Vitamin D, Osteoclastogenesis and Bone Resorption: from Mechanistic Insight to the Development of New Analogs

Abstract

Prologue: 1α,25(OH) 2 D 3 as a bone-resorbing hormone THE vitamin D hormone 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) is a pleiotropic hormone which exerts its effects through the nuclear vitamin D receptor (VDR) [1]. Among these effects, the physiological importance of VDR in maintaining the integrity of mineral and skeletal systems is underscored by the severe hypocalcemia and rickets/osteomalacia observed in VDR gene knockout mice as well as patients with vitamin D deficiency [2]. The connection between vitamin D and bone resorption was first made in 1972, when it was reported that in a classic experiment using bone organ cultures, the so-called "Raisz assay", 1α,25(OH) 2 D 3 stimulates bone resorption, as determined by the release of 45 Ca from pre-labeled fetal long bones [3]. This paper formed the basis of the currently prevailing belief that 1α,25(OH) 2 D 3 is a boneresorbing hormone [4]. In the 1980's, the now wellknown co-culture system of hematopoietic cells with osteoblast/stromal cells for generating osteoclasts was developed [5], and together with the demonstration of 1α,25(OH) 2 D 3 as a differentiation-inducing agent, the dogma that 1α,25(OH) 2 D 3 is essential for osteoclast differentiation became firmly established [4].1997 was a landmark year in the research history of bone biology, especially in terms of the osteoclast. A novel cytokine, named osteoclastogenesis inhibitory factor (OCIF) or osteoprotegerin (OPG), was discovered to protect bone by negatively regulating osteoclast formation. This work was reported by Yukijirushi [6] and Amgen [7]. In the following year, its ligand, OPGL, or currently under the prevailing name of "receptor activator of nuclear factor-κB ligand" (RANKL), was identified by the 2 companies as the long-sought osteoclast differentiation factor (ODF) that is presented on osteoblastic/stromal cells, thereby promoting the terminal differentiation into osteoclasts [8,9]. Yasuda et al. elegantly showed that 1α,25(OH) 2 D 3 at relatively high doses of 10 -8 -10 -7 M, induces the expression of RANKL in the ST2 stromal cell line [8], providing the final molecular proof that 1α,25(OH) 2 D 3 is a pro-osteoclastogenic hormone [4]. It then became widely recognized that in addition to 1α,25(OH) 2 D 3 , many other bone-resorbing hormones and cytokines, such as PTH, prostaglandins, TNF and IL-1, stimulate osteoclastogenesis indirectly by inducing RANKL in stromal/osteoblastic cells.Contrary to this prevailing view, however, we in fact observed in various models of accelerated bone resorption that pharmacological doses of active vitamin D drugs unexpectedly inhibit bone resorption in vivo [10][11][12]. I herein summarize what has been learned from these pharmacological experiments, and discuss the role of VDR-based drugs in the treatment of bone disease, especially osteoporosis. Osteoclasts in osteoporosisOsteoclast-mediated bone resorption plays a central pathogenetic role in the development and progressionCorrespondence to: Kyoji IKEDA, M.D.,

No significant effect on bone mineral density by high doses of vitamin D3 given to overweight subjects for one year

“…However, a positive effect of vitamin D on BMD cannot be ruled out from our study as most of the subjects had normal BMD at baseline, the study only lasted 12 months, and an increase in BMD would therefore be hard to disclose. On the other hand, supplementation with vitamin D could in theory also have a negative effect on BMD as the production of 1,25(OH) 2 D from 25(OH)D is substrate dependent [25] and 1,25(OH) 2 D may induce osteoclastogenesis [5,11]. Our result is therefore of importance as it indicates that high doses of vitamin D, at least when given for a short period of time to healthy subjects, do not have serious adverse effects on bone.…”

“…Traditionally, 1,25(OH) 2 D has been considered a bone-resorbing hormone. This was based on its potent stimulation of bone resorption in tissue cultures [10,11] which was further substantiated by the finding that 1,25(OH) 2 D increased the RANKL expression [5,11]. However, active vitamin D metabolites have also been reported to inhibit bone resorption [12] and may therefore have a dual effect on bone formation [11].…”