From disease to treatment: from rare skeletal disorders to treatments for osteoporosis.

Natasha M Appelman-Dijkstra,Socrates E Papapoulos

doi:10.1007/s12020-016-0888-7

Natasha M Appelman-Dijkstra, Socrates E Papapoulos

Open Access

https://doi.org/10.1007/s12020-016-0888-7

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Journal: Endocrine	Publication Date: Feb 18, 2016
Citations: 29	License type: CC BY 4.0

Affiliation: Leiden University Medical Center

Abstract

During the past 15 years there has been an expansion of our knowledge of the cellular and molecular mechanisms regulating bone remodeling that identified new signaling pathways fundamental for bone renewal as well as previously unknown interactions between bone cells. Central for these developments have been studies of rare bone disorders. These findings, in turn, have led to new treatment paradigms for osteoporosis some of which are at late stages of clinical development. In this article, we review three rare skeletal disorders with case descriptions, pycnodysostosis and the craniotubular hyperostoses sclerosteosis and van Buchem disease that led to the development of cathepsin K and sclerostin inhibitors, respectively, for the treatment of osteoporosis.

Highlights

We review three rare skeletal disorders with case descriptions, pycnodysostosis and the craniotubular hyperostoses sclerosteosis and van Buchem disease that led to the development of cathepsin K and sclerostin inhibitors, respectively, for the treatment of osteoporosis
Osteoporosis is characterized by the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts that leads to loss and structural decay of bone and, reduced bone strength and increased fragility
The relevant clinical question is whether, apart from providing new treatment targets, study of patients with rare skeletal disorders can improve our understanding of the effects of new treatments on bone metabolism. We address this question and we discuss three bone dysplasias pycnodysostosis and the craniotubular hyperostoses sclerosteosis and van Buchem disease, including case descriptions, that led to the development of cathepsin K and sclerostin inhibitors, respectively, for the treatment of osteoporosis

Summary

Introduction

Osteoporosis is characterized by the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts that leads to loss and structural decay of bone and, reduced bone strength and increased fragility. The restricted expression of sclerostin to the skeleton and the lack of abnormalities in organs other than the skeleton in patients with sclerostin deficiency made this protein an attractive target for the development of a new bone forming therapy for the management of osteoporosis This approach was further supported by the gene-dose effect suggested by findings in heterozygous carriers of sclerosteosis who demonstrated decreased serum sclerostin levels associated with increased levels of P1NP and high normal or increased BMD without any clinical symptoms, signs, or complications of sclerosteosis [53, 54]. Increases in BMD with romosozumab treatment in animals and humans were progressive but the slope of the increase changed with time; a finding in line with the observations of patients with sclerostin deficiency in whom stabilization of the disease was invariably observed after the third decade of life. Together these findings suggest that treatment of patients with osteoporosis with sclerostin inhibitors will be of limited duration and will form part of a treatment strategy rather than monotherapy, for patients with severe osteoporosis

Conclusions

Findings

Compliance with ethical standards