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

• Published in: Regulatory peptides 2013-02, Vol.181, p.4-8
• Main Authors: Askov-Hansen, Carsten, Jeppesen, Palle B., Lund, Pernille, Hartmann, Bolette, Holst, Jens J., Henriksen, Dennis B.
• Format: Article
• Language: English
• Subjects: Adult; Area Under Curve; Biomarkers - blood; Bone remodeling; Bone Resorption - prevention & control; Collagen Type I - blood; Dipeptidyl-Peptidase IV Inhibitors - blood; Dipeptidyl-Peptidase IV Inhibitors - pharmacokinetics; Drug Administration Schedule; Female; GLP-2; Glucagon-Like Peptide 2 - blood; Glucagon-Like Peptide 2 - pharmacokinetics; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; p-CTX; Peptide Fragments - blood; Pyrazines - blood; Pyrazines - pharmacokinetics; Sitagliptin Phosphate; Triazoles - blood; Triazoles - pharmacokinetics
• ISSN: 0167-0115; 1873-1686
• DOI: 10.1016/j.regpep.2012.11.002

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. Eight healthy subjects were given: a) three intravenous injections of GLP-2 of 0.1, 0.4 and 0.8nmol/kg, b) one subcutaneous injection of 1.6mg GLP-2 and c) one subcutaneous injection of 1.6mg GLP-2 preceded by an intake of sitagliptin. Blood was sampled for measurements of GLP-2 and p-CTX after each intervention. The 0.1, 0.4 and 0.8nmol/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 0.4nmol/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. 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. ► Prolonged exposure by subcutaneous administration suppressed CTX significantly. ► Administration of sitagliptin had no additional effect. ► In osteoporosis treatment GLP-2 agonists should be long-acting.