Role of gastrointestinal hormones in postprandial reduction of bone resorption.
Collagen type I fragments, reflecting bone resorption, and release of gut hormones were investigated after a meal. Investigations led to a dose escalation study with glucagon like peptide-2 (GLP-2) in postmenopausal women. We found a dose-dependent effect of GLP-2 on the reduction of bone resorption.


BACKGROUND
The C-terminal telopeptide region of type I collagen as measured in serum (s-CTX) can be used to assess bone resorption. This marker of bone resorption has a significant circadian variation that is influenced by food intake. However, the mediator of this variation has not been identified.


METHODS
We studied the release of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2; a representative of the intestinal proglucagon-derived peptides) after ingestion of glucose, fat, protein, and fructose, as well as their effects after parenteral administration in relation to bone turnover processes in healthy volunteers. Furthermore, we studied the effect on bone turnover of a single subcutaneous injection of GLP-2 in four different dosages (100, 200, 400, or 800 microg GLP-2) or placebo in 60 postmenopausal women (mean age, 61 +/- 5 years).


RESULTS
All macronutrients significantly (p < 0.05) reduced bone resorption as assessed by s-CTX (39-52% from baseline), and only the glucagon-like peptides were secreted in parallel. Parenteral administration of GIP and GLP-1 did not result in a reduction of the s-CTX level, whereas GLP-2 caused a statistically significant and dose-dependent reduction in the s-CTX level from baseline compared with placebo (p < 0.05). Urine DPD/creatinine, a marker of bone resorption, was significantly reduced by 25% from baseline in the 800-microg GLP-2 group (p < 0.01). An area under the curve (AUC(0-8h)) analysis for s-CTX after GLP-2 injection confirmed the dose-dependent decrease (ANOVA, p = 0.05). The s-osteocalcin level was unaffected by the GLP-2 treatment.


CONCLUSIONS
These studies exclude both GIP and GLP-1 as key mediators for the immediate reduction in bone resorption seen after a meal. The dose-dependent reduction of bone resorption markers found after subcutaneous injection of GLP-2 warrants further investigation into the mechanism and importance of GLP-2 for the bone turnover processes.
Henriksen
Dennis B
DB
Nordic Bioscience, Herlev, Denmark. dbh@nordicbioscience.com
Alexandersen
Peter
P
Bjarnason
Nina H
NH
Vilsbøll
Tina
T
Hartmann
Bolette
B
Henriksen
Eva E G
EE
Byrjalsen
Inger
I
Krarup
Thure
T
Holst
Jens J
JJ
Christiansen
Claus
C
D000328:Adult; D015992:Body Mass Index; D001862:Bone Resorption / Q000503:physiopathology*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D053767:Glucagon-Like Peptide 2; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D019518:Postprandial Period; D013997:Time Factors; D014280:Triglycerides / Q000494:pharmacology
D005768:Gastrointestinal Hormones; D053767:Glucagon-Like Peptide 2; D010455:Peptides; D014280:Triglycerides; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1