Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat

Martel, Céline; Picard, Sylvain; Richard, Virgile; Bélanger, Alain; Labrie, Claude; Labrie, Fernand

doi:10.1016/s0960-0760(00)00087-x

Cited by 55 publications

(30 citation statements)

References 54 publications

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“…This is a validated postmenopausal model for the study of bone-sparing drugs. For example, at 35 weeks after ovariectomy, lumbar spine bone mineral density (BMD) has been shown to be 19% lower than in intact animals, whereas OVX animals given the selective estrogen receptor modulator (SERM) EM-800 (1 mg/kg) or raloxifene (1 mg/kg) had 93% and 90%, respectively, of the BMD values observed in intact rats (11). The model is also useful to study the lipid profile resulting from treatment with various endocrine therapies, another end-organ effect of interest to us in evaluating the two classes of aromatase inhibitors (12).…”

Section: Introductionmentioning

confidence: 99%

Effects of the Steroidal Aromatase Inhibitor Exemestane and the Nonsteroidal Aromatase Inhibitor Letrozole on Bone and Lipid Metabolism in Ovariectomized Rats

Goss

Cheung

et al. 2004

Clinical Cancer Research

110

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Purpose: Exemestane (EXE) and letrozole (LET) are third-generation aromatase inhibitors currently prescribed for postmenopausal hormone-dependent breast cancer. The impact on end organs of estrogen depletion in menopausal women is of significant clinical importance. We studied the effects of EXE, its principal metabolite, 17-hydroexemestane (17-H-EXE), and LET on bone and lipid metabolism in ovariectomized (OVX) rats.Experimental Design: OVX rats were treated by weekly intramuscular injection for 16 weeks with 20, 50, and 100 mg/kg EXE, 20 mg/kg 17-H-EXE, and daily oral gavage of 1 mg/kg LET. At the end of the treatment period, bone mineral density (BMD), the bone resorption marker serum pyridinoline, the bone formation marker serum osteocalcin, bone mechanical properties, histomorphometry, and serum lipid concentrations were determined.Results: Lumbar vertebral and femoral BMD, bending strength of the femur, compressive strength of the fifth lumbar vertebra, and trabecular bone volume were significantly higher in OVX animals given EXE and 17-H-EXE than in OVX controls. EXE and 17-H-EXE significantly reduced an ovariectomy-induced increase in serum pyridinoline and serum osteocalcin. EXE and 17-H-EXE given to OVX rats caused significant reductions of serum cholesterol and low-density lipoprotein cholesterol. In contrast, OVX rats treated with LET had BMD, bone biomarkers, mechanical failure properties, and lipid levels similar to those of OVX controls.Conclusions: EXE and 17-H-EXE significantly prevent bone loss, enhance bone mechanical strength, and lower serum cholesterol and low-density lipoprotein levels in OVX rats. These protective effects on end-organ function are not seen with the nonsteroidal inhibitor LET.

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Section: Introductionmentioning

confidence: 99%

Effects of the Steroidal Aromatase Inhibitor Exemestane and the Nonsteroidal Aromatase Inhibitor Letrozole on Bone and Lipid Metabolism in Ovariectomized Rats

Goss

Cheung

et al. 2004

Clinical Cancer Research

110

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“…Raloxifene (Ral), on the other hand, has less oestrogenic effects on uterus, but the same beneficial effects on bone and lipid metabolism (Delmas et al, 1997;Barrett-Connor et al, 1999;Cohen et al, 2000) while it is an antagonist of oestrogen action in the breast (Gottardis and Jordan, 1987;Cummings et al, 1999). Other SERMs like idoxifene (Idox) (Chander et al, 1991;Nuttall et al, 1998), GW 5638 (Willson et al, 1994(Willson et al, , 1997Connor et al, 2001) and EM 800 (Luo et al, 1998;Labrie et al, 1999;Martel et al, 2000) are different from tamoxifen and based on their activity in the rodent uterus are more closely related to raloxifene. Resveratrol (Res) does not formally belong to the SERM family, because it is a phytoestrogen found in the plants (Jang et al, 1997), however Res has similar in vivo characteristics to the SERMs (Mizutani et al, 2000;Bhat and Pezzuto, 2001;Wu et al, 2001).…”

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confidence: 99%

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor α

Levenson¹,

Kliakhandler²,

Svoboda³

et al. 2002

Br J Cancer

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The purpose of this study was to classify selective oestrogen receptor modulators based on gene expression profiles produced in breast cancer cells expressing either wtERa or mutant 351 ERa. In total, 54 microarray experiments were carried out by using a commercially available Atlas cDNA Expression Arrays (Clontech), containing 588 cancer-related genes. Nine sets of data were generated for each cell line following 24 h of treatment: expression data were obtained for cells treated with vehicle EtOH (Control); with 10 79 or 10 78 M oestradiol; with 10 76 M 4-hydroxytamoxifen; with 10 76 M raloxifene; with 10 76 M idoxifene, with 10 76 M EM 652, with 10 76 M GW 7604; with 5610 75 M resveratrol and with 10 76 M ICI 182,780. We developed a new algorithm 'Expression Signatures' to classify compounds on the basis of differential gene expression profiles. We created dendrograms for each cell line, in which branches represent relationships between compounds. Additionally, clustering analysis was performed using different subsets of genes to assess the robustness of the analysis. In general, only small differences between gene expression profiles treated with compounds were observed with correlation coefficients ranged from 0.83 to 0.98. This observation may be explained by the use of the same cell context for treatments with compounds that essentially belong to the same class of drugs with oestrogen receptors related mechanisms. The most surprising observation was that ICI 182,780 clustered together with oestrodiol and raloxifene for cells expressing wtERa and clustered together with EM 652 for cells expressing mutant 351 ERa. These data provide a rationale for a more precise and elaborate study in which custom made oligonucleotide arrays can be used with comprehensive sets of genes known to have consensus and putative oestrogen response elements in their promoter regions.

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“…However, in the rat, both HDL and LDL cholesterol are reduced, because rat HDL contains apoprotein E (not found in human HDL), which also binds to the hepatic LDL receptor [32]. Thus, in the rat, as opposed to humans, HDL cholesterol is a predominant form of circulating cholesterol, and estrogen therapy lowers both HDL cholesterol and LDL cholesterol [6]. Thus the reduction in both HDL and LDL cholesterol seen with SCH 57068 in the OVX rat is in the desired direction.…”

Section: Discussionmentioning

confidence: 99%

“…SCH 57068 and its pro-drug, SCH 57050, significantly inhibit growth and prevent development of DMBAinduced mammary carcinomas in the Sprague-Dawley rat [3][4][5]. SCH 57050 also prevents bone loss and decreases serum cholesterol levels in the ovariectomized (OVX) rat [2,6].…”

Section: Introductionmentioning

confidence: 99%

The selective estrogen receptor modulator SCH 57068 prevents bone loss, reduces serum cholesterol and blocks estrogen-induced uterine hypertrophy in ovariectomized rats

Goss

Cheung

et al. 2004

The Journal of Steroid Biochemistry and Molecular Biology

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Our objective was to determine the effects of SCH 57068 alone and with 17β-estradiol (E 2 ) on bone, lipids and uteri in ovariectomized (OVX) rats. In OVX animals lumbar vertebral and femoral bone mineral density (BMD) were significantly higher after 12 weeks of treatment with SCH 57068 than in untreated OVX controls. Similarly BMD was superior in OVX + E 2 + SCH 57068 treated animals than in OVX + E 2 controls. SCH 57068 also significantly reduced the increase in bone turnover markers, serum pyridinoline and serum osteocalcin levels, induced by OVX, and increased mechanical bone strength. SCH 57068 also significantly reduced the rise in serum cholesterol and low-density lipoprotein cholesterol induced by OVX. SCH 57068 had no stimulatory effect on uterine epithelium when given alone in OVX rats. SCH 57068 (1 and 2.5 mg/kg) reduced uterine weight and blocked endometrial stimulation induced by E 2 . In summary, SCH 57068 adds to the positive effects of E 2 on bone and lipid metabolism but blocks the stimulatory effects of E 2 on the uterus. Potentially, E 2 + SCH 57068 could be combined for the treatment and prevention of breast cancer or as a novel hormone replacement therapy.

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Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat

Cited by 55 publications

References 54 publications

Effects of the Steroidal Aromatase Inhibitor Exemestane and the Nonsteroidal Aromatase Inhibitor Letrozole on Bone and Lipid Metabolism in Ovariectomized Rats

Effects of the Steroidal Aromatase Inhibitor Exemestane and the Nonsteroidal Aromatase Inhibitor Letrozole on Bone and Lipid Metabolism in Ovariectomized Rats

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor α

The selective estrogen receptor modulator SCH 57068 prevents bone loss, reduces serum cholesterol and blocks estrogen-induced uterine hypertrophy in ovariectomized rats

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