|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 2019 Dec 12];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.
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