Chronic kidney disease (CKD) causes early skeletal deterioration through disruptions in mineral metabolism, including elevations in fibroblast growth factor-23 (FGF23). Using longitudinal analyses of wild-type, Col4a3−/− CKD, and DMP1-overexpressing mice aged 8–23 weeks, this study evaluated endocrine changes, bone microarchitecture, and histomorphometric markers. CKD mice exhibited rising FGF23, parathyroid hormone, phosphate, and blood urea nitrogen levels in parallel with trabecular and cortical bone loss and suppressed osteoblast activity. Notably, DMP1 overexpression delayed or rescued many of these skeletal defects independent of kidney function, indicating a bone-intrinsic protective mechanism. Findings suggest that excessive FGF23 may act locally within bone to impair mineralization and that DMP1 may counteract this effect. This work clarifies temporal relationships between CKD progression and skeletal decline and identifies potential therapeutic targets within bone–kidney endocrine pathways.