Endocrine Abstracts

Most currently available agents for the treatment of osteoporosis decrease bone resorption and turnover to varying degrees but do not stimulate the formation of new bone that is essential for the management of patients with severe disease. Teriparatide, the most extensively studied bone -forming treatment stimulates not only bone formation but also resorption, acts mainly at sites undergoing active remodeling and increases cortical porosity. The newly developed PTHrP analogue, abaloparatide, has similar but less pronounced effects on bone remodeling and increases hip BMD significantly more than teriparatide. Combination treatment with teripatatide and the resorption inhibitor denosumab increased BMD at all skeletal sites significantly more than either monotherapy after one year suggesting that for optimal therapeutic outcome bone formation and resorption should be modulated in opposite directions. The recognition of the role of Wnt signaling pathway in bone formation by osteoblasts provided a number of potential targets for the development of novel pharmaceuticals (eg. sclerostin, Dkk1 and LRP4). The restricted expression of sclerostin in the skeleton and the lack of abnormalities of organs other than the skeleton in humans and animals with sclerostin deficiency made this protein the most attractive target. Inhibition of sclerostin in animals stimulated cancellous and cortical bone formation, that was mainly modeling-based, and increased bone mass and strength while bone resorption was decreased suggesting a functional uncoupling of bone formation and resorption. Two humanized antibodies to sclerostin, blosozumab and romosozumab were investigated in clinical phase I and II studies. These antibodies given subcutaneously once every 4 weeks induced marked increases in BMD of the spine and the hip associated with rapid transient increases in bone formation markers and decrease of bone resorption markers. On-going phase III studies with romosozumab with fracture outcomes will also provide information about the long-term safety and tolerability of sclerostin inhibitors, essential for the introduction of any new treatment into clinical practice.