Molecular target therapy for bone metastasis: starting a new era with denosumab, a RANKL inhibitor

Abstract

INTRODUCTION:\ud The skeleton is generally the primary, and sometimes the only, site of metastasis in patients with advanced solid tumors. Bone metastases are the most frequent cause of cancer-related pain and the origin of severe morbidity in patients. Among the treatment options available for the prevention of skeletal-related events (SREs) associated with bone metastasis, zoledronic acid, an antiresorptive treatment from the group of bisphosphonates, is currently the standard of care in this setting.\ud AREAS COVERED:\ud Zoledronic acid, together with denosumab (a monoclonal antibody against the receptor activator of nuclear factor kappa B ligand), is the most frequent approach for the prevention of cancer-related events in skeleton. This paper reviews several trials evaluating the efficacy of denosumab in comparison with zoledronic acid in patients with solid osteotropic tumors. In this setting of skeleton-invading cancers, denosumab was demonstrated to be superior to zoledronic acid in preventing or delaying SREs. In comparison with zoledronic acid, denosumab significantly delayed the time to first SRE by 17%.\ud EXPERT OPINION:\ud Current research on denosumab is addressed to prove the immunomodulator effect of this agent in humans. Other avenue of research is focused on its antitumor activity observed in some Phase III trials

NGF Blockade at Early Times during Bone Cancer Development Attenuates Bone Destruction and Increases Limb Use

“…Bisphosphonates and the RANK ligand inhibitor, Denosumab, have been approved for treatment of both pain and preventing bone fracture (6, 7). A therapy showing promise in blocking pain induced by CMB and non-malignant skeletal pain is inhibition of nerve growth factor (NGF) and its primary receptor, tyrosine kinase receptor type 1 (TrkA) (8-10).…”

Reviewing the Osteotropism in Neuroendocrine Tumors: The Role of Epithelial-Mesenchymal Transition

“…The skeleton is the third most frequent recurrent site of metastases after liver and lung in patients with advanced tumors [42]. However, bone metastases have been historically regarded as rare complications of NETs and their clinical relevance has been frequently confined to symptomatic patients [43].…”

Crosstalk between bone niche and immune system: Osteoimmunology signaling as a potential target for cancer treatment

“…By targeting RANKL, Denosumab inhibits osteoclastic function and prevents both bone resorption and destruction [70]. Denosumab has shown to be superior to ZOL in decreasing incidence of SREs, in delaying the onset of SREs and in controlling pain [71][72][73]; efficacy was demonstrated in all subgroups, regardless prior SRE status or age. Disease progression and overall survival, as well as safety profile were similar between the two treatment arms.…”