Pros and Cons of Denosumab Treatment for Osteoporosis and Implication for RANKL Aptamer Therapy.

Ning Zhang,Zhenjian Zhuo,Ge Zhang,Yuanyuan Yu,Zong-Kang Zhang,Bao-Ting Zhang

doi:10.3389/fcell.2020.00325

Abstract

Osteoporosis is age-related deterioration in bone mass and micro-architecture. Denosumab is a novel human monoclonal antibody for osteoporosis. It is a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor, which binds to and inhibits osteoblast-produced RANKL, in turn reduces the binding between RANKL and osteoclast receptor RANK, therefore decreases osteoclast-mediated bone resorption and turnover. However, adverse events have also been reported after denosumab treatment, including skin eczema, flatulence, cellulitis and osteonecrosis of the jaw (ONJ). Extensive researches on the mechanism of adverse reactions caused by denosumab have been conducted and may provide new insights into developing new RANKL inhibitors that achieve better specificity and safety. Aptamers are single-stranded oligonucleotides that can bind to target molecules with high specificity and affinity. They are screened from large single-stranded synthetic oligonucleotides and enriched by a technology named SELEX (systematic evolution of ligands by exponential enrichment). With extra advantages such as high stability, low immunogenicity and easy production over antibodies, aptamers are hypothesized to be promising candidates for therapeutic drugs targeting RANKL to counteract osteoporosis. In this review, we focus on the pros and cons of denosumab treatment in osteoporosis and the implication for novel aptamer treatment.

Highlights

Osteoporosis is a disease in which the microstructure of bone deteriorates, bone mass is low, and bone fragility increases, the risk of fracture increases in affected people (Black and Rosen, 2016; Eastell et al, 2016)
RANK ligand (RANKL) Aptamers for Osteoporosis Treatment is 80 to 20%, while it was reported that male patients developed other clinical complications related to osteoporosis (Alswat, 2017)
This review focuses on the advantages and disadvantages of the use of the anti-RANKL antibody, denosumab, in the treatment of PM osteoporosis

Summary

INTRODUCTION

Osteoporosis is a disease in which the microstructure of bone deteriorates, bone mass is low, and bone fragility increases, the risk of fracture increases in affected people (Black and Rosen, 2016; Eastell et al, 2016). Animal experiments and clinical trials show that RANKL-targeted therapies have the potential to treat diseases relevant to osteoclast-mediated bone loss. RANKL inhibition results in a decrease in osteoclastogenesis and osteoclast activity, thereby reducing bone resorption (Bekker et al, 2004). A targeted antibody that binds and inhibits RANKL to reduce bone resorption, is approved by the U.S Food and Drug Administration (FDA) for the treatment of osteoporosis in postmenopausal (PM) women with a high fracture risk (Dore, 2011; Scott and Muir, 2011). Small single-stranded oligonucleotides, are capable of binding target molecules with high affinity and specificity (Burnett and Rossi, 2012; Song et al, 2012). The prospect and challenge of aptamers targeting RANKL as a therapeutic strategy for osteoporosis are discussed

RANKL AS A PROMISING THERAPEUTIC TARGET FOR OSTEOPOROSIS

CURRENT THERAPEUTIC STRATEGIES TARGETING RANKL

Findings

DISCUSSION AND PROSPECTS