Abstract
Summary
In patients discontinuing long-term denosumab, RANKL levels are high 6 months after the last denosumab injection. Nine and 12 months after the last denosumab injection RANKL levels are lower, but TRAcP 5b levels are higher, suggesting that accumulated RANKL increases the number of active osteoclasts.
Purpose
The rapid increase in bone turnover occurring when discontinuing long-term treatment with denosumab (DMAB), an antibody that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) is not fully understood. We aimed to investigate the mechanisms underlying the rebound activation of bone resorption by measuring tartrate-resistant acid phosphatase 5b (TRAcP 5b), RANKL, osteoprotegerin (OPG), C-terminal collagen crosslinks (CTX), and procollagen type I N-propeptide (P1NP) in patients discontinuing long-term DMAB.
Methods
Sixty-one patients with BMD T-score > − 2.5 at the spine and hip discontinuing long-term DMAB were randomized to treatment with zoledronate (ZOL) 6 months (6 M group, n = 20), 9 months (9 M group, n = 20) or 12 months after the last DMAB injection or when bone turnover was high (12 M group, n = 21). Bone turnover markers were measured immediately before initiation of ZOL treatment.
Results
We found higher CTX and PINP in the 9 M and 12 M groups compared to the 6 M group (p < 0.001). In the 6 M group, TRAcP 5b was lower and RANKL higher than in the other two groups (p < 0.001). TRAcP 5b correlated negatively with RANKL (R = − 0.54), and time since the last DMAB injection correlated positively with CTX (R = 0.56), PINP (R = 0.72), TRAcP 5b (R = 0.51) and negatively with RANKL (R = − 0.70) (p < 0.001 for all). We found no difference in OPG between groups.
Conclusion
Following discontinuation of long-term DMAB, we find high levels of RANKL, which most likely result in an increase in the number of active osteoclasts (illustrated by TRAcP5b) causing an increased bone turnover.
This is a preview of subscription content, log in via an institution to check access.
References
Sølling AS et al (2021) Treatment with zoledronate subsequent to denosumab in osteoporosis: a 2-year randomized study. J Bone Min Res 36(7):1245–1254
Sølling AS et al (2020) Treatment with zoledronate subsequent to denosumab in osteoporosis: a randomized trial. J Bone Min Res 35(10):1858–1870
Lacey DL et al (2012) Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 11(5):401–419
Cummings SR et al (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361(8):756–765
Miller PD et al (2008) 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 43(2):222–229
Bone HG et al (2011) 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 96(4):972–980
Anastasilakis AD et al (2017) Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Min Res 32(6):1291–1296
Anastasilakis AD et al (2019) Zoledronate for the prevention of bone loss in women discontinuing denosumab treatment. a prospective 2-year clinical trial. J Bone Min Res 34(12):2220–2228
McDonald M et al (2021) Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 184(7):1940
Vasikaran S et al (2011) Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 22(2):391–420
Amgen Canada Inc., Prolia® (denosumab) solution for injection. Product monograph. Available: https://www.amgen.ca/-/media/Themes/CorporateAffairs/amgen-ca/amgen-ca/documents/products/en/prolia_pm.pdf. Accessed 17th of Ostober 2022.
Fontalis A et al (2020) The effect of denosumab treatment on osteoclast precursor cells in postmenopausal osteoporosis. Bone Reports 13:100457
D. C. Tourolle et al., ‘Ten-year simulation of the effects of denosumab on bone remodeling in human biopsies’, JBMR plus, vol. 5, no. 6, 2021.
Fassio A et al (2019) Changes in Dkk-1, sclerostin, and RANKL serum levels following discontinuation of long-term denosumab treatment in postmenopausal women. Bone 123:191–195
Burckhardt P et al (2021) Fractures after denosumab discontinuation: a retrospective study of 797 cases’. J Bone Miner Res 36(9):1717–1728
K. M. Cawley et al., ‘Local production of osteoprotegerin by osteoblasts suppresses bone resorption’, Cell rep., vol. 32, no. 10, 2020.
Gifre L et al (2017) Effect of recent spinal cord injury on the OPG/RANKL system and its relationship with bone loss and the response to denosumab therapy. Osteoporos Int 28(9):2707–2715
Funding
The authors have received financial support from Amgen, The Danish Osteoporosis Society, P. Carl Petersen’s Foundation, Torkil Steenbeck’s Foundation, Vilhelm Pedersen and wife’s Foundation, and the Aarhus University during the conduct of the study. The funders of the study had no role in the study design, data collection, data interpretation, or writing of the report. The authors had full access to all the data and had final responsibility for the decision to submit for publication.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
Torben Harsløf received lecture fees from Amgen, Astra Zeneca, and Eli Lilly. Bente Langdahl has received research funding to her institution from Amgen and Novo Nordisk. Bente Langdahl serves on advisory boards and speaker’s bureau for Amgen, UCB, Gilead, and Gedeon-Richter. Niklas Rye Jørgensen has no conflicts of interest relevant to the current study. Anne Sophie Sølling received lecture fees from Amgen and Gedeon-Richter.
Dissemination to participants
After completion of the study, the participants received written information about the results. Also, the participants can seek further information about the project by contacting the investigator.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Sølling, A.S., Harsløf, T., Jørgensen, N.R. et al. Changes in RANKL and TRAcP 5b after discontinuation of denosumab suggest RANKL mediated formation of osteoclasts results in the increased bone resorption. Osteoporos Int 34, 599–605 (2023). https://doi.org/10.1007/s00198-022-06651-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-022-06651-0