Environmental fluoride exposure and bone metabolism: Molecular pathways and health implications

Fluoride, a common environmental pollutant in drinking water and air, poses a major public health risk in endemic regions. Fluorosis disrupts bone structure and density and impairs key physiological processes, including calcium-phosphorus homeostasis, hormone regulation, enzyme activity, and cytokine-mediated signaling-thereby compromising skeletal integrity. This review explores the molecular mechanisms through which chronic environmental fluoride exposure disrupts bone metabolism, leading to structural and functional skeletal damage. Chronic fluoride exposure alters bone mineral crystals due to its high affinity for calcium, reducing mechanical strength and disturbing phosphorus balance. It also inhibits vitamin D hydroxylation, decreasing active vitamin D bioavailability and impairing calcium and phosphorus absorption. Fluoride disrupts endocrine homeostasis by altering secretion of parathyroid hormone, calcitonin, and estrogen. At the enzymatic level, it modulates alkaline phosphatase, acid phosphatase, and matrix metalloproteinases, affecting osteoblast/osteoclast function and bone remodeling. Furthermore, fluorosis modulates cytokine networks, influencing irisin, osteopontin, and hypoxia-inducible factor-α-key regulators of bone metabolism. These insights are vital for environmental health risk assessment and the development of targeted prevention and therapeutic strategies. Future research should clarify these pathways to better address fluorosis-induced skeletal disorders.