Osteoporosis International

, Volume 22, Issue 2, pp 435–446 | Cite as

Do RANKL inhibitors (denosumab) affect inflammation and immunity?

Review

Abstract

Receptor activator of nuclear factor kappa B ligand (RANKL) and its natural antagonist, osteoprotegerin (OPG), are, respectively, an indispensable factor and a potent inhibitor for osteoclast differentiation, activity, and survival. The development of a human monoclonal antibody to RANKL, denosumab, constitutes a novel approach to prevent fragility fractures in osteoporosis, skeletal complications of malignancy, and potentially bone erosions in rheumatoid arthritis (RA). In addition to being expressed by osteoblasts, RANKL is abundantly produced by activated T cells, and synoviocytes in RA, whereas its receptor, RANK, is also expressed by monocytes/macrophages and dendritic cells. However, in preclinical and clinical studies of RA—including patients with some degree of immunosuppression—RANKL inhibitors did not significantly alter inflammatory processes. RANKL, RANK, and OPG deficiency in murine models highlights the important role of this pathway in the development and maturation of the immune system in rodents, including functions of T and/or B cells, whereas OPG overexpression in mice and rats seems innocuous with regard to immunity. In contrast, loss-of-function mutations in humans have more limited effects on immune cells. In clinical studies, the overall rate of infections, cancer, and death was similar with denosumab and placebo. Nevertheless, the risk of severe infections and cancer in some specific tissues remains to be carefully scrutinized.

Keywords

Denosumab Immunity Inflammation OPG Osteoporosis RANKL 

Notes

Acknowledgments

We are grateful to Professor Jean-Michel Dayer and to Roswitha Rehm for helpful and critical reading of this manuscript and to Dr. Marina Stolina (AMGEN Co., Thousand Oaks, CA, USA) for her contribution to this manuscript. This work was supported by grant numbers 310000–108453 and PMPDA-110347 from the Swiss National Science Foundation and from AETAS, Swiss Foundation for Ageing Research (SFL). Serge Ferrari has received consultant and speaker fees and research grants from AMGEN.

Conflicts of interest

None.

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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2010

Authors and Affiliations

  1. 1.Transplantation Immunology Unit, Division of Immunology and Allergy and Division of Laboratory Medicine, Department of Medical and Genetic LaboratoriesGeneva University Hospital and Faculty of MedicineGenevaSwitzerland
  2. 2.Division of Bone Diseases, Department of Rehabilitation and GeriatricsGeneva University Hospital and Faculty of MedicineGenevaSwitzerland
  3. 3.Service des Maladies OsseusesGeneva University Hospital (HUG)Geneva 14Switzerland

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