Effect of glucagon-like peptide-2 exposure on bone resorption: Effectiveness of high concentration versus prolonged exposure

Objective: In healthy subjects, subcutaneous injections of GLP-2 have been shown to elicit dose-related decrease in the bone resorption marker, carboxy-terminal telopeptide of type I collagen (CTX), and have been proposed for the treatment of osteoporosis. This study investigated the relation between GLP-2 exposure and decreases in CTX in order to determine whether high concentrations or prolonged exposure was the most effective mode of administration. High GLP-2 concentrations resulted from iv bolus injections, whereas a more protracted stimulation was obtained by subcutaneous injections and the addition of an inhibitor of GLP-2 degradation, a DPP-4 inhibitor, sitagliptin. Materials and methods: Eight healthy subjects were given: a) three intravenous injections of GLP-2 of 0.1, 0.4 and 0.8 nmol/kg, b) one subcutaneous injection of 1.6 mg GLP-2 and c) one subcutaneous injection of 1.6 mg GLP-2 preceded by an intake of sitagliptin. Blood was sampled for measurements of GLP-2 and p-CTX after each intervention. Results: The 0.1, 0.4 and 0.8 nmol/kg GLP-2 injections dose-dependently elevated plasma GLP-2 concentrations and decreased CTX, but the decrease was similar regardless of dose. Subcutaneous GLP-2 caused a much more prolonged exposure (with a peak concentration corresponding to 0.4 nmol/kg IV) and was associated with a stronger and a more prolonged suppression of CTX, but in spite of significantly increasing exposure, the administration of sitagliptin, had no additional effect. Conclusion: The high concentrations obtained by iv administration were less effective with respect to CTX suppression than the prolonged exposure (with much lower peak concentrations). GLP-2 agonists for osteoporosis treatment should therefore be long-acting for best efficacy. (C) 2012 Elsevier B.V. All rights reserved.