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

M Sato, HU Bryant, P Iversen, J Helterbrand, F Smietana, K Bemis, R Higgs, CH Turner, I Owan, Y Takano and DB Burr

Department of Endocrine Research or Statistics, Lilly Research Laboratories, Indianapolis, Indiana, USA.

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 ovariectomized rats treated with fully efficacious doses of raloxifene (RA), 17 alpha-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.

Volume 279, Issue 1, pp. 298-305, 10/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				Y. L. Ma, H. U. Bryant, Q. Zeng, A. Schmidt, J. Hoover, H. W. Cole, W. Yao, W. S. S. Jee, and M. Sato New Bone Formation with Teriparatide [Human Parathyroid Hormone-(1-34)] Is Not Retarded by Long-Term Pretreatment with Alendronate, Estrogen, or Raloxifene in Ovariectomized Rats Endocrinology, May 1, 2003; 144(5): 2008 - 2015. [Abstract] [Full Text] [PDF]

				A. Saitta, D. Altavilla, D. Cucinotta, N. Morabito, N. Frisina, F. Corrado, R. D'Anna, A. Lasco, G. Squadrito, A. Gaudio, et al. Randomized, Double-Blind, Placebo-Controlled Study on Effects of Raloxifene and Hormone Replacement Therapy on Plasma NO Concentrations, Endothelin-1 Levels, and Endothelium-Dependent Vasodilation in Postmenopausal Women Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1512 - 1519. [Abstract] [Full Text] [PDF]

				K. M. Prestwood, M. Gunness, D. B. Muchmore, Y. Lu, M. Wong, and L. G. Raisz A Comparison of the Effects of Raloxifene and Estrogen on Bone in Postmenopausal Women J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2197 - 2202. [Abstract] [Full Text]

				V. C. Jordan and M. Morrow Tamoxifen, Raloxifene, and the Prevention of Breast Cancer Endocr. Rev., June 1, 1999; 20(3): 253 - 278. [Abstract] [Full Text]

				W. Khovidhunkit and D. M. Shoback Clinical Effects of Raloxifene Hydrochloride in Women Ann Intern Med, March 2, 1999; 130(5): 431 - 439. [Abstract] [Full Text] [PDF]

				B. S. McEwen, P. Tanapat, and N. G. Weiland Inhibition of Dendritic Spine Induction on Hippocampal CA1 Pyramidal Neurons by a Nonsteroidal Estrogen Antagonist in Female Rats Endocrinology, March 1, 1999; 140(3): 1044 - 1047. [Abstract] [Full Text]

				M. Sato, G. Q. Zeng, E. Rowley, and C. H. Turner LY353381{middle dot}HCl: An Improved Benzothiophene Analog with Bone Efficacy Complementary to Parathyroid Hormone-(1-34) Endocrinology, November 1, 1998; 139(11): 4642 - 4651. [Abstract] [Full Text] [PDF]

				M. Sato, C. H. Turner, T. Wang, M. D. Adrian, E. Rowley, and H. U. Bryant LY353381.HCl: A Novel Raloxifene Analog with Improved SERM Potency and Efficacy In Vivo J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 1 - 7. [Abstract] [Full Text]

				J. I. Macgregor and V. C. Jordan Basic Guide to the Mechanisms of Antiestrogen Action Pharmacol. Rev., June 1, 1998; 50(2): 151 - 196. [Abstract] [Full Text] [PDF]

				T. B. Clarkson, M. S. Anthony, and C. P. Jerome Lack of Effect of Raloxifene on Coronary Artery Atherosclerosis of Postmenopausal Monkeys J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 721 - 726. [Abstract] [Full Text]

				T. Österman, L. Laurén, P. Kuurtamo, R. Hannuniemi, P. Isaksson, K. Kippo, Z. Peng, H. K. Väänänen, and R. Sellman The Effect of Orally Administered Clodronate on Bone Mineral Density and Bone Geometry in Ovariectomized Rats J. Pharmacol. Exp. Ther., January 1, 1998; 284(1): 312 - 316. [Abstract] [Full Text]

				M. Sato, G. Q. Zeng, and C. H. Turner Biosynthetic Human Parathyroid Hormone (1-34) Effects on Bone Quality in Aged Ovariectomized Rats Endocrinology, October 1, 1997; 138(10): 4330 - 4337. [Abstract] [Full Text] [PDF]