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

Abstract Background Glucagon-like peptide-2(GLP-2) and glucose-dependent insulinotropic polypeptide(GIP) both inhibit bone resorptionin 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)NH 2 . 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 μg), GLP-2 (800 μg), GIP(3-30)NH 2 (800 pmol/kg/min) + GLP-2 (800 μg), and placebo. The main outcomes were bone resorptionmeasured 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)NH 2  + 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 2  + GLP-2 significantly ( p 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 resorptionfrom formation. Thus, GLP-2 and GIP seem to exert separate effects on bone turnover in humans. Clinical trials information ClinicalTrials.gov ( NCT03159741 ).