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  • Review Article
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Gut hormones and bone homeostasis: potential therapeutic implications

Nature Reviews Endocrinology (2024)Cite this article

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Abstract

Bone resorption follows a circadian rhythm, with a marked reduction in circulating markers of resorption (such as carboxy-terminal telopeptide region of collagen type I in serum) in the postprandial period. Several gut hormones, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and GLP2, have been linked to this effect in humans and rodent models. These hormones are secreted from enteroendocrine cells in the gastrointestinal tract in response to a variety of stimuli and effect a wide range of physiological processes within and outside the gut. Single GLP1, dual GLP1–GIP or GLP1–glucagon and triple GLP1–GIP–glucagon receptor agonists have been developed for the treatment of type 2 diabetes mellitus and obesity. In addition, single GIP, GLP1 and GLP2 analogues have been investigated in preclinical studies as novel therapeutics to improve bone strength in bone fragility disorders. Dual GIP–GLP2 analogues have been developed that show therapeutic promise for bone fragility in preclinical studies and seem to exert considerable activity at the bone material level. This Review summarizes the evidence of the action of gut hormones on bone homeostasis and physiology.

Key points

  • Circulating markers of bone resorption, and to a lesser extent bone formation, follow a circadian pattern, with a notable reduction occurring in humans during the postprandial period.

  • Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and GLP2 modulate circulating markers of bone resorption during the postprandial period in humans.

  • In humans and rodents, GIP–GIP receptor and GLP2–GLP2 receptor have distinct but additive effects on bone turnover and bone material properties, including enhanced enzymatic collagen crosslinking.

  • In rodents, single analogues of GIP, GLP1 and GLP2 improve bone density, microstructure and material properties.

  • In rodent models of bone fragility, dual GIP–GLP2 analogues improve bone strength by acting at the bone material level.

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Fig. 1: Pioneering research in the crosstalk between EECs and bone.
Fig. 2: Schematic representation of EEC–bone tissue crosstalk.
Fig. 3: Expression of gut hormone receptors, their signalling pathways and downstream responses in bone cells.

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Authors and Affiliations

  1. Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France

    Béatrice Bouvard & Guillaume Mabilleau

  2. CHU Angers, Service de Rhumatologie, Angers, France

    Béatrice Bouvard

  3. CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France

    Guillaume Mabilleau

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  1. Béatrice Bouvard
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B.B. and G.M. are employees of the University of Angers and CHU Angers, which have jointly applied for a patent for the use of dual GIP–GLP2 analogues in the treatment of bone fragility disorders (patent application number: WO2020169792A1). G.M. is also listed as a co-inventor on this patent application.

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Bouvard, B., Mabilleau, G. Gut hormones and bone homeostasis: potential therapeutic implications. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-01000-z

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