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. 2024 Sep 16;109(10):e1817-e1826.
doi: 10.1210/clinem/dgae224.

Zoledronate After Denosumab Discontinuation: Is Repeated Administrations More Effective Than Single Infusion?

Giorgia Grassi  1 , Alberto Ghielmetti  2 , Marta Zampogna  2 , Iacopo Chiodini  3   4 , Maura Arosio  1   2 , Giovanna Mantovani  1   2 , Cristina Eller-Vainicher  1
Affiliations

Zoledronate After Denosumab Discontinuation: Is Repeated Administrations More Effective Than Single Infusion?

Giorgia Grassi et al. J Clin Endocrinol Metab. .

Erratum in

Abstract

Background: After denosumab (Dmab) discontinuation C-terminal telopeptide (CTX) levels increase, bone mineral density (BMD) decreases and multiple vertebral fractures (FX) may occur with relevant impacts on women's health. A sequential therapy with bisphosphonates is recommended, and the European Calcified Tissue Society (ECTS) proposed repeated zoledronate (ZOL) administrations in patients with persistently high CTX levels, although the efficacy of this schedule is unknown. In this retrospective study, we describe BMD changes and FX rate in 52 patients managed according to the ECTS recommendations.

Methods: We measured CTX levels and administered ZOL after 1 month from Dmab withdrawal (t0). After 6 months (t1), we administered a second ZOL infusion, if CTX levels were ≥280 ng/L. BMD changes and FX rate were assessed on average after 17 months from Dmab withdrawal.

Results: Seventy-five percent of patients repeated ZOL infusion. In this group, spine BMD declined significantly (-5.5 ± 5.6%), while it remained stable in the group with CTX levels <280 ng/L (-0.1 ± 5.5%, P = 0.008). All fractured patients (9.6%) had received >5 Dmab injections and 2 ZOL infusions. The BMD worsening after Dmab withdrawal was associated with CTX t1 [odds ratio (OR) 2.9, interquartile range (IQR) 1.3-6.6, P = .009] and spine BMD gain during Dmab therapy corrected for the number of Dmab injections (OR 3.0, IQR 1.2-7.2, P = .014). A CTX level at t1 > 212 ng/L had 100% sensitivity in predicting the BMD loss.

Conclusion: In patients with uncontrolled CTX levels after Dmab withdrawal, 2 ZOL infusions 6 months apart do not prevent BMD loss and FX.

Keywords: bone turnover markers; denosumab withdrawal; osteoporosis; rebound effect; sequential therapy; zoledronate.

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Figures

Figure 1.
Figure 1.
The BMD changes during Dmab therapy and after discontinuation in all patients and in the group treated with ZOL1 or in patients who underwent a second zoledronate dose 6 months later. Percent changes (mean ± SD) during Dmab treatment and after Dmab discontinuation in LS, FN, TH. *ΔBMD > LSC. Abbreviations: BMD, bone mineral density; Dmab, denosumab; FN, femoral neck; LS, lumbar spine; LSC, least significant change; TH, total hip; ZOL, zoledronate; ZOL1, single zoledronate infusion; ZOL2, 2 zoledronate infusions after denosumab.
Figure 2.
Figure 2.
The BMD changes overall (since the start of Dmab till the end of the follow-up) and after Dmab discontinuation in patients with different Dmab therapy duration. Data are expressed as mean ± SD. *ΔBMD > LSC. Abbreviations: BMD, bone mineral density; Dmab, denosumab; FN, femoral neck; Inj, injections; LS, lumbar spine; LSC, least significant change; TH, total hip.
Figure 3.
Figure 3.
Correlation between the LS BMD changes after Dmab withdrawal and the number of Dmab injections. Abbreviations: BMD, bone mineral density; Dmab, denosumab; LS, lumbar spine.
Figure 4.
Figure 4.
Correlation between the LS BMD changes after Dmab withdrawal and the CTX measured the day of the first ZOL (t0) or 6 months later (t1). Abbreviations: BMD, bone mineral density; CTX, C-telopeptide of type 1 collagen; Dmab, denosumab; LS, lumbar spine; ZOL, zoledronate.
Figure 5.
Figure 5.
The ROC curve analysis of CTX 6 months after the first ZOL in discriminating patients with worsened bone mass density at follow-up after Dmab discontinuation. Abbreviations: CTX, C-telopeptide of type 1 collagen; Dmab, denosumab; ROC, receiver operating characteristic; ZOL, zoledronate.
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