|Year : 2016 | Volume
| Issue : 2 | Page : 56-60
Topical erythropoietin as a novel preventive and therapeutic agent in bisphosphonate-related osteonecrosis of the jaw
Pantea Nazeman1, Maryam Rezai Rad1, Arash Khojasteh2
1 Dental Research Center, Research Institute of Dental Sciences, Dental School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Tissue Engineering, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
|Date of Web Publication||9-Jun-2016|
Department of Tissue Engineering, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Daneshjou Boulevard, Evin, P. O. 19839, Tehran
Source of Support: None, Conflict of Interest: None
Introduction: One of the most common side effects of bisphosphonate intake is osteonecrosis of the jaw (ONJ) which may develop following dentoalveolar interventions. Despite the vast available protocols, there is no clear guideline in the management of this condition. In osteonecrosis, the number and proliferation of bone-forming cells as well as vascularity are disturbed. Erythropoietin (EPO) is a hematopoietic hormone with angiogenic, osteogenic, and antiapoptotic properties. The Hypothesis: It is suggested to utilize poly lactic-co-glycolic acid hydrogel containing 1500-3000 IU/kg EPO following dentoalveolar surgery in samples receiving bisphosphonates as a preventive or therapeutic agent. Evaluation of the Hypothesis: Considering the pathophysiology of ONJ and therapeutic properties of EPO, it is assumed that EPO may be effective in treatment of ONJ. Furthermore, as a preventive measure, utilizing EPO following dentoalveolar surgery may be beneficial in the patients at risk of ONJ.
Keywords: Bisphosphonate, erythropoietin, osteonecrosis of the jaw
|How to cite this article:|
Nazeman P, Rad MR, Khojasteh A. Topical erythropoietin as a novel preventive and therapeutic agent in bisphosphonate-related osteonecrosis of the jaw. Dent Hypotheses 2016;7:56-60
|How to cite this URL:|
Nazeman P, Rad MR, Khojasteh A. Topical erythropoietin as a novel preventive and therapeutic agent in bisphosphonate-related osteonecrosis of the jaw. Dent Hypotheses [serial online] 2016 [cited 2020 Jan 22];7:56-60. Available from: http://www.dentalhypotheses.com/text.asp?2016/7/2/56/183767
| Introduction|| |
Bisphosphonates (BPs) are antiresorptive medications prescribed in diseases with underlying pathology in osteoblast-mediated bone deposition and osteoclast-mediated bone resorption such as osteoporosis.  It was estimated that by 2020, the population of osteoporotic patients will rise from 10 million to 14 million.  BPs were prescribed to 5.1 million patients older than 55 years in 2008 and seven out of 100 U.S. population had received a prescription for BP.  Fosamax (alendronate), a nitrogenated bisphosphonate, has been widely prescribed and it was known as the second best-selling product by Merck and Co.  Moreover, it was reported among the best-selling pharmaceutical products between 2002 and 2004.  BPs have demonstrated a high affinity to skeleton, mainly jaw bones.  Following dentoalveolar intervention, a decrease in pH occurs in bone which leads to accumulation of BPs in toxic concentrations.  Their mechanism of action relies on apoptosis in osteoclasts,  inhibiting bone remodeling, and exerting antiangiogenic effects  through decreasing vascular endothelial growth factor (VEGF) circulating levels. , A 10-year half-life is estimated in a single intravenous (IV) administration of alendronate. 
The Food and Drug Administration reports have demonstrated that osteonecrosis is among the most prevalent side effects of the BPs administration  and currently has become the most concerning complication.  Osteonecrosis is fundamentally known as a disturbance in the vascular supply. Disruption in angiogenesis is considered as one of the mechanisms underlying this condition. , American Association of Oral and Maxillofacial Surgeons defines osteonecrosis of the jaw (ONJ) as exposed jaw bone for more than 8 weeks with a history of antiresorptive treatment and lack of history of radiation therapy to the head and neck.  The first reports of ONJ were in 2003 and 2004 which presented 119 and 63 patients, respectively, who were receiving BP treatment. , The risk of ONJ development following tooth extraction is estimated 0.5% in oral BPs  and 1-10% in cancer patients receiving IV BPs.  Majority of ONJ cases were developed following dentoalveolar surgery ,,,, and several approaches including the delay in BP treatment after completion of dental treatments, , applying holiday periods,  or discontinuing BP treatments are recommended to avoid this condition. However, continuing the oncologic treatments is the principal treatment goal, and the patient's systemic condition may not permit implementing these approaches.  The common protocol for elimination of ONJ relies on pain control, antibiotic therapy, surgical removal of the necrotic segments, , and hyperbaric oxygen (HBO) as an adjuvant treatment.  The underlying axiom for recruitment of HBO includes the enhancement in VEGF levels and angiogenesis, ,, the inhibition of cell apoptosis  and increase in osteoblast differentiation.  Despite all these measures, some cases may be unresponsive to conservative treatments and surgical outcomes may be overshadowed by limited wound healing in the patients.  In addition, application of HBO is limited due to cost, availability, and controversies regarding its effectiveness.  Some novel treatment strategies such as platelet-rich plasma, , parathyroid hormone,  bone morphogenetic protein,  and stem cell therapy , have been studied in the management of this condition. However, despite all these measurements, there is no clear treatment guideline yet. 
Erythropoietin (EPO) is a pleiotropic cytokine  with well-established hematopoietic effects.  This hormone is routinely administered in the treatment of end-stage renal disease and anemia  and its angiogenic property is well established. ,
EPO has remarkable homology to VEGF. Hypoxia has been shown to stimulates EPO and VEGF by an analogous pathway. , It is demonstrated that increase in VEGF levels increases bone formation and vice versa. Hence, it is assumed that bone formation is coupled with angiogenesis during bone development. ,,
Studies have demonstrated that EPO enhances skin wound healing, , heart ischemia, ,, and acute lung injury.  Moreover, its angiogenic effect is mediated by increasing VEGF expression. , It is demonstrated that EPO protects proerythroblasts by antiapoptotic effects by virtue of activating JAK2/STA5 and subsequently increasing the level of Bcl-X L antiapoptotic gene.  The cardioprotective effects of EPO have been attributed to its angiogenic and antiapoptotic properties as well as reduction in inflammation.  Other than its angiogenic and antiapoptotic properties, some studies have suggested that EPO induces osteoblast proliferation and function and increases the number of osteoclasts. , Considering the underlying etiology for ONJ such as decreased levels of VEGF and number of bone forming cells, the authors assume that EPO with antiapoptotic and antiangiogenic properties may serve as an applicable agent in prevention or treatment of this condition.
| The Hypothesis|| |
Considering the dual pathophysiology of ONJ, an optimal treatment would be the one which enhances both angiogenesis and inhibits cell apoptosis. Given the angiogenic and osteogenic properties of EPO, we hypothesize that local application of EPO may be effective in prevention or treatment of ONJ.
| Evaluation of the Hypothesis|| |
As discussed previously, EPO has been widely studied in ischemic models. ,, Its healing effect has been shown to be correlated with angiogenic property, , increased oxygenation by EPO application  as well as its antiapoptotic effect.  The possible mechanism underlying its positive effects is shown in [Figure 1].  In addition to its significant role in management of ischemic conditions, it has been demonstrated that EPO enhances bone regeneration in bone defects, ,,, recruits stem cells to the defect site, , induces osteoblast proliferation and function, increases the number of osteoclasts , up to 60-80%, and also upregulates their activity.  However, there are conflicting results regarding its effect on osteoclast activity. ,,, As mentioned earlier, the axiom for utilization of HBO in treatment of ONJ relied on properties such as angiogenic, antiapoptotic, and cell differentiation enhancement, ,, which may seem similar to EPO properties, but the literature has failed to provide clear results regarding HBO treatment efficacy. Moreover, therapeutic application of EPO has been suggested in femoral head osteonecrosis,  and promising results are obtained by application in trauma or glucocorticoid-induced osteonecrosis in rat and rabbit models. , It is noteworthy that the underlying etiology for trauma or glucocorticoid-induced osteonecrosis is different from bisphosphonate-related ONJ, and this explains the reason that authors have highlighted the potential of this medication for management of this condition in the current paper. Besides, systemic administration of EPO is assumed to be accompanied with polycythemia and potential complications; ,,, hence, local application of EPO has been suggested to overcome this pitfall. ,
|Figure 1: Possible mechanism for angiogenic and antiapoptotic properties of erythropoietin. EPO: Erythropoietin, EPOR: Erythropoietin receptor, PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase; CASP: Caspase, GSK: Glycogen synthase kinase-3, AP-1: Activator protein-1, BCL-2: B-cell lymphoma 2. This figure is reprinted from a published paper by Gao D, Ning N, Niu X, Dang Y, Dong X, Wei J, et al. Erythropoietin treatment in patients with acute myocardial infarction: A meta-analysis of randomized controlled trials. Am Heart J 2012;164:715-27.e1. With permission granted from ELSEVIER publisher|
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It is planned to test the effect of poly lactic-co-glycolic acid (PLGA) hydrogel containing 1500-3000 IU/kg EPO following dentoalveolar surgery in samples receiving BPs. The following dosage ranges were calculated according to the literature on ischemic models. ,, The exact dosage is proportional to expected therapeutic outcomes and disease stage. Lower doses are considered for preventive and early disease stages, whereas higher doses are utilized for severe stages of ONJ. PLGA hydrogel was suggested as a carrier because its delivery to the defect has minimal invasion,  it is biocompatible, and its degradation rate is adjustable by monomer ratio.  We suggest adjusting the degradation time between 4 and 8 weeks according to the disease severity. Following time was estimated according to previous evidence regarding bone regeneration. ,, This study aims to assess whether this medication prevents development of ONJ and also its therapeutic efficacy will be assessed by application in ONJ models. It is noteworthy that hematocrite levels must be monitored to assure lack of systemic side effects following local application. Once the hypothesis is validated on animal samples, the clinical trial studies will be also performed. It is assumed that by virtue of this approach, prevention and early management of ONJ will decrease morbidity and related costs and consequences.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Paulo S, Abrantes AM, Laranjo M, Carvalho L, Serra A, Botelho MF, et al.
Bisphosphonate-related osteonecrosis of the jaw: Specificities. Oncol Rev 2014;8:254.
National Osteoporosis Foundation. America's Bone Health: The State of Osteoporosis and Low Bone Mass. Washington, DC, USA: National Osteoporosis Foundation; 2002.
Food and Drug Administration. Background Document for Meeting of Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee; September, 2011.
Carreyrou J. Fosamax drug could become next Merck woe. Wall Street Journal Eastern Edition April 12, 2006:B1.
Maggon K. Best-selling human medicines 2002-2004. Drug Discov Today 2005;10:739-42.
Drake MT, Clarke BL, Khosla S. Bisphosphonates: Mechanism of action and role in clinical practice. Mayo Clin Proc 2008;83:1032-45.
Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: Background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:433-41.
Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M, et al.
Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 2002;8:1080-4.
Wood J, Bonjean K, Ruetz S, Bellahcène A, Devy L, Foidart JM, et al.
Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302:1055-61.
Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK, McCloskey EV, et al.
Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 1997;12:1700-7.
Yildirim P, Ekmekci IO, Holzinger A. On knowledge discovery in open medical data on the example of the fda drug adverse event reporting system for alendronate (fosamax). Human-computer Interaction and Knowledge Discovery in Complex, Unstructured, Big Data. Berlin: Springer; 2013. p. 195-206.
Landesberg R, Woo V, Cremers S, Cozin M, Marolt D, Vunjak-Novakovic G, et al.
Potential pathophysiological mechanisms in osteonecrosis of the jaw. Ann N Y Acad Sci 2011;1218:62-79.
Allen MR, Burr DB. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: So many hypotheses, so few data. J Oral Maxillofac Surg 2009;67 5 Suppl:61-70.
Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65:369-76.
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34.
Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 2003;61:1115-7.
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al.
American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw - 2014 update. J Oral Maxillofac Surg 2014;72:1938-56.
Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al
. Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479-91.
Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, et al.
Incidence, risk factors, and outcomes of osteonecrosis of the jaw: Integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012;23:1341-7.
Yamazaki T, Yamori M, Ishizaki T, Asai K, Goto K, Takahashi K, et al.
Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: A cohort study. Int J Oral Maxillofac Surg 2012;41:1397-403.
Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99-102.
Hoff A, Toth B, Altundag K, Guarneri V, Adamus A, Nooka A, et al
., editors. Osteonecrosis of the Jaw in Patients Receiving Intravenous Bisphosphonate Therapy. ASCO Annual Meeting Proceedings; 2006.
Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, et al.
Osteonecrosis of the jaw in multiple myeloma patients: Clinical features and risk factors. J Clin Oncol 2006;24:945-52.
Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, et al.
Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 2009;20:117-20.
Ripamonti CI, Maniezzo M, Campa T, Fagnoni E, Brunelli C, Saibene G, et al.
Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 2009;20:137-45.
Damm DD, Jones DM. Bisphosphonate-related osteonecrosis of the jaws: A potential alternative to drug holidays. Gen Dent 2013;61:33-8.
Jacobson AS, Buchbinder D, Hu K, Urken ML. Paradigm shifts in the management of osteoradionecrosis of the mandible. Oral Oncol 2010;46:795-801.
Spanou A, Lyritis GP, Chronopoulos E, Tournis S. Management of bisphosphonate-related osteonecrosis of the jaw: A literature review. Oral Dis 2015;21:927-36.
Lyons A, Ghazali N. Osteoradionecrosis of the jaws: Current understanding of its pathophysiology and treatment. Br J Oral Maxillofac Surg 2008;46:653-60.
Fok TC, Jan A, Peel SA, Evans AW, Clokie CM, Sándor GK. Hyperbaric oxygen results in increased vascular endothelial growth factor (VEGF) protein expression in rabbit calvarial critical-sized defects. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:417-22.
Sheikh AY, Gibson JJ, Rollins MD, Hopf HW, Hussain Z, Hunt TK. Effect of hyperoxia on vascular endothelial growth factor levels in a wound model. Arch Surg 2000;135:1293-7.
Thom SR. Hyperbaric oxygen: Its mechanisms and efficacy. Plast Reconstr Surg 2011;127 Suppl 1:131S-41S.
Zhang Q, Chang Q, Cox RA, Gong X, Gould LJ. Hyperbaric oxygen attenuates apoptosis and decreases inflammation in an ischemic wound model. J Invest Dermatol 2008;128:2102-12.
Al Hadi H, Smerdon GR, Fox SW. Hyperbaric oxygen therapy accelerates osteoblast differentiation and promotes bone formation. J Dent 2015;43:382-8.
Cheriex KC, Nijhuis TH, Mureau MA. Osteoradionecrosis of the jaws: A review of conservative and surgical treatment options. J Reconstr Microsurg 2013;29:69-75.
Soydan SS, Uckan S. Management of bisphosphonate-related osteonecrosis of the jaw with a platelet-rich fibrin membrane: Technical report. J Oral Maxillofac Surg 2014;72:322-6.
Lee CY, David T, Nishime M. Use of platelet-rich plasma in the management of oral biphosphonate-associated osteonecrosis of the jaw: A report of 2 cases. J Oral Implantol 2007;33:371-82.
Bashutski JD, Eber RM, Kinney JS, Benavides E, Maitra S, Braun TM, et al.
Teriparatide and osseous regeneration in the oral cavity. N Engl J Med 2010;363:2396-405.
Gerard DA, Carlson ER, Gotcher JE, Pickett DO. Early inhibitory effects of zoledronic acid in tooth extraction sockets in dogs are negated by recombinant human bone morphogenetic protein. J Oral Maxillofac Surg 2014;72:61-6.
Kikuiri T, Kim I, Yamaza T, Akiyama K, Zhang Q, Li Y, et al.
Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice. J Bone Miner Res 2010;25:1668-79.
Cella L, Oppici A, Arbasi M, Moretto M, Piepoli M, Vallisa D, et al.
Autologous bone marrow stem cell intralesional transplantation repairing bisphosphonate related osteonecrosis of the jaw. Head Face Med 2011;7:16.
Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, et al.
Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 2004;305:239-42.
Bunn HF. Erythropoietin. Cold Spring Harb Perspect Med 2013;3:a011619.
Haroon ZA, Amin K, Jiang X, Arcasoy MO. A novel role for erythropoietin during fibrin-induced wound-healing response. Am J Pathol 2003;163:993-1000.
Hankenson KD, Dishowitz M, Gray C, Schenker M. Angiogenesis in bone regeneration. Injury 2011;42:556-61.
Goldberg MA, Dunning SP, Bunn HF. Regulation of the erythropoietin gene: Evidence that the oxygen sensor is a heme protein. Science 1988;242:1412-5.
Steinbrech DS, Mehrara BJ, Saadeh PB, Greenwald JA, Spector JA, Gittes GK, et al.
VEGF expression in an osteoblast-like cell line is regulated by a hypoxia response mechanism. Am J Physiol Cell Physiol 2000;278:C853-60.
Zelzer E, McLean W, Ng YS, Fukai N, Reginato AM, Lovejoy S, et al.
Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 2002;129:1893-904.
Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999;5:623-8.
Wu C, Giaccia AJ, Rankin EB. Osteoblasts: A novel source of erythropoietin. Curr Osteoporos Rep 2014;12:428-32.
Sorg H, Krueger C, Schulz T, Menger MD, Schmitz F, Vollmar B. Effects of erythropoietin in skin wound healing are dose related. FASEB J 2009;23:3049-58.
Sayan H, Ozacmak VH, Guven A, Aktas RG, Ozacmak ID. Erythropoietin stimulates wound healing and angiogenesis in mice. J Invest Surg 2006;19:163-73.
Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, et al.
Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A 2003;100:4802-6.
Kobayashi H, Minatoguchi S, Yasuda S, Bao N, Kawamura I, Iwasa M, et al.
Post-infarct treatment with an erythropoietin-gelatin hydrogel drug delivery system for cardiac repair. Cardiovasc Res 2008;79:611-20.
Weng S, Zhu X, Jin Y, Wang T, Huang H. Protective effect of erythropoietin on myocardial infarction in rats by inhibition of caspase-12 expression. Exp Ther Med 2011;2:833-836.
MacRedmond R, Singhera GK, Dorscheid DR. Erythropoietin inhibits respiratory epithelial cell apoptosis in a model of acute lung injury. Eur Respir J 2009;33:1403-14.
Galeano M, Altavilla D, Bitto A, Minutoli L, Calò M, Lo Cascio P, et al.
Recombinant human erythropoietin improves angiogenesis and wound healing in experimental burn wounds. Crit Care Med 2006;34:1139-46.
Holstein JH, Orth M, Scheuer C, Tami A, Becker SC, Garcia P, et al.
Erythropoietin stimulates bone formation, cell proliferation, and angiogenesis in a femoral segmental defect model in mice. Bone 2011;49:1037-45.
Chateauvieux S, Grigorakaki C, Morceau F, Dicato M, Diederich M. Erythropoietin, erythropoiesis and beyond. Biochem Pharmacol 2011;82:1291-303.
Shiozawa Y, Jung Y, Ziegler AM, Pedersen EA, Wang J, Wang Z, et al.
Erythropoietin couples hematopoiesis with bone formation. PLoS One 2010;5:e10853.
Sun H, Jung Y, Shiozawa Y, Taichman RS, Krebsbach PH. Erythropoietin modulates the structure of bone morphogenetic protein 2-engineered cranial bone. Tissue Eng Part A 2012;18:2095-105.
Buemi M, Galeano M, Sturiale A, Ientile R, Crisafulli C, Parisi A, et al.
Recombinant human erythropoietin stimulates angiogenesis and healing of ischemic skin wounds. Shock 2004;22:169-73.
Gao D, Ning N, Niu X, Dang Y, Dong X, Wei J, et al.
Erythropoietin treatment in patients with acute myocardial infarction: A meta-analysis of randomized controlled trials. Am Heart J 2012;164:715-27.e1.
Mihmanli A, Dolanmaz D, Avunduk MC, Erdemli E. Effects of recombinant human erythropoietin on mandibular distraction osteogenesis. J Oral Maxillofac Surg 2009;67:2337-43.
Li C, Ding J, Jiang L, Shi C, Ni S, Jin H, et al.
Potential of mesenchymal stem cells by adenovirus-mediated erythropoietin gene therapy approaches for bone defect. Cell Biochem Biophys 2014;70:1199-204.
Rölfing JH, Bendtsen M, Jensen J, Stiehler M, Foldager CB, Hellfritzsch MB, et al.
Erythropoietin augments bone formation in a rabbit posterolateral spinal fusion model. J Orthop Res 2012;30:1083-8.
Nair AM, Tsai YT, Shah KM, Shen J, Weng H, Zhou J, et al.
The effect of erythropoietin on autologous stem cell-mediated bone regeneration. Biomaterials 2013;34:7364-71.
Li J, Guo W, Xiong M, Han H, Chen J, Mao D, et al.
Effect of SDF-1/CXCR4 axis on the migration of transplanted bone mesenchymal stem cells mobilized by erythropoietin toward lesion sites following spinal cord injury. Int J Mol Med 2015;36:1205-14.
Hiram-Bab S, Liron T, Deshet-Unger N, Mittelman M, Gassmann M, Rauner M, et al.
Erythropoietin directly stimulates osteoclast precursors and induces bone loss. FASEB J 2015;29:1890-900.
Li C, Shi C, Kim J, Chen Y, Ni S, Jiang L, et al.
Erythropoietin promotes bone formation through EphrinB2/EphB4 signaling. J Dent Res 2015;94:455-63.
Bakhshi H, Rasouli MR, Parvizi J. Can local erythropoietin administration enhance bone regeneration in osteonecrosis of femoral head? Med Hypotheses 2012;79:154-6.
Ghoraishian M, Ghanavi J, Ahadi M, Shahi A. Effects of erythropoietin and GCSF on traumatic osteonecrosis of the femoral head in rabbits. JBS J 2015;2:99-106.
Chen S, Li J, Peng H, Zhou J, Fang H. Administration of erythropoietin exerts protective effects against glucocorticoid-induced osteonecrosis of the femoral head in rats. Int J Mol Med 2014;33:840-8.
Holstein JH, Menger MD, Scheuer C, Meier C, Culemann U, Wirbel RJ, et al.
Erythropoietin (EPO): EPO-receptor signaling improves early endochondral ossification and mechanical strength in fracture healing. Life Sci 2007;80:893-900.
Rölfing JH, Jensen J, Jensen JN, Greve AS, Lysdahl H, Chen M, et al.
A single topical dose of erythropoietin applied on a collagen carrier enhances calvarial bone healing in pigs. Acta Orthop 2014;85:201-9.
Chen F, Liu Q, Zhang ZD, Zhu XH. Co-delivery of G-CSF and EPO released from fibrin gel for therapeutic neovascularization in rat hindlimb ischemia model. Microcirculation 2013;20:416-24.
Klopsch C, Furlani D, Gäbel R, Li W, Pittermann E, Ugurlucan M, et al.
Intracardiac injection of erythropoietin induces stem cell recruitment and improves cardiac functions in a rat myocardial infarction model. J Cell Mol Med 2009;13:664-79.
Drury JL, Mooney DJ. Hydrogels for tissue engineering: Scaffold design variables and applications. Biomaterials 2003;24:4337-51.
Kapoor DN, Bhatia A, Kaur R, Sharma R, Kaur G, Dhawan S. PLGA: A unique polymer for drug delivery. Ther Deliv 2015;6:41-58.
Levi B, James AW, Nelson ER, Vistnes D, Wu B, Lee M, et al.
Human adipose derived stromal cells heal critical size mouse calvarial defects. PLoS One 2010;5:e11177.
Patel JJ. Single and Dual Growth Factor Delivery from Poly-å-caprolactone Scaffolds for Pre-Fabricated Bone Flap Engineering: Doctoral dissertation, University of Michigan; 2015.