Altering the Balance of Bone Deposition and Absorption to Treat Osteoporosis

The proximate cause of osteoporosis is a growing imbalance between the activities of osteoclasts, responsible for removing bone, and osteoblasts, responsible for creating bone. As is true of most issues in aging today, there is no clear line to be drawn between the fundamental damage that is the root cause of aging and the final link in the chain, which is to say differing cell behavior in bone remodeling. A great deal remains to be mapped, for all that enough is understood of the root causes to work towards repairing them. Unfortunately the majority of the research community tends to focus on proximate causes, which here means constructing therapies capable of adjusting the balance of activities for osteoclasts and ostoblasts. There are a range of potential approaches, but these researchers have settled on manipulation of a regulatory protein that diminishes bone absorption and increases bone deposition. A number of groups are working on this initiative, and new progress was recently reported:

Osteoporosis particularly affects elderly women: the bone's structure weakens and the risk of suffering fractures rises. Patients are advised to have a healthy diet and perform physical exercises; when the risk of bone fractures is high, medicine preventing further bone loss is prescribed in addition. In the search for better treatments for this disease the protein Sclerostin, which plays an important role in bone metabolism, is of major interest. When its function is impeded, bone resorption diminishes and bone re-growth is stimulated. First clinical trials with a Sclerostin-inhibiting antibody showed promising results in that the bone mass of participants suffering from osteoporosis increased.

Currently, studies are continued at several locations. In a collaborative project novel Sclerostin-inhibiting antibodies were generated and analysed for their suitability as osteoporosis treatment option. Now, for the first time scientists crystallized an antibody effective against Sclerostin and analysed its mode of action in detail. "Our findings could have a positive impact on the design of new inhibitory antibodies targeting Sclerostin." In this project, ten promising antibodies were developed in the initial round. After testing in cell culture one showed the favoured activity to neutralize Sclerostin. An in-depth analysis of the binding epitopes was performed using peptide chemistry and NMR spectroscopy. From these methods the binding site of the antibody in Sclerostin could be deduced. "Until now, we could only determine the structure of the antibody alone."



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