Advantages of raloxifene over alendronate or estrogen on nonreproductive and reproductive tissues in the long-term dosing of ovariectomized rats

Masahiko Sato, Henry U. Bryant, Philip Iversen, Jeff Helterbrand, Frank Smietana, Kerry Bemis, Richard Higgs, Charles H. Turner, Ichiro Owan, Yuichi Takano, David Burr

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Abstract

For the first time, raloxifene or alendronate was administered to rats immediately after ovariectomy for 10 months and compared with estrogen to elucidate mechanisms behind the raloxifene effects observed in nonreproductive and reproductive tissues. Specifically, 75-day-old rats were randomly selected as sham controls (Sham), ovariectomized controls (Ovx) or ocariectomized rats treated with fully efficacious doses of raloxifene (RA), 17α-ethynyl estradiol (EE2) or alendronate (ABP). Lumbar vertebrae and proximal tibiae were examined by computed tomography (QCT) and by histomorphometry. Histomorphometry showed differences in bone architecture between groups when QCT densities were similar, but tibial trabecular bone analysis by QCT correlated with histomorphometry with r = 86 to .93, depending on the parameter. Both techniques confirmed that Ovx had substantially less bone than Sham, with greater loss of trabecular bone in the proximal tibia than vertebrae. Both techniques showed that RA had effects similar to but not identical with EE2 in preventing bone loss in vertebrae and tibiae. ABP partially prevented loss of bone in L-5, but was not significantly different from Ovx in the proximal tibia. This may be caused by ABP suppression of bone apposition, beyond effects observed for EE2 or RA. RA appeared to be more similar to EE2 because ABP significantly depressed bone formation (bone formation rate, mineral apposition rate) to below RA or EE2 levels, especially in L-5. Mechanical loading to failure of L-6 vertebrae showed a rank order of vertebral strength of Sham > RA > EE2 > Ovx > ABP, although significant differences were not observed between treatment groups. These data show that ABP suppression of bone formation can affect bone quality with long-term treatment. In other tissues, RA had minimal uterine effects, while significantly lowering serum cholesterol to below EE2-treated levels. Both EE2 and RA rats had significantly lower body weights than the other groups. ABP had no effect on serum lipids, uterine weight or body weight. Therefore, RA appears to have a broader range of desirable effects on bone, body weight, uteri and cholesterol than ABP or EE2 in ovariectomized rats.

Original languageEnglish
Pages (from-to)298-305
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume279
Issue number1
StatePublished - Oct 1996

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Alendronate
Estrogens
Bone and Bones
Tibia
Osteogenesis
Spine
Body Weight
Raloxifene Hydrochloride
Cholesterol
Lumbar Vertebrae
Ethinyl Estradiol
Ovariectomy
Serum
Uterus
Minerals
Tomography

ASJC Scopus subject areas

  • Pharmacology

Cite this

Advantages of raloxifene over alendronate or estrogen on nonreproductive and reproductive tissues in the long-term dosing of ovariectomized rats. / Sato, Masahiko; Bryant, Henry U.; Iversen, Philip; Helterbrand, Jeff; Smietana, Frank; Bemis, Kerry; Higgs, Richard; Turner, Charles H.; Owan, Ichiro; Takano, Yuichi; Burr, David.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 279, No. 1, 10.1996, p. 298-305.

Research output: Contribution to journalArticle

Sato, M, Bryant, HU, Iversen, P, Helterbrand, J, Smietana, F, Bemis, K, Higgs, R, Turner, CH, Owan, I, Takano, Y & Burr, D 1996, 'Advantages of raloxifene over alendronate or estrogen on nonreproductive and reproductive tissues in the long-term dosing of ovariectomized rats', Journal of Pharmacology and Experimental Therapeutics, vol. 279, no. 1, pp. 298-305.
Sato, Masahiko ; Bryant, Henry U. ; Iversen, Philip ; Helterbrand, Jeff ; Smietana, Frank ; Bemis, Kerry ; Higgs, Richard ; Turner, Charles H. ; Owan, Ichiro ; Takano, Yuichi ; Burr, David. / Advantages of raloxifene over alendronate or estrogen on nonreproductive and reproductive tissues in the long-term dosing of ovariectomized rats. In: Journal of Pharmacology and Experimental Therapeutics. 1996 ; Vol. 279, No. 1. pp. 298-305.
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AU - Helterbrand, Jeff

AU - Smietana, Frank

AU - Bemis, Kerry

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N2 - For the first time, raloxifene or alendronate was administered to rats immediately after ovariectomy for 10 months and compared with estrogen to elucidate mechanisms behind the raloxifene effects observed in nonreproductive and reproductive tissues. Specifically, 75-day-old rats were randomly selected as sham controls (Sham), ovariectomized controls (Ovx) or ocariectomized rats treated with fully efficacious doses of raloxifene (RA), 17α-ethynyl estradiol (EE2) or alendronate (ABP). Lumbar vertebrae and proximal tibiae were examined by computed tomography (QCT) and by histomorphometry. Histomorphometry showed differences in bone architecture between groups when QCT densities were similar, but tibial trabecular bone analysis by QCT correlated with histomorphometry with r = 86 to .93, depending on the parameter. Both techniques confirmed that Ovx had substantially less bone than Sham, with greater loss of trabecular bone in the proximal tibia than vertebrae. Both techniques showed that RA had effects similar to but not identical with EE2 in preventing bone loss in vertebrae and tibiae. ABP partially prevented loss of bone in L-5, but was not significantly different from Ovx in the proximal tibia. This may be caused by ABP suppression of bone apposition, beyond effects observed for EE2 or RA. RA appeared to be more similar to EE2 because ABP significantly depressed bone formation (bone formation rate, mineral apposition rate) to below RA or EE2 levels, especially in L-5. Mechanical loading to failure of L-6 vertebrae showed a rank order of vertebral strength of Sham > RA > EE2 > Ovx > ABP, although significant differences were not observed between treatment groups. These data show that ABP suppression of bone formation can affect bone quality with long-term treatment. In other tissues, RA had minimal uterine effects, while significantly lowering serum cholesterol to below EE2-treated levels. Both EE2 and RA rats had significantly lower body weights than the other groups. ABP had no effect on serum lipids, uterine weight or body weight. Therefore, RA appears to have a broader range of desirable effects on bone, body weight, uteri and cholesterol than ABP or EE2 in ovariectomized rats.

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