Clopidogrel (Plavix), a P2Y12 receptor antagonist, inhibits bone cell function in vitro and decreases trabecular bone in vivo

Susanne Syberg, Andrea Brandao-Burch, Jessal J Patel, Mark Hajjawi, Timothy R Arnett, Peter Schwarz, Niklas R Jorgensen, Isabel R Orriss

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)


Clopidogrel (Plavix), a selective P2Y(12) receptor antagonist, is widely prescribed to reduce the risk of heart attack and stroke and acts via the inhibition of platelet aggregation. Accumulating evidence now suggests that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone, modulating both osteoblast and osteoclast function. In this study, we investigated the effects of clopidogrel treatment on (1) bone cell formation, differentiation, and activity in vitro; and (2) trabecular and cortical bone parameters in vivo. P2Y(12) receptor expression by osteoblasts and osteoclasts was confirmed using qPCR and Western blotting. Clopidogrel at 10 µM and 25 µM inhibited mineralized bone nodule formation by 50% and >85%, respectively. Clopidogrel slowed osteoblast proliferation with dose-dependent decreases in cell number (25% to 40%) evident in differentiating osteoblasts (day 7). A single dose of 10 to 25 µM clopidogrel to mature osteoblasts also reduced cell viability. At 14 days, ≥10 µM clopidogrel decreased alkaline phosphatase (ALP) activity by ≤70% and collagen formation by 40%, while increasing adipocyte formation. In osteoclasts, ≥1 µM clopidogrel inhibited formation, viability and resorptive activity. Twenty-week-old mice (n = 10-12) were ovariectomized or sham treated and dosed orally with clopidogrel (1 mg/kg) or vehicle (NaCl) daily for 4 weeks. Dual-energy X-ray absorptiometry (DXA) analysis showed clopidogrel-treated animals had decreases of 2% and 4% in whole-body and femoral bone mineral density (BMD), respectively. Detailed analysis of trabecular and cortical bone using micro-computed tomography (microCT) showed decreased trabecular bone volume in the tibia (24%) and femur (18%) of clopidogrel-treated mice. Trabecular number was reduced 20%, while trabecular separation was increased up to 15%. Trabecular thickness and cortical bone parameters were unaffected. Combined, these findings indicate that long-term exposure of bone cells to clopidogrel in vivo could negatively impact bone health.

Original languageEnglish
Pages (from-to)2373-86
Number of pages14
JournalJournal of Bone and Mineral Research (JBMR)
Issue number11
Publication statusPublished - Nov 2012


  • Alkaline Phosphatase/metabolism
  • Animals
  • Azo Compounds
  • Biomarkers/blood
  • Bone Density/drug effects
  • Bone Resorption/pathology
  • Bone and Bones/diagnostic imaging
  • Cell Count
  • Cell Survival/drug effects
  • Cells, Cultured
  • Clopidogrel
  • Collagen/metabolism
  • Cyclic AMP/metabolism
  • Gene Expression Regulation/drug effects
  • Intracellular Space/drug effects
  • Mice
  • Osteoblasts/drug effects
  • Osteoclasts/drug effects
  • Osteogenesis/drug effects
  • Purinergic P2Y Receptor Antagonists/pharmacology
  • Radiography
  • Receptors, Purinergic P2Y12/metabolism
  • Solubility
  • Staining and Labeling
  • Ticlopidine/analogs & derivatives


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