BAMBinO: Bile Acids as Metabolic regulators in Osteoporosis – BAMBinO

Wider research content: Osteoporosis is a common metabolic disease, causing high morbidity and major economic costs. Obesity is often linked to bone deterioration leading to a greater risk of peripheral fragility fractures and clinical complications in these patients. The association between obesity and osteoporosis is complex and usually the fracture risk is underestimated in obese patients. Thus, understanding this relationship could improve the diagnosis and treatment of susceptible individuals and provide insights into the mechanisms involved in bone loss. Our preliminary data suggest that diet-induced changes in bile acid metabolism could be related to poor bone health, possibly via changes in the farnesoid X receptor (FXR)-driven metabolic pathways.

Objectives: We aim to investigate the mechanisms underlying bile acid-induced metabolic rewiring in bone, especially focusing on changes in carnitine and amino acid pathways. We also aim to uncover novel metabolic biomarkers for bone loss that could be used to better predict fracture risk and provide stratified clinical care as well as to identify therapeutic targets with potential interest for personalised treatments in osteoporosis, including obesity-related bone loss.

Methods: Bile acid-related metabolic alterations in carnitines and amino acids will be assessed in bone cells and biofluids of a diet-induced rat model for obesity and further investigated in an Fxr-/- murine model treated with rescue diets. Associated molecular, metabolic, and microbiome-related biomarkers will be identified in both models and osteoporotic patients via comprehensive quantitative panels and untargeted -omics methods. Validation of common targets will be carried out in primary human osteoblasts and osteoclasts. A separate analysis of markers for obesity-related bone loss will be performed.

Level of originality: Osteoporosis and obesity are closely linked phenomena, but the underlying mechanisms are not fully understood, hampering the clinical assessment and appropriate management of these patients. We have identified for the first time that obesogenic diet-induced bone loss correlates with changes in bile acid, carnitine and amino acid metabolism in rats. Based on these results, BAMBinO aims to investigate this connection via the bile acid receptor FXR, using innovative methodological approaches and appropriate preclinical models. Moreover, the collaboration with the French groups will allow us to validate the findings in osteoporotic patients and human bone cells, which will ensure the biomarkers found in the project will have clinical applicability to develop targeted medical care. The comprehensive analysis proposed here will uncover metabolic targets to develop novel pharmacological, nutritional and microbiome-based therapies for osteoporosis.