Previous observations that
vitamin D hormone induces the expression of the
receptor activator of nuclear factor kappaB (
NF-kappaB)
ligand (RANKL), thereby stimulating osteoclastogenesis in vitro, led to the widespread belief that 1alpha,25-dihydroxyvitamin D3 [1a,25(
OH)2D3] is a bone-resorbing
hormone. Here, we show that
alfacalcidol, a
prodrug metabolized to 1alpha,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.