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  • Perspective
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Mechanisms underlying the long-term and withdrawal effects of denosumab therapy on bone

Nature Reviews Rheumatology volume 19, pages 307–317 (2023)Cite this article

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Abstract

Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), is a potent inhibitor of osteoclast differentiation and activity. As the first biologic drug used to treat osteoporosis, denosumab has shown potent anti-resorptive properties and anti-fracture efficacy. The effects of this drug are also unique compared with the effects of bisphosphonates: namely, long-term treatment with this drug results in a continuous gain of bone mineral density, whereas withdrawal of the drug results in a transient overshoot in bone turnover and rapid bone loss. Although the mechanisms for these specific effects remain incompletely understood, emerging experimental and clinical data have started to highlight potential biological and pharmacological mechanisms by which denosumab might affect osteoclasts, as well as osteoblasts, and cause both sustained bone gain and bone loss upon treatment cessation. This Perspective discusses those potential mechanisms and the future studies and clinical implications that might ensue from these findings.

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Fig. 1: Potential mechanisms of bone loss following denosumab cessation.
Fig. 2: Potential mechanisms underlying the long-term increase in BMD with denosumab compared with bisphosphonates.

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Authors and Affiliations

  1. Service of Bone Diseases, Department of Medicine, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland

    Serge Ferrari

  2. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

    Bente Langdahl

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S.F. researched data for the article and wrote the article. B.L. contributed to the writing of the article. Both authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Serge Ferrari.

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Competing interests

B.L. has received research grants from Amgen and Novo Nordisk, and is on the advisory board and performs lectures for Amgen, Astellas, AstraZeneca, Eli Lilly, Gedeon-Richter, Gilead and UCB. S.F. has received research support from Agnovos, Alexion, Amgen, and UCB, and is on the scientific advisory board of Agnovos, Alexion, Amgen, Boehringer, Flowbone, Fresenius, Labatec, Myovant, Parexel, Radius and UCB.

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Nature Reviews Rheumatology thanks E. Seeman, R. Eastell and R. Baron for their contribution to the peer review of this work.

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Ferrari, S., Langdahl, B. Mechanisms underlying the long-term and withdrawal effects of denosumab therapy on bone. Nat Rev Rheumatol 19, 307–317 (2023). https://doi.org/10.1038/s41584-023-00935-3

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