ABSTRACT Mineral and bone disorders including osteoporosis are common in dialysis patients and contribute to increased morbimortality. However, whether denosumab and alendronate are effective and safe treatments in hemodialysis patients is not known. Thus, we conducted a prospective, three‐center study of 48 hemodialysis patients who were diagnosed as having osteoporosis and had not received anti‐osteoporotic agents previously. Participants were randomized to either denosumab or intravenous alendronate, and all subjects received elemental calcium and calcitriol during the initial 2 weeks. The primary endpoint was the percent change in lumbar spine bone mineral density (LSBMD) at 12 months of treatment. The secondary endpoints included the following: change in BMD at other sites; change of serum bone turnover markers (BTM), coronary artery calcium score (CACS), ankle‐brachial pressure index (ABI), brachial‐ankle pulse wave velocity (baPWV), flow mediated dilation (FMD), and intima‐media thickness at the carotid artery (CA‐IMT); change from day 0 to day 14 in serum levels of Ca and P; time course of serum calcium (Ca), phosphorus (P), and intact parathyroid hormone (i‐PTH); new fractures; and adverse events. Initial supplementation with elemental calcium and calcitriol markedly ameliorated the decrease of serum corrected calcium (cCa) levels induced by denosumab during the first 2 weeks, whereas serum cCa levels in the alendronate group were increased. Denosumab and alendronate markedly decreased serum levels of BTM and increased LSBMD at 12 months compared with baseline. However, no significant differences were found in the changes in LSBMD between the two groups. The serum cCa, P, and i‐PTH levels in the two groups were maintained within the appropriate range. In contrast to the anti‐osteoporotic effects, no significant differences after 12 months of treatment were found in the CACS, CA‐IMT, ABI, baPWV, and FMD compared with pretreatment in both groups. Denosumab and alendronate treatment improved LSBMD, reduced BTM, and appeared to be safe in hemodialysis patients with osteoporosis. © 2019 American Society for Bone and Mineral Research.