Temporal Patterns of Osteoclast Formation and Activity Following Withdrawal of RANKL Inhibition

Overview

Journal J Bone Miner Res

Publisher Oxford University Press

Date 2024 Mar 13

PMID 38477789

Authors

Albert S Kim

Victoria E Taylor

Ariel Castro-Martinez

Suraj Dhakal

Amjad Zamerli

Sindhu Mohanty

Ya Xiao

Marija K Simic

Jinchen Wen

Ryan Chai

Peter I Croucher

Jacqueline R Center

Christian M Girgis

Michelle M McDonald

Affiliations

Soon will be listed here.

Abstract

Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.

Citing Articles

Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect.

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PMID: 39424806 PMC: 11489716. DOI: 10.1038/s41413-024-00362-4.

Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments.

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References

Samadfam R, Xia Q, Goltzman D . Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice. J Bone Miner Res. 2006; 22(1):55-63. DOI: 10.1359/jbmr.060915. View

McDonald M, Khoo W, Ng P, Xiao Y, Zamerli J, Thatcher P . Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell. 2021; 184(5):1330-1347.e13. PMC: 7938889. DOI: 10.1016/j.cell.2021.02.002. View

Dempster D, Compston J, Drezner M, Glorieux F, Kanis J, Malluche H . Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2012; 28(1):2-17. PMC: 3672237. DOI: 10.1002/jbmr.1805. View

Vasikaran S, Eastell R, Bruyere O, Foldes A, Garnero P, Griesmacher A . Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2010; 22(2):391-420. DOI: 10.1007/s00198-010-1501-1. View

McClung M, Wagman R, Miller P, Wang A, Lewiecki E . Observations following discontinuation of long-term denosumab therapy. Osteoporos Int. 2017; 28(5):1723-1732. PMC: 5391373. DOI: 10.1007/s00198-017-3919-1. View

Eisman J, Bone H, Hosking D, McClung M, Reid I, Rizzoli R . Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res. 2010; 26(2):242-51. DOI: 10.1002/jbmr.212. View

Janckila A, Yam L . Biology and clinical significance of tartrate-resistant acid phosphatases: new perspectives on an old enzyme. Calcif Tissue Int. 2009; 85(6):465-83. DOI: 10.1007/s00223-009-9309-8. View

Mori Y, Kasai H, Ose A, Serada M, Ishiguro M, Shiraki M . Modeling and simulation of bone mineral density in Japanese osteoporosis patients treated with zoledronic acid using tartrate-resistant acid phosphatase 5b, a bone resorption marker. Osteoporos Int. 2018; 29(5):1155-1163. PMC: 5948273. DOI: 10.1007/s00198-018-4376-1. View

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. 2020; 144:115830. DOI: 10.1016/j.bone.2020.115830. View

10.

Solling A, Harslof T, Langdahl B . Treatment with Zoledronate Subsequent to Denosumab in Osteoporosis: a Randomized Trial. J Bone Miner Res. 2020; 35(10):1858-1870. DOI: 10.1002/jbmr.4098. View

11.

Burckhardt P, Faouzi M, Buclin T, Lamy O . Fractures After Denosumab Discontinuation: A Retrospective Study of 797 Cases. J Bone Miner Res. 2021; 36(9):1717-1728. PMC: 8518625. DOI: 10.1002/jbmr.4335. View

12.

Anastasilakis A, Polyzos S, Yavropoulou M, Appelman-Dijkstra N, Ntenti C, Mandanas S . Comparative Effect of Zoledronate at 6 Versus 18 Months Following Denosumab Discontinuation. Calcif Tissue Int. 2021; 108(5):587-594. DOI: 10.1007/s00223-020-00785-1. View

13.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

14.

Tremollieres F, Pouilles J, Ribot C . Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women. Osteoporos Int. 2001; 12(5):385-90. DOI: 10.1007/s001980170107. View

15.

Fu Q, Bustamante-Gomez N, Reyes-Pardo H, Gubrij I, Escalona-Vargas D, Thostenson J . Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation. JCI Insight. 2023; 8(18). PMC: 10561722. DOI: 10.1172/jci.insight.167790. View

16.

Brown J, Dempster D, Ding B, Dent-Acosta R, San Martin J, Grauer A . Bone remodeling in postmenopausal women who discontinued denosumab treatment: off-treatment biopsy study. J Bone Miner Res. 2011; 26(11):2737-44. DOI: 10.1002/jbmr.448. View

17.

Bone H, Bolognese M, Yuen C, Kendler D, Miller P, Yang Y . 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. 2011; 96(4):972-80. DOI: 10.1210/jc.2010-1502. View

18.

Naylor K, Clowes J, Finigan J, Paggiosi M, Peel N, Eastell R . The effect of cessation of raloxifene treatment on bone turnover in postmenopausal women. Bone. 2009; 46(3):592-7. DOI: 10.1016/j.bone.2009.10.043. View

19.

Gossiel F, Ugur A, Peel N, Walsh J, Eastell R . The clinical utility of TRACP-5b to monitor anti-resorptive treatments of osteoporosis. Osteoporos Int. 2022; 33(6):1357-1363. DOI: 10.1007/s00198-022-06311-3. View

20.

Bone H, Wagman R, Brandi M, Brown J, Chapurlat R, Cummings 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. 2017; 5(7):513-523. DOI: 10.1016/S2213-8587(17)30138-9. View