PO:20:004 | Increase in serum Dkk1 levels attenuates the anabolic response to romosozumab in postmenopausal osteoporosis

Giovanni Adami¹, Filippo Montanari¹, Angelo Fassio¹, Francesco Pollastri¹, Anna Piccinelli¹, Davide Gatti¹, Ombretta Viapiana¹, Maurizio Rossini¹. | ¹Università degli Studi di Verona, Verona, Italy.

Background. Romosozumab is a monoclonal antibody against sclerostin that initially exhibits potent anabolic effects in treating osteoporosis. However, its efficacy diminishes after 6 months, 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.

Methods. We conducted a 12-month prospective observational study on post-menopausal 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 months (M12). Bone mineral density (BMD) at the lumbar spine, femoral neck, and total hip was assessed at M0, M6, and M12. Associations between Dkk1 and P1NP were analyzed using linear mixed-effects models.

Results. Fifty-nine post-menopausal women were included in the study. Dkk1 levels increased significantly from 38.9 pmol/L at M0 to 44.2 pmol/L at M12 (p 0.003). P1NP increased from 89.4 ng/mL at M0 to 115.4 ng/mL at M3 (p 0.004) but decreased to 61.5 ng/mL by M12 (p 0.001). CTX decreased significantly throughout the study (p 0.001). BMD increased significantly at all sites by M12 (lumbar spine +13.8%, femoral neck +6.3%, total hip +4.7%; all p 0.01). An inverse association was found between Dkk1 increase and P1NP decrease between M3 and M12 (estimate -0.909; p 0.032). We also found a steep increase in sclerostin serum levels as soon as M3 (from 36.3 pmol/L, SD 15.6, to around 1500 pmol/L at all time points, p 0.001). This increase can probably be attributed to the sequestration of sclerostin from the bone to the bloodstream by romosozumab. Serum marker changes (least square changes from marginal means of the MMRM) are shown in Figure 1.

Conclusion. 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.