The preclinical discovery and development of romosozumab for the treatment of people with severe osteoporosis who are at high risk of fracture

INTRODUCTION: The discovery of romosozumab, a monoclonal antibody to sclerostin and treatment option for severe osteoporosis, resulted from convergent genetic research of persons with rare hyperostotic bone diseases and the discovery of the Wnt-signaling pathway, a vital pathway in bone metabolism. AREAS COVERED: gene in humans and of Wnt signaling in animals, leading to the identification of sclerostin, a major regulator of bone formation and resorption. The authors further provide an overview of the studies that led to the development of romosozumab, a unique dual action monoclonal antibody that increases bone formation while decreasing bone resorption. EXPERT OPINION: In postmenopausal women, the administration of romosozumab over one year decreased the risk of vertebral and clinical fractures versus placebo and versus alendronate. Furthermore, sequential treatment, switching romosozumab over to denosumab, reduced the risk of vertebral fractures compared to switching the placebo to denosumab. Meanwhile, switching romosozumab to alendronate reduced the risk of vertebral, clinical, nonvertebral, and hip fractures compared to continuous alendronate. An imbalance in cardiovascular events was found when using romosozumab in comparison to alendronate but not versus placebo. Romosozumab was eventually approved by EMA and FDA in 2019 for the treatment of patients with very high risk of fractures while considering their cardiovascular risk and is available and reimbursed in many countries.