Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow

Takeshi Shibata, Ayako Shira-Ishi, Takuya Sato, Toshimi Masaki, Aya Sasaki, Yoshiko Masuda, Akinori Hishiya, Nobuyuki Ishikura, Sayumi Higashi, Yasuhiro Uchida, Moto O. Saito, Masako Ito, Etsuro Ogata, Ken Watanabe, Kyoji Ikeda

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71 Citations (Scopus)


Previous observations that vitamin D hormone induces the expression of the receptor activator of nuclear factor κB (NF-κB) ligand (RANKL), thereby stimulating osteoclastogenesis in vitro, led to the widespread belief that 1α, 25-dihydroxyvitamin D3 [1α, 25(OH)2D3] is a bone-resorbing hormone. Here, we show that alfacalcidol, a prodrug metabolized to 1α, 25(OH)2D3, suppresses bone resorption at pharmacologic doses that maintain normocalcemia in an ovariectomized (OVX) mouse model of osteoporosis. Treatment of OVX mice with pharmacologic doses of alfacalcidol does not increase RANKL expression, whereas toxic doses that cause hypercalcemia markedly reduce the expression of RANKL. When bone marrow (BM) cells from OVX mice were cultured with sufficient amounts of macrophage colony-stimulating factor (M-CSF) and RANKL, osteoclastogenic activity was higher than in sham mice. Marrow cultures from alfacalcidol- or estrogen-treated OVX mice showed significantly less osteoclastogenic potential compared with those from vehicle-treated OVX mice, suggesting that the pool of osteoclast progenitors in the marrow of vitamin D-treated mice as well as estrogen-treated mice was decreased. Frequency analysis showed that the number of osteoclast progenitors in bone marrow was increased by OVX and decreased by in vivo treatment with alfacalcidol or estrogen. We conclude that the pharmacologic action of active vitamin D in vivo is to decrease the pool of osteoclast progenitors in BM, thereby inhibiting bone resorption. Because of its unusual activity of maintaining bone formation while suppressing bone resorption, in contrast to estrogens that depress both processes, vitamin D hormone and its bone-selective analogs may be useful for the management of osteoporosis.

Original languageEnglish
Pages (from-to)622-629
Number of pages8
JournalJournal of Bone and Mineral Research
Issue number4
Publication statusPublished - 2002 Jan 1
Externally publishedYes


  • Alfacalcidol
  • Bone resorption
  • Osteoclasts
  • Osteoporosis
  • Ovariectomized mice
  • Receptor activator of nuclear factor κB ligand
  • Vitamin D

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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