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Long-Term Treatment with Eldecalcitol (1α, 25-Dihydroxy-2β- (3-hydroxypropyloxy) Vitamin D3) Suppresses Bone Turnover and Leads to Prevention of Bone Loss and Bone Fragility in Ovariectomized Rats

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Abstract

The purpose of this study is to estimate the efficacy of eldecalcitol (1α, 25-Dihydroxy-2β- (3-hydroxypropyloxy) vitamin D3; ELD) on bone metabolism after long-term administration. Six-month-old Wistar–Imamichi rats were ovariectomized (OVX) and administered ELD orally at doses of 7.5, 15, or 30 ng/kg daily. Bone mineral density (BMD), urinary excretion of deoxypyridinoline (DPD), a bone resorption marker, and serum total alkaline phosphatase (ALP), a surrogate marker of bone formation, were assessed after 3, 6, and 12 months of treatment. After 12 months of treatment, the biomechanical strength of the L4 lumbar vertebra and femoral shaft was measured, and bone histomorphometry was performed on the L3 lumbar vertebra and the tibia diaphysis. ELD prevented OVX-induced decreases in BMD of the lumbar vertebrae and femur throughout the treatment period. ELD significantly suppressed OVX-induced increases in urinary DPD excretion throughout the treatment period with minimal effects on ALP. OVX resulted in significant decreases in ultimate load and stiffness of the L4 lumbar vertebra and femoral shaft, and ELD significantly prevented the reduction in these biomechanical parameters. Bone histomorphometry at the L3 lumbar vertebra revealed that OVX induced increases in bone resorption parameters (osteoclast surface and osteoclast number) and bone formation parameters (osteoblast surface, osteoid surface, and bone formation rate), and ELD suppressed these parameters after 12 months treatment. Activation frequency, which was elevated in the OVX/vehicle group, was significantly suppressed to baseline levels in ELD-treated groups, indicating that ELD maintained bone turnover at a normal level. ELD also prevented OVX-induced deterioration of microstructure in trabecular and cortical bone. These results indicated that long-term treatment of OVX rats with ELD suppressed bone turnover, and prevented OVX-induced bone loss, deterioration of bone microstructure, and reduction in bone biomechanical strength.

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References

  1. Miyamoto K, Murayama E, Ochi K, Watanabe H, Kubodera N (1993) Synthetic studies of vitamin D analogues. XIV. Synthesis and calcium regulating activity of vitamin D3 analogues bearing a hydroxyalkoxy group at the 2 beta-position. Chem Pharm Bull (Tokyo) 41:1111–1113

    Article  CAS  Google Scholar 

  2. Ono Y, Watanabe H, Shiraishi A, Takeda S, Higuchi Y, Sato K, Tsugawa N, Okano T, Kobayashi T, Kubodera N (1997) Synthetic studies of vitamin D analogs. XXIV. Synthesis of active vitamin D3 analogs substituted at the 2 beta-position and their preventive effects on bone mineral loss in ovariectomized rats. Chem Pharm Bull (Tokyo) 45:1626–1630

    Article  CAS  Google Scholar 

  3. Ono Y, Kawase A, Watanabe H, Shiraishi A, Takeda S, Higuchi Y, Sato K, Yamauchi T, Mikami T, Kato M, Tsugawa N, Okano T, Kubodera N (1998) Syntheses and preventive effects of analogues related to 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71) on bone mineral loss in ovariectomized rats. Bioorg Med Chem 6:2517–2523

    Article  CAS  PubMed  Google Scholar 

  4. Okano T, Tsugawa N, Masuda S, Takeuchi A, Kobayashi T, Takita Y, Nishii Y (1989) Regulatory activities of 2β-(3-hydroxypropoxy)-1α, 25-dihydroxyvitamin D3, a novel synthetic vitamin D3 derivative, on calcium metabolism. Biochem Biophys Res Commun 163:1444–1449

    Article  CAS  PubMed  Google Scholar 

  5. Hatakeyama S, Nagashima S, Imai N, Takahashi K, Ishihara J, Sugita A, Nihei T, Saito H, Takahashi F, Kubodera N (2007) Synthesis and biological evaluation of a 3-positon epimer of 1α,25-dihydroxy-2β-(3-hydroxypropoxy) vitamin D3 (ED-71). J Steroid Biochem Mol Biol 103:222–226

    Article  CAS  PubMed  Google Scholar 

  6. Matsumoto T, Ito M, Hayashi Y, Hirota T, Tanigawara Y, Sone T, Fukunaga M, Shiraki M, Nakamura T (2011) A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures—a randomized, active comparator, double-blind study. Bone 49:605–612

    Article  CAS  PubMed  Google Scholar 

  7. Matsumoto T, Takano T, Yamakido S, Takahashi F, Tsuji N (2010) Comparison of the effects of eldecalcitol and alfacalcidol on bone and calcium metabolism. J Steroid Biochem Mol Biol 121:261–264

    Article  CAS  PubMed  Google Scholar 

  8. Uchiyama Y, Higuchi Y, Takeda S, Masaki T, Shira-ishi A, Sato K, Kubodera N, Ikeda K, Ogata E (2002) ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis. Bone 30:582–588

    Article  CAS  PubMed  Google Scholar 

  9. Tanaka Y, Nakamura T, Nishida S, Suzuki K, Takeda S, Sato K, Nishii Y (1996) Effects of a synthetic vitamin D analog, ED-71, on bone dynamics and strength in cancellous and cortical bone in prednisolone-treated rats. J Bone Miner Res 11:325–336

    Article  CAS  PubMed  Google Scholar 

  10. de Freitas PH, Hasegawa T, Takeda S, Sasaki M, Tabata C, Oda K, Li M, Saito H, Amizuka N (2011) Eldecalcitol, a second-generation vitamin D analog, drives bone minimodeling and reduces osteoclastic number in trabecular bone of ovariectomized rats. Bone 49:335–342

    Article  PubMed  Google Scholar 

  11. Saito H, Takeda S, Amizuka N (2013) 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

    Article  CAS  PubMed  Google Scholar 

  12. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301

    Article  CAS  PubMed  Google Scholar 

  13. Schneider JP (2009) Bisphosphonates and low-impact femoral fractures: current evidence on alendronate-fracture risk. Geriatrics 64:18–23

    PubMed  Google Scholar 

  14. Armamento-Villareal R, Napoli N, Diemer K, Watkins M, Civitelli R, Teitelbaum S, Novack D (2009) Bone turnover in bone biopsies of patients with low-energy cortical fractures receiving bisphosphonates: a case series. Calcif Tissue Int 85:37–44

    Article  CAS  PubMed  Google Scholar 

  15. Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B, van der Meulen MC, Lorich DG, Lane JM (2009) Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int 20:1353–1362

    Article  CAS  PubMed  Google Scholar 

  16. Visekruna M, Wilson D, McKiernan FE (2008) Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab 93:2948–2952

    Article  CAS  PubMed  Google Scholar 

  17. Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, Whelan DB, Weiler PJ, Laupacis A (2011) Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA 305:783–789

    Article  CAS  PubMed  Google Scholar 

  18. Ma YL, Bryant HU, Zeng Q, Schmidt A, Hoover J, Cole HW, Yao W, Jee WS, Sato M (2003) 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 144:2008–2015

    Article  CAS  PubMed  Google Scholar 

  19. Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ (1997) Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 100:1475–1480

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Chapurlat RD, Arlot M, Burt-Pichat B, Chavassieux P, Roux JP, Portero-Muzy N, Delmas PD (2007) Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study. J Bone Miner Res 22:1502–1509

    Article  CAS  PubMed  Google Scholar 

  21. Allen MR, Iwata K, Phipps R, Burr DB (2006) Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate. Bone 39:872–879

    Article  CAS  PubMed  Google Scholar 

  22. Komatsubara S, Mori S, Mashiba T, Ito M, Li J, Kaji Y, Akiyama T, Miyamoto K, Cao Y, Kawanishi J, Norimatsu H (2003) Long-term treatment of incadronate disodium accumulates microdamage but improves the trabecular bone microarchitecture in dog vertebra. J Bone Miner Res 18:512–520

    Article  CAS  PubMed  Google Scholar 

  23. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB (2001) Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 28:524–531

    Article  CAS  PubMed  Google Scholar 

  24. Allen MR, Burr DB (2007) Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment. J Bone Miner Res 22:1759–1765

    Article  CAS  PubMed  Google Scholar 

  25. Stepan JJ, Burr DB, Pavo I, Sipos A, Michalska D, Li J, Fahrleitner-Pammer A, Petto H, Westmore M, Michalsky D, Sato M, Dobnig H (2007) Low bone mineral density is associated with bone microdamage accumulation in postmenopausal women with osteoporosis. Bone 41:378–385

    Article  PubMed  Google Scholar 

  26. Turner CH, Burr DB (1993) Basic biomechanical measurements of bone: a tutorial. Bone 14:595–608

    Article  CAS  PubMed  Google Scholar 

  27. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610

    Article  CAS  PubMed  Google Scholar 

  28. Ito M, Nishida A, Koga A, Ikeda S, Shiraishi A, Uetani M, Hayashi K, Nakamura T (2002) Contribution of trabecular and cortical components to the mechanical properties of bone and their regulating parameters. Bone 31:351–358

    Article  CAS  PubMed  Google Scholar 

  29. Harada S, Mizoguchi T, Kobayashi Y, Nakamichi Y, Takeda S, Sakai S, Takahashi F, Saito H, Yasuda H, Udagawa N, Suda T, Takahashi N (2012) 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

    Article  CAS  PubMed  Google Scholar 

  30. Kikuta J, Kawamura S, Okiji F, Shirazaki M, Sakai S, Saito H, Ishii M (2013) Sphingosine-1-phosphate-mediated osteoclast precursor monocyte migration is a critical point of control in antibone-resorptive action of active vitamin D. Proc Natl Acad Sci USA 110:7009–7013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Takasu H, Sugita A, Uchiyama Y, Katagiri N, Okazaki M, Ogata E, Ikeda K (2006) c-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs. J Clin Invest 116:528–535

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Sakai S, Takaishi H, Matsuzaki K, Kaneko H, Furukawa M, Miyauchi Y, Shiraishi A, Saito K, Tanaka A, Taniguchi T, Suda T, Miyamoto T, Toyama Y (2009) 1-Alpha, 25-dihydroxy vitamin D3 inhibits osteoclastogenesis through IFN-beta-dependent NFATc1 suppression. J Bone Miner Metab 27:643–652

    Article  CAS  PubMed  Google Scholar 

  33. Tsurukami H, Nakamura T, Suzuki K, Sato K, Higuchi Y, Nishii Y (1994) 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

    Article  CAS  PubMed  Google Scholar 

  34. Shiraishi A, Takeda S, Masaki T, Higuchi Y, Uchiyama Y, Kubodera N, Sato K, Ikeda K, Nakamura T, Matsumoto T, Ogata E (2000) Alfacalcidol inhibits bone resorption and stimulates formation in an ovariectomized rat model of osteoporosis: distinct actions from estrogen. J Bone Miner Res 15:770–779

    Article  CAS  PubMed  Google Scholar 

  35. Li M, Healy DR, Simmons HA, Ke HZ, Thompson DD (2003) Alfacalcidol restores cancellous bone in ovariectomized rats. J Musculoskelet Neuronal Interact 3:39–46

    CAS  PubMed  Google Scholar 

  36. Liu XQ, Chen HY, Tian XY, Setterberg RB, Li M, Jee WS (2008) Alfacalcidol treatment increases bone mass from anticatabolic and anabolic effects on cancellous and cortical bone in intact female rats. J Bone Miner Metab 26:425–435

    Article  CAS  PubMed  Google Scholar 

  37. Colin EM, Van Den Bemd GJ, Van Aken M, Christakos S, De Jonge HR, Deluca HF, Prahl JM, Birkenhäger JC, Buurman CJ, Pols HA, Van Leeuwen JP (1999) Evidence for involvement of 17beta-estradiol in intestinal calcium absorption independent of 1,25-dihydroxyvitamin D3 level in the Rat. J Bone Miner Res 14:57–64

    Article  CAS  PubMed  Google Scholar 

  38. Dong XL, Zhang Y, Wong MS (2014) Estrogen deficiency-induced Ca balance impairment is associated with decrease in expression of epithelial Ca transport proteins in aged female rats. Life Sci 96:26–32

    Article  CAS  PubMed  Google Scholar 

  39. Liel Y, Shany S, Smirnoff P, Schwartz B (1999) Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa. Endocrinology 140:280–285

    CAS  PubMed  Google Scholar 

  40. Brown AJ, Ritter CS (2011) The vitamin D analog 1α,25-Dihydroxy-2β-(3-Hydroxypropyloxy) vitamin D(3) (Eldecalcitol) is a potent regulator of calcium and phosphate metabolism. Calcif Tissue Int 89:372–378

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the technical support of the technical staff and research scientists at Charles River Laboratories.

Conflict of interest

Satoshi Takeda, Susan Y Smith, Tatsuya Tamura, Hitoshi Saito, Fumiaki Takahashi, Rana Samadfam, Solomon Haile, Nancy Doyle, Koichi Endo have no conflicts of interest.

Human and Animal Rights and Informed Consent

All animal procedures in this study were ethically approved by the Institutional Animal Care and Use Committee at Charles River Laboratories Preclinical Services Montreal.

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Correspondence to Koichi Endo.

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Takeda, S., Smith, S.Y., Tamura, T. et al. Long-Term Treatment with Eldecalcitol (1α, 25-Dihydroxy-2β- (3-hydroxypropyloxy) Vitamin D3) Suppresses Bone Turnover and Leads to Prevention of Bone Loss and Bone Fragility in Ovariectomized Rats. Calcif Tissue Int 96, 45–55 (2015). https://doi.org/10.1007/s00223-014-9937-5

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  • DOI: https://doi.org/10.1007/s00223-014-9937-5

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