Cadmium-Induced Bone Toxicity: Deciphering the Osteoclast–Osteoblast Crosstalk

Cadmium (Cd), a pervasive environmental and industrial toxicant, bioaccumulates and exerts severe detrimental effects on skeletal integrity across diverse animal species. Cd-induced bone injury manifests as osteoporosis, osteomalacia, and increased fracture risk, posing significant health and welfare concerns for wildlife and livestock inhabiting contaminated ecosystems. The pathogenesis hinges critically on the disruption of bone remodeling, a tightly regulated process orchestrated by osteoclasts (OCs) responsible for bone resorption and osteoblasts (OBs) responsible for bone formation. This comprehensive review synthesizes the latest mechanistic insights into how Cd disturbs OC and OB function and their intricate crosstalk, leading to net bone loss. Cd directly impairs OB proliferation, differentiation, and mineralization capacity through multiple pathways, including the inhibition of Wnt/β-catenin signaling, induction of oxidative stress and mitochondrial dysfunction, promotion of apoptosis and senescence, and disruption of extracellular matrix protein synthesis. Simultaneously, Cd potently stimulates excessive OC formation and activity. It achieves this by upregulating the RANKL/OPG axis, enhancing reactive oxygen species (ROS) production which activates key OC transcription factors, modulating key signaling pathways, and promoting pro-osteoclastogenic inflammatory cytokine release from bone marrow and immune cells. Critically, Cd disrupts the vital communication between OBs and OCs, perturbing the coupling signals essential for balanced remodeling. Emerging evidence highlights roles for Cd-induced epigenetic modifications and autophagy/mitophagy flux alterations. This narrative review integrates the findings from in vivo animal models and in vitro cellular studies, providing potential therapeutic interventions and mitigation strategies for Cd-induced bone toxicity. Understanding these complex and interacting mechanisms provides a foundation for identifying potential therapeutic targets to mitigate Cd bone toxicity in animals and informs ecological risk assessment and management strategies in contaminated environments.