Brand Name


Pharmacological Class

Sclerostin-directed monoclonal antibody


Postmenopausal osteoporosis


Romosozumab is a sclerostin-directed monoclonal antibody, the first-in class sclerostin inhibitor, and the second monoclonal antibody to be approved by the FDA for osteoporosis.151 Denosumab, a receptor activator of nuclear factor-κB ligand (RANKL)–directed monoclonal antibody preceded romosozumab to market. Unlike denosumab, romosozumab is labeled as a time-limited (12-month) treatment for osteoporosis.44

Sclerostin is a glycoprotein expressed on osteocytes152,153 and acts as a negative regulator of bone mass through dual mechanisms that culminate in reduced differentiation of bone-forming osteoblasts together with increased differentiation of bone-resorbing osteoclasts.152,154 As an extracellular inhibitor of the β-catenin–dependent Wnt signaling pathway, sclerostin blocks bone formation by binding cell surface low-density LRP 5/6 and frizzled coreceptors to block the following cascade: (1) Wnt signal transduction; (2) inactivation of glycogen synthase kinase 3β; (3) β-catenin phosphorylation, accumulation, translocation into the cell nucleus, and binding to transcription factors; (4) transcription of osteoblast genes; and (5) osteoblast differentiation.151,155159 In addition, sclerostin increases bone resorption as a result of increased osteoclastic differentiation through upregulation of RANKL synthesis by β-catenin–mediated osteoprotegerin expression in osteoblasts and osteocytes.152,154,156,158160

By inhibiting sclerostin, therapy with romosozumab restores signaling in the Wnt pathway.156,158,161 Initially, romosozumab therapy produces a net gain in bone mineral density through mixed osteo-anabolic and -antiresorption effects; however, the pharmacodynamics shift toward a pure osteo-antiresorption effect over time.162 The mechanism of the shift may involve upregulation of endogenous Wnt-binding ligands (i.e., Dickkopf-related protein 1) or other determinants of osteoblast differentiation, but loss of this function and niggling concerns regarding cross-talk and prolonged exogenous signaling in Wnt and RANKL-OPG pathways currently precludes consideration of long-term (>1 year) use of romosozumab.154157,159,160,162167 In addition, clinical enthusiasm for romosozumab is dampened by the confirmation of an increased risk for myocardial infarction, stroke, and cardiovascular death in two large phase 3 premarket studies (ARCH and BRIDGE).151,160,162,167 The adverse cardiovascular outcomes associated with romosozumab are theorized to be related to blockade of an off-target effect of sclerostin inhibition related to vascular calcificaiton.151,159,161,162,168 Regardless of the mechanism, the FDA required that the drug be labeled with a black box warning, and patients with preexisting heart disease or other cardiovascular risk factors (e.g., diabetes or chronic kidney disease) are considered poor candidates for therapy with romosozumab.162,163,168

Romosozumab is a humanized monoclonal IgG2 antibody produced in Chinese hamster ovary cells by recombinant DNA technology.44 It is administered as two monthly subcutaneous injections (totaling 210 mg/dose) for 12 doses.44 Noteworthy unwanted effects are hypersensitivity, hypocalcemia, osteonecrosis of the jaw, femoral fractures unattributable to trauma, and arthralgia (potentially mediated by off-target TNFα-mediated aggravation of arthritis).44,153 FDA approval was granted on the basis of a reduction in the proportion of women with new vertebral fractures compared with placebo (0.5% vs. 1.8%; p<0.001)169 and increased bone mineral density.44 In addition, better bone mineral density increases were obtained with romosozumab followed by alendronate than were associated with alendronate alone.45,170 Importantly, bone mineral density gains return to baseline within 12 months in the absence of follow-on antiresorptive therapy; therefore, follow-on therapy (i.e., with denosumab or alendronate) is typically warranted. The cost of romosozumab is set at approximately $1825 per dose.171 Regulation of bone mass through the Wnt (β-catenin–dependent) signaling pathway has been established as the major positive regulator of osteoblast function and a counter-regulator of osteoclast formation.158 Many compounds that act on components of the regulatory and counter-regulatory Wnt pathways are in clinical development.151,152,171

Further Reading in Goodman & Gilman