Osteocytes within the mineralized bone matrix control bone remodeling by regulating osteoblast and osteoclast activity. Osteocytes express the aging suppressor Klotho, but the functional role of this protein in skeletal homeostasis is unknown. Here we identify Klotho expression in osteocytes as a potent regulator of bone formation and bone mass. Targeted deletion of Klothofrom osteocytes led to a striking increase in bone formation and bone volume coupled with enhanced osteoblast activity, in sharp contrast to what is observed in Klothohypomorphic (kl/kl) mice. Conversely, overexpression of Klothoin cultured osteoblastic cells inhibited mineralization and osteogenic activity during osteocyte differentiation. Further, the induction of chronic kidney disease with high-turnover renal osteodystrophy led to downregulation of Klothoin bone cells. This appeared to offset the skeletal impact of osteocyte-targeted Klothodeletion. Thus, our findings establish a key role of osteocyte-expressed Klothoin regulating bone metabolism and indicate a new mechanism by which osteocytes control bone formation.