Romosozumab had a similar incidence of cardiovascular events compared with placebo, but a higher incidence of serious cardiovascular events compared with alendronate in postmenopausal women.
Does romosozumab increase the risk of cardiovascular events in postmenopausal women with osteoporosis compared with placebo or alendronate?
While preclinical and genetic evidence do not suggest cardiovascular harm from sclerostin inhibition, clinical trial data is conflicting, warranting careful consideration of cardiovascular risk before prescribing romosozumab.
Sclerostin, which is primarily produced by the osteocytes, inhibits the canonical Wnt pathway and thereby the osteoblasts and stimulates RANKL release by the osteocytes and thereby osteoclast recruitment. Inhibition of sclerostin therefore causes stimulation of bone formation and inhibition of resorption. In clinical trials, romosozumab, an antibody against sclerostin, increases bone mineral density and reduces the risk of fractures compared with placebo and alendronate. The cardiovascular safety of romosozumab was adjudicated in 2 large clinical osteoporosis trials in postmenopausal women. Compared with placebo, the incidence of cardiovascular events was similar in the 2 treatment groups. Compared with alendronate, the incidence of serious cardiovascular events was higher in women treated with romosozumab. The incidence of serious cardiovascular adverse events was low and post hoc analyses should therefore be interpreted with caution; however, the relative risk seemed unaffected by preexisting cardiovascular disease or risk factors. Sclerostin is expressed in the vasculature, predominantly in vascular smooth muscle cells in the media. However, preclinical and genetic studies have not demonstrated any increased cardiovascular risk with continuously low sclerostin levels or inhibition of sclerostin. Furthermore, no potential mechanisms for such an effect have been identified. In conclusion, while there is no preclinical or genetic evidence of a harmful effect of sclerostin inhibition on cardiovascular safety, the evidence from the large clinical trials in postmenopausal women is conflicting. Romosozumab should therefore be used for the treatment of postmenopausal women with osteoporosis at high risk of fracture after careful consideration of the cardiovascular risk and the balance between benefits and risks.
Langdahl et al. (Tue,) conducted a review in Osteoporosis. Romosozumab vs. Placebo and alendronate was evaluated on Cardiovascular events. Romosozumab had a similar incidence of cardiovascular events compared with placebo, but a higher incidence of serious cardiovascular events compared with alendronate in postmenopausal women.