Abstract
Romosozumab is a monoclonal antibody against sclerostin that initially exhibits potent anabolic effects in treating osteoporosis. However, its efficacy diminishes after 6 mo, with bone formation markers declining despite continued therapy. We hypothesized that increased levels of Dickkopf-1 (Dkk1), a Wnt pathway inhibitor, may contribute to this attenuation by suppressing osteoblast activity. We conducted a 12-mo prospective observational study on postmenopausal osteoporosis naïve to anti-osteoporosis treatment treated with romosozumab. Serum levels of Dkk1, procollagen type I N-terminal propeptide (P1NP), C-terminal telopeptide of type I collagen (CTX), and sclerostin were measured at baseline (M0) and at 3 (M3), 6 (M6), and 12 mo (M12). BMD at the LS, FN, and TH was assessed at M0, M6, and M12. Associations between Dkk1 and P1NP were analyzed using linear mixed-effects models. Dkk1 levels increased significantly from 38.9 pmol/L at M0 to 44.2 pmol/L at M12 (p = .003). P1NP increased from 89.4 ng/mL at M0 to 115.4 ng/mL at M3 (p = .004) but decreased to 61.5 ng/mL by M12 (p < .001). CTX decreased significantly throughout the study (p < .001). BMD increased significantly at all sites by M12 (LS + 13.8%, FN + 6.3%, TH + 4.7%; all p < .01). An inverse association was found between Dkk1 increase and P1NP decrease between M3 and M12 (estimate = -0.909; p = .032). Romosozumab treatment is associated with a significant rise in Dkk1 levels, which correlates with a decrease in bone formation markers over time. Dkk1 may attenuate the anabolic effects of romosozumab by inhibiting Wnt signaling.