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

Abstract

Our objective was to determine the effects of SCH 57068 alone and with 17 beta-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.

Fig. 1

Molecular structure of SCH 57068.

Fig. 2

Bone mineral density of the lumbar vertebrae (A) and whole femora (B) after 12 weeks of treatment with SCH 57068. Scale bars represent the mean ±S.E.M. (n = 9–12). ^*P < 0.0001 vs. OVX controls;^**P < 0.0001 vs. OVX + E₂ controls.

Fig. 3

Serum pyridinoline (PYD) levels after 12 weeks of treatment with SCH 57068. Scale bars represent the mean ±S.E.M. (n = 9–12). ^*P < 0.0001 vs. OVX controls; ^**P < 0.0001 vs. OVX + E₂ controls.

Fig. 4

Serum osteocalcin (OC) levels after 12 weeks of treatment with SCH 57068. Scale bars represent the mean ±S.E.M. (n = 9–12). ^*P < 00.005 vs. OVX controls; ^**P < 0.005 vs. OVX + E₂ controls.

Fig. 5

Mechanical properties of the femora and lumbar vertebrae after 12 weeks of treatment with SCH 57068. Three-point bending strength of the femora (A). Compressive strength of the fifth lumbar vertebrae (B). Scale bars represent the mean ±S.E.M. (n = 9–12). ^*P < 0.0005 vs. OVX controls; ^**P < 0.0005 vs. OVX + E₂ controls.

Fig. 6

Serum cholesterol levels after 12 weeks of treatment with SCH 57068. Scale bars represent the mean ±S.E.M. (n = 9–12). ^*P < 0.0001 vs. OVX controls; ^**P < 0.0001 vs. OVX + E₂ controls.

Fig. 7

Serum LDL levels after 12 weeks of treatment with SCH 57068. Scale bars represent the mean ±S.E.M. (n = 9–12). ^*P < 0.05 vs. OVX controls; ^**P < 0.05 vs. OVX + E₂ controls.

Fig. 8

Hematoxylin and eosin-stained sections of rat uteri illustrating epithelial lining cells obtained from intact controls (a), OVX controls (b), OVX rats treated for 12 weeks with SCH 57068 0.01 mg/kg (c), 1 mg/kg (d) or 2.5 mg/kg (e), as well as OVX animals bearing an implant of 17 β-estradiol (E₂) (f), OVX rats bearing an E₂ implant treated for 12 weeks with SCH 57068 0.01 mg/kg (g), 1 mg/kg (h) or 2.5 mg/kg (i). Note the absence of stimulatory effect of SCH 57068 on the uterine epithelial cells in the OVX rat, as well as the inhibitory effect of SCH 57068 (1.0 mg and 2.5 mg/kg) on uterine epithelial cells in the OVX plus E₂-treated rat (magnification of ×125).