1. Introduction
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe adverse reaction of bisphosphonates (BPs) treatment; it is a relative rare but potentially serious, painful, and debilitating complication that can significantly affect the quality of life of cancer patients [ 1 , 2 ].
The optimal treatment of BRONJ remains controversial; but the main objectives in the treatment are to control infection, to slow the disease's progression, and to promote tissue healing [ 1 – 4 ].
The BRONJ treatments are classified into surgical and non-surgical options. The non-surgical treatments include the use of systemic antibiotic therapy and oral antiseptic rinses, variably combined with hyperbaric oxygen therapy, low-level laser therapy, and medical ozone applications [ 5 – 9 ]. The surgical treatments proposed in the literature are divided into conservative approaches such as bone debridement, sequestrectomy, or more aggressive therapies such as resections of affected bone and jawbone reconstruction, if indicated [ 4 , 10 – 12 ].
In the past, the surgical treatments were reserved only for advanced stages of BRONJ; the Italian Society of Oral and Maxillofacial Surgery (SICMF) and the Italian Society of Oral Pathology and Medicine (SIPMO) in 2012 recommended conservative surgery in lesions belonging to stages I and II, as defined by both societies, that can provide resolution of acute infection and offers long-term of well-being for patients [ 10 , 11 , 13 – 17 ].
A few clinical studies utilizing Er,Cr:YSGG laser-assisted conservative surgery have showed promising results in BRONJ treatment [ 6 , 10 , 15 , 18 ].
Utilizing the Er,Cr:YSGG laser, during the necrotic tissue removal, eliminates thermal effect in cutting areas and surrounding tissues and provides antibacterial and biostimulative effects to reduce post-operative pain and promotes the tissue healing. The laser acts through a cutting effect in a “contact free” way and avoids any friction, which normally delays the healing's process and causes the thermal and mechanical trauma. It applies microfractures and microexplosions to remove the mineralized tissue and vaporize water to allow the rapid removal of the tissue layers that saves bone surface from any contaminations. The Er,Cr:YSGG laser, in particular, owns all these features, allowing a complete healing for both soft and hard tissues [ 19 – 23 ].
Autologous platelet concentrates, such as platelet-rich plasma (PRP), are increasingly applied as a new approach to regenerate tissues in oral surgery as they release high quantities of growth factors, including platelet-derived growth factor (PDGF), vascular endothelial growth factors (VEGF), and transforming growth factor-b (TGF-b) [ 24 – 27 ]. PDGF plays a role in healing hard and soft tissues by stimulating mitogenesis, chemotaxis, and producing fibronectin. High VEGF in wound sockets improves the formation of bone matrix and stimulates the neoangiogenesis. TGF-b stimulates the fibroblast chemotaxis and produces fibronectin and collagen to repair connective tissues and regenerate bones [ 28 – 30 ]. Indeed, PRP accelerates epithelial wound healing, decreases tissue inflammation, improves the regeneration of bone and soft tissues, and promotes tissue vascularization. Considering these benefits, PRP would be effective in BRONJ patients in the way that releases growth factors and stimulates the bone healing and neoangiogenesis, which is usually suppressed by BPs [ 26 , 31 – 37 ]. Moreover, PRP as an autologous product possesses biocompatibility and safety.
This study aimed to evaluate the effect on clinical healing of a combined treatment consisting of laser-assisted surgery and PRP in cancer patients affected by BRONJ.
2. Patients and Methods
2.1. Study Design
We performed a prospective cohort study on consecutive cancer patients followed at the Unit of Oral Medicine of the University Hospital “P. Giaccone” of Palermo. The Institutional Local Ethics Committee of the University Hospital “P. Giaccone” of Palermo approved the study in 2015.
Technical and surgical procedures were done in accordance with the Declaration of Helsinki revised in 2000. ( Table 1 ). All participants signed the informed consent.
2.2. Entry and Exclusion Criteria
BRONJ was defined as exposed or non-exposed osteonecrosis of the mandible or maxilla [ 2 ]. Patients were eligible for the study if they had (1) age ≥ 18 years; (2) cancer; (3) treatment with BPs because of the underlying cancer. Patients were excluded from the study if they had (1): previous history of irradiation to the maxillofacial area; (2) neoplastic involvement of the jaws; (3) previous surgical treatment to the jaws; (4) poor general conditions.
We diagnosed BRONJ in all cases through a clinical-radiological approach combining clinical examination and Computed Tomography (CT) of the affected jaws. A radiologist with experience and a special interest in head and neck imaging assessed and reported CT scan, while the local clinical team was in charge of the final diagnosis.
2.3. Clinical Examination
At first visit, we collected the clinical, drug, and dental history of patients, which consisted of the following: (1) age; (2) sex; (3) reason for BPs usage; (4) BPs type; (5) duration of BPs treatment; (6) cumulative dose of BPs; (7) concurrent use of steroids; (8) history of chemotherapy; (9) concurrent use of antiangiogenics; (10) concomitant diseases; (11) risk factors for BRONJ (e.g. history of diabetes); (12) clinical features of BRONJ; and (13) patients' habits (e.g. smoking and oral hygiene). We classified lesions following SICMF-SIPMO clinical and radiological staging system of BRONJ [ 2 , 5 ].
2.4. Surgical Treatment
All patients underwent perioperative pharmacological treatment based on the administration of ampicillin and sulbactam (pre-operative regimens: 1g i.m. 2xdaily starting 1 day pre-operatively; post-operative regimens: 1g i.m. 2xdaily for 7 days) and metronidazole (pre-operative regimens: 500 mg per os 3xdaily starting 1 day pre-operatively; post-operative regimens: 500 mg per os 3xdaily for 7 days). The use of antiseptic (chlorhexidine 0,2% mouthwashes 30 ml swished up to 60 seconds, 3x daily 7 days pre-operatively and 15 days post-operatively) and sodium-hyaluronate (local application 3x daily 10 days post-operatively) was also prescribed ( Table 2 ); autologous PRP (Plateltex ACT System, Biomed, Modena, IT) and surgical therapy were then prepared. To prepare the PRP and to induce its gelation, the materials provided by the manufacturer were used and the provided instructions followed [ 38 ].
All surgical procedures were performed under local anesthesia using 3% mepivacaine hydrochloride without adrenaline.
The surgical protocol consisted of elevation of a full-thickness mucoperiosteal flap to expose the surgical area; bony curettage (debridement) and sequestrectomy of the necrotic bone, whether required, using a Er,Cr:YSGG laser (Waterlase MD, Biolase Technology, San Clemente, CA, USA); application of autologous PRP; tension-free soft tissue closure ( Figure 1 ).
The Er,Cr:YSGG laser permits photons with wavelength of 2.78 μ m and a pulsed duration of 140-200 microseconds with a repetition rate of 20 Hz. The laser device uses a pulsed energy source; a sapphire MS75 tip (Biolase, Inc.) with a length of 6 mm and diameter of 750 μ m was used with an 80% water and 40% air spray during irradiation. The sapphire tip was positioned 1 to 2 mm from the target tissue and was kept perpendicular to the irradiated bone surface. The power output of the laser can be varied from 0 to 6 W, while the beam spot size at the tip was 1.26·10 3 mm 2 .
2.5. Follow-Up
We scheduled follow-up visits to remove the suture seven days after surgery and visited patients on the fifteenth day, and the visits were continued on months one, three, six, and twelve (Figures 2 - 3 ).
We performed Computer Tomography (CT) scans for all patients preoperatively and at the 12-month follow-up (T 1 ) to restage the disease.
2.6. Main Outcome
We defined successful treatment as the absence of clinical and radiological signs of BRONJ relapse (healing) or, in turn, the transition from a higher stage to a lower one (improvement).
2.7. Statistical Analysis
Statistical units are the patients who satisfy the inclusion criteria of the study. Descriptive statistic was carried out. We summarized continuous variables with means and standard deviations and computed categorical variables frequencies distributions. We analyzed qualitative variables, staging and bone status, and compared them at baseline (T0) and after the treatment (T1). We applied the Wilcoxon signed-rank test with continuity correction for BRONJ staging. We analyzed all data using R software version 3.3.2. A p-value less than 0.05 was considered statistically significant.
3. Results
3.1. Patients' Features
During the study period, ten cancer patients completed the protocol and were available for the analysis. They were mostly females (70%), with a mean age 75,2 ± 5,94 years. Multiple myeloma was the most common diagnosis (40%), followed by breast (30%) and prostate cancer (30%).
All patients but one had been on monthly infusions of zoledronic acid (mean duration: 31,8 ± 25,76 months); this latter was shifted from zoledronic acid to ibandronic acid during treatment. Two patients (20%) were on systemic corticosteroid therapy and five had been exposed to chemotherapy; only one patient received both steroids and chemotherapy ( Table 3 ).
Mandible was the most frequent site of BRONJ (90%). Eight patients showed frank bone exposure at the first visit (80%), while 20% did not and were classified as non-exposed BRONJ cases, based on the presence of oral pain and radiological signs of bone necrosis.
At baseline (T 0 ), six patients were classified in stage IB (60%), two in stage IIA (20%), and the remaining two in stage IIB (20%) ( Table 3 ), according to the SICMF-SIPMO clinical and radiological staging system of BRONJ [ 2 ].
3.2. Main Outcome
The wound healing was completed at the time of suture removal in 30% of patients. At the latest follow-up period (T 1 ), we observed a clinical improvement in 80% of patients after surgical therapy that was confirmed by Wilcoxon test (p-value = 0.01187). In particular, six patients showed non-exposed bone (60%). Among them, three (30%) had no clinical and radiological signs of BRONJ (complete healing). Five patients showed a clinical improvement of symptoms (50%), while 2 did not show clinical improvement (20%). These latter had been preoperatively classified in stage IIA. Overall, at T 1 four patients were in stage IA (40%) and three patients in IIA (30%). Results are shown in Table 4 .
4. Discussion
We succeeded to manage BRONJ patients performing the conservative surgery treatment through Er,Cr:YSGG laser combined PRP, both able to enhance the bone and mucosal healing, with a successful outcome of 80% (30% patients with no clinical and radiological signs of BRONJ relapse and 50% with clinical improvement).
The use of laser technology for BRONJ treatment and its beneficial effects on tissue healing has been widely investigated in the last years. Many authors suggested the combination of low-level laser therapy (LLLT) with traditional surgical approach, to biostimulate the tissues healing [ 6 , 39 – 41 ].
The use of Er,Cr:YSGG laser has a great potential in the hard tissues surgery; indeed Er,Cr:YSGG laser enables efficient resection of the maxilla without using conventional rotary instruments, as the laser produces a clear and precise cut with minimal injury to contiguous hard and soft tissues [ 6 , 20 , 23 , 42 , 43 ].
This device showed good results in conservative surgery approach of BRONJ treatment in different stages. Vescovi et al. reported several studies regarding the use of Er:YAG laser to treat BRONJ lesions, showing that Er:YAG seems to represent a high percentage of success, with significantly better results compared with the traditional surgical approaches [ 15 , 39 , 44 , 45 ].
Many authors suggested the application of PRP to improve postsurgical wound healing. PRP gel stimulates the release of growth factors and promotes angiogenesis and bone and mucosal healing. In addition, PRP is autologous, biocompatible, and safe product [ 24 – 27 , 29 ].
The properties of autologous platelet concentrates appear particularly useful in BRONJ surgical therapy, as the lack of vascularization represents one of the major factors on pathogenesis of BRONJ.
Coviello et al. reported a case series with seven patients taking BPs and affected by BRONJ referable to tooth extraction. They treated four of BRONJ patients by standard surgical debridement and sequestrectomy, while applying supplementary autologous PRP in the three. The authors observed wound healing's improvement and bone exposure reduction in the PRP group [ 46 ].
Martins et al. also studied the association of laser phototherapy (LPT) and PRP on healing outcome of BRONJ in cancer patients. These authors retrospectively compared the effects on wound healing of this protocol with a non-surgical (pharmacological therapy) and a surgical (pharmacological plus surgical therapy) one. They obtained higher rates of success, in terms of mucosal wound healing, in patients surgically treated with the LPT plus PRP protocol [ 47 ].
Longo et al. also achieved good results by studying the therapeutic effects in surgery therapy associated with PRP to promote BRONJ wounds healing [ 48 ]; performing a comparison with a surgical approach without PRP. They present higher success rate among patients treated with PRP (PRP group 93% of complete response versus control group 53% of complete response).
Lately, Kim et al. reported the application of leucocyte-rich and platelet-rich fibrin (L-PRF) in the treatment of BRONJ, with a complete resolution in 77% of cases treated and a delayed resolution in 18% of cases [ 49 ]. Comparing these results with ours, the success percentages are almost similar.
Notably, Mozzati et al. described the treatment of 32 BRONJ cases all belonging to stage IIB with the application of plasma rich in growth factors (PRGF) and reported a success rate of 100% with only temporary postoperative complications[ 24 ]. In 2017, also Maluf et al. reported two cases of medication related ONJ (classifiable as stage II) completely healed after a surgical treatment combined with the application of L-PRF[ 50 ].
Del Fabbro et al., in their systematic review, illustrated the data about fourteen studies published between 2007 and 2014; the BRONJ surgical treatment with an adjunct autologous platelet concentrates showed a satisfactory healing in 91,6% of the cases [ 36 ]. All these data are in agreement with our results in the treatment of BRONJ stage IIB.
Our study's limitations include the limited sample size and the presence of confounding factors, such as applied comedications (e.g. corticosteroids and/or different chemotherapy) in some patients. Indeed, these drugs could inhibit cell proliferation and with an antiangiogenic action could suppress vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) [ 51 – 53 ].
5. Conclusion
Despite progress in the prevention of BRONJ, a specific treatment protocol to manage BRONJ is still missing.
Surgical removal of the necrotic bone should be performed with the Er,Cr:YSGG laser, that possesses remarkable properties with antibacterial and biostimulative effects, reduce postoperative pain and promote the tissue healing. Additionaly, PRP is an autologous product, biocompatible, easy to handle, and rich in growth factors and ameliorates the tissues healing in residual postsurgical wounds.
More prospective studies are needed to confirm this statement with a larger patients' sample. Considering the limitation of the present study, we could show that conservative surgical approach with Er,Cr:YSGG laser combined PRP benefits the management of early stages' BRONJ in cancer patients.
Acknowledgments
The authors want to thank Professor Antonio Lo Casto for his active radiological assistance during the study.
Ethical Approval
All procedures performed in this study that involved human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Consent
All participants included in this study signed the informed consent.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
1 Ruggiero S. L. Dodson T. B. Fantasia J. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw—2014 update Journal of Oral and Maxillofacial Surgery 2014 72 10 1938 1956 10.1016/j.joms.2014.04.031 25234529
2 Campisi G. Fedele S. Fusco V. Pizzo G. Di Fede O. Bedogni A. Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents Future Oncology 2014 10 2 257 275 2-s2.0-84893820808 10.2217/fon.13.211 24490612
3 Rollason V. Laverrière A. Macdonald L. C. I. Walsh T. Tramèr M. R. Vogt-Ferrier N. B. Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) Cochrane Database of Systematic Reviews 2016 2016 2 1 35 CD008455 10.1002/14651858.CD008455.pub2 2-s2.0-84961966645 PMC7173706 26919630
4 Beth-Tasdogan N. H. Mayer B. Hussein H. Zolk O. Interventions for managing medication- related osteonecrosis of the jaw The Cochrane Database of Systematic Reviews 2017 D012432 10.1002/14651858.CD012432.pub2 PMC6485859 28983908
5 Ramaglia L. Guida A. Iorio-Siciliano V. Cuozzo A. Blasi A. Sculean A. Stage-specific therapeutic strategies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol Clinical Oral Investigations 2018 22 2 597 615 10.1007/s00784-017-2325-6 29332231
6 Weber J. B. B. Camilotti R. S. Ponte M. E. Efficacy of laser therapy in the management of bisphosphonate-related osteonecrosis of the jaw (BRONJ): a systematic review Lasers in Medical Science 2016 31 6 1261 1272 2-s2.0-84962250977 10.1007/s10103-016-1929-4 27025860
7 Ripamonti C. I. Cislaghi E. Mariani L. Maniezzo M. Efficacy and safety of medical ozone (O 3 ) delivered in oil suspension applications for the treatment of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: preliminary results of a phase I-II study Oral Oncology 2011 47 3 185 190 10.1016/j.oraloncology.2011.01.002 2-s2.0-79952281080 21310650
8 Zandi M. Dehghan A. Mohammadi-Mofrad A. Amini P. Vahdatinia F. Short-term perioperative teriparatide therapy for the prevention of medication-related osteonecrosis of the jaw: A randomized, controlled preclinical study in rats Journal of Cranio-Maxillo-Facial Surgery 2017 45 2 275 280 2-s2.0-85009216272 10.1016/j.jcms.2016.12.010 28087282
9 Momesso G. A. C. de Souza Batista F. R. de Sousa C. A. Successful use of lower-level laser therapy in the treatment of medication-related osteonecrosis of the jaw Journal of Lasers in Medical Sciences 2017 8 4 201 203 2-s2.0-85030118882 10.15171/jlms.2017.37 29071028 PMC5642170
10 Vescovi P. Merigo E. Meleti M. etal. Conservative surgical management of stage i bisphosphonate-related osteonecrosis of the jaw International Journal of Dentistry 2014 2014 10.1155/2014/107690 PMC3933473 24648841
11 Nisi M. La Ferla F. Karapetsa D. Conservative surgical management of patients with bisphosphonate-related osteonecrosis of the jaws: a series of 120 patients British Journal of Oral and Maxillofacial Surgery 2016 54 8 930 935 10.1016/j.bjoms.2016.06.015 2-s2.0-84994336851 27418080
12 Bedogni A. Saia G. Bettini G. Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis Oral Oncology 2011 47 5 420 424 2-s2.0-79956202286 10.1016/j.oraloncology.2011.02.024 21439892
13 Bedogni A. Campisi G. Fusco V. Agrillo A. Raccomandazioni clinico-terapeutiche sull′osteonecrosi delle ossa mascellari associata a bisfosfonati e sua prevenzione SICMF-SIPMO 2013
14 Graziani F. Vescovi P. Campisi G. Resective surgical approach shows a high performance in the management of advanced cases of bisphosphonate-related osteonecrosis of the jaws: A retrospective survey of 347 cases Journal of Oral and Maxillofacial Surgery 2012 70 11 2501 2507 2-s2.0-84867571111 10.1016/j.joms.2012.05.019 22883322
15 Vescovi P. Manfredi M. Merigo E. Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT) Lasers in Medical Science 2010 25 1 101 113 10.1007/s10103-009-0687-y 2-s2.0-72349097564 19543768
16 Kim H. Y. Lee S.-J. Kim S. M. Extensive Surgical Procedures Result in Better Treatment Outcomes for Bisphosphonate-Related Osteonecrosis of the Jaw in Patients With Osteoporosis Journal of Oral and Maxillofacial Surgery 2017 75 7 1404 1413 2-s2.0-85011095628 10.1016/j.joms.2016.12.014 28039736
17 Eguchi T. Kanai I. Basugi A. Miyata Y. Inoue M. Hamada Y. The assessment of surgical and non-surgical treatment of stage II medication-related osteonecrosis of the jaw Medicina Oral Patología Oral y Cirugia Bucal 2017 22 6 e788 e795 10.4317/medoral.22013 PMC5813999 29053660
18 Atalay B. Yalcin S. Emes Y. Bisphosphonate-related osteonecrosis: Laser-assisted surgical treatment or conventional surgery? Lasers in Medical Science 2011 26 6 815 823 2-s2.0-83255185211 10.1007/s10103-011-0974-2 21809068
19 Hafner S. Ehrenfeld M. Storz E. Wieser A. Photodynamic Inactivation of Actinomyces naeslundii in Comparison with Chlorhexidine and Polyhexanide - A New Approach for Antiseptic Treatment of Medication-Related Osteonecrosis of the Jaw? Journal of Oral and Maxillofacial Surgery 2016 74 3 516 522 2-s2.0-84958747096 10.1016/j.joms.2015.09.014 26450798
20 Noba C. Mello-Moura A. C. Gimenez T. Tedesco T. K. Moura-Netto C. Laser for bone healing after oral surgery: systematic review Lasers in Medical Science 2018 33 3 667 674 10.1007/s10103-017-2400-x 29196831
21 Rupel K. Ottaviani G. Gobbo M. A systematic review of therapeutical approaches in bisphosphonates-related osteonecrosis of the jaw (BRONJ) Oral Oncology 2014 50 11 1049 1057 2-s2.0-84922815291 10.1016/j.oraloncology.2014.08.016 25240948
22 Zeitouni J. Clough B. Zeitouni S. Saleem M. Al Aisami K. Gregory C. The effects of the Er:YAG laser on trabecular bone micro-architecture: Comparison with conventional dental drilling by micro-computed tomographic and histological techniques F1000Research 2017 6 p. 1133 10.12688/f1000research.12018.1 PMC5782408 29416849
23 Baek K. Deibel W. Marinov D. A comparative investigation of bone surface after cutting with mechanical tools and Er:YAG laser Lasers in Surgery and Medicine 2015 47 5 426 432 10.1002/lsm.22352 25945815
24 Del Fabbro M. Bucchi C. Lolato A. Corbella S. Testori T. Taschieri S. Healing of Postextraction Sockets Preserved With Autologous Platelet Concentrates. A Systematic Review and Meta-Analysis Journal of Oral and Maxillofacial Surgery 2017 75 8 1601 1615 2-s2.0-85015981135 10.1016/j.joms.2017.02.009 28288724
25 Marcazzan S. Taschieri S. Weinstein R. L. Del Fabbro M. Efficacy of platelet concentrates in bone healing: A systematic review on animal studies – Part B: Large-size animal models Platelets 2018 29 4 338 346 10.1080/09537104.2017.1384537 29206070
26 Etulain J. Platelets in wound healing and regenerative medicine Platelets 2018 1 13 10.1080/09537104.2018.1430357 29442539
27 Albanese A. Licata M. E. Polizzi B. Campisi G. Platelet-rich plasma (PRP) in dental and oral surgery: from the wound healing to bone regeneration Immunity & Ageing 2013 10 1, article 23 10.1186/1742-4933-10-23 2-s2.0-84878814656 PMC3683340 23763951
28 Dohan Ehrenfest D. M. Bielecki T. Jimbo R. Do the fibrin architecture and leukocyte content influence the growth factor release of platelet concentrates? An evidence-based answer comparing a pure Platelet-Rich Plasma (P-PRP) gel and a leukocyte- and Platelet-Rich Fibrin (L-PRF) Current Pharmaceutical Biotechnology 2012 13 7 1145 1152 10.2174/138920112800624382 2-s2.0-84861155987 21740377
29 Griffin X. L. Wallace D. Parsons N. Costa M. L. Platelet rich therapies for long bone healing in adults Cochrane Database of Systematic Reviews 2012 7 CD009496 2-s2.0-84866456609 10.1002/14651858.CD009496.pub2 PMC11927760 22786528
30 Dohan Ehrenfest D. M. Rasmusson L. Albrektsson T. Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF) Trends in Biotechnology 2009 27 3 158 167 2-s2.0-60349120413 10.1016/j.tibtech.2008.11.009 19187989
31 Passaretti F. Tia M. D'esposito V. Growth-promoting action and growth factor release by different platelet derivatives Platelets 2014 25 4 252 256 2-s2.0-84899956672 10.3109/09537104.2013.809060 23855408
32 Tong S. Yin J. Liu J. Platelet-rich plasma has beneficial effects in mice with osteonecrosis of the femoral head by promoting angiogenesis Experimental and Therapeutic Medicine 2017 15 2 1781 1788 10.3892/etm.2017.5655 29434765 PMC5776555
33 Prataap N. Sunil P. Sudeep C. Ninan V. Tom A. Arjun M. Platelet-rich plasma and incidence of alveolar osteitis in high-risk patients undergoing extractions of mandibular molars: A case–control study Journal of Pharmacy and Bioallied Sciences 2017 9 5 p. 173 10.4103/jpbs.JPBS_151_17 PMC5731008 29284959
34 Mozzati M. Gallesio G. Arata V. Pol R. Scoletta M. Platelet-rich therapies in the treatment of intravenous bisphosphonate-related osteonecrosis of the jaw: A report of 32 cases Oral Oncology 2012 48 5 469 474 2-s2.0-84859937627 10.1016/j.oraloncology.2011.12.004 22265335
35 Scoletta M. Arata V. Arduino P. G. Tooth extractions in intravenous bisphosphonate-treated patients: A refined protocol Journal of Oral and Maxillofacial Surgery 2013 71 6 994 999 2-s2.0-84878108804 10.1016/j.joms.2013.01.006 23434159
36 Del Fabbro M. Gallesio G. Mozzati M. Autologous platelet concentrates for bisphosphonate-related osteonecrosis of the jaw treatment and prevention. A systematic review of the literature European Journal of Cancer 2015 51 1 62 74 2-s2.0-84925411684 10.1016/j.ejca.2014.10.015 25466505
37 Fornaini C. Cella L. Oppici A. Laser and Platelet-Rich Plasma to treat Medication-Related Osteonecrosis of the Jaws (MRONJ): a case report Laser Therapy 2017 26 3 223 227 10.5978/islsm.17-CR-04 29133970 PMC5675913
38 Mazzucco L. Balbo V. Cattana E. Borzini P. Platelet-rich plasma and platelet gel preparation using Plateltex® Vox Sanguinis 2008 94 3 202 208 2-s2.0-40749125699 10.1111/j.1423-0410.2007.01027.x 18179680
39 Ghidini G. Manfredi M. Giovannacci I. etal. Medication-related osteonecrosis of the jaw: risk factors in patients under biphosphonate versus patients under antiresorptive-antiangiogenic drugs Minerva Stomatol 2017 66 4 135 140 28497661 10.23736/S0026-4970.17.04056-0
40 Momesso G. A. de Souza Batista F. R. de Sousa C. A. Successful Use of Lower-Level Laser Therapy in the Treatment of Medication-Related Osteonecrosis of the Jaw Journal of Lasers in Medical Sciences 2017 8 4 201 203 10.15171/jlms.2017.37 29071028 PMC5642170
41 Latifyan S. Genot M. T. Klastersky J. Bisphosphonate-related osteonecrosis of the jaw: a review of the potential efficacy of low-level laser therapy Supportive Care in Cancer 2016 24 9 3687 3693 10.1007/s00520-016-3139-9 27029476
42 Panduric D. G. Juric I. B. Music S. Molčanov K. Sušic M. Anic I. Morphological and ultrastructural comparative analysis of bone tissue after Er:YAG laser and surgical drill osteotomy Photomedicine and Laser Surgery 2014 32 7 401 408 2-s2.0-84903937692 10.1089/pho.2014.3711 24992274
43 Esteves J. C. De Souza Faloni A. P. Macedo P. D. Effects on bone repair of osteotomy with drills or with erbium, chromium: Yttrium-scandium-gallium-garnet laser: Histomorphometric and immunohistochemical study Journal of Periodontology 2016 87 4 452 460 2-s2.0-84964330414 10.1902/jop.2015.150406 26693695
44 Vescovi P. Giovannacci I. Otto S. Medication-related osteonecrosis of the jaw: an autofluorescence-guided surgical approach performed with Er:YAG laser Photomedicine and Laser Surgery 2015 33 8 437 442 10.1089/pho.2015.3927 2-s2.0-84938362459 26226174
45 Giovannacci I. Meleti M. Corradi D. Vescovi P. Clinical Differences in Autofluorescence Between Viable and Nonvital Bone: A Case Report With Histopathologic Evaluation Performed on Medication-Related Osteonecrosis of the Jaws Journal of Oral and Maxillofacial Surgery 2017 75 6 1216 1222 2-s2.0-85011003441 10.1016/j.joms.2016.12.011 28061356
46 Coviello V. Peluso F. Dehkhargani S. Z. etal. Platelet-rich plasma improves wound healing in multiple myeloma bisphosphonate-associated osteonecrosis of the jaw patients Journal of BIOLOGICAL REGULATORS & Homeostatic Agents 2018 26 1 151 155 http://www.ncbi.nlm.nih.gov/pubmed/22475108 22475108
47 Martins M. A. T. Martins M. D. Lascala C. A. Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: A preliminary study Oral Oncology 2012 48 1 79 84 2-s2.0-84855901323 10.1016/j.oraloncology.2011.08.010 21940198
48 Longo F. Guida A. Aversa C. Platelet Rich Plasma in the Treatment of Bisphosphonate-Related Osteonecrosis of the Jaw: Personal Experience and Review of the Literature International Journal of Dentistry 2014 2014 7 10.1155/2014/298945 298945 PMC4071853 25013411
49 Kim J.-W. Kim S.-J. Kim M.-R. Leucocyte-rich and platelet-rich fibrin for the treatment of bisphosphonate-related osteonecrosis of the jaw: A Prospective Feasibility Study British Journal of Oral and Maxillofacial Surgery 2014 52 9 854 859 10.1016/j.bjoms.2014.07.256 2-s2.0-84908227739 25138613
50 Maluf G. Caldas R. J. Silva Santos P. S. Use of Leukocyte- and Platelet-Rich Fibrin in the Treatment of Medication-Related Osteonecrosis of the Jaws Journal of Oral and Maxillofacial Surgery 2017 76 1 88 96 2-s2.0-85025633625 10.1016/j.joms.2017.06.004 28675810
51 Soundia A. Hadaya D. Esfandi N. Zoledronate Impairs Socket Healing after Extraction of Teeth with Experimental Periodontitis Journal of Dental Research 2017 97 3 312 320 10.1177/0022034517732770 28954199 PMC5833182
52 Jabbour Z. El-Hakim M. Henderson J. E. De Albuquerque R. F. Jr. Bisphosphonates inhibit bone remodeling in the jaw bones of rats and delay healing following tooth extractions Oral Oncology 2014 50 5 485 490 2-s2.0-84898817913 10.1016/j.oraloncology.2014.02.013 24630257
53 Hagelauer N. Pabst A. M. Ziebart T. Ulbrich H. Walter C. In vitro effects of bisphosphonates on chemotaxis, phagocytosis, and oxidative burst of neutrophil granulocytes Clinical Oral Investigations 2015 19 1 139 148 2-s2.0-85016393588 10.1007/s00784-014-1219-0 24668343