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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 48-57

Platelet concentrates as an adjunctive therapy for medication-related osteonecrosis of the Jaw: A systematic review and meta-analysis


1 Department of Biomedical, Surgical and Dental Sciences, University of Milan; Dental Clinic, IRCCS Galeazzi Orthopedic Institute, Milan, Italy
2 Department of Biomedical, Surgical and Dental Sciences, University of Milan; Dental Clinic, IRCCS Galeazzi Orthopedic Institute, Milan, Italy; Faculty of Dental Surgery, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

Date of Web Publication3-Aug-2018

Correspondence Address:
Prof. Massimo Del Fabbro
IRCCS Istituto Ortopedico Galeazzi, Via Riccardo Galeazzi 4, Milan 20161
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/GFSC.GFSC_19_18

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  Abstract 


Medication-related osteonecrosis of the jaw (MRONJ) is a drug-related adverse event consisting of progressive bone destruction in the maxillofacial region of patients under current or previous treatment with antiresorptive or antiangiogenic medications. Autologous platelet concentrates (APC) demonstrated to enhance bone and soft-tissue healing in many oral surgery procedures. This systematic review aimed to evaluate APC effect for treatment and prevention of MRONJ in patients under antiresorptive therapy. An electronic search was performed on MEDLINE, Scopus, Web of Science, and Cochrane databases using specific search terms, combined with AND, OR. Both prospective and retrospective studies with at least three patients and 3 months' follow-up were included, and they underwent data extraction and risk of bias assessment. When possible, a meta-analysis was undertaken. Eighteen studies reporting on 946 patients were included in this study. Postsurgery follow-up ranged from 3 to 94 months. The adjunct of APC in MRONJ treatment significantly reduced osteonecrosis recurrence with respect to control (P = 0.001). APC was also beneficial for MRONJ prevention, being associated with a lower MRONJ incidence after tooth extraction (P = 0.03). Heterogeneity was found regarding medication type, clinical indication, triggering factors, study design, follow-up duration, type of APC, and outcomes adopted to evaluate treatment success. Although the results of this review must be cautiously interpreted, due to the low-evidence level and limited sample size of the studies included, they are suggestive for possible benefits of APC when associated with surgical procedures for treatment of MRONJ. To confirm such indication, further prospective comparative studies with large sample size are urgently needed.

Keywords: Antiangiogenic agents, antiresorptive agents, bisphosphonates, medication-related osteonecrosis of the jaw, oral surgery, platelet concentrates, tooth extraction


How to cite this article:
Fabbro MD, Taschieri S, Goker F. Platelet concentrates as an adjunctive therapy for medication-related osteonecrosis of the Jaw: A systematic review and meta-analysis. Int J Growth Factors Stem Cells Dent 2018;1:48-57

How to cite this URL:
Fabbro MD, Taschieri S, Goker F. Platelet concentrates as an adjunctive therapy for medication-related osteonecrosis of the Jaw: A systematic review and meta-analysis. Int J Growth Factors Stem Cells Dent [serial online] 2018 [cited 2018 Dec 11];1:48-57. Available from: http://www.cellsindentistry.org/text.asp?2018/1/2/48/238556




  Introduction Top


Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare and severe adverse drug side effect that may occur in cancer and osteoporosis patients being treated with bisphosphonate medications. It is progressive bone destruction in the maxillofacial region of the patients which can be accompanied by pain, paresthesia, swelling, soft-tissue ulceration, suppuration, and intraoral and extraoral sinus tracts. Marx, in 2003, was the first to report BRONJ in patients, and since then more than 1000 papers have been published in PubMed indexed journals.[1] More recently, other antiresorptive agents, antiangiogenic medications, and novel anticancer drugs such as denosumab, bevacizumab, sirolimus, sorafenib, and sunitinib have been correlated to the development of ONJ [Table 1]. As a consequence, in 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS), introduced the term medication-related osteonecrosis of the jaw (MRONJ).[2] The updated definition of “MRONJ” according to the AAOMS is “Area of exposed or probable bone in the maxillofacial region with no resolution for longer than 8 weeks in patients treated with an antiresorptive or an antiangiogenic agent and with no history of radiation therapy to the to the head and neck region.”[2]
Table 1: Antiresorptive agents, antiangiogenic medications correlated to the development of ONJ

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The most important predisposing factors for the development of MRONJ in humans appears to be the type and total dosage of antiresorptive or antiangiogenic therapies, and the main triggering factor seems to be an oral surgery procedure to the oro-maxillofacial region even though some spontaneous cases have been reported.[3],[4] Risk factors for MRONJ can be listed as following: increasing age, sex (females seem to have a higher risk), anemia, diabetes, rheumatoid arthritis, hemodialysis, tobacco use, cancer type, concurrent therapies (e.g., corticosteroids and chemotherapy), antiangiogenic agents in combination with antiresorptive medicines, poor oral hygiene, history of periodontitis, and single-nucleotide polymorphisms in the RBMS3 gene which is associated with bone density and collagen formation.[2]

Treatment strategies

The treatment of MRONJ is generally difficult, and there is no gold standard therapy.[5],[6] Treatment objectives for patients with MRONJ are mainly focused on eliminating pain, controlling infection, and minimizing the progression or occurrence of bone necrosis. Patients with established MRONJ should avoid additional dentoalveolar surgical procedures, to avoid additional surgical sites that may result in areas of exposed necrotic bone. During the initial stages, treatment strategies are mostly based on conservative measures, such as antibiotics and 0.12% chlorhexidine mouthwashes.[2] Surgical interventions are considered more appropriate for patients at advanced stages.[7] Many adjunctive therapies were proposed by researchers and were documented in the literature, such as low-level laser therapy, hyperbaric oxygen, ozone therapy, and platelet concentrates.[8],[9],[10],[11],[12]

The additional use of autologous platelet concentrates (APC) for improving bone healing in the oral and maxillofacial region was first proposed by Robert Marx in 1998,[13] and the use of APC has gained popularity since then among oral and maxillofacial surgeons as well as in other medical fields for increasing the predictability of the bone and soft-tissue regeneration procedures.

The first clinical report on the use of APC in the treatment of MRONJ was published by Adornato et al. in 2007.[11] Since then, APC has been used as an adjunctive option for enhancing the tissue healing after MRONJ treatment as well as to prevent MRONJ occurrence after dentoalveolar surgery procedures.[12],[14]

The primary aim of this systematic review was to evaluate if the use of platelet-rich preparations, in patients under antiresorptive drug treatment may be advantageous for improving the success of the surgical treatment of MRONJ. Further aims were to evaluate if in these patients platelet concentrates may prove beneficial for the following: (a) improving healing of bone and soft tissue at the surgical site; (b) reducing the incidence of MRONJ as well as any other postsurgical complication and side effect after dentoalveolar surgery; and (c) improving patients' quality of life (by reducing pain, swelling, and other common symptoms) in the postsurgical period and increasing treatment acceptance by patients.


  Materials and Methods Top


Search strategy

An electronic search was performed on the following databases: MEDLINE using PubMed search engine (http://www.ncbi.nlm.nih.gov/sites/pubmed), Scopus (http://www.scopus.com), WEB of Science, and Cochrane Central Register of Controlled Trials. Gray literature databases were searched as follows: HealthInfoNet (http://www.healthinfonet.ecu.edu.au), Closing the Gap Clearinghouse (http://www.aihw.gov. au/closingthegap), and OpenGrey (http://www.opengrey.eu). The last search was performed on May 7, 2018. The following search terms were used: (“bisphosphonate*,” “denosumab,” “antiresorptive agents,” “antiresorptive therapy,” “BRONJ,” “MRONJ,” “osteoporosis,” “osteonecrosis,” “maxilla,” “mandible,” “platelet-rich plasma (PRP),” “platelet concentrates,” “platelet growth factors,” “platelet-rich fibrin (PRF),” “PRP,” “plasma rich in growth factor (PRGF),” “PRF,” “Platelet-Derived Growth Factor (PDGF),” “oral surgery,” “extraction socket,” “tooth extraction.” These terms were used alone or in combination using Boolean operators OR and AND. An example of a search string is: (MRONJ OR BRONJ) AND (platelet concentrates OR PRP OR PRF OR PRGF) AND (bisphosphonate OR denosumab OR antiresorptive agents OR antiresorptive therapy). The limit “humans” was applied. Furthermore, a hand search of issues from 2000 up to the last issue available, including the “Early view” (or equivalent) section was undertaken on the following journals: British Journal of Oral and Maxillofacial Surgery, International Journal of Oral and Maxillofacial Surgery, Journal of Oral and Maxillofacial Surgery, Oral Oncology, and Oral Surgery Oral Medicine Oral Pathology Oral Radiology. The reference list of the retrieved literature reviews and the included studies as well as related articles indicated by PubMed was also manually checked for possible additional eligible studies not identified by the electronic search.

Inclusion criteria

For being included, studies had to report clinical results of oral surgery procedures in patients under antiresorptive therapy, in which APC was used for improving the clinical outcome. Articles reporting on the treatment of an existing condition of MRONJ (such as surgical resection of the necrotic tissue), and those reporting on the incidence/onset of MRONJ in patients undergoing oral surgery procedures (such as tooth extraction, cyst removal, and dental implant placement) were considered.

The search was limited to clinical studies involving human subjects. Restrictions were not placed regarding the language and the year of publication. Both prospective and retrospective studies were included. Only studies reporting on at least three patients were considered. The studies had to provide details on the type and dosage of antiresorptive drug taken, the indication for antiresorptive therapy, and the duration of the treatment at the time of surgery. They also had to provide clear definitions of the clinical outcomes for considering success or failure of the procedure, and details on the type of platelet concentrate used.

Publications that did not meet the above inclusion criteria and those that were not dealing with original clinical cases (e.g., reviews, technical reports, and expert opinions) were excluded. Multiple publications of the same pool of patients were also excluded. When papers from the same group of authors, with very similar databases of patients, materials, methods, and outcomes were identified; the authors were contacted for clarifying if the pool of patients was indeed the same. In case of multiple publications relative to consecutive phases of the same study or enlargements of the original sample size, only the most recent data (those with the longer follow-up and the larger sample size) were considered.

Selection of the studies

The articles retrieved through the electronic and manual searches were initially evaluated for relevance based on their titles and abstracts by two reviewers independently (MDF and FG). The concordance between reviewers was assessed by means of the Cohen's Kappa coefficient. In case of disagreement, a joint decision was taken by discussion. The full texts of all studies of possible relevance (eligible studies) were independently assessed by the same two reviewers to check if they met all inclusion criteria. Cases of disagreement were discussed together until an agreement was reached. For articles excluded at this stage, the reason for exclusion was recorded. The identified suitable articles were subject to data extraction and analysis and were also assessed for their methodological quality, and for their suitability to inclusion in a meta-analysis.

Data extraction

Data were extracted by two reviewers independently (MDF and FG), using an ad hoc data collection form. Cases of disagreement were subject to joint evaluation until an agreement was reached.

The main variables extracted from each included study were the following: study design, study setting (university, hospital, and private practice), support of a sponsor, sample size, patients' gender and age, proportion of smokers, type, dosage and administration route of antiresorptive drug taken, reason for antiresorptive treatment, dosage, duration of treatment at surgery, type of platelet concentrate used, jaw (maxilla or mandible), any outcome variable used to evaluate treatment success, follow-up duration, complications, adverse events, and postsurgical onset/recurrence of MRONJ. When possible, we adopted the MRONJ staging definition proposed by the AAOMS.[2] Further variables extracted, when reported, were the type of oral surgery procedure before MRONJ onset, the quality of life of patients assessed by means of questionnaires or interviews.

The primary outcome was the number of adverse events (MRONJ and bone exposure occurrence) after a follow-up of at least 3 months from surgery.

Quality assessment and risk-of-bias assessment

The following methodological parameters were assessed: only for randomized studies (if any), the method for generating the random sequence and the allocation concealment; for all studies, clear definition of the inclusion and exclusion criteria, clear definition of outcomes assessment and success criteria; blinding of outcome assessment (for controlled studies); the number of surgeons involved; completeness of the results (outcome data) reported, the patients' recall rate (it was assumed adequate if a dropout <20% was reported), explanation had to be provided for dropouts/withdrawal (when applicable), sample size (it was assumed adequate if more than 20 patients were treated), and the length of follow-up period (it was assumed adequate if the mean follow-up duration was at least 2 years).

The methodological quality of the included studies was evaluated independently and in duplicate by two reviewers (MDF and FG) according to the above methodological parameters. The criteria for assessing the risk of bias of RCTs were adapted from the guidelines reported in the Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 (www.cochrane-handbook.org).[15] All the criteria were assessed as adequate, unclear, or inadequate. The authors of the included studies were contacted for providing clarifications or missing information as needed. Based on previously published systematic reviews,[12],[16] studies were considered at low risk of bias if more than 2/3 of the parameters were judged as adequate, and no parameter was judged as inadequate. Studies were considered at high risk if 1/3 or more of the parameters were judged as inadequate.

Statistical analysis

Descriptive statistics will be done of the included studies by summarizing the total number of cases treated with each surgical approach and the percentage of successful cases, of postsurgical adverse events (MRONJ occurrence or recurrence for prevention or treatment studies, respectively) in cases treated with and without platelet concentrates adjunct for each surgery procedure considered. For studies reporting a comparison between cases treated with and without biological agents, the estimates of the effects of platelet concentrates were expressed as odds ratio (OR) together with 95% confidence intervals. The statistical evaluation was conducted considering both the surgical site and the patient as the analysis unit, when possible. When two or more studies presented similar comparison (same type of intervention in similar patients' groups, with similar follow-up) a meta-analysis was performed and ORs were combined using a fixed-effects model (Mantel–Haenszel method). The Software RevMan (Review Manager Version 5.3, 2014; The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark) was used to estimating the mean difference in primary outcome between groups. The effect of location (maxilla vs. mandible), gender, antiresorptive drug, and administration route (oral vs. intravenous) on the incidence of adverse events was also investigated. P = 0.05 was considered as the significance level. When meta-analysis was not feasible due to the absence of studies with similar features, the only qualitative analysis was done, and the outcomes were presented in a narrative way.


  Results Top


The flowchart summarizing the screening process is presented in [Figure 1]. The electronic search yielded a total of 547 articles. Two additional articles were found by hand searching. After a first screening of the titles and abstracts, a total of 29 articles reporting results of clinical studies on patients under antiresorptive therapy that underwent oral surgery procedures in combination with the use of APC were selected. The agreement between the two evaluators was very high, yielding a Kappa value of 0.92. After evaluation of the full-text of these articles, 11 of them were excluded [Table 2].[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27] The reason for exclusion is listed in [Table 2]. Finally, 18 studies (946 patients) were included, and they underwent data extraction and analysis.[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45] APCs used were PRP, PRGFs, and PRF. Postsurgery follow-up ranged from 3 to 94 months.
Figure 1: Flowchart of the article selection process

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Table 2: Excluded studies and reason for exclusion

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Treatment studies

A total of 13 studies regarded MRONJ treatment (four retrospective studies, one case–control study, and eight prospective case series), reporting on a total of 305 patients (315 sites) undergoing oral surgery [Table 3] and [Table 4].[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40] These studies evaluated the effectiveness of APC as an adjunct for the treatment of an existing MRONJ condition in patients undergoing resection and debridement of necrotic sites. All studies were conducted in a university setting. Seven studies used PRP, five studies used leukocyte-PRF (L-PRF), and one used PRGF. Eleven studies were judged as having a medium risk of bias, and two had a high risk of bias. Overall, the adjunct of APC in MRONJ treatment consistently reduced osteonecrosis recurrence with respect to control.
Table 3: General features of the studies about MRONJ treatment

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Table 4: Specific features and outcomes of the studies on MRONJ treatment

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Prevention studies

Five studies were included for prevention (one retrospective, one prospective controlled study, one with a mixed retrospective/prospective design, and two prospective case series), reporting on a total of 641 patients (406 undergoing tooth extraction and 235 undergoing implant surgery) [Table 5].[41],[42],[43],[44],[45] Four studies used PRGF and one used L-PRF. One study was judged at low risk of bias, two at medium risk, and two at high risk.
Table 5: MRONJ prevention. Summary of studies in which patients under antiresorptive drugs underwent oral surgery procedures in combination with platelet concentrates

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Heterogeneity was found regarding medication type, clinical indication, triggering factors, study design, follow-up duration, type of APC, and outcomes adopted to evaluate treatment success.

When combining the comparative studies into a meta-analysis, it was found that the use of APCs produces a statistically significant beneficial effect in terms of both treatment (reduction of the recurrence of MRONJ after surgery, [Figure 2], P = 0.001) and prevention (reduction of the incidence of MRONJ/bone exposure after dentoalveolar surgery, [Figure 3], P = 0.03). No quantitative evaluation could be performed for other parameters, though a general trend for beneficial effects of using APCs was observed, consisting of improvement in the quality of life, reduction of pain, swelling and other postoperative symptoms, faster soft-tissue healing, and better radiographic bone healing.
Figure 2: Forest plot per site of the effect of autologous platelet concentrates after medication-related osteonecrosis of the jaw treatment in patients taking antiresorptive drugs. A statistically significant lower recurrence of adverse effects was observed (P = 0.001), suggesting a beneficial effect of autologous platelet concentrates in the treatment of medication-related osteonecrosis of the jaw

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Figure 3: Forest plot per site of the effect of autologous platelet concentrates after tooth extraction in patients taking antiresorptive drugs. A statistically significant lower incidence of adverse effects was observed (P = 0.03), suggesting a beneficial effect of autologous platelet concentrates in the prevention of medication-related osteonecrosis of the jaw

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  Discussion Top


A prompt and precise diagnosis of any condition is a primary step that leads to achievement in the treatment. Since the publication of the first case series, the diagnostic approach challenges two controversial aspects which are as follows: (1) the diagnosis of ONJ in the absence of bone exposure and (2) the need for radiological or imaging confirmation of the diagnosis.[45],[46]

Staging system

The diagnosis of ONJ in the absence of exposed bone still represents a major problem, and according to Patel et al., this can produce a delay in diagnosis, prolong the disease, and cause it to become refractory to treatment.[47] The most authors have accepted the definition of ONJ proposed by the AAOMS.[2] However, particularly in the early stages of the disease, ONJ may manifest without bone exposure.[45],[48] Schiodt et al. indicated that the proportion of ONJ without bone exposure may be as high as 29%–45% of all cases of ONJ.[46]

A modification of the AAOMS staging or classification system was proposed by many authors with updated diagnostic and therapeutic approaches to the cases of ONJ without bone exposure based on the symptoms, assessment of the risk factors, the radiographic evidence, and patient refractoriness to medical treatment.[45],[46],[48],[49],[50],[51],[52] The authors' opinion, based on the personal experience, is in agreement with these statements about the need for a more appropriate staging system.

Risk factors and prevalence

Dentoalveolar surgery is considered a major local risk factor for developing MRONJ, and tooth extraction is the most common predisposing event. Poor oral hygiene and concurrent oral disease such as periodontal disease or periapical pathology and removable dentures (for their possible traumatic effect to soft tissues) are also considered as other predisposing factors besides surgical interventions. Anatomical factors also play a role as MRONJ is more likely to appear in the mandible than in the maxilla.[52],[53]

The prevalence of ONJ in the literature varies greatly (0.001%–12%) and shows a positive correlation with high doses of medications and longer treatment duration.[2],[54] The growing number of MRONJ cases appear to be related to accumulated doses.[45],[46],[49]

Treatment

The treatment approach for MRONJ should be minimally invasive, in order not to create future problems with additive necrotic fields. In fact, since most antiresorptive drugs slow down bone metabolism, healing may be impaired and the risk for tissue infection, poor vascularization, bone exposure, and necrosis increases. Surgical debridement of the necrotic bone should be the choice in advanced stages of MRONJ. Any adjunctive, safe therapy that enhances the bone and soft-tissue healing, reducing pain, improving quality of life, and minimizing the risk of infection and relapses is certainly useful. Platelet concentrates seem to have all those features for being considered as an effective adjunct to bring benefits and enhance to the quality of life of the patient suffering from MRONJ.[2],[11],[12]

In recent years, platelet concentrates were used to promote healing and accelerate tissue regeneration in many dental and oral surgery procedures.[16],[55],[56],[57],[58] Platelet concentrate is a derivative from patient's own blood. The rationale for APC application is based on its high concentration of platelets and leukocytes that are rich of many mitogenic growth factors and other substances that have an important influence on wound healing, such as PDGF, transforming growth factor-beta, epidermal growth factor, vascular endothelial growth factor, procoagulant factor and cytokines, chemokines, and antimicrobial proteins.[55],[58],[59] Antimicrobial properties of platelet concentrates against oral microorganisms also seems to be beneficial for the patients in the early postoperative period.[60]

After the first introduction of PRP in the maxillofacial field by Marx 1998,[13] a number of commercial systems for APCs have been launched on the market allowing the availability to clinicians to choose among the several different types of products such as PRP, PRGF, CGF (concentrated growth factors), and L-PRF.[61] Each of these products has its own feature and biological activity. On the one hand, this gives the opportunity to the clinicians to be able to choose the most suitable APC for the specific intervention they are going to perform. On the other hand, this might create confusion for the clinicians since the true difference in the clinical effect among the various APCs is still unclear. Some classifications were proposed based on standardized parameters and biological properties and effectiveness of different APCs, but a consensus is still lacking.[61],[62],[63] Furthermore, the legislation regarding the use of nontransfusional hemocomponents in many countries might still represent an issue for the widespread diffusion of the technology.[24]

The use of PRP has also been proposed by many authors in the management of BRONJ with the aim of enhancing wound healing and bone maturation, as we have seen in the present review. Based on the present results, the combination of necrotic bone curettage and PRP applications seems to be encouraging for the treatment of MRONJ cases. Since application of platelet concentrates is minimally invasive, free from potential risks for patients, and easy to obtain; it might be feasible to use it as an adjunctive in oral and dental surgical procedures. However, further evidence-based studies are required to support this evidence.

The results of the present review need to be cautiously interpreted due to some limitations. For example, the low-evidence level of most of the included studies, especially case series and retrospective studies, which are considered to have high risk of bias. Another issue is the heterogeneity among the studies regarding the type of medication, the patients' primary disease, the route of administration, the duration of therapy before the early signs of MRONJ become apparent, the MRONJ staging, the associated risk factors, the duration of follow-up, patient's health condition and concomitant therapies, type of platelet concentrate, outcome variables, and success criteria adopted in the studies.

In spite of such heterogeneity, studies that included a control group consistently reported a trend toward a beneficial effect of platelet concentrates, for both treatment and prevention.

Unfortunately, very few studies reported a quality of life evaluation for the postsurgical period, which is expected to be improved using platelet concentrates, as suggested by recent randomized studies on different oral surgery procedures.[64],[65]

The short follow-up period reported from most of the studies which did not allow to detect delayed complications and adverse events that might eventually occur. In addition, healing of the hard and soft tissues at the surgical sites were neither investigated systematically nor with consistent or standardized methods. The most studies used conventional computed tomography or cone-beam computed tomography; however, a quantitative assessment of bone healing at the surgical sites was lacking or it was performed at different follow-ups, thus preventing any comparison. It was also unfeasible to assess the effect of MRONJ staging on the results due to the presence of many confounding factors.

Finally, we pooled the results of the different types of platelet concentrates (PRP, L-PRF, and PRGF); even though it is known that they have different characteristics and composition, it can have different biological activity.[60],[61],[65] A comparison of the effects of various APCs on MRONJ treatment or prevention requires specific comparative studies and a wide sample size. Unfortunately, as far as we know, no study has been conducted yet to compare two different APCs for such purpose.


  Conclusion Top


In spite of the substantial lack of evidence, the results of this review suggest that platelet concentrates might be beneficial for reducing the postsurgical occurrence and recurrence of MRONJ and other adverse events in patients under antiresorptive therapy. We hope that in the future, additional evidence-based studies with wide sample size will confirm the promising results of the present review.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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