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Comparative Effect of Zoledronate at 6 Versus 18 Months Following Denosumab Discontinuation

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Abstract

Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (− 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures.

Trial Registration: NCT02499237; July 16, 2015

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Data Availability

Data are available upon request.

Code Availability

Statistical analysis was performed with SPSS for Macintosh, version 21.0 (IBM Corporation, New York, USA).

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Acknowledgements

We would like to express our deep appreciation to Prof. Socrates Papapoulos for his constructive comments and criticism.

Funding

The present study received no funding from any source and was supported from authors’ own resources.

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Authors and Affiliations

  1. Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece

    Athanasios D. Anastasilakis & Stylianos Mandanas

  2. First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Stergios A. Polyzos & Charikleia Ntenti

  3. 1st Department of Propaedeutic Internal Medicine, Endocrinology Unit, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

    Maria P. Yavropoulou

  4. Department of Internal Medicine, Center for Bone Quality, Section Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

    Natasha M. Appelman-Dijkstra

  5. Department of Endocrinology and Diabetes and Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, 3 Kanellopoulou str, 115 25, Goudi, Athens, Greece

    Maria P. Yavropoulou, Athanasios Papatheodorou & Polyzois Makras

Authors
  1. Athanasios D. Anastasilakis
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  2. Stergios A. Polyzos
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  3. Maria P. Yavropoulou
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  4. Natasha M. Appelman-Dijkstra
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  5. Charikleia Ntenti
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  6. Stylianos Mandanas
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  7. Athanasios Papatheodorou
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  8. Polyzois Makras
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Contributions

ADA and PM involved in study design, study conduct, and data collection. ADA, SAP, PM, CN, and AP performed the data analysis. ADA, NMA-D, SAP, MPY, and PM did data interpretation. ADA, SM, SAP, and PM drafted the manuscript. ADA, PM, SAP, NMA-D, MPY, CN, and PM involved in revising the manuscript content. ADA, NMA-D, SAP, MPY, SM, CN, AP, and PM approved the final version of manuscript. ADA, SAP, and PM took responsibility for the integrity of the data analysis.

Corresponding author

Correspondence to Polyzois Makras.

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Conflict of interest

Athanasios D. Anastasilakis has received lecture fees from Amgen; Natasha M Appelman-Dijkstra has served on the national advisory board for Prolia and has received lecture fees from Amgen; Polyzois Makras has received lecture fees and research grants from Amgen; Stergios A. Polyzos, Maria P. Yavropoulou, Charikleia Ntenti, Stylianos Mandanas and Athanasios Papatheodorou have nothing to declare.

Human and Animal Rights and Informed Consent

Medical Ethical Committees of the 424 General Military Hospital and the 251 Hellenic Air Force & VA General Hospital and it was performed in accordance with the ethical standards as laid down in the 1964 declaration of Helsinki and its later amendments. All patients provided informed consent for their participation and publication of their results.

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Anastasilakis, A.D., Polyzos, S.A., Yavropoulou, M.P. et al. Comparative Effect of Zoledronate at 6 Versus 18 Months Following Denosumab Discontinuation. Calcif Tissue Int 108, 587–594 (2021). https://doi.org/10.1007/s00223-020-00785-1

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