Sclerostin/SOST is a robust negative regulator of bone formation. Loss-of-function mutations of the sclerostin gene (SOST) cause sclerosteosis and Van Buchem disease characterized by bone overgrowth. Mediated by myocyte enhancer factor 2 (MEF2) transcription factors, parathyroid hormone (PTH) suppresses SOST expression through formation of complexes of parathyroid hormone-parathyroid hormone-related peptide receptor 1 (PTH1R) and lipoprotein receptor-related protein 6 (LRP6). N-cadherin has been shown to negatively regulate Wnt/beta-catenin and PTH induced, protein kinase-dependent beta-catenin signaling. Here, we investigated whether N-cadherin mediates the inhibitory effects of PTH on sclerostin/SOST. In vitro, overexpression of N-cadherin resulted in blunted PTH suppressive effects on sclerostin/SOST expression, as detected by immunoblot and qPCR analysis; PTH-induced downregulation of MEF2A, C, and D was impaired by N-cadherin; and N-cadherin reduced LRP6-PTHR1 interaction and endocytosis in response to PTH. In vivo, intermittent PTH (iPTH)-induced suppression of sclerostin/SOST was accentuated in Dmp1-cre; Cdh2(f/f) (Cdh2(Delta Dmp1)) mice, compared with Cdh2(f/f) mice. Additionally, iPTH had greater bone anabolic effects in Cdh2(Delta Dmp1) mice compared to Cdh2(f/f) mice. These data indicate that N-cadherin negatively mediates PTH suppressive effects on sclerostin/SOST by regulating LRP6-PTHR1 interaction, ultimately influencing PTH anabolic effects on bone.