▸ 1,25(OH)2D promotes intestinal calcium transport during normal/low calcium intake. ▸ High 1,25(OH)2D levels minimize skeletal calcium content to maintain normocalcemia. ▸ High 1,25(OH)2D levels increase bone resorption leading to osteopenia. ▸ Increased VDR signaling in osteoblasts/osteocytes suppresses bone mineralization. The serum calcium levels and the calcium content of the skeleton are highly interdependent. Indeed, bone requires calcium to preserve its strength, but it is at the same time also the predominant calcium storage from which calcium can be mobilized to supply the serum pool. The active form of vitamin D 1,25(OH)2D plays a crucial role in regulating the transfer of calcium between blood and bone, evidenced by experimental data obtained from systemic, intestinal-specific and osteocyte-specific vitamin D receptor (Vdr) null mice. In fact, 1,25(OH)2D is required to maintain normocalcemia and bone health by enhancing intestinal calcium absorption when dietary calcium intake is normal/low. When, however, insufficient calcium is absorbed via the intestine, 1,25(OH)2D levels will increase and will act on mature osteoblasts and osteocytes to minimize calcium levels in bone tissue in favor of the blood calcium pool. Mechanistically, the high 1,25(OH)2D levels enhance bone remodeling which leads to osteopenia, and suppress bone matrix mineralization by increasing the levels of mineralization inhibitors, which causes hyperosteoidosis and hypomineralization. Thus, depending on the intestinal calcium acquisition, 1,25(OH)2D will target the intestine and/or the skeleton to maintain calcium levels in serum within a normal range.