Calcimimetic and vitamin D receptor agonist therapy associates with lower mortality and fractures in hemodialysis patients: an international DOPPS analysis

ABSTRACT Background Evidence linking chronic kidney disease-mineral and bone disorder (CKD-MBD) therapies to hard clinical outcomes in hemodialysis remains limited. Treatment with vitamin D receptor activators (VDRAs) and calcimimetics is often adjusted or discontinued in response to parathyroid hormone values, which complicates the evaluation of their associations with clinical outcomes in observational research. Methods Because VDRA/calcimimetic prescriptions change over time in response to CKD-MBD markers that also predict outcomes, data from Phases IV–VII (2009–2022) of the Dialysis Outcomes and Practice Patterns Study were analyzed using marginal structural models with time-updated, four-category exposure status (neither use, VDRA only, calcimimetics only, or both) to investigate the hazard ratios (HRs) associated with all-cause mortality, cardiovascular disease (CVD) mortality, bone fractures, and hip fractures. Results A total of 117 452 hemodialysis patients were included in the all-cause mortality analysis, 50 111 patients in the CVD mortality analysis, and 33 906 patients in the fracture analysis. Compared with neither use, VDRA-only use (HR 0.71, P < .001), calcimimetics-only use (HR 0.76, P < .001), and combination therapy (HR 0.58, P < .001) were significantly associated with a reduced risk of all-cause mortality. For CVD mortality, VDRA-only (HR 0.83, P < .001), calcimimetics-only (HR 0.71, P < .001), and combination therapy (HR 0.71, P < .001) were significantly associated with a lower risk of CVD mortality. For bone fractures, calcimimetics-only (HR 0.59, P < .001) and combination therapy (HR 0.74, P < .01) were associated with lower risk of fracture, whereas VDRA-only was not (HR 0.89, P = .102). For hip fractures, only combination therapy was associated with lower hip fracture risk (HR 0.56, P < .01), while VDRA-only (HR 0.93, P = .494) and calcimimetics-only (HR 0.67, P = .082) were not statistically significant. Exploratory subgroup analyses by baseline characteristics showed broadly similar directions of association, although several estimates were imprecise. Conclusions Calcimimetics and combination therapy were associated with lower fracture risk in addition to lower mortality, but these findings should be interpreted cautiously and regarded as hypothesis-generating.