Maintenance of bone resorption markers in the low premenopausal range during the year following denosumab discontinuation is associated to bone density preservation:​ the ReoLaus study

Liebich, Giovanni<sup>1</sup>; Lamy, Olivier<sup>2,3</sup>; Aubry-Rozier, Bérengère<sup>2</sup>; Gonzalez-Rodriguez, Elena<sup>2</sup>

Affiliations

¹Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland

²Interdisciplinary Center for Bone Diseases, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland

³Service of Internal Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland

Abstract and keywords

Purpose: Denosumab discontinuation (DD) is associated with serum C-terminal X-linked telopeptides (sCTX) increase, bone mineral density (BMD) loss and vertebral fractures (VFs) risk increase. We compared clinical characteristics of women losing or not lumbar spine (LS) BMD one-year after DD, and their sCTX values at different time-points.

Methods: We included women from the ReoLaus cohort having received ≥2 denosumab 60 mg injections, with three BMD measurements on the same device (before (DXA1), at the end of denosumab treatment (DXA2), and one-year after (DXA3)) and sCTX measured at different time-points. Losers (LS DXA3-DXA2 > 2.8 %) and stable groups were compared.

Results: 63 postmenopausal women were included (mean age 64.2 ± 9.1 years, 7.9 ± 2.7 denosumab injections). 19 months after last denosumab injection, 65 % had lost LS BMD. Losers were younger, had lower BMD and higher sCTX before denosumab, received more injections and gained more BMD under denosumab, and had higher sCTX after DD. Same proportion of patients received bisphosphonates in both groups, but 11 (all in losers group) received ≥1 zoledronate infusion. Three women developed VFs in the losers group (none in the stable). Mean sCTX at 10 and 19 months were 590 ± 372 versus 221 ± 101, and 598 ± 324 versus 293 ± 157 ng/l, respectively (premenopausal range < 573 ng/l, p < 0.01 for both). LS BMD loss and sCTX levels measured at 10 and 19 months were correlated (r² = 0.29, p = 0.01, and r² = 0.16, p < 0.005).

Conclusion: Maintenance of BMD gained with denosumab is associated with sCTX in the low premenopausal range after DD. Whether this could be achieved by regular sCTX monitoring and adjustment of bisphosphonates doses or frequency administration needs to be confirmed by further studies.

Keywords: Denosumab discontinuation; Rebound effect; BMD loss; Spontaneous vertebral fractures; Serum C-terminal X-linked telopeptides; Bisphosphonates

Links

DOI: 10.1016/j.bone.2023.116764

PubMed: 37062514

History

Received: 2022-12-22

Revised: 2023-03-17

Accepted: 2023-04-11

Online: 2023-04-14

Cited Works (13)

Year	Entry
2021	Sølling AS, Harsløf T, Langdahl B. Treatment with zoledronate subsequent to denosumab in osteoporosis: a 2-year randomized study. J Bone Miner Res. July 2021;36(7):1245-1254.
2018	Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen J-EB, McClung M, Roux C, Törring O, Valter I, Wang AT, Brown JP. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. February 2018;33(2):190-198.
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.
2022	Cosman F, Huang S, McDermott M, Cummings SR. Multiple vertebral fractures after denosumab discontinuation: FREEDOM and FREEDOM extension trials additional post hoc analyses. J Bone Miner Res. November 2022;37(11):2112-2120.
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.
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.
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.
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.
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.
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.
2020	Sølling AS, Harsløf T, Langdahl B. Treatment with zoledronate subsequent to denosumab in osteoporosis: a randomized trial. J Bone Miner Res. October 2020;35(10):1858-1870.
2022	Everts-Graber J, Reichenbach S, Gahl B, Häuselmann H, Ziswiler H-R, Studer U, Lehmann T. Effects of zoledronate on bone mineral density and bone turnover after long-term denosumab therapy: observations in a real-world setting. Bone. October 2022;163:116498.
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.