Vitamin D was discovered as an anti-rachitic agent, but even at present, there is no direct evidence to support the concept that
vitamin D directly stimulates osteoblastic bone formation and mineralization. It appears to be paradoxical, but
vitamin D functions in the process of osteoclastic
bone resorption. In 1952, Carlsson reported that administration of
vitamin D(3) to rats fed a
vitamin D-deficient, low
calcium diet raised serum
calcium levels. Since the diet did not contain appreciable amounts of
calcium, the rise in serum
calcium was considered to be derived from bone. Since then, this assay has been used as a standard bioassay for
vitamin D compounds. Osteoclasts, the cells responsible for
bone resorption, develop from hematopoietic cells of the monocyte-macrophage lineage. Several lines of evidence have shown that the active form of
vitamin D(3), 1α,25-dihydroxyvitamin D(3) [1α,25(
OH)(2)D(3)] is one of the most potent inducers of receptor activator of NF-κB
ligand (RANKL), a key molecule for osteoclastogenesis, in vitro. In fact, 1α,25(
OH)(2)D(3) strongly induced osteoclast formation and
bone resorption in vitro. Nevertheless, 1α,25(
OH)(2)D(3) and its
prodrug,
Alfacalcidol (1α-hydroxyvitamin D(3)) have been used as therapeutic agents for
osteoporosis since 1983, because they increase bone mineral density and reduce the incidence of
bone fracture in vivo. Furthermore, a new
vitamin D analog,
Eldecalcitol [2β-(3-hydroxypropoxy)-1α,25(
OH)(2)D(3)], has been approved as a new drug for
osteoporosis in Japan in January 2011. Interestingly, these beneficial effects of in vivo administration of
vitamin D compounds are caused by the suppression of osteoclastic
bone resorption. The present review article describes the mechanism of the discrepancy of
vitamin D compounds in osteoclastic
bone resorption between in vivo and in vitro.