Role of Gastrointestinal Hormones in Postprandial Reduction of Bone Resorption

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Abstract
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. Introduction: 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. Materials and 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 μg 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‐μg GLP‐2 group (p < 0.01). An area under the curve (AUC0–8h) 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. Conclusion: 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.