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Potential new drug targets for osteoporosis

Nature Clinical Practice Rheumatology volume 5, pages 20–27 (2009)Cite this article

An Erratum to this article was published on 01 March 2009

Abstract

Osteoporosis is a worldwide health problem with a high prevalence. Agents for the treatment of osteoporosis are classified as either antiresorptive or anabolic. Antiresorptive agents work by inhibiting the activity of osteoclasts and, therefore, reducing bone resorption. Currently available antiresorptive agents include bisphosphonates, selective estrogen-receptor modulators, calcitonin and estrogen. Various novel antiresorptive agents are in development. Receptor activator of nuclear factor κ B ligand is an important cytokine involved in osteoclast activation; denosumab, a fully human monoclonal antibody to this molecule, has finished a major fracture trial. Assessment is underway of odanacatib—an inhibitor of cathepsin K, which is an osteoclast enzyme required for resorption of bone matrix. Glucagon-like peptide 2 is being evaluated for the prevention of the nocturnal rise in bone resorption without affecting bone formation. Anabolic agents act by stimulating formation of new bone. The only anabolic agent currently available in the US is teriparatide—recombinant human parathyroid hormone (PTH)1–34—and recombinant human PTH1–84 is available in Europe. PTH stimulates osteoblast function and bone formation. Novel anabolic agents in development include: antibodies such as sclerostin and dickkopf-1 that target molecules involved in Wnt signaling, a pathway that regulates gene transcription of proteins that are important for osteoblast function; an antagonist to the calcium-sensing receptor; and an activin receptor fusion protein, which functions as an activin antagonist and has shown promise as an anabolic agent in early human trials.

Key Points

  • Drugs that influence bone mass do so by acting directly on cells that are integral to the bone remodeling unit

  • Antiresorptive agents inhibit osteoclasts and prevent bone resorption

  • Anabolic agents stimulate osteoblasts and, therefore, bone formation

  • Potential new therapeutic agents include denosumab, an antibody to receptor activator of nuclear factor κ B ligand, and odanacatib, a cathepsin K inhibitor

  • Potential new anabolic agents include those that target the calcium-sensing receptor and proteins in the Wnt signaling pathway

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Figure 1: The sequence of bone remodeling in healthy individuals.
Figure 2: Proposed mechanism of action for denosumab.
Figure 3: Therapeutic manipulation of the calcium-sensing receptor.
Figure 4: Simplified view or Wnt and beta-catenin signaling.

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Author notes

  1. Center for Osteoporosis and Metabolic Bone Disease, Orthopedic and Rheumatologic Institute (A50), Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA dealc@cct.org

Authors and Affiliations

  1. C Deal is Head of the Center for Osteoporosis and Metabolic Bone Disease at the Orthopedic and Rheumatology Institute, Cleveland Clinic, Cleveland, OH, USA.,

    Chad Deal

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Competing interests

C Deal is on the advisory board for Amgen, Lilly and Novartis, and has received speaker's bureau from Proctor & Gamble, GSK/Roche, Lilly and Novartis.

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Deal, C. Potential new drug targets for osteoporosis. Nat Rev Rheumatol 5, 20–27 (2009). https://doi.org/10.1038/ncprheum0977

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