Association Between Simvastatin Therapy and Bone Health in Cyclophosphamide-Induced Osteoporosis in Rats

Dawood, Attaa S.; Bairam, Ahsan F.

doi:10.29079/qjvms.2023.183396

	Association Between Simvastatin Therapy and Bone Health in Cyclophosphamide-Induced Osteoporosis in Rats
Al-Qadisiyah Journal of Veterinary Medicine Sciences
Volume 22, Issue 2, September 2023, Pages 56-63 PDF (397.53 K)
Document Type: Research Paper
DOI: 10.29079/qjvms.2023.183396
Authors
Attaa S. Dawood; Ahsan F. Bairam^*
Department of Pharmacology and toxicology, Faculty of Pharmacy, University of Kufa, Kufa, Iraq.
Abstract
Osteoporosis, including drug-induced type, is a crucial health problem because it affects directly the quality of life and increases mortality. Simvastatin (SIM), shares the mevalonate pathway as nitrogen-containing bisphosphonate drugs which may impose a beneficial effect on bone health. This study aimed to explore the beneficial effects of SIM alone or in combination with alendronate (ALD) to prevent cyclophosphamide (CPA)-induced osteoporosis in rats. Six study groups (n = 7 rats each) were generated from 42 healthy female albino rats at the age of six months: Group 1 (control) received 1 ml/day of 0.9% NaCl orally for 6 weeks. Group 2 received CPA (4.5 mg/kg/day) orally for 15 days. Group 3 received ALD (1 mg/kg/day) orally for 6 weeks plus CPA. Group 4 received SIM (20 mg/kg/day) orally for 6 weeks plus CPA. Group 5 received a combination of the corresponding doses of ALD plus SIM in addition to CPA. Group 6 received SIM alone orally for 6 weeks. Finally, serum receptor activator of nuclear factor kappa-β ligand (RANKL) and tartrate-resistant acid phosphatase-5b (TRACP-5b) levels were evaluated in addition to the histopathological analysis of the right tibia. The osteoporosis effect of CPA was significantly reduced by SIM. Additionally, it is interesting to note that ALD plus SIM combination demonstrated an additional protective effect against osteoporosis compared to mono-therapy. Our findings suggest that SIM may be associated with bone-protective effect, the combination therapy administered group demonstrated an extra protective effect compared to mono-therapy.
Keywords
Simvastatin; osteoporosis; cyclophosphamide; alendronate; bones

References
1. Barnsley J, Buckland G, Chan PE, Ong A, Ramos AS, Baxter M, et al. Pathophysiology and treatment of osteoporosis: challenges for clinical practice in older people. Aging Clin Exp Res. 2021 Apr;33:759-73.https://doi.org/10.1007/s40520-021-01817-y 2. Fouad M. Anti-osteoporotic drug use and quality of life in persons with osteoporosis-The Tromsø Study (Master's thesis, UiT Norges arktiske universitet). Available from:https://munin.uit.no/handle/10037/12337 3. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006 Dec;17:1726-33. https://doi.org/10.1007/s00198-006-0172-4 4. Berry SD, Kiel DP, Donaldson MG, Cummings SR, Kanis JA, Johansson H, et al. Application of the National Osteoporosis Foundation Guidelines to postmenopausal women and men: the Framingham Osteoporosis Study. Osteoporos Int. 2010 Jan;21:53-60. https://doi.org/10.1007/s00198-009-1127-3 5. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002 May 18;359(9319):1761-7. https://doi.org/10.1016/S0140-6736(02)08657-9 6. Kenkre JS, Bassett JH. The bone remodelling cycle. Ann Clin Biochem. 2018 May;55(3):308-27.https://doi.org/10.1177/0004563218759371 7. Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci. 2006 Dec;1092(1):385-96.https://doi.org/10.1196/annals.1365.035 8. Ferrari SL, Roux C, editors. Pocket Reference to Osteoporosis. Springer International Publishing; 2019.https://doi.org/10.1007/978-3-319-26757-9 9. Maeda K, Yoshida K, Nishizawa T, Otani K, Yamashita Y, Okabe H, et al. Inflammation and bone metabolism in rheumatoid arthritis: molecular mechanisms of joint destruction and pharmacological treatments. Int J Mol Sci. 2022 Mar 6;23(5):2871.https://doi.org/10.3390/ijms23052871 10. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3540-5.https://doi.org/10.1073/pnas.96.7.3540 11. Simonet WS, Lacey DL, Dunstan CR, Kelley MC, Chang MS, Lüthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997 Apr 18;89(2):309-19.https://doi.org/10.1016/S0092-8674(00)80209-3 12. Kang MJ, Lim JS. Bone mineral density deficits in childhood cancer survivors: Pathophysiology, prevalence, screening, and management. Korean J Pediatr. 2013 Feb;56(2):60.https://doi.org/10.3345/kjp.2013.56.2.60 13. Pei Y, Zheng K, Shang G, Wang Y, Wang W, Qiu E, et al. Therapeutic effect of strontium ranelate on bone in chemotherapy-induced osteopenic rats via increased bone volume and reduced bone loss. Biol Trace Elem Res. 2019 Feb;187:472-81.https://doi.org/10.1007/s12011-018-1401-3 14. Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol. 2002 Dec 15;20(24):4628-35. https://doi.org/10.1200/JCO.2002.05.042 15. Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol. 2001 Jul 15;19(14):3306-11.https://doi.org/10.1200/JCO.2001.19.14.3306 16. Oostra DR, Lustberg MB, Reinbolt RE, Pan X, Wesolowski R, Shapiro CL. Association of osteoprotegerin and bone loss after adjuvant chemotherapy in early-stage breast cancer. Mol Cell Endocrinol. 2015 Feb 15;402:51-6. https://doi.org/10.1016/j.mce.2014.12.028 17. Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, et al. Estrogen prevents bone loss via estrogen receptor α and induction of Fas ligand in osteoclasts. Cell. 2007 Sep 7;130(5):811-23.https://doi.org/10.1016/j.cell.2007.07.025 18. Manolagas SC, O'brien CA, Almeida M. The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol. 2013 Dec;9(12):699. https://doi.org/10.1038/nrendo.2013.179 19. Plowchalk DR, Mattison DR. Reproductive toxicity of cyclophosphamide in the C57BL/6N mouse: 1. Effects on ovarian structure and function. Reprod Toxicol. 1992 Sep 1;6(5):411-21.https://doi.org/10.1016/0890-6238(92)90004-D 20. Zaidi M, Blair HC, Iqbal J, Zhu LL, Kumar TR, Zallone A, et al. Proresorptive actions of FSH and bone loss. Ann N Y Acad Sci. 2007 Nov;1116(1):376-82. https://doi.org/10.1196/annals.1402.056 21. Delmas PD. Treatment of postmenopausal osteoporosis. Lancet. 2002 Jun 8;359(9322):2018-26.https://doi.org/10.1016/S0140-6736(02)08827-X 22. Cruz AC, Gruber BL. Statins and osteoporosis: can these lipid-lowering drugs also bolster bones? Cleve Clin J Med. 2002 Apr 1;69(4):277-8. https://doi.org/10.3949/ccjm.69.4.277 23. Singh M, Gonegandla GS. Bisphosphonate-induced osteonecrosis of the jaws (BIONJ). J Maxillofac Oral Surg. 2020 Jun;19:162-7.https://doi.org/10.1007/s12663-019-01211-2 24. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest. 2005 Dec 1;115(12):3318-25. https://doi.org/10.1172/JCI27071 25. Grundy SM, Stone NJ. 2018 American Heart Association/American College of Cardiology/Multisociety Guideline on the Management of Blood Cholesterol-Secondary Prevention. JAMA Cardiol. 2019 Jun 1;4(6):589-91.https://doi.org/10.1001/jamacardio.2019.0911 26. Moghadasian MH. Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Life Sci.1999 Aug 20;65(13):1329-37. Available from:https://www.sciencedirect.com/science/article/abs/pii/S002432059900199X 27. Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, et al. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999 Dec 3;286(5446):1946-9.https://doi.org/10.1126/science.286.5446.1946 28. Yu Q, Lyu S, Cui L, Wu T. Preventive effects of CoQ10 on trabecular microstructure and biomechanical properties of femur in a rat model of cyclophosphamide-induced bone loss. Chin Pharm Bull. 2015;31(3):421-5. Available from:https://web.s.ebscohost.com/abstract?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=10067108&AN=130214505&h 29. Wang W, Gao Y, Liu H, Feng W, Li X, Guo J, Li M. Eldecalcitol, an active vitamin D analog, effectively prevents cyclophosphamide‑induced osteoporosis in rats. Exp Ther Med. 2019 Sep 1;18(3):1571-80. Available from: https://www.spandidos-publications.com/etm/18/3/1571 30. Jin J, Zhang X, Lu Z, Li Y, Lopes‐Virella MF, Yu H, et al. Simvastatin inhibits lipopolysaccharide‐induced osteoclastogenesis and reduces alveolar bone loss in experimental periodontal disease. J Periodontal Res. 2014 Aug;49(4):518-26. https://doi.org/10.1111/jre.12132 31. Cole ZA, Dennison EM, Cooper C. Osteoporosis epidemiology update. Curr Rheumatol Rep. 2008;10(2):92-6. https://doi.org/10.1007/s11926-008-0017-6 32. Song C, Wang J, Song Q, Li X, Chen Z, Ma Q, et al. Simvastatin induces estrogen receptor-alpha (ER-alpha) in murine bone marrow stromal cells. J Bone Miner Metab. 2008;26(3):213-7.https://doi.org/10.1007/s00774-007-0820-6 33. Rachner TD, Coleman R, Hadji P, Hofbauer LC. Bone health during endocrine therapy for cancer. Lancet Diabetes Endocrinol. 2018;6(11):901-10. https://doi.org/10.1016/S2213-8587(18)30047-0 34. Li Y, Zhang R, Ren M, Liu H, Yang M. Experimental study on the effects of simvastatin in reversing the femoral metaphyseal defects induced by sodium valproate in normal and ovariectomized rats. Heliyon. 2022;8(9):e10480. https://doi.org/10.1016/j.heliyon.2022.e10480 35. Xu XC, Chen H, Zhang X, Zhai ZJ, Liu XQ, Qin A, Lu EY. Simvastatin prevents alveolar bone loss in an experimental rat model of periodontitis after ovariectomy. J Transl Med. 2014;12:1-9. https://doi.org/10.1186/s12967-014-0284-0 36. Russell RG. Bisphosphonates: from bench to bedside. Ann N Y Acad Sci. 2006 Apr;1068(1):367-401.https://doi.org/10.1196/annals.1346.041 37. Mansueto P, Vitale G, Seidita A, Guarneri FP, Pepe I, Rinollo C, et al. Mevalonate pathway: role of bisphosphonates and statins. Acta Med Mediterr. 2011 Jan 1;27(2):85-95. Available from: https://core.ac.uk/download/pdf/53273434.pdf Lin S, Huang J, Fu Z, Liang Y, Wu H, Xu L, et al. The effects of atorvastatin on the prevention of osteoporosis and dyslipidemia in the high-fat-fed ovariectomized rats. Calcif Tissue Int. 2015 Jun;96:541-51.https://doi.org/10.1007/s00223-015-9975-7
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