Same signals, different conductors: A gut–brain perspective on bone regulation—parallels and particularities

Osteoporosis, a systemic metabolic bone disorder characterized by reduced bone mineral density (BMD) and compromised bone microarchitecture, poses a significant public health challenge globally. Emerging evidence underscores the pivotal role of the gut-brain-bone axis in modulating skeletal homeostasis through a complex interplay of neurotransmitters, immune responses, and endocrine signals. This review elucidates the molecular mechanisms by which gut-derived and brain-derived signals converge, diverge, or synergize to regulate bone metabolism. We explore the contrasting effects of sympathetic and parasympathetic nervous systems on bone remodeling, highlighting the role of neurotransmitters such as serotonin, dopamine, and GABA. Furthermore, we discuss the contribution of gut microbiota to bone health via the synthesis of neurotransmitters and modulation of immune responses. The endocrine interactions between the brain and gut, involving hormones like cortisol, leptin, and GLP-1, are also examined. By identifying potential drug targets, this review aims to pave the way for novel, mechanism-based interventions for osteoporosis, emphasizing the importance of a holistic approach that integrates gut, brain, and bone health.