Changes in RANKL and TRAcP 5b after discontinuation of denosumab suggest RANKL mediated formation of osteoclasts results in the increased bone resorption

Sølling, Anne Sophie; Harsløf, Torben; Jørgensen, Niklas Rye; Langdahl, Bente

doi:10.1007/s00198-022-06651-0

Cited by 10 publications

(5 citation statements)

References 16 publications

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“…The mechanism, as well as strategies to prevent this occurrence are just now being elucidated 10,11 . Sølling et al 12 measured changes in the receptor activator of nuclear factor kappa-B ligand (RANKL) and tartrate-resistant acid phosphatase 5b (TRAcP 5b) after discontinuation of denosumab and postulated that the RANKL stimulation of osteoclasts resulted in increased bone resorption and subsequent enhanced risk of vertebral fracture. This team clearly defined a series of changes in the bone status after the discontinuation of denosumab.…”

Section: Osteoporosis Drug Therapymentioning

confidence: 99%

What’s New in Osteoporosis and Fragility Fractures

Lane

Witayakom

2023

Journal of Bone and Joint Surgery

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Update This article was updated on April 10, 2024, because of a previous error. On page 1304, the term “protein” that appeared incorrectly three times in the text that had read as “Their studies did reveal that metabolites from the protein pump inhibitor ingestion may directly and indirectly influence bone density through plasma metabolites involved in the sex hormone pathway. This article plus others have broadened the possible altered pathways related to protein pump inhibitor use. Regardless, these commonly used agents will compromise bone health. Clinicians should be alerted to this possibility when protein pump inhibitors are ingested.,” has now been replaced with the term “proton” so that the text now reads as “Their studies did reveal that metabolites from the proton pump inhibitor ingestion may directly and indirectly influence bone density through plasma metabolites involved in the sex hormone pathway. This article plus others have broadened the possible altered pathways related to proton pump inhibitor use. Regardless, these commonly used agents will compromise bone health. Clinicians should be alerted to this possibility when proton pump inhibitors are ingested.”

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Section: Osteoporosis Drug Therapymentioning

confidence: 99%

What’s New in Osteoporosis and Fragility Fractures

Lane

Witayakom

2023

Journal of Bone and Joint Surgery

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“…Our data align with cross-sectional clinical analyses of serum RANKL and TRAP at 6, 9, and 12 mo following the last dose of denosumab. 26 In this clinical study, higher RANKL was observed 6 mo following the last denosumab dose, compared to levels measured at 9- and 12-mo, whereas serum TRAP was highest in the 9- and 12-mo groups, 26 though the temporal relationship to changes in BMD was not examined.…”

Section: Discussionmentioning

confidence: 73%

“…Sølling and colleagues hypothesized that this difference may be due to the difference in the number and mean age of participants and the RANKL assay utilized. 26 TRAP was not measured in the study by Fassio and colleagues so the temporal relationship between RANKL and TRAP following denosumab discontinuation could not be examined in this study.…”

Section: Discussionmentioning

confidence: 95%

Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition

Kim,

Taylor,

Castro-Martinez

et al. 2024

Journal of Bone and Mineral Research

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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 present 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 are 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.

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“…The rationale of our choice of sampling time was as follows. In previous studies, including our earlier reported prospective RCT, a rapid increase in serum CTX between 6 and 9 months following Dmab discontinuation has been documented [14][15][16]. In addition, rebound-associated vertebral fractures have been reported already at 8 months after the last Dmab injection [12].…”

Section: Discussionmentioning

confidence: 82%

“…Apart from these considerations and the failure of our study to meet its objectives, the significant correlation between serum TRAcP5b and CTX levels confirm the value of this biomarker in the evaluation of bone resorption in general and following Dmab use in particular. Solling et al recently reported also a significant correlation between serum TRAcP5b and CTX 6 months after the last injection of Dmab [16].…”

Section: Discussionmentioning

confidence: 87%

The relationship between length of denosumab treatment for postmenopausal osteoporosis and serum TRAcP5b measured six months after the last injection

Makras,

Yavropoulou,

Polyzos

et al. 2023

Osteoporos Int

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To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab. Purpose In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years. Methods TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months ± 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 ± 2.3 years (range 1-10 years). Of these, 38 were treatment naïve (group 1) and 21 had received other treatments prior Dmab (group 2). Results Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (r s = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites. Conclusion Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption.

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Changes in RANKL and TRAcP 5b after discontinuation of denosumab suggest RANKL mediated formation of osteoclasts results in the increased bone resorption

Cited by 10 publications

References 16 publications

What’s New in Osteoporosis and Fragility Fractures

What’s New in Osteoporosis and Fragility Fractures

Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition

The relationship between length of denosumab treatment for postmenopausal osteoporosis and serum TRAcP5b measured six months after the last injection

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