Renal osteodystrophy (ROD) is a disorder of bone metabolism that affects virtually all patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes including fractures, cardiovascular events, and death. In this study, we showed that hepatocyte nuclear factor 4α (HNF4α), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseousHNF4αexpression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion ofHnf4αresulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressingHnf4α1andHnf4α2, we showed that HNF4α2 is the main osseousHnf4αisoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression ofHnf4α2prevented bone loss in mice with CKD. Our results showed that HNF4α2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.