Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab

Abstract

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. Denosumab treatment is associated with a rapid, sustained, and reversible reduction in bone turnover markers, a continuous marked increase in bone mineral density at all sites, and a marked decrease in the risk of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis. Therefore, it could be considered as an effective alternative to previous bisphosphonate treatment as well as first-line treatment of severe osteoporosis. Cost-effectiveness studies support this suggestion. In addition, denosumab seems to be the safest treatment option in patients with impaired renal function. Denosumab is characterized by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. Large-scale clinical trials, including the extension of FREEDOM trial for up to 5 years, are reassuring for its safety. However, given its brief post-market period, vigilance regarding adverse events related to putative RANKL inhibition in tissues other than bone, as well as those related to bone turnover oversuppression, is advised.

Denosumab and osteonecrosis of the jaws - the pharmacology, pathogenesis and a report of two cases

“…25 It is critically important that prescribers of denosumab, patients and dentists are vigilant in advance of patients commencing and during treatment with all forms of denosumab. [26][27][28] Our clinical experience of DONJ agrees with the literature reports that ONJ related to denosumab may resolve more quickly with a drug holiday than BRONJ. Nevertheless the importance of good oral hygiene, limiting of alcohol intake and stopping smoking must be stressed to these patients.…”

A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life

“…Denosumab was produced by Amgen. 81 All mAbs were produced under GMP conditions with a CHO cell manufacturing cell line. The four pre-clinical mAbs are also human IgG1s that bind an exogenous soluble target and were manufactured, purified and formulated by MassBiologics under GMP-like conditions using similar methods as the clinical mAbs.…”

Novel therapies for osteoporosis

“…Denosumab is a human monoclonal IgG2 antibody that binds and inhibits the receptor activator of nuclear factor κ-Β ligand (RANKL) with high specificity and affinity [1].…”

“…The decrease of bone remodeling reduces serum calcium and phosphate levels, causing an increase of parathyroid hormone (PTH) levels, especially during the first 1-2 months [4,8]. The approved dose for osteoporosis treatment is 60 mg s.c. every 6 months, which inhibits RANKL equally to equivalent weight-based dose adjustments, with no need for modifications based on age, gender, and race or in renal function [1,9].…”

“…The first category includes concerns related to suboptimal tissue specificity (elevated risk for serious infections, eczema, non-dermatologic reactions, etc. ), while the second category involves concerns regarding adverse events (AEs) on bone and calcium metabolism, including hypocalcemia, atypical femoral fractures (AFF), impaired fracture healing, and osteonecrosis of the jaw (ONJ) [1]. In brief, with the exception A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 10 10 of patients with stage 5 chronic kidney disease (CKD) or hepatic dysfunction, it appears that denosumab is a relatively safe medication.…”