Endocrine Abstracts

During the past few years there have been important developments in the pharmacotherapy of osteoporosis. These developments were paralleled by significant progress in our understanding of the local regulation of bone metabolism. Studies of human and animal genetics led to identification of novel signaling pathways in bone cells, such as the Wnt signaling pathway, that provide targets for new bone building therapeutics for patients with osteoporosis. Fundamental for these developments have been studies of two rare bone sclerosing dysplasias, sclerosteosis and van Buchem disease, with closely related phenotypes characterized by bone overgrowth, which are due to defective production of sclerostin, a negative regulator of bone formation. The expression of sclerostin is restricted to osteocytes and is modified, among other, by mechanical loading and PTH. In addition, sclerostin stimulates bone resorption by a RANKL-mediated mechanism in osteocytes. An antibody to sclerostin given to OVX rats or intact monkeys increased bone formation at all bone envelopes without affecting, or even decreasing, bone resorption and improved bone strength. A single injection of an antibody to sclerostin to healthy postmenopausal women increased serum P1NP transiently decreased serum CTX and increased BMD after only 3 months. A recently reported phase II clinical study of monthly administration of a sclerostin antibody to postmenopausal women with low bone mass showed that this treatment increased BMD at all skeletal sites to levels higher than those attained with teriparatide and was well tolerated. Phase III studies are currently under way. The kinetics of bone remodeling in response to repeated administration of sclerostin inhibitors to humans need, however, to be clarified, particularly the nature and the magnitude of the response (transient or sustained). Apart from establishing the efficacy of these new molecules a critical issue for their introduction into clinical practice will be their tolerability and safety profile.