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New targets for intervention in the treatment of postmenopausal osteoporosis

Nature Reviews Rheumatology volume 7, pages 631–638 (2011)Cite this article

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Abstract

Postmenopausal osteoporosis is a disease of high bone remodeling, with an imbalance of bone resorption over bone formation, resulting in decreased bone mineral density and disruption of bone microarchitecture. With our improved understanding of the molecular and cellular regulators and mediators of bone remodeling, new targets for therapeutic intervention have been identified. Receptor activator of nuclear factor κB ligand (RANKL) is the principal regulator of osteoclast differentiation, activity, and survival; denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and is approved for the treatment of women with postmenopausal osteoporosis at high risk of fractures. Cathepsin K is a protease produced by activated osteoclasts that degrades the protein matrix of bone. An inhibitor of cathepsin K, odanacatib, is in phase III clinical trials for the treatment of postmenopausal osteoporosis; it decreases bone resorption while seeming to suppress bone formation less than other antiresorptive agents. Sclerostin is a cytokine produced by osteocytes that inhibits osteoblastic bone formation; investigational monoclonal antibodies to sclerostin, such as AMG 785, have osteoanabolic properties with the potential to improve clinical outcomes in patients with osteoporosis. These and other novel interventions that target newly recognized regulators of bone remodeling are promising agents for the treatment of osteoporosis.

Key Points

  • Postmenopausal osteoporosis is a disease of excessive bone remodeling, with an imbalance of bone resorption greater than bone formation

  • Understanding of the regulation of bone remodeling has led to the identification of novel pharmacological targets for the treatment of postmenopausal osteoporosis

  • Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL) that is an approved treatment for women with postmenopausal osteoporosis at high risk of fractures

  • Odanacatib, an investigational inhibitor of cathepsin K, increases bone mineral density (BMD) with a mode of action that might partially uncouple bone resorption and formation

  • Investigational antibodies against sclerostin, such as AMG 785, increase BMD by stimulating bone formation and reducing bone resorption

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Figure 1: A conceptual view of bone remodeling on the surface of trabecular bone in health, disease, and in response to drug treatment.
Figure 2: RANKL–RANK–OPG regulatory pathway and osteoclastic bone resorption.
Figure 3: Wnt signaling.

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  1. New Mexico Clinical Research & Osteoporosis Center, 300 Oak Street NE, Albuquerque, 87106, NM, USA

    E. Michael Lewiecki

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E. M. Lewiecki has received grant/research support from Amgen, Eli Lilly, Novartis, Merck, Warner Chilcott, and Genentech, and served on the scientific advisory board and/or received speakers' bureau from Amgen, Eli Lilly Novartis, Genentech and Merck.

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Lewiecki, E. New targets for intervention in the treatment of postmenopausal osteoporosis. Nat Rev Rheumatol 7, 631–638 (2011). https://doi.org/10.1038/nrrheum.2011.130

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