GLP-2 and GIP exert separate effects on bone turnover: A randomized, placebo-controlled, crossover study in healthy young men

Bacicground: Glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) both inhibit bone resorption in humans but the underlying mechanisms are poorly understood. In vitro, GLP-2 activates the GIP-receptor (GIPR). Objective: Based on in vitro studies, we hypothesized that the antiresorptive effect of GLP-2 was mediated through the GIPR. This was tested using the selective GIPR-antagonist GIP(3-30)NH2. Methods: The study was a randomized, single-blinded, placebo-controlled, crossover study conducted at Hvidovre University Hospital, Denmark. Eight healthy young men were included and studied on four study days: GIP (200 mu g), GLP-2 (800 mu g), GIP(33-0)NH2 (800 pmol/kg/min) + GLP-2 (800 mu g), and placebo. The main outcomes were bone resorption measured as collagen type 1 C-terminal telopeptide (CTX) and bone formation measured as procollagen type 1 N-terminal propeptide (P1NP). Results: CTX (mean +/- SEM) significantly decreased after both GIP (to 55.3 +/- 6.3% of baseline at t = 90 min) and GLP-2 (to 60.5 +/- 5.0% of baseline at t = 180 min). The maximal reduction in CTX after GIP(3-30) NH2 + GLP-2 (to 63.2 +/- 3.1% of baseline) did not differ from GLP-2 alone (p = 0.95) nor did net AUC(0-240) (-6801 +/- 879%*min vs -6027 +/- 648%*min, p = 0.56). At t = 30 min, GIP significantly (p < 0.0001) increased P1NP to 115.1 +/- 2.2% of baseline compared with 103.1 +/- 1.5% after placebo. Both GLP-2 and GIP(3-30)NH2 + GLP-2 significantly (p < 0.0001) decreased P1NP to 91.3 +/- 1.1% and 88.1 +/- 3.0% of baseline, respectively (at t = 45 min) compared with placebo. Conclusions: GIPR antagonism did not inhibit the GLP-2-induced reduction in bone resorption (CTX) in healthy young men. In contrast to GLP-2, GIP increased P1NP despite decreasing CTX indicating an uncoupling of bone resorption from formation. Thus, GLP-2 and GIP seem to exert separate effects on bone turnover in humans. Clinical trials information: ClinicalTrials.gov (NCT03159741).