Long-term Effects of Raloxifene on Bone Mineral Density, Bone Turnover, and Serum Lipid Levels in Early Postmenopausal Women

Johnston, C. Conrad; Bjarnason, Nina H.; Cohen, Fredric J.; Shah, Aarti S.; Lindsay, Robert; Mitlak, Bruce; Huster, William J.; Draper, Michael W.; Harper, Kristine D.; Heath, Hunter; Gennari, C; Christiansen, Claus; Arnaud, Claude D.; Delmas, Pierre D.

doi:10.1001/archinte.160.22.3444

Cited by 188 publications

(101 citation statements)

References 28 publications

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“…Several SERMs are well known to protect against bone loss related to the menopause-related deficit in estrogen, and a wide variety of studies in multiple species and conditions have demonstrated the efficacy of SERMs to reduce bone turnover, and to prevent bone or BMD loss. 31,32,45,46 The effect of estrogen on BMD is ERa-dependent, 21 and the ERa and ERb appear to exert opposing actions: 47 activation of the ERa promotes longitudinal bone growth, whereas that of the ERb represses it. In the present study, substantial changes in BMD over a 28-day period in 5-month-old mice were obviously not expected, but the data nevertheless point to interesting trends.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

et al. 2005

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OBJECTIVE:The selective estrogen receptor (ER) modulator (SERM) acolbifene (ACOL), a potent and pure antiestrogen in the mammary gland and uterus, exerts beneficial pro-estrogenic actions on energy balance, insulin sensitivity and lipid metabolism. ACOL binds ERs a and b, both of which have been involved in the metabolic actions of estrogen. This study aimed at determining the identity of the ER involved in the beneficial metabolic actions of ACOL. DESIGN AND MEASUREMENTS: ACOL was administered for 4 weeks to male and female wild-type and ERa knockout (KO) mice, and indices of energy balance as well as plasma and liver lipid concentrations were determined. RESULTS: ERa KO mice were heavier, gained more fat mass and had larger adipose depots than their wild-type counterparts. In both genders, ACOL decreased fat gain (50%) and white adipose tissue mass in male and female wild-type, but not in ERa KO mice. ACOL reduced plasma cholesterol in female wild-type mice (À27%), whereas the compound remained ineffective in their ERa KO counterparts. Plasma triglycerides were unaffected by ACOL. Finally, ACOL decreased liver cholesterol and triglyceride concentrations only in wild-type female animals. CONCLUSION: The beneficial metabolic actions of the SERM ACOL on adiposity and on plasma and liver lipids are entirely due to its interaction with the ERa.

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Section: Discussionmentioning

confidence: 99%

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

et al. 2005

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“…A number of clinical trials [1][2][3][4][5][6] evaluating the effects of RLX on bone, including MORE trial [1], the largest double-blind placebo-controlled one, have clearly demonstrated that RLX improves accelerated bone turnover, increases bone mineral density (BMD) at the lumbar spine (LS) and at the femoral neck (FN), and reduces the risk of new vertebral fractures. In addition, favorable effects on lipid metabolism have also been repeatedly reported in the literature [2,3].…”

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confidence: 99%

Clinical Significance of 1-year Treatment with Raloxifene on Bone and Lipid Metabolism in Japanese Postmenopausal Women with Osteoporosis

et al. 2007

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Abstract. It has been well established that raloxifene (RLX) has beneficial effects on bone primarily in Caucasian women. However, to date, there is a dearth of data for Japanese postmenopausal women. In this study, we prospectively evaluated the effects of RLX on bone and lipid metabolism in fifty Japanese postmenopausal patients with untreated osteoporosis. We measured bone mineral density (BMD) by dual-energy X-ray absorptiometry at 7 sites including the lumbar spine, femoral neck, and distal radius. BMD was significantly increased at the lumbar spine both at 6 months and at 12 months compared with at baseline (p<0.01 for both), although the possibility could not be completely excluded that this increase may be partly explained by an apparent increase induced by degenerative changes in lumbar vertebrae since we had no control subjects to compare and be more certain of the findings in this study. Both bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) significantly decreased both at 6 months (p<0.01 for both) and at 12 months (p<0.01 for both) compared with at baseline, but not below the lower limit of the reference value. Total cholesterol and low-density lipoprotein cholesterol were significantly improved while triglycerides and high-density lipoprotein cholesterol were unaltered. Although longer and larger studies with fracture endpoints are needed to draw definite conclusions, our findings suggest the favorable effects of RLX on bone and lipid metabolism in Japanese postmenopausal women with osteoporosis as in Caucasian women.

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“…It has been well documented that estrogen and estrogen-like substances such as raloxifene and tamoxifen reduce total serum cholesterol in rats and reduce the LDL cholesterol in human (21,22). Using the OVX rat model, we found that LAS significantly reduced total serum cholesterol as compared with both the sham and OVX controls, as shown in Figure 6A (27).…”

Section: Effects Of Las On Total Serum Cholesterol In Female Ratsmentioning

confidence: 55%

“…A tissue selective estrogen receptor modulator without estrogenic activity in the breast and uterus would improve the negative side-effect profile of estrogen and overcome these compliance hurdles. A new class of agents, named selective estrogen receptor modulators (SERMs), has been investigated as an alternative to estrogen or hormone replacement therapy in preclincal and clinical studies (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). It has been reported that raloxifene, the first agent from this class approved for the prevention and treatment of postmenopausal osteoporosis, prevented bone loss, increased bone mineral density, reduced skeletal fracture, reduced risk of breast cancer, and decreased serum low-density lipoprotein cholesterol without uterine stimulating effects in postmenopausal women (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Lasofoxifene (CP-336,156), a novel selective estrogen receptor modulator, in preclinical studies

Brown

Thompson

2002

AGE

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Estrogen replacement therapy is reported to reduce the incidence of vertebral fractures in postmenopausal women, however, its compliance is limited because of side effects and safety concerns. Estrogen's side effects on breast and uterine tissues leading to the potential increased risk of uterine and breast cancer limit widespread estrogen usage. Thus, there is a significant medical need for a therapy that protects against postmenopausal bone loss but is free of estrogen's negative effects on reproductive tissues. Selective estrogen receptor modulators (SERMs) have been investigated as an alternative to hormone replacement therapy. One such compound, raloxifene, has been approved for the prevention and treatment of osteoporosis.Lasofoxifene (LAS), a new, nonsteroidal, and potent SERM, is an estrogen antagonist or agonist depending on the target tissue. LAS selectively binds with high affinity to human estrogen receptors. In ovariectomized (OVX) rat studies, LAS prevented the decrease in femoral bone mineral density, tibial and lumbar vertebral trabecular bone mass at an EDlo o of about 60 ~g/kg/day. LAS inhibited the activation of trabecular and endocortical bone resorption and bone turnover in tibial metaphyses and diaphyses, and lumbar vertebral body in OVX rats. In addition, LAS decreased total serum cholesterol, inhibited body weight gain and increased soleus muscle weight in OVX rats. Similarly, LAS prevented bone loss induced by orchidectomy or aging in male rats by decreasing bone resorption and bone turnover while it had no effect in the prostate. Further, LAS decreased total serum cholesterol in intact aged male rats or in orchidectomized male rats. Synergestic skeletal effects were found with LAS in combination with bone anabolic agents such as prostaglandin E 2 (PGE2), parathyroid hormone (PTH) or a growth hormone secretagoue (GHS) in OVX rats. In combination with estrogen, LAS inhibited the uterine stimulating effects of estrogen but did not block the bone protective effects of estrogen. In immature and aged female rats, LAS did not affect the uterine weight and uterine histology. In OVX adult female rats, LAS slightly but significantly increased uterine weight. These results demonstrated that LAS produced effects on the skeleton indistinguishable from estrogen in female and male rats. However, unlike estrogen, I_AS had little effect on uterine weight and cellular proliferation of uterus in female rats. In preclinical anti-tumor studies, LAS inhibited human breast cancer growth in mice bearing MCF7 tumors, prevented NMU-induced mammary carcinomas and possessed chemotherapeutic effects in NMU-induced carcinomas in rats.Therefore, we conclude that LAS possesses the antiestrogenic effects in breast tissue and estrogenic effects in bone and serum cholesterol, but lacks estrogen's side effects on uterine tissue. These data support the therapeutic potential of I_AS for the prevention and treatment of postmenopausal bone loss and mammary carcinomas in humans.

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Long-term Effects of Raloxifene on Bone Mineral Density, Bone Turnover, and Serum Lipid Levels in Early Postmenopausal Women

Cited by 188 publications

References 28 publications

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

Clinical Significance of 1-year Treatment with Raloxifene on Bone and Lipid Metabolism in Japanese Postmenopausal Women with Osteoporosis

Lasofoxifene (CP-336,156), a novel selective estrogen receptor modulator, in preclinical studies

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