Vitamin D is essential for optimal calcium absorption needed for maintaining normal bone mineral density (BMD). Consequently, vitamin D-deficiency leads to poorly mineralized bone with diminished strength and load bearing capacity. Surprisingly, several animal and clinical studies have identified suppressive effects of high dose vitamin D supplementation on bone formation. These data suggest that while vitamin D is necessary for basal bone homeostasis, excessive concentrations may be detrimental to the skeleton. To further examine the direct effects of high dose vitamin D on the function of osteoblasts we differentiated primary osteoblast precursors and MC3T3 preosteoblastic cells, in the presence of supraphysiological doses of the active metabolite, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. In vitro osteoblast mineralization was potently suppressed by high dose 1,25(OH)2D3. To investigate the mechanism we used a bioassay to examine nuclear factor-κB (NF-κB) activation in MC3T3 cells. Although NF-κB agonists are generally potent inhibitors of osteoblast differentiation, surprisingly, 1,25(OH)2D3 dose-dependently suppressed, rather than stimulated, NF-κB activation. Interestingly, 1,25(OH)2D3 also suppressed Smad activation induced by the osteoblast commitment and differentiation factors transforming growth factor-β (TGF-β) and bone morphogenetic protein 2 (BMP2), which may account for the inhibitory activities of 1,25(OH)2D3 on mineralization. Our data suggest that vitamin D has complex pleiotropic effects on osteoblast signal transduction. As the net balance of high dose 1,25(OH)2D3 appears to be an inhibitory action on osteoblasts, our data suggest that the therapeutic value of vitamin D to maximize bone mass through indirect actions on calcium absorption may need to be carefully balanced with potential inhibitory direct effects on mineralizing cells. Our data suggest that indiscriminate over-dosing may be detrimental to bone formation and optimal concentrations need to be established for humans in vivo.

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