for both agents, but at the 7-month point, remodeling suppression was greater for estrogen than for raloxifene. Calcium balance, however, was similar for both agents at both time points.
2. Bone mass. Raloxifene is being tested in both osteoporosis
prevention studies where bone mass is the major end point and in an
osteoporosis treatment study where fracture is the primary outcome.
There have been three large prevention studies, one in North America,
one in Europe, and one international study in women who had had a
hysterectomy, where raloxifene was compared with conjugated estrogen
(77). Data from a 2-yr interim analysis of the European study have now
been published (90). Healthy postmenopausal women (n = 601)
between the ages of 45 and 60, within 2–8 yr of menopause with lumbar
spine mass in the normal or low bone mass range, were recruited into
the trial. After baseline evaluation, patients were randomized to
receive one of three raloxifene doses (30, 60, or 150 mg/day) or
placebo. Bone density, bone turnover, and lipid biochemistry were
evaluated serially over 2 yr; 149 subjects (25%) dropped out of the
study, but there were no differences in discontinuation rates between
raloxifene and control groups. Bone mass increased at all measured
sites, including the lumbar spine, total hip, and total body, with all
raloxifene doses resulting in increments between 1 and 2%, compared
with losses in the placebo group of about 1% at each site (Fig. 4 and Ref. 90).
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3. Fracture occurrence. Raloxifene has been investigated as an osteoporosis treatment agent in a large trial of 7,705 women with osteoporosis defined by bone mass, with a subgroup of about 30% of the women also having prevalent osteoporotic vertebral deformity at study initiation. This study, entitled MORE (Multiple Outcomes of Raloxifene Evaluation), is being conducted over 180 sites in 25 countries. Subjects were randomized to receive either 60 or 120 mg raloxifene/day or placebo, in addition to 500 mg calcium and 400 IU vitamin D/day. Lateral spine radiographs were analyzed at 2 yr using a semiquantitative grading technique followed by quantitative morphometry to determine vertebral fracture incidence. Over the 2 yr, 5.5% of the participants had one or more vertebral fractures. Raloxifene treatment resulted in a reduction in relative risk for vertebral fracture of 44%, and an even larger reduction in risk (61%) was seen for the occurrence of multiple vertebral fractures (137). In contrast, there was no difference in the proportion of women reporting nonspine fractures in this 2-yr interim analysis (raloxifene group, 6.3%, vs. placebo, 6.8%).
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V. Vascular System Effects: Intermediate Markers and Disease Outcomes |
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TopAbstractI. IntroductionII. Breast EffectsIII. Reproductive System EffectsIV. Skeletal Effects: Bone...V. Vascular System Effects:...VI. Central Nervous System...VII. Hepatic EffectsVIII. Miscellaneous EffectsIX. ConclusionReferences |
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An extremely small (n = 8) prospective study in women with stable breast cancer showed similar effects on serum lipoproteins after only 3 months of tamoxifen treatment (139). In 140 postmenopausal women with breast cancer, Love et al. (140) showed mean reductions of 12% in total cholesterol and 20% in LDL cholesterol. In contrast to estrogen’s effect, high-density lipoprotein (HDL) cholesterol was not increased by tamoxifen, but actually decreased slightly in that study. Similarly to estrogen’s effect, serum triglycerides increased. Serum apolipoprotein A1 levels increased, while apolipoprotein B levels decreased. In a 5-yr follow-up of the same study, the total cholesterol and LDL cholesterol changes were still present, and in addition, reduction in serum lipoprotein (a) was also documented (141). In 153 women with breast cancer evaluated for tamoxifen-induced changes in serum lipoproteins from two separate adjuvant trials of tamoxifen, current postmenopausal users of tamoxifen had lower serum levels of total cholesterol, LDL cholesterol, and HDL cholesterol with higher serum triglyceride levels (127).
A more recent investigation, also in women with a diagnosis of breast cancer, that compared tamoxifen, 20 mg/day, with toremifene, 60 mg/day (142), after 1 yr of therapy, documented that both estrogen analogs reduced total and LDL cholesterol and apolipoprotein B levels. Furthermore, both tamoxifen and toremifene decreased serum levels of lipoprotein (a) (34% and 41%, respectively). Interestingly, in that study, although tamoxifen did not increase serum HDL level as shown previously, toremifene increased serum HDL levels by 14%.
In healthy postmenopausal women, tamoxifen reduced serum lipoprotein
(a) by 34% at 3 months (143). Furthermore, in 57 normal postmenopausal
women, tamoxifen reduced serum total cholesterol by 12% and LDL by
19% (144) during 2 yr of therapy. Serum HDL and HDL
subfractions and triglyceride and apolipoprotein A1 levels were not
significantly altered (Fig. 5 and Ref.
144). Lipoprotein changes induced by tamoxifen are more prominent in
postmenopausal than in premenopausal women (145). There is also some
evidence that tamoxifen might reduce LDL oxidation (146, 147).
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for the 60-mg raloxifene dose
(148). Serum LDL was lowered to a similar extent by raloxifene and HRT
(12–14%) but lipoprotein (a) was lowered only 7–8% by raloxifene in
contrast to 19% by HRT. Furthermore, HRT increased total serum HDL
cholesterol by 11%, whereas raloxifene produced no total HDL
increment. The HDL-2 subclass, however, was increased 33% by HRT
compared with 15–17% increases with raloxifene.
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In the multicenter European osteoporosis prevention study, within 3 months, total and LDL cholesterol were decreased with all raloxifene doses, with no subsequent change thereafter. Consistent with the investigation above, there was no change in serum HDL or triglycerides (90). Similar results were obtained in the short-term investigation (8 weeks) of higher doses of raloxifene in normal postmenopausal women (91).
2. Coagulation factors. A significant body of literature suggests that tamoxifen lowers serum levels of antithrombin III, as does estrogen (138, 149, 150, 151, 152, 153), although there is one small conflicting cross-sectional study (154). In none of the investigations was serum antithrombin III level reduced by more than 30%. Serum fibrinogen levels were reduced 15–18% by tamoxifen in at least three separate investigations, one in healthy women (144) and two in women with breast cancer (127, 151). A small decrease (9%) in platelet count (151), reduced serum Protein C activity (153), and an increase in serum plasminogen have also been reported with tamoxifen exposure (127).
In the Italian Breast Cancer Prevention trial, the first 77 healthy postmenopausal women enrolled were evaluated for effects on coagulation factors over the first 6 months (152). Platelet count and hemoglobin decreased in tamoxifen-treated patients. Both placebo-treated and tamoxifen-treated patients decreased serum fibrinogen levels, without a clear treatment effect. No changes in Factor VII were documented, but von Willebrand factor was increased in tamoxifen-treated patients compared with those receiving placebo. As shown previously, serum levels of antithrombin III decreased in tamoxifen-treated patients as did Protein C.
In the study of healthy postmenopausal women, comparing continuous combined HRT with raloxifene, 60 mg/day (148), raloxifene lowered plasma fibrinogen level to a similar degree as seen with tamoxifen (12–14%), whereas estrogen had no effect in this study. Neither raloxifene nor HRT changed determinations of fibrinopeptide A or prothrombin fragments 1 and 2. While HRT decreased Plasminogen Activator Inhibitor-1, raloxifene had no effect on this variable.
B. Vascular disease outcomes
1. Cardiovascular and cerebrovascular diseases.Two
separate European breast cancer studies using adjuvant tamoxifen
reported the occurrence of coronary heart disease. In the Scottish
breast cancer trial, McDonald originally reported that fatal myocardial
infarction (MI) was 63% less common in those patients who received
tamoxifen than in those who did not receive tamoxifen (155). In a
follow-up of this same study, vascular disease outcomes were tabulated
in 1,312 women after mastectomy who were randomly assigned to
receive adjuvant tamoxifen or no treatment unless a relapse occurred
(156). Women were followed on tamoxifen for a maximum of 14 yr.
Eighteen percent of these women were premenopausal at study entry and
mean age was 58–59 yr. In the tamoxifen arm of the study, risk of MI
was reduced, and there was a trend toward reduction in other ischemic
heart disease events. When comparing women who had ever used tamoxifen
to women who had never used tamoxifen, relative risk for MI was
significantly higher for never used (2.03, P = 0.03),
and there was a trend toward increased development of ischemic heart
disease (RR 1.55, P = 0.16). There was no suggestion of
any change in risk of cerebrovascular disease. Results were similar
qualitatively but quantitatively even stronger if current tamoxifen
users were compared with never users.
In the Stockholm Breast Cancer Study, which investigated vascular morbidity in 2,365 patients, a significant reduction in cardiac disease was seen in tamoxifen-treated patients, and incidence of cardiac disease requiring hospital admission was 32% less common in those allocated to receive tamoxifen after breast cancer surgery (157). Similar to the Scottish study (156), no difference in cerebrovascular disease was noted.
Data from the NCI-sponsored breast cancer treatment study NSABP B-14 trial (112) are consistent with the findings of the Scottish and Swedish breast cancer studies, in terms of degree of effect against fatal heart disease; however, findings were not statistically significant. In this protocol, 2,885 women with breast cancer were randomly assigned to tamoxifen or placebo and an additional 1,200 women were later assigned to the tamoxifen arm of the protocol. Although the cardiovascular mortality was lower in tamoxifen-treated patients, data did not reach statistical significance. Relative risk for definite fatal MI was 0.66 for tamoxifen users (confidence interval = 0.27–1.61). If death from possible MI was added, relative risk became 0.85 (confidence interval = 0.46–1.58).
The most distinct data on arteriovascular disease outcomes are from the
Breast Cancer Prevention Trial (55). This was the largest and cleanest
study and the only one performed in women who did not have a diagnosis
of breast cancer. Rates for ischemic heart and cerebrovascular disease
are shown in Table 1
. There was no significant difference in the number
of women in the tamoxifen group vs. placebo group who had a
MI, had angina requiring bypass graft or angioplasty, those diagnosed
with acute ischemic syndrome, or total events due to ischemic heart
disease (71 vs. 62). If events in women less than age 49 are
excluded, total ischemic episodes were 61 in the tamoxifen group and 57
in the placebo group. Furthermore, cerebrovascular disease was no less
common in women receiving tamoxifen vs. placebo, as was seen
in the breast cancer treatment studies. A total of 24 cerebrovascular
events occurred in the placebo group compared with 38 in the tamoxifen
group (difference not statistically significant). Excluding events in
younger women left 20 cerebrovascular events in placebo-treated and 35
in tamoxifen-treated women, a difference that nearly met statistical
significance (95% CI = 0.98–3.20).
To evaluate the vascular disease outcomes of raloxifene treatment, Eli Lilly & Co. (Indianapolis, IN) has embarked on a large prospective clinical trial entitled the RUTH (Raloxifene Use for the Heart) study (158). The planned enrollment is approximately 10,000 postmenopausal women over the age of 55, with established heart disease or at increased risk for heart disease. The primary outcomes will be fatal and nonfatal MI, and secondary outcomes will be all-cause mortality, all-cause hospitalization, revascularization incidence, cerebrovascular events, and breast cancer. Results of this trial will probably be available within about 7 yr. Frequency of cardiovascular and cerebrovascular disease events from ongoing osteoporosis prevention and treatment trials should be available sooner, but no data have yet been published concerning these outcomes.
2. Venous thromboembolic disease. Although there was no increase in venous thromboembolic disease documented in the Swedish breast cancer study (157), in the Scottish Breast Cancer study (156), risk was almost 2.5-fold in patients receiving tamoxifen compared with the risk in untreated patients. Many other reports have confirmed the increase in venous thromboembolic disease in women with breast cancer treated with tamoxifen (68, 110, 159, 160, 161, 162). Furthermore, in healthy women in the NCI-sponsored Breast Cancer Prevention Trial, relative risk for pulmonary emboli in tamoxifen-treated to untreated was 3.01 (CI= 1.15–9.27), and for deep vein thrombosis was 1.60 (CI = 0.91–2.86). Similarly, raloxifene, like tamoxifen and estrogen (11, 20, 21, 22), has been associated with a 3-fold increase in risk of venous thromboembolic disease, including deep venous thrombosis of the leg veins, pulmonary embolism, and retinal vein thrombosis (77 162A ). The absolute risk of venous thromboembolism is still quite small, however, at approximately 2 or 3 cases for every 10,000 women each year.
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VI. Central Nervous System Effects |
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Effects of raloxifene on cognitive function have been studied in a formal clinical trial of 143 postmenopausal women with osteoporosis between the ages of 45 and 75 yr before and during assignment to raloxifene, 60 mg/day, raloxifene, 120 mg/day, or placebo (164). Cognitive tests included measures from the Memory Assessments Clinic computerized psychometric battery and the Walter Reed Performance Assessment Battery. An assessment of mood was also performed using the Geriatric Depression Scale. Subjects underwent testing at baseline, 1, 6, and 12 months. At 6 and 12 months there were no significant differences in performance on any of these tests among any of the groups. These data suggest that raloxifene does not hinder or improve performance on cognitive function testing or mood over a 1-yr period. Ongoing studies of raloxifene’s effect on the central nervous system (from the MORE study) should provide further confirmatory data.
B. Eye disease
Tamoxifen use has been associated with ocular toxicity including
retinopathy in several small studies (165, 166, 167, 168, 169, 170, 171, 172, 173, 174). Many of these
findings, particularly the retinopathy, have not been substantiated,
however, in larger studies (55, 175). A subgroup of the NSABP B-14
breast cancer treatment study, with primary focus on ophthalmic
outcomes, indicated no vision-threatening ocular toxicity other than
posterior subcapsular opacities in tamoxifen-treated women (175).
Moreover, in the largest study involving tamoxifen use in healthy
women, the NCI Breast Cancer Prevention Trial (55), there was no
evidence of an increase in the risk of macular degeneration or any
other retinal toxicity. In contrast, there was an increase in the
relative risk of cataract development (RR 1.14; 95% CI =
1.01–1.29) and an increase in the relative risk of cataract surgery
(RR 1.57; 95% CI, 1.16–2.14). Raloxifene use has been associated with
increased risk of retinal vein thrombosis, but no other ocular toxicity
has been so far noted (77).
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VII. Hepatic Effects |
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VIII. Miscellaneous Effects |
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IX. Conclusion |
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Footnotes |
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1 Supported in part by NIH Grants DK-46381 and AR-39191. 
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References |
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