Early and multiple doses of zoledronate mitigates rebound bone loss following withdrawal of receptor activator of nuclear factor kappa-B ligand inhibition

Kim AS; Taylor VE; Castro-Martinez A; Dhakal S; Zamerli A; Mohanty ST; Xiao Y; Simic MK; Pantalone A; Chu J; Cheng TL; Croucher PI; Center JR; Girgis CM; McDonald MM

doi:10.1530/ey.22.5.9

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 5.9 | DOI: 10.1530/ey.22.5.9

ESPEYB25 5. Bone, Growth Plate and Mineral Metabolism Novel Treatments (6 abstracts)

5.9. Early and multiple doses of zoledronate mitigates rebound bone loss following withdrawal of receptor activator of nuclear factor kappa-B ligand inhibition

Kim AS , Taylor VE , Castro-Martinez A , Dhakal S , Zamerli A , Mohanty ST , Xiao Y , Simic MK , Pantalone A , Chu J , Cheng TL , Croucher PI , Center JR , Girgis CM & McDonald MM

Journal of Bone and Mineral Research, (2025). 40(3), 413-427. https://doi.org/10.1093/jbmr/zjaf008

Brief Summary: This mouse model study investigated strategies for the sequential administration of zoledronate following the withdrawal of denosumab. Administration of multiple doses of zoledronate at an early stage mitigated the rebound of bone loss, improves bone microarchitecture, and increases fracture resistance.

Commentary: Denosumab is a humanised monoclonal antibody that inhibits RANKL with potent anti-osteoclastic effects. However, it presents a significant clinical challenge upon discontinuation due to rapid and severe rebound bone loss, which often leads to an increased risk of fractures. This study investigated the effect of an earlier, multi-dose zoledronate intervention strategy. Preclinical data have revealed that the processes driving rebound bone loss, particularly the increase in osteoclast activity (as indicated by serum TRAP levels), occur at an earlier stage than previously recognised clinical markers such as the rise in CTX levels or the loss of BMD. This provides a crucial ’earlier intervention window’.

This study demonstrates that, when administered early (before detectable bone loss) and in multiple doses, zoledronate can successfully prevent overshooting osteoclast activity and consolidate the gains in bone mineral density achieved with denosumab. These findings were validated in both young, growing mice and older, skeletally mature mice, enhancing their potential for translation to diverse patient populations. Furthermore, this early, multi-dose approach preserves bone density and improves trabecular and cortical bone microarchitecture, thereby increasing fracture resistance in skeletally mature mice. These findings could be used to improve the management of patients who are discontinuing denosumab treatment.