Hyperparathyroidism in humans and continuous PTH treatment (cPTH) in mice stimulate bone resorption and cause bone loss by regulating RANKL/OPG production by stromal cells (SCs) and osteoblasts. Reports have shown that T cells markedly potentiate the bone catabolic effect of cPTH by inducing CD40 signaling in SCs through their surface receptor CD40L. In addition, cPTH stimulate T cells to secrete the osteoclastogenic cytokine TNF, a factor that potentiates the osteoclastogenic activity of RANKL. A search for additional mechanisms by which T cells potentiate cPTH induced bone loss revealed that in vivo cPTH treatment for 2 weeks increased by ~2-3 fold the frequency of Th17 cells in the BM. Th17 are a highly osteoclastogenic population of CD4+ cells defined by the capacity to produce IL-17, a potent inducer of RANKL and TNF production. To investigate the mechanism by which cPTH expands Th17 cells we assessed Th17 cell differentiation, proliferation and homing. We found that cPTH increased the differentiation of naïve CD4+ cells into Th17 cells. However, cPTH did not regulate Th17 proliferation and homing. Th17 cell differentiation is induced by several cytokines including TGFβ, IL-6 and TNF. All of these factors are upregulated by cPTH. We found that cPTH increased the relative frequency of Th17 cells in the BM in WT mice, but not in TNF-/- mice. Reconstitution experiments revealed that cPTH expanded Th17 cells in T cell null mice reconstituted with WT T cells or TNFR2-/- T cells but not in those reconstituted with TNFR1-/- T cells. These findings demonstrate that cPTH requires TNF and TNFR1 signaling in T cells to expand Th17 cells. To investigate the contribution of Th17 cells to cPTH induced bone loss, mice were treated with cPTH and either Irr. Antibody (Ab) or anti IL-17 Ab for 2 weeks. IL-17 Ab completely blocked the loss of trabecular and cortical bone (as measured by μCT), and the increase in bone resorption (as measured by histomorphometry and serum CTX). By contrast, treatment with Irr Ig did not antagonize the bone catabolic effects of cPTH. Furthermore, IL-17 Ab completely blocked the increase in SC production of TNFα and RANKL induced by cPTH, demonstrating that cPTH stimulates SC osteoclastogenic function through T cell produced IL17. In summary, these findings demonstrate that cPTH polarizes the differentiation of CD4+ cells toward the Th17 subset via TNF, and that cPTH induces bone loss through IL-17. Neutralization of IL-17 may thus represent a novel therapeutic strategy for hyperparathyroidism.