Clopidogrel and the risk of osteoporotic fractures: a nationwide cohort study

Jørgensen, Niklas Rye; Grove, Erik Lerkevang; Schwarz, Peter; Vestergaard, Peter

doi:10.1111/j.1365-2796.2012.02535.x

Cited by 33 publications

(31 citation statements)

References 18 publications

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“…A cohort study including all patients treated with clopidogrel in Denmark during a 10-year period (n ¼ 77,503) and an age-and gender-matched control group (n ¼ 232,510) showed that patients on clopidogreltreatment had an increased risk of fracture of approximately 50% compared to the control group. (54) This study focused on the effects of clopidogrel, which is the major compound currently in therapeutic use. However, other P2Y 12 receptor antagonists (Prasugrel, Elinogrel, and Tricagrel) are now becoming available therapeutically; whether these drugs effect bone cell function in vitro and in vivo is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

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

Syberg

Brandao-Burch

Patel

et al. 2012

Journal of Bone and Mineral Research

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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 mM and 25 mM 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 mM clopidogrel to mature osteoblasts also reduced cell viability. At 14 days, !10 mM clopidogrel decreased alkaline phosphatase (ALP) activity by 70% and collagen formation by 40%, while increasing adipocyte formation. In osteoclasts, !1 mM clopidogrel inhibited formation, viability and resorptive activity. Twenty-week-old mice (n ¼ 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 clopidogreltreated 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. ß

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Section: Discussionmentioning

confidence: 99%

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

Syberg

Brandao-Burch

Patel

et al. 2012

Journal of Bone and Mineral Research

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“… 4 As patients with cardiac comorbidities requiring these drugs are often similarly at risk for osteoporosis and thus for fragility fractures, this population presents a unique dilemma for orthopedic surgeons who perform emergent, urgent, as well as elective operations on these patients. 5 Additionally, a nationwide cohort study published in 2012 by Jørgensen et al concluded clopidogrel taken by itself in the recommended dose range is associated with a risk of fractures, although the in vivo effects of antiplatelet drugs on bone metabolism are uncertain. 5 …”

Section: Introductionmentioning

confidence: 99%

“… 5 Additionally, a nationwide cohort study published in 2012 by Jørgensen et al concluded clopidogrel taken by itself in the recommended dose range is associated with a risk of fractures, although the in vivo effects of antiplatelet drugs on bone metabolism are uncertain. 5 …”

Section: Introductionmentioning

confidence: 99%

Current Practices Regarding Perioperative Management of Patients With Fracture on Antiplatelet Therapy

Pean

Goch

Christiano

et al. 2015

Geriatr Orthop Surg Rehabil

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Objective:There continues to be controversy over whether operative delay is necessary for patients on antiplatelet therapy, particularly for elderly patients with hip fractures. This study sought to assess current clinical practices of orthopedic surgeons regarding perioperative management of these patients.Methods:A 12-question, Web-based survey was distributed to orthopedic surgeons via e-mail. Questions regarding timing of surgery assumed patients were on antiplatelet therapy and assessed attitudes toward emergent and nonemergent orthopedic cases as well as operative delay for specific closed fracture types. Responses were compared using unpaired, 2-tailed Student t tests for continuous variables and Pearson chi-square tests with odds ratios (ORs) and 95% confidence intervals (CIs) for categorical variables. Statistical significance was defined as a P value <.05.Results:Overall 67 orthopedic surgeons responded. Fifty-two percent (n = 35) of the respondents described their practice as academic. Thirty-nine percent (n = 25) of the surgeons indicated that no delay was acceptable for urgent but nonemergent surgery, and 78% (n = 50) reported no delay for emergent surgery was acceptable. Sixty-eight percent (n = 46) of respondents felt patients on antiplatelet therapy with closed hip fractures did not require operative delay. Surgeons who opted for surgical delay in hip fractures were more likely to delay surgery in other lower extremity fracture types (OR = 16.4, 95% CI 4.48-60.61, P < .001). Sixty-four percent (n = 41) of the surgeons indicated there was no protocol in place at their institution.Conclusions:There continues to be wide variability among orthopedic surgeons with regard to management of patients with fracture on antiplatelet therapy. Over a quarter of surgeons continue to opt for surgical delay in patients with hip fracture. This survey highlights the need to formulate and better disseminate practice management guidelines for patients with fracture on antiplatelet therapy, particularly given the aging population in the United States.

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“…In this study, individuals who took clopidogrel for more than one year had an increased risk of fracture while patients who took the drug for less than one year had a lower risk of developing a fracture compared to those who had never taken the drug (Jorgensen et al, 2012a). The reason for the time-dependent differences in results is not yet known, but this large study demonstrates that P2Y 12 is likely an important mediator of normal bone maintenance.…”

Section: P2 Receptors and Bonementioning

confidence: 89%

Control of bone development by P2X and P2Y receptors expressed in mesenchymal and hematopoietic cells.

Lenertz

Baughman

Waldschmidt

et al. 2015

Gene

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Bone development and homeostasis require the interplay between several cell types, including mesenchymal osteoblasts and osteocytes, as well as hematopoietic osteoclasts. Recent evidence suggests that cell proliferation, differentiation and apoptosis of both mesenchymal and hematopoietic stem cells, which are fundamental for tissue regeneration and treatment of degenerative diseases, is controlled by P2 receptors (i.e., P2X and P2Y receptors). Both types of P2 receptors are versatile transducers of diverse signals activated by extracellular nucleotides like ATP that are released in response to tissue injury, infection or shear stress. The P2X family of receptors has been shown to mediate multiple signaling events including the influx of calcium, activation of mitogen activated protein kinases (MAPKs) and induction of AP-1 family members known to regulate bone development. Support for the significance of P2X7 in regulating bone development and homeostasis has been provided by several studies focusing on animal models and single nucleotide polymorphisms. P2 receptors are functionally expressed in both bone forming osteoblasts and bone resorbing osteoclasts, while recent findings also suggest that these receptors translate mechanical stimuli in osteocytes. Their ability to respond to external nucleotide analogs renders these cell surface proteins excellent targets for skeletal regenerative therapies. This overview summarizes mechanisms by which nucleotide receptors control skeletal cells and contribute to bone tissue development remodeling and repair.

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Clopidogrel and the risk of osteoporotic fractures: a nationwide cohort study

Cited by 33 publications

References 18 publications

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

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

Current Practices Regarding Perioperative Management of Patients With Fracture on Antiplatelet Therapy

Control of bone development by P2X and P2Y receptors expressed in mesenchymal and hematopoietic cells.

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