Endocrine Abstracts (2009) 20 PL2

Current and novel treatment targets for bone diseases

Socrates Papapoulos


Leiden University Medical Center, Leiden, The Netherlands.


During the past few years there have been significant developments in the pharmacotherapy of bone diseases, especially of osteoporosis, and effective treatments have become available to physicians. These developments were paralleled by significant progress in our understanding of the local regulation of bone metabolism. Particularly, studies of human and animal genetics have led to identification of novel, more specific, signaling pathways in bone cells that can provide targets for new therapeutics.

Such novel targets in osteoclasts include, among others, RANKL and cathepsin-K. A fully human monoclonal antibody to RANKL (denosumab) was developed and a large phase three study in osteoporosis has just been completed while cathepsin-K inhibitors have been evaluated in phase two studies and one of them (odanacatib) is currently in phase three clinical development.

The PTH paradigm illustrated the possibility of stimulating bone formation in osteoporotic patients and opened the way for the development of bone forming agents and novel forms of PTH (e.g. PTH 1-31) or PTHrP. A particularly interesting approach has been the development of molecules that antagonize the calcium sensing receptor of the parathyroid cells and stimulate PTH secretion (calcilytics). The most exciting development of recent years has been, however, the recognition of the central role of the Wnt signaling pathway in bone formation which, in turn provided, a number of attractive targets for the development of pharmaceuticals. For example, inhibition of this pathway by blocking the action of sclerostin represents a very promising novel approach to stimulating bone formation in patients with osteoporosis.

The new developments may allow in the future tailoring pharmacotherapy to the specific needs and pathophysiological profile of the individual patient. However, 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.

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