Romosozumab is a humanized immunoglobulin G2 monoclonal antibody that binds and 
blocks the action of sclerostin, a protein secreted by the osteocyte and an 
extracellular inhibitor of canonical Wnt signaling. Blockade of sclerostin 
binding to low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and 
LRP6) allows Wnt ligands to activate canonical Wnt signaling in bone, increasing 
bone formation and decreasing bone resorption, making sclerostin an attractive 
target for osteoporosis therapy. Because romosozumab is a bone-forming agent and 
an activator of canonical Wnt signaling, questions have arisen regarding a 
potential carcinogenic risk. Weight-of-evidence factors used in the assessment 
of human carcinogenic risk of romosozumab included features of canonical Wnt 
signaling, expression pattern of sclerostin, phenotype of loss-of-function 
mutations in humans and mice, mode and mechanism of action of romosozumab, and 
findings from romosozumab chronic toxicity studies in rats and monkeys. Although 
the weight-of-evidence factors supported that romosozumab would pose a low 
carcinogenic risk to humans, the carcinogenic potential of romosozumab was 
assessed in a rat lifetime study. There were no romosozumab-related effects on 
tumor incidence in rats. The findings of the lifetime study and the 
weight-of-evidence factors collectively indicate that romosozumab administration 
would not pose a carcinogenic risk to humans.