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Fracture risk following intermission of osteoporosis therapy

  • E.M. Dennison
  • C. CooperEmail author
  • J.A. Kanis
  • O. Bruyère
  • S. Silverman
  • E. McCloskey
  • B. Abrahamsen
  • D. Prieto-Alhambra
  • S. Ferrari
  • On behalf of the IOF Epidemiology/Quality of Life Working Group
Original Article

Abstract

Summary

Given the widespread practice of recommending drug holidays, we reviewed the impact of medication discontinuation of two common anti-osteoporosis therapies (bisphosphonates and denosumab). Trial evidence suggests the risk of new clinical fractures, and vertebral fracture increases when osteoporosis treatment with bisphosphonates or denosumab is stopped.

Introduction

The aim of this paper was to review the available literature to assess what evidence exists to inform clinical decision-making with regard to drug holidays following treatment with bisphosphonates (BiP) or denosumab.

Methods

Systematic review.

Results

Differing pharmacokinetics lead to varying outcomes on stopping therapy. Prospective and retrospective analyses report that the risk of new clinical fractures was 20–40% higher in subjects who stopped BiP treatment, and vertebral fracture risk was approximately doubled. Rapid bone loss has been well described following denosumab discontinuation with an incidence of multiple vertebral fractures around 5%. Studies have not identified risk factors for fracture after stopping treatment other than those that provide an indication for treatment (e.g. prior fracture and low BMD). Studies that considered long-term continuation did not identify increased fracture risk, and reported only very low rates of adverse skeletal events such as atypical femoral fracture.

Conclusions

The view that patients on long-term treatment with bisphosphonates or denosumab should always be offered a drug holiday is not supported by the existing evidence. Different pharmacokinetic properties for different therapies require different strategies to manage drug intermission. In contrast, long-term treatment with anti-resorptives is not associated with increased risk of fragility fractures and skeletal adverse events remain rare.

Keywords

Atypical fracture Bisphosphonates Denosumab Drug holiday 

Notes

Acknowledgements

This study was supported by an unrestricted grant from MSD. The sponsor did not have any role in preparation, review or approval of the manuscript. The initial systematic review was performed by Nadia Corp. We are grateful to the Committee of Scientific Advisors of the International Osteoporosis Foundation for their review and endorsement of this paper.

Compliance with ethical standards

Competing interests

JAK reports grants from Amgen, Eli Lilly and Radius Health; non-financial support from Medimaps and Asahi; and other support from AgNovos. JAK is the architect of FRAX but has no financial interest. CC reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB. OB reports research grants from Biophytis, IBSA, MEDA, Servier and SMB outside the submitted work. DPA reports grants from Amgen, Servier and UCB, and departmental fees for speaker or consultancy services from Amgen and UCB. BA declares research grants from Novartis and UCB, speaker fees from Amgen and consulting and speaker fees from UCB. SF reports consulting and/or speaker honoraria from Amgen, UCB, Lilly, Labatec, Agnovos and Pfizer. EM reports Consultant/Advisor/Speaker fees from ActiveSignal, AgNovos, Amgen, AstraZeneca, Consilient Healthcare, Fresenius Kabi, GSK, Hologic, Internis, Lilly, Medtronic, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, Synexus, Tethys, UCB, Warner Chilcott, research support from ActiveSignal, AgNovos, Amgen, AstraZeneca, Consilient Healthcare, Fresenius Kabi, GSK, Hologic, Internis, Lilly, Medtronic, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, Synexus, Tethys, UCB, Warner Chilcott, ARUK, I3 Innovus, MRC, IOF, Unilever. ED reports consulting and speaker fees from Pfizer and UCB.

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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2019

Authors and Affiliations

  • E.M. Dennison
    • 1
  • C. Cooper
    • 1
    • 2
    Email author
  • J.A. Kanis
    • 3
    • 4
  • O. Bruyère
    • 5
  • S. Silverman
    • 6
  • E. McCloskey
    • 7
  • B. Abrahamsen
    • 8
    • 9
  • D. Prieto-Alhambra
    • 10
    • 11
  • S. Ferrari
    • 12
  • On behalf of the IOF Epidemiology/Quality of Life Working Group
  1. 1.MRC Lifecourse Epidemiology UnitUniversity of SouthamptonSouthamptonUK
  2. 2.Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesUniversity of OxfordOxfordUK
  3. 3.Centre for Metabolic Bone Diseases, University of Sheffield Medical SchoolUniversity of SheffieldSheffieldUK
  4. 4.Mary McKillop Health InstituteAustralian Catholic UniversityMelbourneAustralia
  5. 5.World Health Organization Collaborating Center for Public Health Aspects of Musculoskeletal Health and Ageing, Department of Public Health, Epidemiology and Health EconomicsUniversity of LiègeLiègeBelgium
  6. 6.Cedars-Sinai/UCLA Medical Center and OMC Clinical Research CenterBeverly HillsUSA
  7. 7.Academic Unit of Bone Metabolism, Department of Oncology and Metabolism, The Mellanby Centre For Bone ResearchUniversity of SheffieldSheffieldUK
  8. 8.Department of MedicineHolbaek HospitalHolbaekDenmark
  9. 9.OPEN, Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
  10. 10.Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesUniversity of OxfordOxfordUK
  11. 11.GREMPAL Research Group, Idiap Jordi Gol and CIBERFesUniversitat Autonoma de Barcelona and Instituto de Salud Carlos IIIBarcelonaSpain
  12. 12.Division of Bone Disease, Faculty of MedicineGeneva University HospitalGenevaSwitzerland

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