A Pilot Study Showing Acute Inhibitory Effect of GLP-1 on the Bone Resorption Marker CTX in Humans

Anne Nissen; Simone Marstrand; Kirsa Skov-Jeppesen; Lasse Bremholm; Mads Hornum; Ulrik B Andersen; Jens Juul Holst; Mette Marie Rosenkilde; Bolette Hartmann

doi:10.1002/jbm4.10209

A Pilot Study Showing Acute Inhibitory Effect of GLP-1 on the Bone Resorption Marker CTX in Humans

JBMR Plus. 2019 Aug 23;3(10):e10209. doi: 10.1002/jbm4.10209. eCollection 2019 Oct.

Authors

Anne Nissen^{1

2}, Simone Marstrand^{1

2}, Kirsa Skov-Jeppesen^{1

2}, Lasse Bremholm³, Mads Hornum^{4

5}, Ulrik B Andersen⁶, Jens Juul Holst^{1

2}, Mette Marie Rosenkilde^{1

2}, Bolette Hartmann^{1

2}

Affiliations

¹ Department of Biomedical Sciences The Panum Institute, University of Copenhagen Copenhagen Denmark.
² NNF Center for Basic Metabolic Research The Panum Institute, University of Copenhagen Copenhagen Denmark.
³ Department of Surgery (Gastroenterology Section) Zealand University Hospital, University of Copenhagen Copenhagen Denmark.
⁴ Department of Nephrology Rigshospitalet Copenhagen Denmark.
⁵ Institute for Clinical Medicine University of Copenhagen Copenhagen Denmark.
⁶ Department of Clinical Physiology and Nuclear Medicine and PET Rigshospitalet (Glostrup Section), University of Copenhagen Copenhagen Denmark.

Abstract

Bones have been suggested to be a target for glucagon-like peptide -1 (GLP-1); however, studies of the effects on human bones so far have given diverging results. We hypothesized that GLP-1, together with glucagon-like peptide-2 and glucose-dependent insulinotropic polypeptide, plays a role in the gut-bone axis. We examined the acute effect of three GLP-1 receptor ligands [GLP-1 (7-36)amide, GLP-1 (9-36)amide, and exenatide] on markers of bone remodeling. Eight healthy, normal-weight participants, with a mean age of 24.3 years, were studied for 4 days in a double-blinded, randomized clinical trial. Blood was collected before and after s.c. injection of GLP-1 (7-36)amide (1.5 nmol/kg), GLP-1 (9-36)amide (1.5 nmol/kg), exenatide (2.4 nmol/subject), or saline. Plasma was analyzed for bone markers and for osteoprotegerin (OPG), PTH, and IGF-1 levels. All ligands were tested in vitro for their cAMP-inducing activity on the human GLP-1 receptor. GLP-1 (7-36)amide decreased CTX-levels, compared with placebo (area under the curve [AUC] ±SD 0 to 120 min = -2143 ± 1294 % × min versus -883 ± 1557 % × min; p < 0.05). No difference was observed between placebo and GLP-1 (9-36)amide, or between placebo and exenatide, although exenatide had a similar potency as GLP-1 (7-36)amide for cAMP formation in vitro (EC₅₀ of 0.093 and 0.054 nmol/L). However, exenatide reached maximum plasma concentration at 90 min versus 15 min for GLP-1 (7-36)amide, and plasma CTX was significantly decreased during the second hour of the study after exenatide injections compared with placebo (AUC ±SD -463.1 ± 218 % × min and -136 ± 91 % × min; p < 0.05). There was no effect of the injections on bone formation markers (P1NP and osteocalcin) or on OPG, PTH and IGF-1 levels. In conclusion, we show that GLP-1 receptor agonists, but not the primary metabolite GLP-1 (9-36)amide, decrease bone resorption, and suggest that GLP-1 may be part of the gut-bone axis. © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Keywords: BONE REMODELING; BONE RESORPTION; CTX; EXENATIDE; GLUCAGON‐LIKE PEPTIDE‐1.