Fracture risk following intermission of osteoporosis therapy

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.

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Fig. 1

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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.

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Correspondence to C. Cooper.

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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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Dennison, E., Cooper, C., Kanis, J. et al. Fracture risk following intermission of osteoporosis therapy. Osteoporos Int 30, 1733–1743 (2019). https://doi.org/10.1007/s00198-019-05002-w

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Keywords

  • Atypical fracture
  • Bisphosphonates
  • Denosumab
  • Drug holiday