A new article in Nature Medicine sheds light on the mechanisms by which WNT16 regulates bone homeostasis. Analysis of Wnt16−/− mice showed that they are substantially more prone to experience bone fracture than wild-type mice. Although trabecular bone volume is normal in Wnt16−/− mice, they have thinner cortical bones and higher cortical porosity than wild-type mice. WNT16 inhibited differentiation of human and mouse osteoclasts directly (via the noncanonical pathway) by acting on osteoclast progenitors and indirectly (via the canonical and noncanonical pathways) by stimulating osteoprotegerin expression. Analysis of mice with a conditional inactivation of Wnt16 in osteoblasts revealed that these cells are the main source of WNT16 and that the absence of WNT16 increases fracture risk.