Targeting sclerostin as potential treatment of osteoporosis

Ann Rheum Dis. 2011 Mar:70 Suppl 1:i119-22. doi: 10.1136/ard.2010.141150.

Abstract

In recent years, study of rare bone diseases has led to the identification of signalling pathways that regulate bone formation and provided targets for the development of novel therapeutic agents to stimulate bone formation in patients with osteoporosis. Studies of two bone sclerosing dysplasias, sclerosteosis and van Buchem disease led to the identification of sclerostin, a negative regulator of bone formation. Sclerostin binds to LRP5/6 and inhibits Wnt signalling, but its precise molecular mechanism of action is not yet known. Its expression is restricted in the skeleton to osteocytes and is modified by mechanical loading and parathyroid hormone treatment. Sclerostin deficiency reproduces the findings of the human diseases in mice, while sclerostin excess leads to bone loss and reduced bone strength. An antibody to sclerostin increased bone formation dramatically at all bone envelopes in ovariectomised rats and intact monkeys, without affecting bone resorption and improved bone strength. In initial human studies, a single injection of the antibody to postmenopausal women increased serum P1NP and transiently decreased serum CTX. Clinical phase II studies with this antibody are currently underway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Bone Density Conservation Agents / pharmacology
  • Bone Density Conservation Agents / therapeutic use*
  • Bone Morphogenetic Proteins / antagonists & inhibitors*
  • Bone Morphogenetic Proteins / metabolism
  • Disease Models, Animal
  • Genetic Markers
  • Humans
  • Hyperostosis / metabolism
  • Molecular Targeted Therapy / methods
  • Osteoporosis / drug therapy*
  • Osteoporosis / metabolism
  • Syndactyly / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Bone Density Conservation Agents
  • Bone Morphogenetic Proteins
  • Genetic Markers
  • SOST protein, human

Supplementary concepts

  • Sclerosteosis