Modeling rebound bone loss following denosumab discontinuation and sequential zoledronate therapy in TgRANKL
Vagelis Rinotas1, Eleftheria-Dimitra Ntouskou1, Melina Dragolia2
1Institute for Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
Background:
Receptor activator of nuclear factor-κB ligand (RANKL) plays a central role in regulating osteoclast formation and bone resorption, while its inhibition by the monoclonal antibody denosumab serves as an effective antiresorptive treatment for postmenopausal osteoporosis. However, denosumab discontinuation triggers a severe rebound effect involving rapid bone mineral density (BMD) loss, accompanied by an overshooting of bone turnover markers (BTMs), and increased risk of multiple fractures. Preclinical studies investigating this rebound phenomenon after denosumab discontinuation have been limited, mainly because denosumab does not cross-react with murine RANKL. This study explores the rebound phenomenon in a transgenic mouse model of osteoporosis expressing human RANKL (TgRANKL) and evaluates the impact of sequential zoledronate therapy.
Methods:
TgRANKL mice were divided into four experimental groups: vehicle control, continuous denosumab treatment, denosumab withdrawal, and sequential denosumab followed by zoledronate, including an additional follow-up phase after zoledronate discontinuation. Skeletal alterations were characterized using microCT, histomorphometric assessments, serum bone turnover markers (BTMs), and bone gene expression analyses.
Results:
Denosumab therapy rescued the osteoporotic phenotype of TgRANKL mice, whereas its discontinuation resulted in a rebound bone loss accompanied by elevated bone turnover markers. Denosumab also inhibited bone marrow adipose tissue formation in TgRANKL mice, while its discontinuation led to moderate reformation of marrow adiposity. Sequential administration of zoledronate effectively prevented the rebound bone loss response. However, discontinued therapy after denosumab-zoledronate sequence, showed that the protective effects of zoledronate were not persistent.
Conclusions:
Our findings establish TgRANKL mice as a unique osteoporotic model for investigating the mechanisms driving denosumab rebound and testing sequential antiresorptive strategies.
Insights
Discontinuation of denosumab treatment for osteoporosis causes rapid bone loss. Sequential zoledronate therapy effectively prevents this rebound effect in a novel transgenic mouse model, though its benefits are temporary.
Area of Science:
- Bone Biology and Osteoporosis Research
- Pharmacology and Therapeutics
- Translational Medicine
Background:
- Receptor activator of nuclear factor-κB ligand (RANKL) inhibition via denosumab is a key osteoporosis treatment.
- Denosumab discontinuation causes severe rebound bone loss and fracture risk.
- Existing preclinical models are limited due to species-specific RANKL interactions.
Purpose of the Study:
- Investigate denosumab discontinuation rebound in a human RANKL transgenic mouse model.
- Evaluate the efficacy of sequential zoledronate therapy in mitigating rebound bone loss.
- Characterize skeletal changes and bone turnover markers during rebound and recovery phases.
Main Methods:
- Utilized transgenic mice expressing human RANKL (TgRANKL) for osteoporosis modeling.
- Compared four groups: vehicle control, continuous denosumab, denosumab withdrawal, and sequential denosumab-zoledronate.
- Assessed skeletal alterations via microCT, histomorphometry, bone turnover markers (BTMs), and gene expression.
Main Results:
- Denosumab treatment reversed osteoporosis in TgRANKL mice; withdrawal induced rebound bone loss and elevated BTMs.
- Denosumab inhibited bone marrow adipose tissue; withdrawal led to partial reformation.
- Sequential zoledronate administration prevented rebound bone loss, but effects were not persistent after its discontinuation.
Conclusions:
- TgRANKL mice provide a unique model for studying denosumab rebound mechanisms.
- Sequential zoledronate therapy effectively manages denosumab-induced rebound bone loss.
- The protective effects of zoledronate require sustained administration for long-term efficacy.
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