The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review

Sohn, Winnie; Simiens, Mary Ann; Jaeger, Kelly; Hutton, Shauna; Jang, Graham

doi:10.1111/bcp.12355

Cited by 44 publications

(47 citation statements)

References 34 publications

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“…The choice of the timeline schedule was based on in vitro data 36 , showing that short-term culture (2 days) can detect functional effects of RANKL variants on osteoclastogenic capacity, and on in vivo studies of pharmacokinetics and pharmacodynamics of denosumab 37 . Indeed, in advanced cancer patients with bone metastases, denosumab reach a peak in serum within the first week, and bone resorption decreases significantly as early as 1 day after administration of denosumab 37 .…”

Section: Association Between Ctc Subsets and Clinical Parameters Or Omentioning

confidence: 99%

Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer

Pantano

Rossi

Iuliani

et al. 2020

Sci Rep

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Receptor-activator of nuclear-factor-κB-ligand (RANKL) and its receptor RANK have been recently identified as key players in breast cancer bone metastases. Since Circulating Tumor Cells (CTCs) are considered a crucial step of metastatic process, we explored RANK expression on CTCs in metastatic breast cancer (MBC), and the predictive value of RANK-positive CTCs in monitoring patients during treatment with denosumab (anti-RANKL antibody). To this purpose, we developed a novel CTC assay to quantify RANK-positive CTCs in forty-two bone MBC patients, candidates to denosumab treatment. Companion algorithms ΔAUC and Slope were developed, and correlated with time to first skeletal-related-events (SRE), time to bone metastasis progression and time to visceral metastasis progression. Twenty-seven patients had at least one CTC at baseline and, among these, nineteen (70%) had one or more RANK-positive CTCs. Notably, the baseline total CTCs, but not the RANK-positive, were associated with Time-to-first-SRE, Time-to-Bone-Metastasis-Progression and Time-to-Visceral-Metastasis-Progression. Conversely, during treatment monitoring, positive ΔAUC value, expression of RANK-positive CTCs persistence, correlated with longer Time-to-first-SRE (p = 0.0002) and Timeto-Bone-Metastasis-progression (p = 0.0012). Furthermore, the early increase at second day, in RANK-positive CTCs (Positive-Slope) was associated with delay in time-to-first-SRE (p = 0.0038) and time-to-Bone-Metastasis-progression (p = 0.0024). We demonstrate, for the first time, the expression of RANK on CTCs in MBC patients and that the persistence of RANK expression determines denosumab effectiveness. Receptor activator of nuclear factor-kappaB ligand (RANKL)/RANK axis represents the main characterized therapeutic target to prevent bone metastasis in solid tumors 1. About 70% metastatic breast cancer (MBC) patients develops skeletal metastases often associated to skeletal related events (SREs) with a serious negative impact on patients' quality of life 2. Accumulating evidences suggest that RANKL/RANK signaling, not only influences bone microenvironment, mediating osteoclast activity and survival, but also promotes BC metastases 1,3. Indeed, RANK-RANKL blocking antibodies showed antitumor efficacy in bone MBC preclinical models both in preventive 4,5 and therapeutic settings 4,6,7. This antitumor effect could be either "indirect" through the inhibition of bone resorption that, in

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Section: Association Between Ctc Subsets and Clinical Parameters Or Omentioning

confidence: 99%

Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer

Pantano

Rossi

Iuliani

et al. 2020

Sci Rep

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“…The elimination half-life of denosumab through the reticuloendothelial system is 25-30 days. 29 In previous studies, patients who developed hypocalcaemia after being treated with denosumab for osteoporosis had a median time to serum calcium nadir of 21 days 25 or 25 days (interquartile range: 10.9-45 days) 26 . This compares with a median time to hypocalcaemia of 35 days (all grades) and 15 days (grade 4 hypocalcaemia) in our cohort.…”

Section: Discussionmentioning

confidence: 99%

“…The time from denosumab dosing to calcium nadir is not known. The elimination half‐life of denosumab through the reticuloendothelial system is 25–30 days . In previous studies, patients who developed hypocalcaemia after being treated with denosumab for osteoporosis had a median time to serum calcium nadir of 21 days or 25 days (interquartile range: 10.9–45 days) .…”

Section: Discussionmentioning

confidence: 99%

Acute hypocalcaemia following denosumab in heart and lung transplant patients with osteoporosis

Shrosbree

Elder

Eisman

2018

Internal Medicine Journal

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“…RANK and RANKL knockout mice demonstrate a severe lack of osteoclastogenesis and associated osteopetrosis, defective B & T lymphocytes and a number of skeletal defects (Ono & Nakashima, ). Therapeutics targeting the RANK/RANKL axis have been developed to assist in the management of osteoporosis, metastases to bone and giant cell tumour of bone (Deeks, ; Diedhiou et al., ; Jamshidi et al., ; Sohn, Simiens, Jaeger, Hutton, & Jang, ) but to date no significant trials have been undertaken to determine whether these have any effect on bone remodelling associated with bone repair and regeneration (Vannucci & Brandi, ).…”

Section: Biologic Factors In Bone Formation and Regenerationmentioning

confidence: 99%

Mesenchymal stem cells and biologic factors leading to bone formation

Bartold

Gronthos

Haynes

et al. 2019

J Clinic Periodontology

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Background Physiological bone formation and bone regeneration occurring during bone repair can be considered distinct but similar processes. Mesenchymal stem cells (MSC) and associated biologic factors are crucial to both bone formation and bone regeneration. Aim To perform a narrative review of the current literature regarding the role of MSC and biologic factors in bone formation with the aim of discussing the clinical relevance of in vitro and in vivo animal studies. Methods The literature was searched for studies on MSC and biologic factors associated with the formation of bone in the mandible and maxilla. The search specifically targeted studies on key aspects of how stem cells and biologic factors are important in bone formation and how this might be relevant to bone regeneration. The results are summarized in a narrative review format. Results Different types of MSC and many biologic factors are associated with bone formation in the maxilla and mandible. Conclusion Bone formation and regeneration involve very complex and highly regulated cellular and molecular processes. By studying these processes, new clinical opportunities will arise for therapeutic bone regenerative treatments.

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The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review

Cited by 44 publications

References 34 publications

Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer

Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer

Acute hypocalcaemia following denosumab in heart and lung transplant patients with osteoporosis

Mesenchymal stem cells and biologic factors leading to bone formation

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