Discontinuation of denosumab therapy for osteoporosis:​ a systematic review and position statement by ECTS

Tsourdi, Elena<sup>1,2</sup>; Langdahl, Bente<sup>3</sup>; Cohen-Solal, Martine<sup>4</sup>; Aubry-Rozier, Bérengere<sup>5</sup>; Eriksen, Erik Fink<sup>6</sup>; Guañabens, Nuria<sup>7</sup>; Obermayer-Pietsch, Barbara<sup>8,9</sup>; Ralston, Stuart H.<sup>10</sup>; Eastell, Richard<sup>11</sup>; Zillikens, M. Carola<sup>12</sup>

Affiliations

¹Department of Medicine III, Technische Universität Dresden, Dresden, Germany

²Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany

³Medical Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark

⁴Inserm U1132 and University Paris-Diderot, Department of Rheumatology, Lariboisière Hospital, Paris, France

⁵Centre of bone diseases, Lausanne University Hospital, Lausanne, Switzerland

⁶Department of Clinical Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Institute of Clinical Medicine, Oslo University, Oslo, Norway

⁷Department of Rheumatology, Metabolic Bone Diseases Unit, Hospital Clínic, Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain

⁸Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Austria

⁹Center for Biomarker Research in Medicine (CBmed), Graz, Austria

¹⁰Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK

¹¹Mellanby Centre for Bone Research, University of Sheffield, UK

¹²Bone Center, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

Abstract and keywords

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 5 years of denosumab treatment. Patients considered at high fracture risk should either continue denosumab therapy for up to 10 years or be switched to an alternative treatment. For patients at low risk, a decision to discontinue denosumab could be made after 5 years, 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.

Keywords: Osteoporosis treatment; Denosumab; Discontinuation; Fractures; Position paper

Links

DOI: 10.1016/j.bone.2017.08.003

PubMed: 28789921

WoS: 000413994500002

History

Received: 2017-07-3

Revised: 2017-08-04

Accepted: 2017-08-04

Online: 2017-08-5

Cited Works (15)

Year	Entry
2016	Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O. Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int. May 2016;27(5):1923-1925.
2011	Russell RGG. Bisphosphonates: the first 40 years. Bone. July 2011;49(1):2-19.
2016	Popp AW, Zysset PK, Lippuner K. Rebound-associated vertebral fractures after discontinuation of denosumab—from clinic and biomechanics. Osteoporos Int. May 2016;27(5):1917-1921.
2012	Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, Cummings SR, Hue TF, Lippuner K, Lakatos P, Leung PC, Man Z, Martinez RLM, Tan M, Ruzycky ME, Su G, Eastell R. The effect of 3 versus 6 years of Zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. February 2012;27(2):243-254.
2017	McClung MR, Wagman RB, Miller PD, Wang A, Lewiecki EM. Observations following discontinuation of long-term denosumab therapy. Osteoporos Int. May 2017;28(5):1723-1732.
2009	Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. NEJM. August 20, 2009;361(8):756-765.
2008	Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J; AMG 162 Bone Loss Study Group. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. August 2008;43(2):222-229.
2016	Adler RA, Fuleihan GE-H, Bauer DC, Camacho PM, Clarke BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ, Greenspan SL, McKinney R Jr, Pignolo RJ, Sellmeyer DE. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;31(1):16-35.
2005	Prince R, Sipos A, Hossain A, Syversen U, Ish-Shalom S, Marcinowska E, Halse J, Lindsay R, Dalsky GP, Mitlak BH. Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment. J Bone Miner Res. September 2005;20(9):1507-1513.
2012	Freemantle N, Satram-Hoang S, Tang E-T, Kaur P, Macarios D, Siddhanti S, Borenstein J, Kendler DL; DAPS Investigators. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. January 2012;23(1):317-326.
2017	Reid IR, Horne AM, Mihov B, Gamble GD. Bone loss after denosumab: only partial protection with zoledronate. Calcif Tiss Int. October 2017;101(4):371-374.
2006	Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the fracture intervention trial long-term extension (FLEX): a randomized trial. JAMA. December 27, 2006;296(24):2927-2938.
2017	Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwiński E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster J-Y, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. July 2017;5(7):513-523.
2011	Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang Y-C, Grazette L, San Martin J, Gallagher JC. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. April 2011;96(4):972-980.
2017	Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. June 2017;32(6):1291-1296.

Cited By (23)

Year	Entry
2020	Tripto-Shkolnik L, Fund N, Rouach V, Chodick G, Shalev V, Goldshtein I. Fracture incidence after denosumab discontinuation: real-world data from a large healthcare provider. Bone. January 2020;130:115150.
2020	LaCombe JM, Roper RJ. Skeletal dynamics of Down syndrome: a developing perspective. Bone. April 2020;133:115215.
2020	Tamaki S, Kuroshima S, Hayano H, Nakajima K, Kakehashi H, Ishisaki A, Sawase T. Dynamic polarization shifting from M1 to M2 macrophages in reduced osteonecrosis of the jaw-like lesions by cessation of anti-RANKL antibody in mice. Bone. December 2020;141:115560.
2021	Everts-Graber J, Reichenbach S, Gahl B, Ziswiler H, Studer U, Lehmann T. Risk factors for vertebral fractures and bone loss after denosumab discontinuation: a real-world observational study. Bone. March 2021;144:115830.
2021	Mok CC, Ho LY, Leung SMT, Cheung HN, Chen SPL, Ma KM. Denosumab versus alendronate in long-term glucocorticoid users: a 12-month randomized controlled trial. Bone. May 2021;146:115902.
2021	D'Oronzo S, Wood S, Brown JE. "The use of bisphosphonates to treat skeletal complications in solid tumours". Bone. June 2021;147:115907.
2021	Anastasilakis AD, Polyzos SA, Yavropoulou MP, Appelman-Dijkstra NM, Ntenti C, Mandanas S, Papatheodorou A, Makras P. Comparative effect of zoledronate at 6 versus 18 months following denosumab discontinuation. Calcif Tiss Int. May 2021;108(5):587-594.
2019	Anastasilakis AD, Papapoulos SE, Polyzos SA, Appelman-Dijkstra NM, Makras P. Zoledronate for the prevention of bone loss in women discontinuing denosumab treatment: a prospective 2-year clinical trial. J Bone Miner Res. December 2019;34(12):2220-2228.
2020	Black DM, Sellmeyer DE. Now that you can get what you want, can you keep what you need? J Bone Miner Res. February 2020;35(2):217-218.
2020	Nyström A, Kiritopoulos D, Ullmark G, Sörensen J, Petrén‐Mallmin M, Milbrink J, Hailer NP, Mallmin H. Denosumab prevents early periprosthetic bone loss after uncemented total hip arthroplasty: results from a randomized placebo‐controlled clinical trial. J Bone Miner Res. February 2020;35(2):239-247.
2020	Shao L, Wu X. The efficacy of denosumab for prevention of early periprosthetic bone loss after cementless total hip arthroplasty. J Bone Miner Res. May 2020;35(5):998-999.
2020	Ferrari S. Zoledronate following denosumab discontinuation: partial reassurance but no confidence. J Bone Miner Res. July 2020;35(7):1205-1206.
2020	Everts‐Graber J, Reichenbach S, Ziswiler HR, Studer U, Lehmann T. A single infusion of zoledronate in postmenopausal women following denosumab discontinuation results in partial conservation of bone mass gains. J Bone Miner Res. July 2020;35(7):1207-1215.
2022	Geusens P, Bevers MSAM, van Rietbergen B, Messina OD, Lespessailles E, Oliveri B, Chapurlat R, Engelke K, Chines A, Huang S, Saag KG, van den Bergh JP. Effect of denosumab compared with risedronate on bone strength in patients initiating or continuing glucocorticoid treatment. J Bone Miner Res. June 2022;37(6):1136-1146.
2023	Alarkawi D, Tran T, Chen W, March LM, Blyth FM, Blank RD, Bliuc D, Center JR. Denosumab and mortality in a real-world setting: a comparative study. J Bone Miner Res. December 2023;38(12):1757-1770.
2019	Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. May 2019;104(5):1595-1622.
2019	Kanis JA, Cooper C, Rizzoli R, Reginster J-Y; Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO); Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. January 2019;30(1):3-44.
2020	Girgis CM, Clifton-Bligh RJ. Osteoporosis in the age of COVID-19. Osteoporos Int. July 2020;31(7):1189-1191.
2020	Piponov HI, Goldstein JM, Eisenberg GM. Multiple ipsilateral femoral stress fractures in a patient taking denosumab for osteoporosis: a case report. Osteoporos Int. November 2020;31(11):2263-2267.
2021	Hiligsmann M, Maggi S, Veronese N, Sartori L, Reginster J-Y. Cost-effectiveness of buffered soluble alendronate 70 mg effervescent tablet for the treatment of postmenopausal women with osteoporosis in iItaly. Osteoporos Int. March 2021;32(3):595-606.
2020	Axelsson KF. Aspects of Fracture Prevention: The Role of Fracture Liaison Services and Alendronate [PhD thesis]. University of Gothenburg; 2020.
2018	Raina DB. Biomaterials as Carriers for Bone Active Molecules: An Approach to Create Off-the-Shelf Bone Substitutes [PhD thesis]. Lund, Sweden: Lund University; 2018.
2020	Hadaya D. Osteonecrosis of the Jaws: Investigations Into Pathophysiology and Prevention [PhD thesis]. Los Angeles (UCLA), University of California; 2020.