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A lthough active vitamin D drugs have been used for the treatment of osteoporosis, how the vitamin D receptor (VDR) regulates bone cell function remains largely unknown. Using osteoprotegerin-deficient mice, which exhibit severe osteoporosis due to excessive receptor activator of NF-κB ligand/receptor activator of NF-κB (RANKL/RANK) stimulation, we show herein that oral treatment of these mice with 1α,25-dihydroxyvitamin D₃ [1α,25(OH)₂D₃] inhibited bone resorption and prevented bone loss, suggesting that VDR counters RANKL/RANK signaling. In M-CSF–dependent osteoclast precursor cells isolated from mouse bone marrow, 1α,25(OH)₂D₃ potently and dose-dependently inhibited their differentiation into multinucleate osteoclasts induced by RANKL. Among signaling molecules downstream of RANK, 1α,25(OH)₂D₃ inhibited the induction of c-Fos protein after RANKL stimulation, and retroviral expression of c-Fos protein abrogated the suppressive effect of 1α,25(OH)₂D₃ on osteoclast development. By screening vitamin D analogs based on their c-Fos–suppressing activity, we identified a new analog, named DD281, that inhibited bone resorption and prevented bone loss in ovariectomized mice, more potently than 1α,25(OH)₂D₃, with similar levels of calcium absorption. Thus, c-Fos protein is an important target of the skeletal action of VDR-based drugs, and DD281 is a bone-selective analog that may be useful for the treatment of bone diseases with excessive osteoclastic activity.