| | Selective estrogen receptors modulators in the prevention and treatment of postmenopausal osteoporosis
Osteoporosis is a metabolic bone disorder characterized by low bone mass and microarchiectural deterioration of bone tissue leading to increased bone fragility and fracture risk. The reduction in circulating estrogens at menopause induces accelerated bone loss. Hormone replacement therapy (HRT) prevents postmenopausal bone loss, but long-term use is probably necessary to reduce the risk of fragility fractures, most of which occur after the age of 60 years [1]. The long-term compliance to HRT is limited by side effects, such as uterine bleeding and breast tenderness, and by the fear of breast cancer, the risk of which seems to increase after prolonged treatment [2], [3]. Clinical interest in selective estrogen receptors modulators (SERMs) in the management of osteoporosis is related to these limitations of HRT. The concept of SERMs is derived from the observation that tamoxifen, used in breast cancer for its antiestrogen effects on breast tissue, has estrogen-like effects on the skeleton and lipoproteins. Although tamoxifen has an excellent benefit-to-risk ratio as an adjuvant treatment in breast cancer, its use in healthy postmenopausal women is questionable because of its increased risk of endometrial cancer. Several synthetic SERM molecules that have been developed seem to be devoid of the undesirable estrogen effects on breast and endometrial tissue. Among these compounds, raloxifene is a nonsteroidal benzothiofene that has undergone extensive clinical investigation. Preclinical studies have shown that raloxifene preserves bone mass [4], [5] and increases bone strength in ovariectomized rats. There was no significant difference in bone strength of the femoral neck, femur, and lumbar spine after estrogen or raloxifene treatment [6]. A recent study has shown that a SERM and a bisphosphonate could restore biomechanical properties of the proximal tibia metaphysis of ovariectomized rats without completely restoring their cancellous bone volume [7].
Raloxifene is marketed widely for the prevention and treatment of postmenopausal osteoporosis. New SERMs are currently under investigation.
The effects of SERMs on bone turnover  Effects of tamoxifen Data on the effects of tamoxifen on bone turnover in healthy women are limited. A small study on 10 healthy elderly women (70 to 85 years of age) receiving tamoxifen 20 mg per day for 10 weeks has shown a decrease in the urinary excretion of pyridinoline (Pyr) and deoxypyridinoline (DPyr) by 23% and 25%, respectively. These bone resorption markers returned to baseline values after therapy was discontinued [8]. In postmenopausal women with breast cancer who were treated with toremifene (40 mg/d) or with tamoxifen (20 mg/d) [9], urinary Pyr and Dpyr were significantly decreased at 6 and 12 months in the tamoxifen group. Other markers of bone turnover in a similar population [10] have been studied. At 12 months of treatment, the decrease was about 40%, 25%, and 22% for urinary cross-linked amino-terminal telopeptide of type I collagen (NTX), osteocalcin, and serum amino-terminal propeptide of type I collagen (PINP), respectively, in the tamoxifen group. The decrease in bone turnover markers was significantly less in the toremifene group, and neither tamoxifen nor toremifene induced significant changes in bone alkaline phoshatase (ALP) and serum cross-linked carboxy-terminal telopeptide of type I collagen. Effects of raloxifene Short-term effects of raloxifene on bone turnover have been reported in 250 healthy postmenopausal women receiving placebo, raloxifene (200 or 600 mg), or conjugated equine estrogens (0.625 mg once daily) [11]. After 8 weeks of treatment, a significant decrease was observed in serum alkaline phosphatase, serum osteocalcin, urinary pyridinoline, and urinary calcium with the two doses of raloxifene. Changes in the bone turnover markers were not significantly different between the raloxifene and estrogen treatment groups. A recent randomized, double-blind study compared markers of bone turnover in postmenopausal patients treated with raloxifene (60 mg/d) or conjugated equine estrogen (0.625 mg/d) [12]. After 24 weeks of treatment, all markers of resorption and formation decreased significantly from baseline in the two groups except for deoxypyridinoline. Changes were significantly different between the two groups, with a marked decreased in urinary type I collagen C-telopeptide (CTX) and NTX in the estrogen-treated women (53% and 43% from baseline, respectively) compared with a decrease of 23% and 22% in CTX and NTX in raloxifene-treated women. For bone formation markers (osteocalcin, bone alkaline phosphatase, and C-terminal type I procollagen peptide), the mean decreases were significantly greater in the estrogen group. These results were confirmed by the histomorphometric analysis with a significant decrease in the activation frequency and bone formation rate/bone volume in the estrogen group compared with a nonsignificant decrease in the raloxifene group from baseline to endpoint [12]. Bone turnover was assessed in a study of 600 postmenopausal women without osteoporosis who were randomly assigned to receive 30, 60, or 150 mg of raloxifene or placebo daily for 24 months. Each of the raloxifene groups had a significant decrease of serum osteocalcin, bone alkaline phosphatase (BAP), and CTX compared with the placebo [13]. Bone turnover decreased to premenopausal levels with a reduction of serum osteocalcin, BAP, and CTX of 23%, 15%, and 34%, respectively, with the 60-mg dose. The 3-year data from this study have been pooled with data from another study with a similar design performed in North America [14]. A total of 1145 postmenopausal women were randomly assigned to receive 30, 60, and 150 mg of raloxifene or placebo daily. Bone turnover was significantly decreased to premenopausal levels throughout the 3 years of the study. Similar effects on bone turnover have been found in osteoporotic patients treated with raloxifene [15], [16]. The Multiple Outcomes of Raloxifene Evaluation (MORE) study has assessed bone mineral density (BMD) and risk fractures in 7705 postmenopausal women defined by low BMD or vertebral fractures [16]. Women were randomized to receive placebo or 60 or 120 mg of raloxifene daily. After 36 months of treatment, serum osteocalcin decreased by a median of 8.6%, 26.3%, and 31.1%, and the urinary CTX decreased by 8.1%, 34%, and 31.5%, respectively, in the placebo, 60-mg, and 120-mg raloxifene groups. The decrease was significant in both raloxifene groups compared with the placebo and was sustained throughout the study. Effects of SERMs on BMD Effects of tamoxifen A large trial in healthy pre- and postmenopausal women has evaluated the toxicity and feasibility of tamoxifen for the chemoprevention of breast cancer. Women were randomized to receive tamoxifen (20 mg/d) or placebo for 8 years. Total hip and lumbar spine BMD was available from 179 women [17], [18]. In women who remained premenopausal during the trial (n =125), lumbar spine BMD significantly decreased from baseline in the tamoxifen group (about 3.3%±1.6% at 3 years) and was significantly lower in women on tamoxifen compared with women on placebo at 1, 2, and 3 years of treatment. Total hip BMD was significantly decreased from baseline at 3 years of tamoxifen treatment (1.6%±1.4%), contrasting with a significant increase in the placebo group (2.7%±2.3%). Compared with the placebo group, total hip BMD was significantly lower in the tamoxifen group at 2 and 3 years of treatment. In the 59 postmenopausal women, BMD increased by 1.2% and 1.7% per year at the lumbar spine and total hip, respectively, in the tamoxifen group, contrasting with a nonsignificant decrease in women in the placebo group [18]. In contrast to its effect in postmenopausal women, tamoxifen acts as an antiestrogen on bone tissue in premenopausal women and results in bone loss (Fig. 1). Several studies have shown a prevention of bone loss in postmenopausal patients with breast cancer treated by tamoxifen compared with healthy postmenopausal control subjects, suggesting an estrogen-like effect on bone despite antiestrogenic activity on the breast [19], [20]. In a large prospective, double-blind, randomized, controlled study, Love et al [21] showed an increased BMD at the spine (1.2% at 2% years) in breast cancer patients treated with tamoxifen (20 mg/d) compared with a decreased BMD in a placebo group (2% at 2 years). The rate of bone loss at the radius did not differ between the two groups. These results were maintained at 5 years of treatment [22]. A small study of about 30 postmenopausal patients with nonmetastatic breast cancer treated either by tamoxifen (20 mg/d) or by toremifene (40 mg/d) showed a mean increase in BMD of 2% at the lumbar spine and 1% at the femoral neck after 12 months of treatment [10]. Tamoxifen has also been shown to reduce bone loss at the spine and hip by about 50% in patients with a recent artificial menopause due to adjuvant chemotherapy of breast cancer, whereas the use of a cyclic treatment with risedronate (a new bisphosphonate) resulted in an increased BMD in these women [23]. In healthy postmenopausal women, tamoxifen has induced an increase in lumbar spine BMD of 1.5% compared with placebo [24], [25]. Effects of raloxifene In the multicentric European and North American studies that included 1145 early postmenopausal women (55 years old) without osteoporosis treated by 30, 60, or 150 mg of raloxifene or placebo for 36 months, raloxifene prevented bone loss at all skeletal sites at the three doses, with a 2.6% increase in BMD at the lumbar spine and total hip over placebo in the 60-mg raloxifene group [14]. In 129 postmenopausal osteoporotic women (50 to 75 years of age) treated for 2 years with 60 or 120 mg raloxifene or placebo, BMD increased by 3.2% at the lumbar spine and by 2.1% and 1.6% in the femoral neck and total hip, respectively, with the 60-mg dose [26]. In the MORE study [16], which included 7705 postmenopausal women with osteoporosis, BMD increased significantly compared with the placebo by 2.1% and 2.6% at the femoral neck and spine, respectively, in the 60-mg raloxifene group and by 2.4% and 2.7%, respectively, in the 120-mg raloxifene group after 36 months of treatment (Fig. 2). In a recent study that compared the skeletal effects of raloxifene (60 mg/d for 24 weeks) with conjugated equine estrogen (0.625 mg/d for 24 weeks), the increase in lumbar spine and total body BMD was twice as high for conjugated estrogen than for raloxifene. At the proximal femur, the increase in BMD was not significantly different between the two groups [12]. Effects of SERMs on risk of fractures Effects of tamoxifen Tamoxifen has estrogen-like effects on the skeleton in postmenopausal women (eg, reducing bone turnover markers and preventing bone loss), but the effects of tamoxifen on the incidence of fragility fractures has not been adequately studied. A large placebo-controlled study [27] using tamoxifen (20 mg/d) in the prevention of breast cancer in more than 13,000 patients at high risk showed a nonsignificant reduction of about 20% in the overall incidence of hip, Colle's, and spine fracture. Because the population was not selected on the basis of a low BMD, the number of fracture events was quite low, and, therefore, the study was underpowered to show a reduction of osteoporotic fractures. Love et al [22] reported no significant difference in the rate of fracture between tamoxifen (20 mg/d) and placebo after 5 years of treatment in postmenopausal women with breast cancer, but, again, the number of events was low (7 versus 10 fractures, respectively). Effects of raloxifene Lufkin et al studied 143 postmenopausal women with at least one vertebral fracture and low BMD. Patients were randomized to receive placebo, 60 mg raloxifene, or 120 mg raloxifene for 1 year. Vertebral fractures were significantly reduced in the two raloxifene groups compared with the placebo group. There were no differences among groups for nonvertebral fractures [15]. The MORE study assessed the risk fractures in 7705 postmenopausal women with osteoporosis defined as low BMD or vertebral fractures [16]. Women were randomized to receive placebo or 60 or 120 mg of raloxifene daily. All patients received daily supplements of 500 mg of calcium and 400 to 600 IU of cholecalciferol. Group 1 included women with a T score below −2.5 at the femoral neck or lumbar spine without prevalent vertebral fractures. Group 2 included women with low BMD and one or more vertebral fractures or two or more vertebral fractures regardless of the BMD level. All women had vertebral radiographs at baseline, 24, and 36 months. Radiographs were also performed in case of a painful syndrome that suggested a recent vertebral fracture. Baseline and follow-up radiographs were available in 6828 women (88% at end point). After 36 months of treatment, the risk of new vertebral fracture defined by vertebral morphometry was reduced in both groups receiving raloxifene, with a relative risk (RR) of 0.7 (95% confidence interval [CI] 0.5–0.8) with 60 mg and 0.5 (95% CI 0.4–0.7) with 120 mg. Although the absolute risk was about fourfold higher in women with prevalent vertebral fractures, the reduction with raloxifene was significant in women with and without prevalent vertebral fractures (Fig. 3). With the recommended daily dose of 60 mg, the RR was 0.7 (95% CI 0.6–0.9) and 0.5 (95% CI 0.4–0.8) in women with and without prevalent vertebral fractures, respectively. There was no difference in the incidence of fractures in the 120-mg raloxifene group and in the 60-mg group (5.4% and 6.6%, respectively). There was a lower incidence of vertebral fractures in the 120-mg raloxifene group in women with prevalent vertebral fractures but not in women without prevalent vertebral fractures. The overall occurrence of nonvertebral fractures was low, with a 3-year incidence of 9.3% in the placebo group and 8.5% in the raloxifene group. There was a 10% reduction with raloxifene that did not reach the level of significance (RR 0.9; 95% CI 0.8–1.1). After 4 years, the reduction of vertebral fracture was maintained, with a RR of 0.64 in the group treated with 60 mg raloxifene group compared with placebo [28]. The mechanisms by which raloxifene decreases the risk of vertebral fracture are poorly understood. The relationship between the magnitude of the increase in BMD and the risk of fracture under anti-resorptive therapy is a matter of controversy. A recent study analyzed, in the MORE cohort, the relationship between percentage changes in femoral neck and lumbar spine BMD and the observed fracture risk reduction under raloxifene therapy [29]. The change in femoral neck and lumbar spine BMD at 1 or 3 years of treatment was found to be poorly predictive of the fracture risk reduction observed with raloxifene; raloxifene decreased vertebral fracture risk irrespective of the change of BMD, which accounts for less than 10% of the effect of raloxifene on the risk of vertebral fracture. On the other hand, in the same study, changes in bone turnover were significantly related to future risk of vertebral fracture. Patients showing the largest decrease of serum osteocalcin and bone alkaline phosphatase after 6 months of treatment had the lowest vertebral fracture incidence over 3 years (Fig. 4). Extraskeletal effects of tamoxifen and raloxifene Effects on lipid profile and cardiovascular disease Tamoxifen reduces the serum levels of total and low-density lipoprotein (LDL) cholesterol [24] and may reduce the risk of coronary heart disease in postmenopausal women with breast cancer [30]. However, in the National Surgical Adjuvant Breast and Bowel Project P-1 (NSABP P-1) study (a large placebo-controlled study using tamoxifen [20 mg/d] in the prevention of breast cancer in about 13,000 patients with high risk [27]), there were no differences in the incidence of myocardial infarction or events related to ischemic heart disease, regardless of age. In an osteoporosis prevention and treatment study [11], [12], [14], raloxifene induced a dose-dependent decrease of serum total and LDL cholesterol (about 11% with 60 mg) without significant changes in high-density lipoprotein (HDL) cholesterol or triglycerides. In a 6-month randomized, placebo- and HRT-controlled trial with cardiovascular markers as a primary end-point, raloxifene was found to favorably alter biochemical markers of cardiovascular risk while increasing the HDL2 subfraction of cholesterol and decreasing LDL cholesterol, lipoprotein a, and plasma fibrinogen without changing plasminogen activator inhibitor levels [31]. The Raloxifene Use for The Heart (Ruth) study, which is a large placebo-controlled study testing the effect of raloxifene on cardiovascular morbidity and mortality in more than 10,000 postmenopausal women at high risk, has been initiated [32]. A post-hoc analysis in the MORE study has been made on 1035 women (317 in the placebo group, 359 in the 60-mg raloxifene group, and 359 in the 120-mg raloxifene group) with high risk of cardiovascular disease based on the RUTH study criteria. There was no significant difference between the group at baseline except a greater proportion of patients with diabetes and lipid-lowering therapy in the raloxifene group. After 4 years of treatment, raloxifene significantly reduced the number of cardiovascular events (RR 0.6; CI 95% 0.38–0.95) in women with high risk of cardiovascular disease, whereas there was no significant effect in the overall cohort (Fig. 5) [33]. Effects on the uterus Tamoxifen increases the endometrial thickness and significantly increases the risk of endometrial adenocarcinoma. In the NSABP P1 trial, the RR in tamoxifen users was 2.5 and reached 4 in women over the age of 50 years [27]. The overall analysis of Phase III trials of raloxifene shows no increase in endometrial thickness by transvaginal ultrasonography and no increased incidence of hyperplastic endometrium on biopsies. In the MORE study, the RR of endometrial cancer was 0.8 (nonsignificant) after 40 months of follow-up [34]. In the analysis of eight randomized trials [35], the incidence of vaginal bleeding in women treated with raloxifene did not differ from placebo and was lower than in women treated with hormonal therapy. Thus, in contrast to tamoxifen, raloxifene has no estrogen agonist activity on the endometrium, and its clinical use does not require specific gynecologic surveillance. Effects on breast Tamoxifen is known to reduce tumor recurrence and to prolong survival when administered after breast cancer surgery [36]. The NSABP P-1 study [27] showed that tamoxifen reduced the risk of breast cancer by about 50% in women with high risk of breast cancer. In the MORE study, raloxifene caused a significant reduction of invasive breast cancer incidence compared with the placebo after 3 years [34] of treatment; this result was confirmed after 4 years of treatment [37] with a significant (72%) risk reduction (Fig. 6). Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% but had no effect on estrogen receptor-negative tumors. A head-to-head comparison of raloxifene with tamoxifen for prevention of breast cancer that would enroll 22,000 women with high risk of breast cancer has been started (Study of Tamoxifen and Raloxifene [STAR]). Adverse events The safety profile of tamoxifen was well documented in the NSABP P-1 trial [27]. There was an age-related increase of deep venous thrombosis and pulmonary embolism (RR 1.6 and 3.01, respectively) compared with placebo. Tamoxifen use was also associated with a significant increase of vaginal discharge, hot flashes, and cataracts. The safety profile of raloxifene is well documented in the MORE study [16], [34], [37]. The magnitude of the increased risk of venous thrombosis and pulmonary embolism is of comparable magnitude to those observed with tamoxifen and with HRT, with a significantly increased risk in the raloxifene group compared with placebo (1.44, 3.32, and 3.63 events per 1000 women-years for placebo, 60 mg raloxifene, and 120 mg raloxifene, respectively) [37]. Flu syndrome, hot flashes, and leg cramps were significantly increased in raloxifene-treated women but did not lead to treatment discontinuation. A recent study has shown that raloxifene does not impair cognitive function in postmenopausal women [38]. There was a trend toward less decline in raloxifene-treated women on the two tests of verbal memory (RR 0.77) and attention (RR 0.87) compared with placebo-treated women [38]. Development of other SERMs Droloxifene and idoxifene are two other SERMs with an estrogen-agonist effect on bone but also on the endometrium, which has hindered their clinical development. Levormeloxifene has been studied in a Phase II, 12-month interim analysis of a 2-year, double-blind, placebo-controlled study including 301 healthy postmenopausal women [39]. Participants were randomly assigned to receive 1.25, 5, 10, or 20 mg levormeloxifene per day, low-dose continuous combined HRT (17β-estradiol 1 mg/d and norethisterone 0.5 mg/d), or placebo. Spine BMD increased significantly by about 2% and 5%, respectively, in the all levormeloxifene groups and in the HRT group. Total hip BMD increased by about 2% and 2.5%, respectively, in the levormeloxifene and HRT groups. Biochemical bone markers (crosslaps and osteocalcin) were significantly decreased in the levormeloxifene and HRT groups (60% and 80%, respectively, for crosslaps and about 50% in both treatments for osteocalcin). Levormeloxifene decreased total cholesterol and LDL cholesterol by about 13% to 20% and 22% to 30%, respectively, without changing HDL cholesterol. Endometrial thickness increased significantly in the levormeloxifene group compared with HRT and placebo without inducing significant endometrial proliferation. The development of levormeloxifene was subsequently discontinued because of uterine adverse events, including urinary incontinence and prolapsus. Lasofoxifene and bazedoxifene are two other SERMs under clinical development. Summary 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 suggestion that raloxifene could have a beneficial effect on cardiovascular disease in high-risk patients needs to be confirmed in prospective study. 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Hôpital Edouard Herriot, Place d'Arsonval, Pavillon F, 69437 Lyon, Cedex 03, France  Corresponding author
PII: S0889-8529(02)00057-9 doi:10.1016/S0889-8529(02)00057-9 © 2003 Elsevier Science (USA). All rights reserved. | |
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