Gastrointestinal hormones including gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2) are secreted immediately after meal ingestion, and GIP and GLP-2 have been shown to regulate bone turnover. We hypothesize that endogenous GLP-1 may also be important for control of skeletal homeostasis. We investigated the role of GLP-1 in the regulation of bone metabolism using GLP-1 receptor knockout (Glp-1r^-/-) mice. A combination of bone density and histomorphometry, osteoclast activation studies, biochemical analysis of calcium and parathyroid hormone, and RNA analysis was used to characterize bone and mineral homeostasis in Glp-1r^-/- and Glp-1r^+/+ littermate controls. Glp-1r^-/- mice have cortical osteopenia and bone fragility by bone densitometry, as well as increased osteoclastic numbers and bone resorption activity by bone histomorphometry. Although GLP-1 had no direct effect on osteoclasts and osteoblasts, Glp-1r^-/- mice exhibited higher levels of urinary deoxypyridinoloine (DPD), a marker of bone resorption, and reduced levels of calcitonin mRNA transcripts in the thyroid. Moreover, calcitonin treatment effectively suppressed urinary levels of DPD in Glp-1r^-/- mice and the GLP-1 receptor agonist exendin-4 increased calcitonin gene expression in the thyroid of wildtype mice. These findings establish an essential role for endogenous GLP-1 receptor signaling in the control of bone resorption, likely through a calcitonin-dependent pathway.