P2Y12 inhibition, adenosine signaling, and bone remodeling: differential skeletal pharmacology of antiplatelet agents

Cardiovascular disease, osteoporosis, and fragility fractures frequently coexist in older adults, creating an important overlap between antiplatelet therapy and orthopedic care. This narrative review examines mechanistic, preclinical, observational, and perioperative evidence concerning the skeletal effects of aspirin, P2Y 12 inhibitors, and other clinically relevant antiplatelet agents. Purinergic signaling provides biological plausibility for interactions between platelet inhibition and bone remodeling because P2Y 12 , P2Y 1 , P2X 7 , adenosine receptors, and equilibrative nucleoside transporter 1 (ENT1) regulate osteoblast differentiation, osteoclast activity, inflammatory responses, and tissue repair. Aspirin shows dose- and context-dependent skeletal effects, whereas clopidogrel has been associated with impaired osteoblast mineralization in preclinical studies and conflicting fracture-risk estimates in observational cohorts. Direct skeletal evidence for prasugrel and other agents remains limited. Selected preclinical studies suggest that ticagrelor-associated ENT1 inhibition can enhance adenosine-dependent osteogenic signaling; however, clinical evidence is limited to one retrospective cohort in which ticagrelor-based dual antiplatelet therapy (DAPT) was associated with lower fracture risk than clopidogrel-based DAPT, while prospective skeletal outcome data are lacking. Perioperative antiplatelet management in orthopedic surgery should remain guided by cardiovascular indications, thrombotic risk, and bleeding risk. A conceptual framework may help define priorities for evaluating skeletal outcomes during antiplatelet therapy. However, current evidence is insufficient to support antiplatelet selection or switching on the basis of presumed skeletal effects.