Eldecalcitol, an active vitamin D analog, effectively prevents cyclophosphamide‑induced osteoporosis in rats

Wang,Wei; Gao,Yuan; Liu,Hongrui; Feng,Wei; Li,Xiaoyan; Guo,Jie; Li,Minqi

doi:10.3892/etm.2019.7759

Eldecalcitol, an active vitamin D analog, effectively prevents cyclophosphamide‑induced osteoporosis in rats

Authors:
- Wei Wang
- Yuan Gao
- Hongrui Liu
- Wei Feng
- Xiaoyan Li
- Jie Guo
- Minqi Li
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Affiliations: Department of Bone Metabolism, School of Stomatology, Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, Shandong 250012, P.R. China, Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong 250001, P.R. China
Published online on: July 9, 2019 https://doi.org/10.3892/etm.2019.7759
Pages: 1571-1580
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cyclophosphamide (CTX) as an alkylating agent is used for treating a range of tumor types and allergic diseases. However, high‑dose application may induce rapid bone loss and increase the risk of osteoporotic fractures. Eldecalcitol (ED‑71), a clinically approved active vitamin D analog, has been approved for osteoporosis treatment. It potently inhibited bone resorption while maintaining osteoblastic function in estrogen‑deficient and high‑turnover osteoporosis in model rats. The aim of the present study was to clarify the treatment effect of ED‑71 on bone loss in a well‑established rat model of osteoporosis with CTX administration. After 15 days of CTX treatment, ED‑71 was administered, while estradiol valerate (E2V) was used as a positive control. At 2 and 4 weeks after ED‑71 or E2V administration, rats were sacrificed and fixed. The tibiae were extracted for histochemical analysis using hematoxylin and eosin staining and immunohistochemistry. When compared with the untreated control group, the CTX group displayed clear osteoporotic features, including a decreased number of bone trabeculae and increased trabecular separation. ED‑71 and E2V successfully rescued CTX‑induced bone loss. The ED‑71 group displayed denser and increasingly mature trabecular bone than the E2V group. Furthermore, ED‑71 administration led to significant suppression of tartrate‑resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase 9 (MMP9), alkaline phosphatase (ALP) and Osteopontin (OPN), which was less pronounced than in E2V administration but was similar to the values exhibited in the normal control group. These results indicated that ED‑71 had a moderate and increased effect on bone turnover compared with E2V. Therefore, the present study suggests that ED‑71 is a potential inhibitor of CTX‑induced osteoporosis, successfully rescuing bone loss without excessively suppressing bone turnover, and may be a suitable treatment for preventing bone loss in patients receiving CTX.

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1	Drugs of choice for cancer. Treat Guidel Med Lett. 1:41–52. 2003.PubMed/NCBI
2	Swenerton K, Jeffrey J, Stuart G, Roy M, Krepart G, Carmichael J, Drouin P, Stanimir R, O'Connell G and MacLean G: Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: A randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 10:718–726. 1992. View Article : Google Scholar : PubMed/NCBI
3	Bonadonna G, Valagussa P, Moliterni A, Zambetti M and Brambilla C: Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med. 332:901–906. 1995. View Article : Google Scholar : PubMed/NCBI
4	The American Society of Health-System Pharmacists: Cyclophosphamide. https://www.drugs.com/monograph/cyclophosphamide.html8–May. 2018
5	Bines J, Oleske DM and Cobleigh MA: Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 14:1718–1729. 1996. View Article : Google Scholar : PubMed/NCBI
6	Saarto T, Blomqvist C, Välimäki M, Mäkelä P, Sarna S and Elomaa I: Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: A randomized study in premenopausal breast cancer patients. J Clin Oncol. 15:1341–1347. 1997. View Article : Google Scholar : PubMed/NCBI
7	Mattison DR, Chang L, Thorgeirsson SS and Shiromizu K: The effects of cyclophosphamide, azathioprine, and 6-mercaptopurine on oocyte and follicle number in C57BL/6N mice. Res Commun Chem Pathol Pharmacol. 31:155–161. 1981.PubMed/NCBI
8	Plowchalk DR and Mattison DR: Reproductive toxicity of cyclophosphamide in the C57BL/6N mouse: 1. Effects on ovarian structure and function. Reprod Toxicol. 6:411–421. 1992. View Article : Google Scholar : PubMed/NCBI
9	Wang TM and Shih C: Study of histomorphometric changes of the mandibular condyles in neonatal and juvenile rats after administration of cyclophosphamide. Acta Anat (Basel). 127:93–99. 1986. View Article : Google Scholar : PubMed/NCBI
10	Fan C, Georgiou KR, McKinnon RA, Keefe DM, Howe PR and Xian CJ: Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats. J Bone Miner Metab. 34:277–290. 2016. View Article : Google Scholar : PubMed/NCBI
11	Georgiou KR, Hui SK and Xian CJ: Regulatory pathways associated with bone loss and bone marrow adiposity caused by aging, chemotherapy, glucocorticoid therapy and radiotherapy. Am J Stem Cells. 1:205–224. 2012.PubMed/NCBI
12	Oostra DR, Lustberg MB, Reinbolt RE, Pan X, Wesolowski R and Shapiro CL: Association of osteoprotegerin and bone loss after adjuvant chemotherapy in early-stage breast cancer. Mol Cell Endocrinol. 402:51–56. 2015. View Article : Google Scholar : PubMed/NCBI
13	Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, 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. 20:4628–4635. 2002. View Article : Google Scholar : PubMed/NCBI
14	Shapiro CL and Recht A: Side effects of adjuvant treatment of breast cancer. N Engl J Med. 344:1997–2008. 2001. View Article : Google Scholar : PubMed/NCBI
15	Shapiro CL, Manola J and Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol. 19:3306–3311. 2001. View Article : Google Scholar : PubMed/NCBI
16	Vehmanen L, Saarto T, Elomaa I, Mäkelä P, Välimäki M and Blomqvist C: Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment. Eur J Cancer. 37:2373–2378. 2001. View Article : Google Scholar : PubMed/NCBI
17	Rizzoli R, Body JJ, Brandi ML, Cannata-Andia J, Chappard D, El Maghraoui A, Glüer CC, Kendler D, Napoli N, Papaioannou A, et al: Cancer-associated bone disease. Osteoporos Int. 24:2929–2953. 2013. View Article : Google Scholar : PubMed/NCBI
18	Atanes-Bonome P, Atanes-Bonome A, Rios-Lage P and Atanes-Sandoval AD: Bisphosphonate-related osteonecrosis of the jaw. Semergen. 40:143–148. 2014.(In Spanish). View Article : Google Scholar : PubMed/NCBI
19	Hatakeyama S, Yoshino M, Eto K, Takahashi K, Ishihara J, Ono Y, Saito H and Kubodera N: Synthesis and preliminary biological evaluation of 20-epi-eldecalcitol [20-epi-1alpha,25-dihydroxy-2beta- (3-hydroxypropoxy)vitamin D3: 20-epi-ED-71]. J Steroid Biochem Mol Biol. 121:25–28. 2010. View Article : Google Scholar : PubMed/NCBI
20	Saito H, Takeda S and Amizuka N: Eldecalcitol and calcitriol stimulates ‘bone minimodeling,’ focal bone formation without prior bone resorption, in rat trabecular bone. J Steroid Biochem Mol Biol. 136:178–182. 2013. View Article : Google Scholar : PubMed/NCBI
21	Sakai S, Endo K, Takeda S, Mihara M and Shiraishi A: Combination therapy with eldecalcitol and alendronate has therapeutic advantages over monotherapy by improving bone strength. Bone. 50:1054–1063. 2012. View Article : Google Scholar : PubMed/NCBI
22	Harada S, Mizoguchi T, Kobayashi Y, Nakamichi Y, Takeda S, Sakai S, Takahashi F, Saito H, Yasuda H, Udagawa N, et al: Daily administration of eldecalcitol (ED-71), an active vitamin D analog, increases bone mineral density by suppressing RANKL expression in mouse trabecular bone. J Bone Miner Res. 27:461–473. 2012. View Article : Google Scholar : PubMed/NCBI
23	Harada S, Takeda S, Uno A, Takahashi F and Saito H: Eldecalcitol is less effective in suppressing parathyroid hormone compared to calcitriol in vivo. J Steroid Biochem Mol Biol. 121:281–283. 2010. View Article : Google Scholar : PubMed/NCBI
24	Hatakeyama S, Nagashima S, Imai N, Takahashi K, Ishihara J, Sugita A, Nihei T, Saito H, Takahashi F and Kubodera N: Synthesis and biological evaluation of a 3-positon epimer of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71). J Steroid Biochem Mol Biol. 103:222–226. 2007. View Article : Google Scholar : PubMed/NCBI
25	Sato Y, Miyauchi Y, Yoshida S, Morita M, Kobayashi T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Tando T, et al: The vitamin D analogue ED71 but Not 1,25(OH)2D3 targets HIF1α protein in osteoclasts. PLoS One. 9:e1118452014. View Article : Google Scholar : PubMed/NCBI
26	Sakai S, Takeda S, Sugimoto M, Shimizu M, Shimonaka Y, Yogo K, Hashimoto J, Bauss F and Endo K: Treatment with the combination of ibandronate plus eldecalcitol has a synergistic effect on inhibition of bone resorption without suppressing bone formation in ovariectomized rats. Bone. 81:449–458. 2015. View Article : Google Scholar : PubMed/NCBI
27	Nakamichi Y, Udagawa N, Horibe K, Mizoguchi T, Yamamoto Y, Nakamura T, Hosoya A, Kato S, Suda T and Takahashi N: VDR in osteoblast-lineage cells primarily mediates vitamin D treatment-induced increase in bone mass by suppressing bone resorption. J Bone Miner Res. 32:1297–1308. 2017. View Article : Google Scholar : PubMed/NCBI
28	de Freitas PH, Hasegawa T, Takeda S, Sasaki M, Tabata C, Oda K, Li M, Saito H and Amizuka N: Eldecalcitol, a second-generation vitamin D analog, drives bone minimodeling and reduces osteoclastic number in trabecular bone of ovariectomized rats. Bone. 49:335–342. 2011. View Article : Google Scholar : PubMed/NCBI
29	Ettinger B, Genant HK and Cann CE: Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med. 102:319–324. 1985. View Article : Google Scholar : PubMed/NCBI
30	Hornby SB, Evans GP, Hornby SL, Pataki A, Glatt M and Green JR: Long-term zoledronic acid treatment increases bone structure and mechanical strength of long bones of ovariectomized adult rats. Calcif Tissue Int. 72:519–527. 2003. View Article : Google Scholar : PubMed/NCBI
31	Shibata T, Shira-Ishi A, Sato T, Masaki T, Masuda A, Hishiya A, Ishikura N, Higashi S, Uchida Y, Saito MO, et al: Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow. J Bone Miner Res. 17:622–629. 2002. View Article : Google Scholar : PubMed/NCBI
32	Xia W, Meng X and Xing X: Effects of estradoil valerate on osteoporosis in ovariectomized rats. Zhonghua Fu Chan Ke Za Zhi. 36:606–609. 2001.(In Chinese). PubMed/NCBI
33	Zhang Z, Song C, Fu X, Liu M, Li Y, Pan J, Liu H, Wang S, Xiang L, Xiao GG and Ju D: High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio. Int J Mol Sci. 15:17130–17147. 2014. View Article : Google Scholar : PubMed/NCBI
34	Sato M, Lu J, Iturria S, Stayrook KR, Burris LL, Zeng QQ, Schmidt A, Barr RJ, Montrose-Rafizadeh C, Bryant HU and Ma YL: A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia. J Bone Miner Res. 25:1326–1336. 2010. View Article : Google Scholar : PubMed/NCBI
35	Reagan-Shaw S, Nihal M and Ahmad N: Dose translation from animal to human studies revisited. FASEB J. 22:659–661. 2008. View Article : Google Scholar : PubMed/NCBI
36	Li M, Hasegawa T, Hogo H, Tatsumi S, Liu Z, Guo Y, Sasaki M, Tabata C, Yamamoto T, Ikeda K and Amizuka N: Histological examination on osteoblastic activities in the alveolar bone of transgenic mice with induced ablation of osteocytes. Histol Histopathol. 28:327–335. 2013.PubMed/NCBI
37	Ma Y, Ma L, Guo Q and Zhang S: Expression of bone morphogenetic protein-2 and its receptors in epithelial ovarian cancer and their influence on the prognosis of ovarian cancer patients. J Exp Clin Cancer Res. 29:852010. View Article : Google Scholar : PubMed/NCBI
38	Hadji P, Ziller M, Maskow C, Albert U and Kalder M: The influence of chemotherapy on bone mineral density, quantitative ultrasonometry and bone turnover in pre-menopausal women with breast cancer. Eur J Cancer. 45:3205–3212. 2009. View Article : Google Scholar : PubMed/NCBI
39	Shapiro CL, Phillips G, Van Poznak CH, Jackson R, Leboff MS, Woodard S and Lemeshow S: Baseline bone mineral density of the total lumbar spine may predict for chemotherapy-induced ovarian failure. Breast Cancer Res Treat. 90:41–46. 2005. View Article : Google Scholar : PubMed/NCBI
40	Tsangari H, Findlay DM, Zannettino AC, Pan B, Kuliwaba JS and Fazzalari NL: Evidence for reduced bone formation surface relative to bone resorption surface in female femoral fragility fracture patients. Bone. 39:1226–1235. 2006. View Article : Google Scholar : PubMed/NCBI
41	Tsurukami H, Nakamura T, Suzuki K, Sato K, Higuchi Y and Nishii Y: A novel synthetic vitamin D analogue, 2 beta-(3-hydroxypropoxy)1 alpha, 25-dihydroxyvitamin D3 (ED-71), increases bone mass by stimulating the bone formation in normal and ovariectomized rats. Calcif Tissue Int. 54:142–149. 1994. View Article : Google Scholar : PubMed/NCBI
42	Khalid AB and Krum SA: Estrogen receptors alpha and beta in bone. Bone. 87:130–135. 2016. View Article : Google Scholar : PubMed/NCBI
43	Sliwinski L, Folwarczna J, Nowińska B, Cegieła U, Pytlik M, Kaczmarczyk-Sedlak I, Trzeciak H and Trzeciak HI: A comparative study of the effects of genistein, estradiol and raloxifene on the murine skeletal system. Acta Biochim Pol. 56:261–270. 2009. View Article : Google Scholar : PubMed/NCBI
44	Erben RG, Scutt AM, Miao D, Kollenkirchen U and Haberey M: Short-term treatment of rats with high dose 1,25-dihydroxyvitamin D3 stimulates bone formation and increases the number of osteoblast precursor cells in bone marrow. Endocrinology. 138:4629–4635. 1997. View Article : Google Scholar : PubMed/NCBI
45	Erben RG, Bromm S and Stangassinger M: Therapeutic efficacy of 1alpha,25-dihydroxyvitamin D3 and calcium in osteopenic ovariectomized rats: Evidence for a direct anabolic effect of 1alpha,25-dihydroxyvitamin D3 on bone. Endocrinology. 139:4319–4328. 1998. View Article : Google Scholar : PubMed/NCBI