It is known that pharmacological or toxic doses of vitamin D induce bone resorption both in vivo and in vitro, whereas physiological doses of the vitamin have a protective effect on bone in vivo. To investigate the discrepancies of the dose‐dependent effect of vitamin D on bone resorption, we examined the in vivo effect of 1,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃] on the expression of the receptor activator of nuclear factor‐κB (NF‐κB) ligand (RANKL) and osteoprotegerin (OPG) mRNAs in bone of thyroparathyroidectomized (TPTX) rats infused with or without parathyroid hormone (PTH). Continuous infusion of 50 ng/h of PTH greatly increased the expression of RANKL mRNA in bone of TPTX rats. Expression of OPG mRNA was not altered by PTH infusion. When graded doses of 1,25(OH)₂D₃ was daily administered orally for 14 days to normocalcemic TPTX rats constantly infused with PTH, 0.01 and 0.1 μg/kg of 1,25(OH)₂D₃ inhibited the PTH‐induced RANKL mRNA expression, but 0.5 μg/kg of the vitamin did not inhibit it. Regulator of G protein signaling‐2 (RGS‐2) gene expression was suppressed by 1,25(OH)₂D₃ dose‐dependently, but PTH/PTHrP receptor mRNA expression was not altered. Bone morphometric analyses revealed that 1,25(OH)₂D₃ suppressed PTH‐induced osteoclast number in vivo. These results suggest that pharmacological or toxic doses of 1,25(OH)₂D₃ stimulate bone resorption by inducing RANKL, but a certain range of physiological doses of the vitamin inhibit PTH‐induced bone resorption, the latter mechanism appeared to be mediated, at least in part, by the suppression of the PTH/PTHrP receptor‐mediated signaling. J. Cell. Biochem. 90: 267–277, 2003. © 2003 Wiley‐Liss, Inc.