Abstract
We aimed to investigate the effects of the aromatase inhibitor letrozole on femur fracture and serum levels of alkaline phosphatase (ALP), calcium and phosphate in female rats. Intact 32 Sprague-Dawley female rats were divided into four groups (n=8): control, letrozole 0.2 , letrozole 1 (treatment of 0.2 and 1 mg/kg for six weeks) and recovery (letrozole-treated 1 mg/kg for six weeks then allowed to recover for two weeks). Besides, 24 ovariectomized rats were divided into three groups (n=8): ovariectomized+control, ovariectomized+letrozole and ovariectomized+letrozole+ estradiol (10 μg/rat). After experimental period, rats’ femur bones were removed for biomechanical studies following decapitation. Serum ALP, calcium and phosphate were measured. Biomechanical values, ALP and phosphate significantly increased by letrozole in a dose-dependent manner (p<0.05) while calcium levels and net bone area decreased (p<0.05). Ultimate strength was positively correlated with ALP and phosphate and negatively correlated with calcium. The results indicate that letrozole may increase risk of bone fracture and affect bone biomarkers such as ALP, calcium and phosphate in both intact and ovariectomized rats.
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Ramaswamy B., Shapiro C.L. (2003) Osteopenia and osteoporosis in women with breast cancer.Semin Oncol,30, 763–75.
Garnero P., Sornay-Rendu E., Chapuy M.C., Delmas P.D. (1996) Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis.J Bone Miner Res,11, 337–49.
Gelber R.D., Bonetti M., Castiglione-Gertsch M., Coates A.S., Goldhirsch A. (2003) Tailoring adjuvant treatments for the individual breast cancer patient.Breast,12, 558–68.
Goss P.E., Ingle J.N., Martino S., Robert N.J., Muss H.B., Piccart M.J., Castiglione M., Tu D., Shepherd L.E., Pritchard K.I., Livingston, R.B., Davidson N.E., Norton L., Perez E.A., Abrams J.S., Therasse P., Palmer M.J., Pater J.L. (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.N Engl J Med,349, 1793–802.
Gail M.H., Costantino J.P., Bryant J., Croyle R., Freedman L., Helzlsouer K., Vogel V. (1999) Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer.J Natl Cancer Inst,91, 1829–46.
Cole P.A., Robinson C.H. (1990) Mechanism and inhibition of cytochrome P-450 aromatase.J Med Chem,33, 2933–42.
Santen R.J., Manni A., English H.F., Heitjan D. (1990) Androgen-primed chemotherapy-experimental confirmation of efficacy.J Steroid Biochem Mol Biol,37, 1115–20.
Howell A., Buzdar A. (2005) Are aromatase inhibitors superior to antiestrogens?J Steroid Biochem Mol Biol,93, 237–47.
Osborne C., Tripathy D. (2005) Aromatase inhibitors: rationale and use in breast cancer.Annu Rev Med,56, 103–16.
Kilic-Okman T., Kucuk M., Altaner S. (2003) Comparison of the effects of letrozole and clomiphene citrate on ovarian follicles, endometrium, and hormone levels in the rat.Fertil Steril,80, 1330–2.
Pérez E.A., Weilbaecher K. (2006) Aromatase inhibitors and bone loss.Oncology (Williston Park),20, 1029–39; discussion 1039-40, 1042, 1048.
Goss P.E., Ingle J.N., Martino S., Robert N.J., Muss H.B., Piccart M.J., Castiglione M., Tu D., Shepherd L.E., Pritchard K.I., Livingston R.B., Davidson N.E., Norton L., Perez E.A., Abrams J.S., Cameron D.A., Palmer M.J., Pater J.L. (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17.J Natl Cancer Inst,97, 1262–71.
Howell A., Cuzick J., Baum M., Buzdar A., Dowsett M., Forbes J.F., Hoctin-Boes G., Houghton J., Locker G.Y., Tobias J.S. (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer.Lancet,365, 60–2.
Heshmati H.M., Khosla S., Robins S.P., O’Fallon W.M., Melton L.J., Riggs B.L. (2002) Role of low levels of endogenous estrogen in regulation of bone resorption in late postmenopausal women.J Bone Miner Res,17, 172–8.
Gasser J.A., Green J.R., Shen V., Ingold P., Rebmann A., Bhatnagar A.S., Evans D.B. (2006) A single intravenous administration of zoledronic acid prevents the bone loss and mechanical compromise induced by aromatase inhibition in rats.Bone,39, 787–95.
Coombes R.C., Hall E., Gibson L.J., Paridaens R., Jassem J., Delozier T., Jones S.E., Alvarez I., Bertelli G., Ortmann O., Coates A.S., Bajetta E., Dodwell D., Coleman R.E., Fallowfield L.J., Mickiewicz E., Andersen J., Lonning P.E., Cocconi G., Stewart A., Stuart N., Snowdon C.F., Carpentieri M., Massimini G., Bliss J.M., van de Velde C. (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.N Engl J Med,350, 1081–92.
Coates A.S., Keshaviah A., Thurlimann B., Mouridsen H., Mauriac L., Forbes J.F., Paridaens R., Castiglione-Gertsch M., Gelber R.D., Colleoni M., Lang I., Del Mastro L., Smith I., Chirgwin J., Nogaret J.M., Pienkowski T., Wardley A., Jakobsen E.H., Price K.N., Goldhirsch A. (2007) Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrineresponsive early breast cancer: update of study BIG 1–98.J Clin Oncol,25, 486–92.
Thurlimann B., Keshaviah A., Coates A.S., Mouridsen H., Mauriac L., Forbes J.F., Paridaens R., Castiglione-Gertsch M., Gelber R.D., Rabaglio M., Smith I., Wardley A., Price K.N., Goldhirsch A. (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.N Engl J Med,353, 2747–57.
Pérez E.A., Josse R.G., Pritchard K.I., Ingle J.N., Martino S., Findlay B.P., Shenkier T.N., Tozer R.G., Palmer M.J., Shepherd L.E., Liu S., Tu D., Goss P.E. (2006) Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17.J Clin Oncol,24, 3629–35.
Eastell R. (2007) Aromatase inhibitors and bone.J Steroid Biochem Mol Biol,106, 157–61.
Harper-Wynne C., Ross G., Sacks N., Salter J., Nasiri N., Iqbal J., A’Hern R., Dowsett M. (2002) Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention.Cancer Epidemiol Biomarkers Prev,11, 614–21.
Eghbali-Fatourechi G., Khosla S., Sanyal A., Boyle W.J., Lacey D.L., Riggs B.L. (2003) Role of RANK ligand in mediating increased bone resorption in early postmenopausal women.J Clin Invest,111, 1221–30.
Aydin M., Yilmaz B., Alcin E., Nedzvetsky V.S., Sahin Z., Tuzcu M. (2008) Effects of letrozole on hippocampal and cortical catecholaminergic neurotransmitter levels, neural cell adhesion molecule expression and spatial learning and memory in female rats.Neuroscience,151, 186–94.
Ross P.D., Kress B.C., Parson R.E., Wasnich R.D., Armour K.A., Mizrahi I.A. (2000) Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective study.Osteoporos Int,11, 76–82.
National Osteoporosis Foundation InNational Osteoporosis Foundation: Physician’s Guide to Prevention and Treatment of Osteoporosis. (2003). Available at http: // www.nof.org Washington, DC.
Kumru S., Yildiz A.A., Yilmaz B., Sandal S., Gurates B. (2007) Effects of aromatase inhibitors letrozole and anastrazole on bone metabolism and steroid hormone levels in intact female rats.Gynecol Endocrinol,23, 556–61.
Benito M., Gomberg B., Wehrli F.W., Weening R.H., Zemel B., Wright A.C., Song H.K., Cucchiara A., Snyder P.J. (2003) Deterioration of trabecular architecture in hypogonadal men.J Clin Endocrinol Metab,88, 1497–502.
Bagi C.M., Hanson N., Andresen C., Pero R., Lariviere R., Turner C.H., Laib A. (2006) The use of micro-CT to evaluate cortical bone geometry and strength in nude rats: correlation with mechanical testing, pQCT and DXA.Bone,38, 136–44.
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Yonden, Z., Aydin, M., Alcin, E. et al. Effects of letrozole on bone biomarkers and femur fracture in female rats. J Physiol Biochem 65, 267–275 (2009). https://doi.org/10.1007/BF03180579
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DOI: https://doi.org/10.1007/BF03180579