Clinical advantages and disadvantages of anabolic bone therapies targeting the WNT pathway.

The WNT signalling pathway is a key regulator of bone metabolism, particularly bone formation, which has helped to define the role of osteocytes - the most abundant bone cells - as orchestrators of bone remodelling. Several molecules involved in the control of the WNT signalling pathway have been identified as potential targets for the development of bone-building therapeutics for patients with osteoporosis. Several of these molecules have been investigated in animal models, but only inhibitors of sclerostin (which is produced by osteocytes) have been investigated in phase III clinical studies. Here, we review the rationale for these developments and the specificity and potential off-target actions of WNT-based therapeutics. We also describe the available preclinical and clinical studies and discuss the benefits and risks of using sclerostin inhibitors for the management of patients with osteoporosis.