Profile of romosozumab and its potential in the management of osteoporosis

Abstract

Increased understanding of bone biology has led to the discovery of several unique signaling pathways that regulate bone formation and resorption. The Wnt signaling pathway plays a significant role in skeletal development, adult skeletal homeostasis, and bone remodeling. Sclerostin is an inhibitor of the Wnt signaling pathway. Romosozumab, a humanized monoclonal antibody that binds to sclerostin, prevents sclerostin from exerting this inhibitory effect. Therefore, in the presence of romosozumab, the Wnt signaling pathway is activated leading to bone formation and bone mineral density gain. Clinical studies of romosozumab have shown that this agent is one of the most potent bone anabolic agents in development to date. Romosozumab does not act solely as an anabolic agent, but rather, it has effects on increasing bone formation as well as reducing bone resorption. In the clinical studies, patients tolerated romosozumab well with no major safety signals reported. In a Phase III study, romosozumab as compared to placebo has been shown to reduce vertebral fractures by 73% after 1 year of treatment. Sequential therapy with romosozumab for 1 year followed by denosumab in the second year reduced vertebral fractures by 75% as compared to the group that received placebo for 1 year and denosumab in the second year. Romosozumab holds significant potential, by a novel mechanism of action, to expand our ability to treat osteoporosis. More studies are needed to determine the ideal setting in which romosozumab may be used to optimize osteoporosis treatment.

Keywords: bone mineral density; osteoporosis; romosozumab; sclerostin.

Figure 1

The canonical Wnt-β-catenin signaling pathway and the effects of inhibition through loss of function mutations and sclerostin inhibition. Notes: (A) When Wnt binds to the LRP-5 and -6 coreceptors and the specific Frizzled family receptor, inhibition of the β-catenin destruction complex occurs. Accumulated β-catenin in the cytoplasm enters the nucleus, leading to transcription of Wnt-responsive genes and bone formation. Panels (B), (C), and (D) show how various mechanisms inhibit the canonical Wnt-β-catenin signaling pathway. Due to the inability of Wnt to exert its effect due to (B) the loss of mutation of LRP-5 and LRP-6 coreceptors, (C) the loss of mutation of Wnt, and (D) the prevention of Wnt from binding to LRP-5 or LRP-6 coreceptors by sclerostin, the β-catenin destruction complex is assembled. β-Catenin is phosphorylated and degraded. Wnt-responsive genes are not activated, leading to an increased bone resorption and a decreased bone formation. Copyright ©2015. Dove Medical Press. Shah AD, Shoback D, Lewiecki EM. Sclerostin inhibition: a novel therapeutic approach in the treatment of osteoporosis. Int J Womens Health. 2015;7:565–580. Abbreviation: LRP, LDL-receptor-related protein.

Figure 2

Mechanism of action of romosozumab. Notes: Romosozumab is a human monoclonal antibody that binds sclerostin (an inhibitor of Wnt pathway signaling). When this monoclonal antibody binds to sclerostin, sclerostin cannot bind to the LRP-5 and LRP-6 receptors and is unable to exert its inhibitory effect. Wnt binds to LRP-5 or LRP-6 coreceptors and specific Frizzled family receptor, leading to activation of the Wnt signaling pathway and bone formation. Copyright ©2015. Dove Medical Press. Shah AD, Shoback D, Lewiecki EM. Sclerostin inhibition: a novel therapeutic approach in the treatment of osteoporosis. Int J Womens Health. 2015;7:565–580. Abbreviation: LRP, LDL-receptor-related protein.

Figure 3

Changes in the levels of bone formation markers and bone resorption markers with subcutaneous injections of TPTD (20 μg daily) or ROMO (210 mg once monthly) for 1 year. Notes: Reproduced from Appelman-Dijkstra NM, Papapoulos SE. Modulating bone resorption and bone formation in opposite directions in the treatment of postmenopausal osteoporosis. Drugs. 2015;75(10):1049–1058 which was originally sourced from Leder BZ, Tsai JN, Uihlein AV, et al, Two years of Denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial, J Clin Endocrinol Metab, 2014;99(5):1694–1700, by permission of Oxford University Press. Abbreviations: ROMO, romosozumab; TPTD, teriparatide.