P2Y12 inhibition, adenosine signaling, and bone remodeling: differential skeletal pharmacology of antiplatelet agents
- 1Second Ward, Cardiovascular Disease Treatment Center, Honghui Hospital, Xi’an Jiaotong University, Xi’an, China
Abstract
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, P2Y12 inhibitors, and other clinically relevant antiplatelet agents. Purinergic signaling provides biological plausibility for interactions between platelet inhibition and bone remodeling because P2Y12, P2Y1, P2X7, 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.
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BibTeX
@article{ma2026p2y12,
title = {{P2Y12 inhibition, adenosine signaling, and bone remodeling: differential skeletal pharmacology of antiplatelet agents}},
author = {Zhuoqun Ma and Wei Luo and Yuanbo Li and Hong Li and Chaomin Li},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1897702},
url = {https://doi.org/10.3389/fphar.2026.1897702},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - P2Y12 inhibition, adenosine signaling, and bone remodeling: differential skeletal pharmacology of antiplatelet agents
AU - Zhuoqun Ma
AU - Wei Luo
AU - Yuanbo Li
AU - Hong Li
AU - Chaomin Li
PY - 2026
DA - 2026/10/12
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1897702
UR - https://doi.org/10.3389/fphar.2026.1897702
AB - 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, P2Y12 inhibitors, and other clinically relevant antiplatelet agents. Purinergic signaling provides biological plausibility for interactions between platelet inhibition and bone remodeling because P2Y12, P2Y1, P2X7, 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.
SN - 1663-9812
ER -