Elena Tsourdi1, Bente Langdahl2, Martine Cohen-Solal3, Bérengere Aubry-Rozier4, Erik Fink Eriksen5, Nuria Guañabens6, Barbara Obermayer-Pietsch7, Stuart H Ralston8, Richard Eastell9, M Carola Zillikens10. 1. Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany. 2. Medical Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark. 3. Inserm U1132 and University Paris-Diderot, Department of Rheumatology, Lariboisière Hospital, Paris, France. 4. Centre of bone diseases, Lausanne University Hospital, Lausanne, Switzerland. 5. Department of Clinical Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Institute of Clinical Medicine, Oslo University, Oslo, Norway. 6. Department of Rheumatology, Metabolic Bone Diseases Unit, Hospital Clínic, Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain. 7. Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Austria; Center for Biomarker Research in Medicine (CBmed), Graz, Austria. 8. Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK. 9. Mellanby Centre for Bone Research, University of Sheffield, UK. 10. Bone Center, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. Electronic address: m.c.zillikens@erasmusmc.nl.
Abstract
INTRODUCTION: The optimal duration of osteoporosis treatment is controversial. As opposed to bisphosphonates, denosumab does not incorporate into bone matrix and bone turnover is not suppressed after its cessation. Recent reports imply that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures. METHODS: The European Calcified Tissue Society (ECTS) formed a working group to perform a systematic review of existing literature on the effects of stopping denosumab and provide advice on management. RESULTS: Data from phase 2 and 3 clinical trials underscore a rapid decrease of bone mineral density (BMD) and a steep increase in bone turnover markers (BTMs) after discontinuation of denosumab. Clinical case series report multiple vertebral fractures after discontinuation of denosumab and a renewed analysis of FREEDOM and FREEDOM Extension Trial suggests, albeit does not prove, that the risk of multiple vertebral fractures may be increased when denosumab is stopped due to a rebound increase in bone resorption. CONCLUSION: There appears to be an increased risk of multiple vertebral fractures after discontinuation of denosumab although strong evidence for such an effect and for measures to prevent the occurring bone loss is lacking. Clinicians and patients should be aware of this potential risk. Based on available data, a re-evaluation should be performed after 5years of denosumab treatment. Patients considered at high fracture risk should either continue denosumab therapy for up to 10years or be switched to an alternative treatment. For patients at low risk, a decision to discontinue denosumab could be made after 5years, but bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover. However, since the optimal bisphosphonate regimen post-denosumab is currently unknown continuation of denosumab can also be considered until results from ongoing trials become available. Based on current data, denosumab should not be stopped without considering alternative treatment in order to prevent rapid BMD loss and a potential rebound in vertebral fracture risk.
INTRODUCTION: The optimal duration of osteoporosis treatment is controversial. As opposed to bisphosphonates, denosumab does not incorporate into bone matrix and bone turnover is not suppressed after its cessation. Recent reports imply that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures. METHODS: The European Calcified Tissue Society (ECTS) formed a working group to perform a systematic review of existing literature on the effects of stopping denosumab and provide advice on management. RESULTS: Data from phase 2 and 3 clinical trials underscore a rapid decrease of bone mineral density (BMD) and a steep increase in bone turnover markers (BTMs) after discontinuation of denosumab. Clinical case series report multiple vertebral fractures after discontinuation of denosumab and a renewed analysis of FREEDOM and FREEDOM Extension Trial suggests, albeit does not prove, that the risk of multiple vertebral fractures may be increased when denosumab is stopped due to a rebound increase in bone resorption. CONCLUSION: There appears to be an increased risk of multiple vertebral fractures after discontinuation of denosumab although strong evidence for such an effect and for measures to prevent the occurring bone loss is lacking. Clinicians and patients should be aware of this potential risk. Based on available data, a re-evaluation should be performed after 5years of denosumab treatment. Patients considered at high fracture risk should either continue denosumab therapy for up to 10years or be switched to an alternative treatment. For patients at low risk, a decision to discontinue denosumab could be made after 5years, but bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover. However, since the optimal bisphosphonate regimen post-denosumab is currently unknown continuation of denosumab can also be considered until results from ongoing trials become available. Based on current data, denosumab should not be stopped without considering alternative treatment in order to prevent rapid BMD loss and a potential rebound in vertebral fracture risk.
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