Effectiveness of platelet-rich plasma as an adjunctive material to bone graft: a systematic review and meta-analysis of randomized controlled clinical trials

Abstract

The use of platelet-rich plasma (PRP) has become a strategic therapy in tissue regeneration medicine. PRP represents a good source of growth factors. Due to this property, it has been considered a reliable adjunctive material in bone augmentation procedures, such as the sinus lift technique. The aim of this review was to assess the scientific evidence on the effectiveness of PRP as an adjunctive material in the sinus floor elevation technique. The following databases were searched for relevant published studies: Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, Science Direct, ISI Web of Knowledge, and SCOPUS. Only randomized controlled clinical trials comparing a group receiving PRP as an adjunctive material to a control group without PRP, involving adult human subjects (age >18 years) with no systemic disease, were included. Of the studies identified, only one reported a significant difference in bone augmentation in favour of the adjunctive use of PRP, while four studies did not find any significant difference. None of the studies included reported a significant difference in the implant survival rate. Further randomized clinical trials are needed to clarify the effectiveness of adjunctive PRP.

Platelet-rich plasma (PRP) is an autologous concentration of platelets in a small volume of plasma. PRP represents a good source of growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF), insulin growth factor 1 (IGF-1), and basic fibroblast growth factor (bFGF). PRP gel is formed by mixing PRP, derived from centrifugation of autologous whole blood, with thrombin and calcium chloride. Since its introduction, PRP has been used widely in dentistry, including in procedures such as sinus floor elevation, alveolar ridge augmentation, mandibular reconstruction, maxillary cleft repair, treatment of periodontal defects, and treatment of extraction sockets.

Augmentation of the sinus floor is a surgical technique intended to allow the placement of dental implants in an otherwise atrophic maxilla. Several materials such as autologous bone, allografts, alloplasts, and xenografts have been proposed as bone substitutes with osteoconductive properties; the use of these materials has produced largely successful outcomes. However, in addition to these materials, the use of biological mediators with osteoinductive properties has been proposed with the aim of reducing the consolidation of the osteoconductive materials and accelerating the formation of newly formed bone.

With this aim, PRP has been proposed as an adjunct to osteoconductive materials. However, no general consensus has been reached regarding its effectiveness. Some studies have reported positive effects, while other studies have shown limited effects in relation to the efficacy of PRP in bone formation. A previous meta-analysis on this topic has been reported; however, the systematic review included few studies and these were non-randomized, therefore potentially biased conclusions were reached. There is, therefore, a need to systemically assess the literature on this topic.

The aim of the present systematic review was to assess the scientific evidence on the effectiveness of PRP as an adjunctive material in the sinus floor elevation technique.

Materials and methods

The present meta-analysis was conducted in accordance with the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.

Search strategy

A literature search of the following databases, up to and including 3 November 2014, was performed: Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, Science Direct, ISI Web of Knowledge, and SCOPUS. The following search algorithm was used to explore the databases, using Boolean operators and the asterisk symbol (*) as truncation: (sinus lift OR sinus elevation OR ((“paranasal sinuses”[MeSH Terms] OR sinus) AND (“lifting”[MeSH Terms] OR lift))) AND (platelet rich plasma OR platelet gel OR platelet rich-plasma OR “Platelet-Rich Plasma”[MeSH]). The MeSH terms were not used in the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, SCOPUS, ISI Web of Knowledge, or Science Direct databases. Additionally, a hand-search was performed of issues of the following journals published in the last 15 years: Clinical Oral Implants Research , Clinical Implant Dentistry and Related Research , European Journal of Oral Implantology , International Journal of Oral and Maxillofacial Implants , Journal of Oral Implantology , Implant Dentistry , International Journal of Oral and Maxillofacial Surgery , Journal of Oral and Maxillofacial Surgery , Journal of Dental Research , and Clinical Oral Investigations . To be as inclusive as possible, no restrictions were applied with regard to the year of publication of the studies. In addition, the references of all selected full-text articles and related reviews were cross-checked.

Study selection

Two independent reviewers (LS, AP) screened the titles and the abstracts of the articles identified during the literature search in duplicate. Inter-reviewer reliability in the study selection process was determined by Cohen kappa test, assuming an acceptable threshold value of 0.61. Disagreements in the inclusion or the exclusion of studies were resolved by discussion.

Eligibility criteria

The study selection process was performed by two blinded reviewers (LS, AP). Only randomized controlled clinical trials comparing a group receiving PRP as an adjunctive material to a control group without PRP, involving adult human subjects (age >18 years) with no systemic disease, were included.

Outcome variables

The radiographic outcome assessed was bone to implant contact. The histomorphometric outcome assessed was bone formation at least 3 months after the bone graft. The clinical outcome assessed was implant survival at least 12 months after implant insertion at the patient and implant levels.

Data extraction

A specific extraction form was used to collect the following data from the articles included: patient demographic characteristics, presence of smokers, and radiographic and histomorphometric outcomes; the data were extracted by two independent reviewers (LS, AP). A separate ad hoc extraction sheet focusing on the quality of the studies was also used by the two independent reviewers (LS, AP).

Assessment of risk of bias

The methodological quality of all included studies was evaluated independently by two blinded reviewers (LS, AP) on the basis of the revised recommendations of the CONSORT statement ( Table 1 ) ; the level of agreement between reviewers was calculated as reported above. After determining the scores for each study, an overall estimation of the plausible risk of bias (low, moderate, or high) was performed for each selected study. When all of the criteria were met, the study was considered as having a low risk of bias. When one or more criteria were partly met, the risk of bias was determined to be moderate. A high risk of bias was considered when one or more criteria were not met ( Cochrane Handbook for Systematic Reviews of Interventions , version 5.1.0; ).

Table 1
Categories used to assess the quality of the studies included.
Category Description Grading
A Sample size calculation, estimating the minimum number of participants required to detect a significant difference among compared groups 0 = did not exist/not mentioned/not clear
1 = was reported, but not confirmed
2 = reported and confirmed
B Randomization and allocation concealment methods 0 = clearly inadequate
1 = possibly adequate
2 = clearly adequate
C Clear definition of inclusion and/or exclusion criteria 0 = no
1 = yes
D Completeness of follow-up (specified reasons for withdrawals and dropouts in each study group) 0 = no/not mentioned/not clear
1 = yes/no withdrawals or dropouts occurred
E Experimental and control groups comparable at study baseline for important prognostic factors 0 = no
1 = unclear/possibly not comparable for one or more important prognostic factors
2 = clearly adequate
F Presence of masking 0 = no
1 = unclear/not complete
2 = yes
G Appropriate statistical analysis 0 = no
1 = unclear/possibly not the best method applied
2 = yes

Quantitative analysis

Data were combined for the meta-analysis using RevMan statistical software, version 5.0 (The Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). For continuous outcomes, such as bone density and bone formation, the effect size was estimated and reported as the standardized mean difference (SMD), and the 95% confidence interval (CI) was calculated. For dichotomous data, such as implant survival, a risk ratio (RR) with the 95% CI was used to pool the results of each treatment group. Due to the expected inter-study heterogeneity, a random-effects model was used. The pooled effect was considered significant if the P -value was <0.05. Forest plots were drawn for each meta-analysis to present the raw data (i.e., the means, SDs, and sample sizes), point estimates (displayed as blocks), and CIs (displayed as lines) for the chosen effect, the heterogeneity statistic ( I 2 ), total number of participants per group, overall average effect (SMD and Z -statistic) in the random-effects model, and the percentage weight given to each study. Heterogeneity was assessed by χ 2 -based Q -statistic method and I 2 measurement, with significance indicated by P < 0.1. Publication bias was investigated for each outcome of interest through two methods. Visual detection was used to analyze the funnel plot. Quantitative analysis was performed by the regression asymmetry test and the trim-and-fill method. The analysis of publication bias was performed using Stata 12 software (StataCorp LP, College Station, TX, USA).

Results

Results of the search

The results of the search are presented in Fig. 1 . The database search identified 612 publications: 92 in Medline, four in the Cochrane Central Register of Controlled Trials, two in the Cochrane Database of Systematic Reviews, eight in CINAHL, 228 in Science Direct, 48 in ISI Web of Knowledge, and 230 in SCOPUS. No additional articles were identified through the manual search. Following the removal of duplicates, 414 articles remained. After reading the titles and abstracts, a total of 31 of the initial 414 articles were selected. Twenty-four of these articles were excluded ( Table 2 ). Thus, a total of seven articles were included in the systematic review, of which six were subjected to meta-analysis.

Fig. 1
PRISMA flow chart of the search strategy.

Table 2
List of studies excluded.
Study Year of publication Reason for exclusion
Yilmaz et al. 2013 No data available
Dasmah et al. 2013 Clinical trial
Inchingolo et al. 2012 No data available
Poeschl et al. 2012 Controlled clinical trial
Cabbar et al. 2011 Controlled clinical trial
Stenport et al. 2011 Comparative study
Bae et al. 2011 Meta-analysis
Badr et al. 2010 No outcome of interest
Riaz et al. 2010 Comparative study
Hieu et al. 2010 Controlled clinical trial
Esposito et al. 2010 Meta-analysis
Arora et al. 2010 Review
Esposito et al. 2010 Meta-analysis
Papa et al. 2009 Comparative study
Schaaf et al. 2008 No data available
Schaaf et al. 2008 No data available
Schlegel et al. 2007 Animal study
Galindo-Moreno et al. 2007 Clinical trial
Esposito et al. 2006 Meta-analysis
Klongnoi et al. 2006 Animal study
Boyapati et al. 2006 Review
Steigmann and Garg 2005 PRP not adjunctive to control
Thor et al. 2005 Controlled clinical trial
Graziani et al. 2005 Clinical trial
PRP, platelet-rich plasma.

Description of the studies included

The main characteristics of the studies included are shown in Table 3 . All studies used a split-mouth design, with the exception of one that used a parallel design. Three studies reported grafting from the iliac crest , two studies used intraoral sites as donor sites for grafting, while one study reported the use of freeze-dried bone allograft and one the use of anorganic bovine bone. PRP was obtained using similar procedures.

Table 3
Characteristics of the studies included.
Study Design Study location Population
Mean age
Age range
F/M ratio Intervention Outcomes Follow-up PRP preparation technique
Aimetti et al., 2008 RCT, SM Private office 4 patients
58.5 ± 5.8
51–65
2/2 Mandibular ramus bone graft vs. mandibular ramus bone graft + PRP Bone to implant contact 6 months Commercially available kit (Platelet Concentration Collection System Kit; 3i/Implant Innovations)
Bettega et al., 2009 RCT, SM 18 patients
50.5
13/5 Iliac crest bone graft vs. iliac crest bone graft + PRP Bone formation 6 months Citrate as an anticoagulant; centrifugation; final platelet concentration of 3 × 10 11
Consolo et al., 2007 RCT, SM 16 patients
18–60
11/5 Iliac crest bone graft vs. iliac crest bone graft + PRP Bone formation 7 months Citrate as an anticoagulant; centrifugation; activation of platelets by CaCl/thrombin
Kassolis and Reynolds 2005 RCT, SM University of Maryland, Dental School 10 patients FDBA + membrane vs. FDBA + PRP Bone formation 4.5–6 months Citrate as an anticoagulant; centrifugation; activation of platelets by CaCl
Khairy et al., 2012 RCT, P Clinic of the Oral Surgery Department, Faculty of Oral and Dental Medicine, Cairo University, Egypt 15 patients
38
22–54
Intraoral bone graft vs. intraoral bone graft + PRP Bone formation 6 months Citrate as an anticoagulant; centrifugation; activation of platelets by CaCl/thrombin
Raghoebar et al., 2005 RCT, SM Department of Oral and Maxillofacial Surgery of the University Hospital, Groningen, Netherlands 5 patients
58.4 ± 1.9
57–62
3/2 Iliac crest bone graft vs. iliac crest bone graft + PRP Bone formation, implant survival 3 months Commercially available kit (Platelet Concentration Collection System Kit; 3i/Implant Innovations)
Torres et al., 2009 RCT, SM Clínica Dental Alcalá, Madrid, Spain 87 patients
ABB vs. ABB + PRP Implant survival 6 months Centrifugation; activation of platelets by CaCl
F, female; M, male; PRP, platelet-rich plasma; RCT, randomized controlled trial; SM, split-mouth; FDBA, freeze-dried bone allograft; P, parallel; ABB, anorganic bovine bone.

Outcomes

Only one of the studies included reported a significant difference in bone augmentation in favour of the adjunctive use of PRP, while five studies did not find any significant difference. None of the studies reported a significant difference in the implant survival rate.

Quality assessment

The results of the CONSORT-based quality assessment are reported in Table 4 . After the evaluation of the methodological quality, all studies were considered to be at high risk of bias. The criteria most frequently not satisfied were sample size calculation (criterion A) and the adequacy of the methods used for randomization and allocation concealment (criterion B). Moreover, two studies did not perform masking (criterion F).

Table 4
Quality assessment of the studies included.
Study A (0–2) B (0–2) C (0–1) D (0–1) E (0–2) F (0–2) G (0–2) Estimated risk of bias
Aimetti et al., 2008 0 0 1 1 2 0 2 High
Bettega et al., 2009 0 0 1 1 2 2 2 High
Consolo et al., 2007 0 0 1 1 2 2 2 High
Kassolis and Reynolds 2005 0 2 1 1 2 2 2 High
Khairy et al., 2012 0 0 1 1 2 0 2 High
Raghoebar et al., 2005 0 0 1 1 2 2 2 High
Torres et al., 2009 0 2 1 1 2 2 2 High
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Jan 16, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Effectiveness of platelet-rich plasma as an adjunctive material to bone graft: a systematic review and meta-analysis of randomized controlled clinical trials
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