Sina Salem Ahim
1 
, Sara Aghaei
2 , Farzin Banei
3 , Mohammad Mousavi
4 , Mohammad Shahsavan
5 , Kamran Safa
6 , Amin Norouzbeygi
7 , Elahe Zaremoghadam
8,9 , Faezeh Nesaei
10* 1 Fasa University of Medical Sciences, Fasa, Iran.
2 Private Dermatology Independent Practice, Tehran, Iran.
3 Department of Neurology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
4 Department of Internal Medicine, Clinical Research Development Unit, Hajar Hospital, Shahrekord University of Medical Sciences, Shahrekord, Iran.
5 Department of Orthopedic Surgery, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
6 Department of Emergency Medicine, Imam Hossein Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
7 Department of Orthopedic and Trauma Surgery, School of Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.
8 Department of Internal Medicine, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran.
9 Digestive Diseases Research Institute, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
10 Department of Nursing, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Abstract
The brain-gut-bone axis plays a crucial and complex role in regulating bone metabolism, particularly in the context of osteoporosis. This multidirectional communication network integrates signals from several physiological systems, including the gut microbiota, immune system, nervous system, and hormonal environment, all of which collectively influence the balance between bone formation by osteoblasts and bone resorption by osteoclasts. The gut microbiota contributes to this axis by producing metabolites such as short-chain fatty acids (SCFAs) and modulating systemic inflammation, which in turn can affect bone cell activity and mineralization processes. The immune system participates through cytokine signaling that either promotes or inhibits bone resorption and formation, linking inflammation to bone health. Meanwhile, the nervous system, via autonomic and sensory pathways, regulates nutrient absorption, bone blood flow, and directly modulates bone cell function through neuropeptides and neurotransmitters. Hormonal factors, including parathyroid hormone, sex steroids, and gut-derived hormones like serotonin, further modulate bone turnover by fine-tuning osteoblast and osteoclast activity. Disruptions in any component of this axis, such as dysbiosis of the gut microbiota, chronic inflammation, neurotransmitter imbalance, or hormonal deficiencies can lead to dysregulated bone remodeling, favoring increased bone resorption, decreased bone formation, and eventually decreased bone density. This manifests clinically as osteoporosis, characterized by fragile bones and elevated fracture risk. Therefore, understanding and targeting the brain-gut-bone axis presents promising therapeutic opportunities. Interventions such as probiotics, anti-inflammatory therapies, neuromodulation, and hormone replacement can potentially restore the balance in this axis, improving bone health and reducing osteoporosis progression. This integrative approach highlights the importance of systemic interactions and opens new avenues for precision medicine in bone metabolic disorders.