Eldecalcitol is more effective in promoting osteogenesis than alfacalcidol in Cyp27b1-knockout mice

Yoshihisa Hirota, Kimie Nakagawa, Keigo Isomoto, Toshiyuki Sakaki, Noboru Kubodera, Maya Kamao, Naomi Osakabe, Yoshitomo Suhara, Toshio Okano

Research output: Contribution to journalArticle

Abstract

Calcium (Ca) absorption from the intestinal tract is promoted by active Vitamin D (1α,25D3). Vitamin D not only promotes Ca homeostasis, but it also inhibits bone resorption and promotes osteogenesis, thus playing a role in the maintenance of normal bone metabolism. Because 1α,25D3 plays an important role in osteogenesis, Vitamin D formulations, such as alfacalcidol (ALF) and eldecalcitol (ELD), are used for treating osteoporosis. While it is known that, in contrast to ALF, ELD is an active ligand that directly acts on bone, the reason for its superior osteogenesis effects is unknown. Cyp27b1-knockout mice (Cyp27b1-/-mice) are congenitally deficient in 1α,25D3 and exhibit marked hypocalcemia and high parathyroid hormone levels, resulting in osteodystrophy involving bone hypocalcification and growth plate cartilage hypertrophy. However, because the Vitamin D receptor is expressed normally in Cyp27b1-/-mice, they respond normally to 1α,25D3. Accordingly, in Cyp27b1-/-mice, the pharmacological effects of exogenously administered active Vitamin D derivatives can be analyzed without being affected by 1α,25D3. We used Cyp27b1-/-mice to characterize and clarify the superior osteogenic effects of ELD on the bone in comparison with ALF. The results indicated that compared to ALF, ELD strongly induces ECaC2, calbindin-D9k, and CYP24A1 in the duodenum, promoting Ca absorption and decreasing the plasma concentration of 1α,25D3, resulting in improved osteogenesis. Because bone morphological measurements demonstrated that ELD has stronger effects on bone calcification, trabecular formation, and cancellous bone density than ALF, ELD appears to be a more effective therapeutic agent for treating postmenopausal osteoporosis, in which cancellous bone density decreases markedly. By using Cyp27b1 -/-mice, this study was the first to succeed in clarifying the osteogenic effect of ELD without any influence of endogenous 1α,25D3.

Original languageEnglish
Article numbere0199856
JournalPLoS One
Volume13
Issue number10
DOIs
Publication statusPublished - 2018 Oct 1
Externally publishedYes

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1alpha-hydroxycholecalciferol
vitamin D
bone formation
Bone
bones
mice
osteoporosis
bone density
Vitamin D
calcium
calbindin
bone mineralization
bone metabolism
hypocalcemia
growth plate
bone resorption
parathyroid hormone
Calcium
duodenum
hypertrophy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Hirota, Y., Nakagawa, K., Isomoto, K., Sakaki, T., Kubodera, N., Kamao, M., ... Okano, T. (2018). Eldecalcitol is more effective in promoting osteogenesis than alfacalcidol in Cyp27b1-knockout mice. PLoS One, 13(10), [e0199856]. https://doi.org/10.1371/journal.pone.0199856

Eldecalcitol is more effective in promoting osteogenesis than alfacalcidol in Cyp27b1-knockout mice. / Hirota, Yoshihisa; Nakagawa, Kimie; Isomoto, Keigo; Sakaki, Toshiyuki; Kubodera, Noboru; Kamao, Maya; Osakabe, Naomi; Suhara, Yoshitomo; Okano, Toshio.

In: PLoS One, Vol. 13, No. 10, e0199856, 01.10.2018.

Research output: Contribution to journalArticle

Hirota, Yoshihisa ; Nakagawa, Kimie ; Isomoto, Keigo ; Sakaki, Toshiyuki ; Kubodera, Noboru ; Kamao, Maya ; Osakabe, Naomi ; Suhara, Yoshitomo ; Okano, Toshio. / Eldecalcitol is more effective in promoting osteogenesis than alfacalcidol in Cyp27b1-knockout mice. In: PLoS One. 2018 ; Vol. 13, No. 10.
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