The discovery of the SOST gene, whose protein product, sclerostin, is an osteocyte-derived inhibitor of Wnt signalling and bone formation, has provided a major advance in bone biology. It gives us new insights into the communicating networks among bone cells and, importantly, to new ways of restoring bone once it has been lost. In the current issue of JBMR, Kramer and colleagues complement their earlier demonstration that parathyroid hormone (PTH) inhibits sclerostin expression to show that the anabolic effect of PTH is blunted both in mice overexpressing sclerostin and in SOST null mice. PTH administered by daily injection is the only currently available anabolic therapy for bone. While a number of contributing pathways, including direct prodifferentiation and antiapoptotic actions on osteoblasts, as well as couplingrelated activity through the osteoclast, have been proposed, the full mechanism of action of anabolic PTH remains obscure. Another contributory mechanism was introduced by the discovery of sclerostin and its regulation by both PTH and PTH-related protein (PTHrP) via a distal enhancer of the SOST gene. The experiments reported by Kramer and colleagues provide further evidence that sclerostin regulation may play a part in PTH anabolic action. Mice overexpressing sclerostin have less bone as a result of decreased bone-formation rate, as described previously. When these mice were treated with a high dose of PTH, sufficient to increase trabecular bone volume (BV/TV) in wild-type mice, no increase in trabecular bone volume was detected despite a robust reduction in sclerostin expression. It is worth noting that even though sclerostin mRNA levels are reduced by PTH in the transgenic model, total sclerostin expression after PTH treatment is still greater than in wild-type mice. This high level of sclerostin expression, the basal phenotype of a mild reduction in bone remodeling, or both impair the effect of PTH on BV/TV. Surprisingly, even though BV/ TV was not increased, all histomorphometric markers of bone formation, as well as the osteoclast surface, were substantially elevated by PTH treatment in the sclerostin transgenic mice to approximately the same extent as that observed in wild-type mice. Thus a question in the sclerostin transgenic model remains