New and emerging concepts in the use of denosumab for the treatment of osteoporosis

Abstract

Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine expressed by cells of the osteoblast lineage that is a key regulator of osteoclastic bone resorption. By binding and neutralizing RANKL, denosumab inhibits osteoclast differentiation, activity, and survival. Clinical trials in postmenopausal women with osteoporosis have shown that it reduces the risk of vertebral fractures, nonvertebral fractures, and hip fractures, with a generally favorable safety profile. With a dose of 60 mg subcutaneously every 6 months, it is approved for: treatment of postmenopausal women and men with osteoporosis, and for women and men with glucocorticoid-induced osteoporosis who are at high risk for fracture; treatment to increase bone mass in men at high risk for fracture receiving androgen-deprivation therapy for nonmetastatic prostate cancer; and treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. Atypical femur fractures and osteonecrosis of the jaw have been reported in patients treated with denosumab. Discontinuation of denosumab is followed by rapidly rising bone turnover markers, decreasing bone density, and vertebral fracture risk that returns to baseline, with a possible increase in the risk of multiple vertebral fractures. Further study is needed to clarify this potential risk. After stopping long-term denosumab, patients should be switched to another antiresorptive agent to maintain the benefit achieved with denosumab.

Pharmacological Management of Osteoporosis in Rheumatoid Arthritis Patients: A Review of the Literature and Practical Guide

“…Denosumab is a fully human monoclonal antibody to an activator of osteoclastic differentiation and proliferation, soluble RANK-L. RANK-L is upregulated in postmenopausal women and in patients in an inflammatory state, such as RA [63, 64]. In postmenopausal women, denosumab has shown strong bone protective properties, as reported in the FREEDOM phase III trial.…”

The RANKL-RANK Axis: A Bone to Thymus Round Trip

“…Specifically, denosumab binds to the DE loop region of the ligand, which is one of the surface loop structures interacting with the functional receptor on responding cells (44). Denosumab is used as an antiresorptive drug for diverse indications, such as osteoporosis (45), primary bone tumors (46), and osteolytic bone metastases (47). Its use is under evaluation also in other fields, such as solid tumors (11) and Rheumatoid Arthritis (48), and has been very recently proposed in the prevention of BRCA1-associated breast cancer (49).…”

Can Denosumab be used in combination with Doxorubicin in Osteosarcoma?

“…It mimics the action of OPG and limits OCs differentiation and activation, preventing bone resorption. Den is an approved and effective therapy for OP [22,23,39] and other skeletal disorders characterized by bone mass loss [27]. Since 2010 Den has been studied also as possible therapy to contrast cancer progression [19,26].…”