How zoledronic acid improves osteoporosis by acting on osteoclasts

Abstract

Osteoporosis is called a silent disease, because it is difficult to detect until comprehensive examinations for osteoporosis are performed or osteoporotic fractures occur. Zoledronic acid is currently the first-line anti-osteoporotic drug, with good efficacy and treatment compliance. A major advantage of zoledronic acid is that intravenous zoledronic acid often guarantees a therapeutic effect for up to 1 year after infusion. The reasons why zoledronic acid is effective in improving osteoporosis are that it can inhibit osteoclast differentiation and induce osteoclast apoptosis, thus suppressing bone resorption and increasing bone density. The story between zoledronic acid and osteoclasts has been written long time ago. Both the canonical receptor activator of the receptor activator of nuclear factor-κB ligand (RANKL) pathway and the non-canonical Wnt pathway are the main pathways by which zoledronic acid inhibits osteoclast differentiation. Farnesyl pyrophosphate synthase (FPPS), reactive oxygen species (ROS), and ferroptosis that was first proposed in 2012, are all considered to be closely associated with zoledronic acid-induced osteoclast apoptosis. Here, we provide a brief review of the recent progress on the study of zoledronic acid and osteoclasts, and hope to elaborate how zoledronic acid improves osteoporosis by acting on osteoclasts.

Keywords: apoptosis; differentiation; osteoclasts; osteoporosis; signaling; signaling pathways; zoledronic acid.

FIGURE 1

ZA can inhibit the RANKL/RANK signaling pathway. The bind of RANKL and RANK can activate a series of signaling pathways, such as nuclear factor kappa B (NF-κB) pathway, mitogen-activated protein kinases (MAPK) pathway, and AMP-activated protein kinase (AMPK) pathway. These signaling pathways can in turn cause tartrate-resistant acid phosphatase (TRAP), c-Jun, c-Fos, nuclear factor of activation of T cells-1 (NFATc1), c-Jun N-terminal kinase (JNK), dendritic cell Expression of specific transmembrane protein (DC-STAMP), spleen tyrosine kinase (SYK), cathepsin K (CTSK) and other signaling molecules. It is through the RANKL/RANK signaling pathway that ZA regulates the expression of these signaling pathways and signaling molecules to inhibit osteoclast differentiation and bone resorption.

FIGURE 2

ZA can inhibit the mevalonate pathway. Farnesyl pyrophosphate synthase (FPPS), as a key regulatory enzyme in the mevalonate pathway, can promote the formation of geranylgeranyl diphosphate (GGPP) from geranyl pyrophosphate synthase (GGPPS) and farnesyl diphosphate (FPP), and GGPP can promote the prenylation of Rab GTPases, this pathway is closely related to the apoptosis of osteoclasts. ZA promotes osteoclast apoptosis by inhibiting the activity of FPPS. In addition, ZA can promote osteoclast apoptosis through reactive oxygen species (ROS). Recent findings suggest that ZA may promote ferroptosis in osteoclasts through p53.