Reframing Osteoblast Homeostasis as a Systemic Endocrine–Metabolic Node: Mechanisms, Inter‐Organ Crosstalk, and Translational Strategies

ABSTRACT

Traditionally viewed as a static scaffold, bone is now unequivocally recognized as a dynamic, metabolically active organ intricately integrated into the systemic endocrine and metabolic landscape. Osteoblast homeostasis is central to this paradigm as an emergent property of systemic integration rather than being governed solely by local bone surface dynamics. Diverse systemic inputs—ranging from classical mineral metabolism and sex/stress hormones to energy metabolism and inter‐organ communication via the brain‐bone and gut‐bone axes—converge upon common intracellular effector modules within osteoblasts. Disruption of these delicate endocrine–metabolic networks is critical to the pathogenesis of postmenopausal osteoporosis, diabetic bone disease, obesity, aging, and chronic kidney disease‐mineral and bone disorder. Crucially, such systemic disruptions elucidate why bone fragility frequently reflects defective bone quality and profound osteoanabolic failure, rather than merely a reduction in bone mass. Therapeutic strategies are undergoing a critical shift away from purely antiresorptive strategies towards precision medicine aimed at actively restoring osteoblast function. This review synthesizes multi‐scale evidence to establish osteoblast homeostasis as a unifying framework for skeletal endocrinology, highlighting mechanism‐driven osteoanabolics, targeted metabolic interventions, multi‐omics stratification, and microbiota‐based therapeutics to advance the individualized management of metabolic bone diseases.