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Effects of raloxifene and estradiol on bone turnover parameters in intact and ovariectomized rats

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Abstract

This study was designed to investigate effects of raloxifene (RLX) and estradiol on bone formation and resorption in intact and ovariectomized (ovx) rat models. In the intact model, a total of 24 adult female rats were divided into three groups: Controls subcutaneously received saline alone. RLX (2 mg/kg) and estradiol (30 μg/kg) were injected to two groups of animals for a period of 6 weeks at two daily intervals. In the second model, rats (n = 24) were ovx and allowed to recover for a period of at least 3 weeks. Control group received vehicle alone. Remaining rats were divided into two groups and injected with RLX (2 mg/kg) and estradiol (30 µg/kg) for 6 weeks. Urine samples were collected from all animals 24 h after the last drug administration. Urinary deoxypyridinoline (DPD) was measured by ELISA. Serum parathyroid hormone (PTH), calcitonin, and osteocalcin levels were measured by immunoradiometric method. Serum concentrations of alkaline phosphatase (ALP), Ca, and inorganic phosphate were determined by enzymatic–colorimetric method. Lumbar vertebrae (L2) of all animals were dissected out and processed for histopathological evaluation. Removal of ovaries significantly elevated urinary DPD levels (p < 0.01) compared with intact controls. Treatment of both intact and ovx rats with estradiol resulted in significant decreases (p < 0.01) in DPD values. RLX administration had no significant effect in the intact rats, but it remarkably reduced bone turnover in the ovx animals (p < 0.001). Both estradiol and RLX produced conflicting effects on serum ALP, osteocalcin, and PTH levels in both animal models. These findings suggest that RLX exerts its protective effects by reducing bone resorption, similar to that of estradiol, in ovx rats.

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References

  1. Allen MR, Gineyts E, Leeming DJ, Burr DB, Delmas PD (2008) Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra. Osteoporos Int 19:329–337

    Article  PubMed  CAS  Google Scholar 

  2. Bryant HU, Glasebrook AL, Yang NN, Sato M (1999) An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem 69:37–44

    Article  CAS  Google Scholar 

  3. Buelke-Sam J, Bryant HU, Francis PC (1998) The selective estrogen receptor modulator, raloxifene: an overview of nonclinical pharmacology and reproductive and developmental testing. Reprod Toxicol 12:217–221

    Article  PubMed  CAS  Google Scholar 

  4. Cakmak A, Posaci C, Dogan E, Caliskan S, Guclu S, Altunyurt S (2005) Raloxifene increases serum leptin levels in postmenopausal women: a prospective study. Am J Obstet Gynecol 193:347–351

    Article  PubMed  CAS  Google Scholar 

  5. Castracane VD, Kraemer GR, Ogden BW, Kraemer RR (2006) Inter-relationships of serum estradiol, estrone, and estrone sulfate, adiposity, biochemical bone markers, and leptin in post-menopausal women. Maturitas 53:217–225

    Article  PubMed  CAS  Google Scholar 

  6. Cheung J, Mak YT, Papaioannou S, Evans BA, Fogelman I, Hampson G (2003) IL-6, IL-1, RANKL and osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene. J Endocrinol 177:423–433

    Article  PubMed  CAS  Google Scholar 

  7. Clowes JA, Riggs BL, Khosla S (2005) The role of the immune system in the pathophysiology of osteoporosis. Immunol Rev 208:207–227

    Article  PubMed  CAS  Google Scholar 

  8. Curiel MD, Calero JA, Guerrero R, Gala J, Gazapo R, de la Piedra C (1998) Effects of LY-117018 HCl on bone remodeling and mineral density in the oophorectomized rat. Am J Obstet Gynecol 178:320–325

    Article  PubMed  CAS  Google Scholar 

  9. Davis AM, Ellersieck MR, Grimm KM, Rosenfeld CS (2006) The effects of the selective estrogen receptor modulators, methyl-piperidino-pyrazole (MPP), and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus. Mol Reprod Dev 73:1034–1044

    Article  PubMed  CAS  Google Scholar 

  10. De Leo V, Ditto A, la Marca A, Lanzetta D, Massafra C, Morgante G (2000) Bone mineral density and biochemical markers of bone turnover in peri- and postmenopausal women. Calcif Tissue Int 66:263–267

    Article  PubMed  Google Scholar 

  11. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C (1997) Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641–1647

    Article  PubMed  CAS  Google Scholar 

  12. Delmas PD, Davis SR, Hensen J, Adami S, van Os S, Nijland EA (2008) Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women. Osteoporos Int 19:1153–1160

    Article  PubMed  CAS  Google Scholar 

  13. Diez JL (2000) Skeletal effects of selective oestrogen receptor modulators (SERMs). Hum Reprod Updat 6:255–258

    Article  CAS  Google Scholar 

  14. Epstein E, Silver J, Almogi G, Livni N, Naveh-Many T (1996) Parathyroid hormone mRNA levels are increased by progestins and vary during rat estrous cycle. Am J Physiol-Endocrinol Metab 270:E158–163

    CAS  Google Scholar 

  15. Erben RG, Brunner KS, Breig B (2004) Long-term sensitivity of uterus and hypothalamus/pituitary axis to 17beta-estradiol is higher than that of bone in rats. J Bone Miner Res 19:1827–1832

    Article  PubMed  CAS  Google Scholar 

  16. Evans GL, Bryant HU, Magee DE, Turner RT (1996) Raloxifene inhibits bone turnover and prevents further cancellous bone loss in adult ovariectomized rats with established osteopenia. Endocrinology 137:4139–4144

    Article  PubMed  CAS  Google Scholar 

  17. Fiorelli G, Brandi ML (1999) Skeletal effects of estrogens. J Endocrinol Investig 22:589–593

    CAS  Google Scholar 

  18. Hansdottir H, Franzson L, Prestwood K, Sigurdsson G (2004) The effect of raloxifene on markers of bone turnover in older women living in long-term care facilities. J Am Geriat Soc 52:779–783

    Article  PubMed  Google Scholar 

  19. Horn LC, Dietel M, Einenkel J (2005) Hormone replacement therapy (HRT) and endometrial morphology under consideration of the different molecular pathways in endometrial carcinogenesis. Eur J Obstet Gynecol Reprod Biol 122:4–12

    Article  PubMed  CAS  Google Scholar 

  20. Iwamoto J, Yeh JK, Schmidt A, Rowley E, Stanfield L, Takeda T, Sato M (2005) Raloxifene and vitamin K2 combine to improve the femoral neck strength of ovariectomized rats. Calcif Tissue Int 77:119–126

    Article  PubMed  CAS  Google Scholar 

  21. Jarvinen TL, Kannus P, Sievanen H (2003) Estrogen and bone—a reproductive and locomotive perspective. J Bone Miner Res 18:1921–1931

    Article  PubMed  Google Scholar 

  22. Lane NE (2006) Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol 194:S3–11

    Article  PubMed  CAS  Google Scholar 

  23. Li X, Takahashi M, Kushida K, Inoue T (1998) The preventive and interventional effects of raloxifene analog (LY117018 HCL) on osteopenia in ovariectomized rats. J Bone Miner Res 13:1005–1010

    Article  PubMed  CAS  Google Scholar 

  24. Martel C, Picard S, Richard V, Belanger A, Labrie C, Labrie F (2000) Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat. J Steroid Biochem 74:45–56

    Article  CAS  Google Scholar 

  25. McClung MR, Siris E, Cummings S, Bolognese M, Ettinger M, Moffett A, Emkey R, Day W, Somayaji V, Lee A (2006) Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene. Menopause 13:377–386

    Article  PubMed  Google Scholar 

  26. Miller PD, Baran DT, Bilezikian JP, Greenspan SL, Lindsay R, Riggs BL, Watts NB (1999) Practical clinical application of biochemical markers of bone turnover: consensus of an expert panel. J Clin Densitom 2:323–342

    Article  PubMed  CAS  Google Scholar 

  27. Murano T, Izumi S, Kika G, Haque SF, Okuwaki S, Mori A, Suzuki T, Matsubayashi H, Ikeda M, Goya K, Makino T (2003) Impact of menopause on lipid and bone metabolism and effect of hormone replacement therapy. Tokai J Exp Clin Med 28:109–119

    PubMed  CAS  Google Scholar 

  28. Palomba S, Numis FG, Mossetti G, Rendina D, Vuotto P, Russo T, Zullo F, Nappi C, Nunziata V (2003) Raloxifene administration in post-menopausal women with osteoporosis: effect of different BsmI vitamin D receptor genotypes. Hum Reprod 18:192–8

    Article  PubMed  CAS  Google Scholar 

  29. Prestwood KM, Gunness M, Muchmore DB, Lu Y, Wong M, Raisz LG (2000) A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women. J Clin Endocrinol Metab 85:2197–2202

    Article  PubMed  CAS  Google Scholar 

  30. Reginster JY, Devogelaer JP (2006) Raloxifene reduces fractures in postmenopausal women with osteoporosis. Clin Orthop Relat Res 443:48–54

    Article  PubMed  Google Scholar 

  31. Saitta A, Morabito N, Frisina N, Cucinotte D, Corrado F, D'Anna R, Altavilla D, Squadrito G, Minutoli L, Arcoraci V, Cancellieri F, Squadrito F (2001) Cardiovascular effects of raloxifene hydrochloride. Cardiovasc Drug Rev 19:57–74

    Article  PubMed  CAS  Google Scholar 

  32. Schulz SR, Morris HA (1999) Ionized calcium and bone turnover in the estrogen-deficient rat. Calcif Tissue Int 65:78–82

    Article  PubMed  CAS  Google Scholar 

  33. Seibel MJ (2005) Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev 26:97–122

    PubMed  Google Scholar 

  34. Seidlova-Wuttke D, Jarry H, Wuttke W (2004) Pure estrogenic effect of benzophenone-2 (BP2) but not of bisphenol A (BPA) and dibutylphtalate (DBP) in uterus, vagina and bone. Toxicology 205:103–112

    Article  PubMed  CAS  Google Scholar 

  35. Temrine JD, Wong M (1998) Post-menopausal women and osteoporosis: available choices for maintenance of skeletal health. Maturitas 30:241–245

    Article  Google Scholar 

  36. Tormey SM, Malone CM, McDermott EW, O'Higgins NJ, Hill AD (2006) Current status of combined hormone replacement therapy in clinical practice. Clin Breast Cancer, Suppl 2:S51–57

    Article  Google Scholar 

  37. Uebelhart D, Gineyts E, Chapuy MC, Delmas PD (1990) Urinary excretion of pyridinium crosslinks. A new marker of bone resorption in metabolic bone disease. Bone Miner 8:87–96

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank Novartis Turkey for providing RLX used in the present study and to Dr. Yusuf Turkoz of Inonu University Medical School for his courtesy in biochemical assays.

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  1. S. Canpolat

    Present address: Department of Physiology, Karadeniz Technical University, Medical School, Trabzon, Turkey

Authors and Affiliations

  1. Faculty of Medicine, Department of Physiology, Yeditepe University, Istanbul, Turkey

    S. Canpolat & B. Yilmaz

  2. Faculty of Medicine, Department of Obstetrics and Gynaecology, Fırat University, Elazığ, Turkey

    N. Tug & S. Kumru

  3. Faculty of Medicine, Department of Physiology, Fırat University, Elazığ, Turkey

    A. D. Seyran

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  1. S. Canpolat
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Correspondence to B. Yilmaz.

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Canpolat, S., Tug, N., Seyran, A.D. et al. Effects of raloxifene and estradiol on bone turnover parameters in intact and ovariectomized rats. J Physiol Biochem 66, 23–28 (2010). https://doi.org/10.1007/s13105-010-0008-8

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  • DOI: https://doi.org/10.1007/s13105-010-0008-8

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