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Outcomes of Bone Morphogenetic Protein-2 and iliac cancellous bone transplantation on alveolar cleft bone grafting: A Meta-Analysis
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Outcomes of Bone Morphogenetic Protein-2 and iliac cancellous bone transplantation on alveolar cleft bone grafting: A Meta-Analysis Wen-lin Xiao , Kai-ning Jia , Guo Yu , Ning Zhao PII: DOI: Reference:
S1748-6815(20)30031-0 https://doi.org/10.1016/j.bjps.2020.01.011 PRAS 6398
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received date: Accepted date:
26 May 2019 15 January 2020
Please cite this article as: Wen-lin Xiao , Kai-ning Jia , Guo Yu , Ning Zhao , Outcomes of Bone Morphogenetic Protein-2 and iliac cancellous bone transplantation on alveolar cleft bone grafting: A Meta-Analysis, Journal of Plastic, Reconstructive & Aesthetic Surgery (2020), doi: https://doi.org/10.1016/j.bjps.2020.01.011
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.
Review
Outcomes of Bone Morphogenetic Protein-2 and iliac cancellous bone
transplantation
on
alveolar
cleft
bone
grafting:
A
Meta-Analysis
Wen-lin Xiao*, Kai-ning Jia, Guo Yu, Ning Zhao
Department of Stomatology, the Affiliated Hospital of Qingdao University, Qingdao 266003, China
*Address correspondence to: Professor, Wen-lin Xiao, Department of Stomatology, the Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, China. E-mail: [email protected]
Abstract Background: To systematically evaluate the effect of bone morphogenetic protein-2 (BMP-2) and iliac cancellous bone graft (ICBG) on alveolar cleft bone grafting (ACBG) in cleft lip and palate. Method: Online databases were searched for case-control studies related to the application of BMP-2 and ICBG in ACBG. Result: Meta-analysis showed that the filling rate (OR = 4.1, 95% CI (0.06, 2.63), the volume of bone graft area (OR=-0.42, 95% CI (-1.44, 0.60), the height of bone graft area (OR=-21.38, 95% CI (-23.00, -19.76), the density of bone graft area (OR = 0.43, 95% CI (-0.79, 1.64), the failure rate of bone graft (OR = 0.02, 95% CI (-0.03, 0.06), infection after operation, the rate (OR = 0.20, 95% CI (0.05, 0.73)) and the incidence of postoperative oronasal fistula (OR = 4.1, 95% CI (0.06, 2.63)) were no significant statistical difference for the effect of BMP-2 and ICBG in ACBG. There were obvious statistical differences in operative time (OR = -3.64, 95% CI (-7.35, 0.06)) and the length of hospital stay (OR = -1.97, 95% CI (-2.41，-1.53)). Conclusion: The meta-analysis shows that there is no significant difference between BMP-2 and ICBG in filling rate, volume, density, failure rate and the occurrence of oronasal fistula after ACBG. There were significant differences between BMP-2 and ICBG in the operation time and hospitalization time of ACBG. Compared with ICBG bone graft, BMP-2 has more advantages in ACBG area height remained, postoperative infection rate, the operative time and the length of hospital stay.
Key Words BMP-2; iliac cancellous bone; bone graft; meta-analysis; case-control study
Introduction The treatment of cleft alveolar process is a very important part in the sequential treatment of cleft lip and palate. Only through good bone grafting can we lay a good foundation for the follow-up orthodontic treatment and denture restoration. The bone source of alveolar cleft bone graft is mostly iliac bone, because iliac bone has abundant cancellous bone. Transplanted cancellous bone can respond to the moving teeth, and has strong anti-infective ability. The method of bone extraction is simple and the wound is concealed. However, autogenous bone transplantation also has many problems, such as trauma, pain, skin scar, limb movement limitation and so on. Autogenous bone mass cannot meet the needs of surgery because of the bone mass in donor site, wider fissures or bilateral alveolar cleft, etc 1, 2. In recent years, BMP-2 has become an artificial material to repair alveolar cleft instead of autogenous bone, and has become a research hotspot 3. However, BMP-2 and autologous ICBG did not systematically evaluate the effect of ACBG. Therefore, this study systematically analyzed the effects of BMP-2 and ICBG after ACBG using Meta-analysis method. Information and methods Literature retrieval strategies The meta-analysis was conducted according to the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines. According to the principle of PICOS4 the search strategies of this study were extracted: P, alveolar cleft patients; I, BMP-2; C, IBCG; O: ACBG effect; S, case-control study. According to PICOS principle, the search terms are alveolar cleft, BMP-2, IBCG. By searching PubMed, The Cochrane Library, Embase, Google Scholar, Ovid, Springer, Elsevier, Chinese National Knowledge Infrastructure, and the Chinese Biomedical Database, the relevant literature published before November 2018 was searched.
Inclusion and exclusion criteria Inclusion criteria: Alveolar cleft bone graft patients, no other unrelated control, IBCG,
BMP-2 case-control study, language unlimited. Exclusion criteria: duplicate documents with the same data, the original data cannot be obtained or the full text of the literature cannot be obtained. The inclusion and exclusion of literature should be carried out independently by two researchers. When the two researchers fail to reach a consensus conclusion, the two sides should discuss and solve the problem first. If they fail to reach a consensus conclusion, the third party should discuss and decide. Data collection Data collection and two researchers used "two-person independent extraction method" to extract data. At the same time, the basic characteristics of the included literature were extracted, including the author of the literature, the year of publication, the sample size of the experimental group and the control group, and the outcome indicators.
Quality assessment Two researchers independently assessed the literature risk according to the Newcastle-Ottawa scale5. This scale includes three categories and eight items: the selection of study population (case determination, case representation, control selection, control determination), inter-group comparability, measurement of exposure factors (determination of exposure factors, determination of exposure factors by the same method in case group and control group, ineffective response rate). Among the categories of "selection" and "exposure", a quality item of a study was rated at most one point, and the category of "comparability" was rated at most two points. Articles with 6 or more points are generally considered to be of high quality.
Statistical analysis Meta-analysis of data was carried out using Review Manager 5.3 software.
Results Literature search results
216 literatures were preliminarily retrieved and 9 literatures6-13 were finally included after screening step by step. The process and results of literature screening are shown in Figure 1. Basic characteristics and bias risk assessment results included in the literature The basic characteristics of the literature and the results of bias risk assessment are shown in Table 1. Table 1 shows that the NOS scores of the included studies are higher than 6 points, indicating that the quality of the included studies is higher. Meta-analysis results Bone graft filling rate Four articles were included in this study. Meta-analysis showed that OR=-0.05, 95% CI (-2.13, 0.96), I2=56%, P=0.90, which showed good heterogeneity. BMP-2 and ICBG had no significant difference in filling rate of alveolar cleft bone (Figure 2).
Volume of bone graft area The meta-analysis showed that OR=-0.42, 95% CI (-1.44, 0.60), I2=50%, P=0.42. The results showed that there was no significant difference between BMP-2 and ICBG in the volume of alveolar cleft bone graft area (Figure 3).
Height of bone graft area Two papers were included in this study. Meta-analysis showed that OR=-21.38, 95% CI (-23.009, -19.76), I2=80%, P_0.00001. The results showed that BMP-2 was significantly different from ICBG in the height of alveolar cleft bone graft area, and BMP-2 was a protective factor (Figure 4).
Density of bone graft area Two papers were included in this study. Meta analysis showed that OR = 0.43, 95% CI (-0.79, -1.64), I2 = 70%, P_0.49. The results showed that BMP-2 and ICBG had no significant difference in the density of alveolar cleft bone graft area (Figure 5).
Failure rate of bone graft Five papers were included in this study. Meta analysis showed that OR = 0.02, 95% CI (-0.03, 0.06), I2 = 0%, P 0.50. The results showed that there was no significant difference between BMP-2 and ICBG in the failure rate of alveolar cleft bone graft area (Figure 6).
Infection rate after bone grafting Two papers were included in this study. Meta analysis showed that OR = 0.20, 95% CI (0.05, 0.73), I2 = 0%, P_0.01. The results showed that there was a significant difference between BMP-2 and ICBG in the infection rate of alveolar cleft bone graft area after operation, which indicated that BMP-2 was a protective factor to reduce the infection rate after bone graft (Figure 7).
Oral and nasal fistula after bone grafting Two papers were included in this study. Meta analysis showed that OR = 0.41, 95% CI (0.06, 2.633), I 2 = 13%, P 0.35. The results showed that there was no significant difference between BMP-2 and ICBG in the situation of oronasal fistula after ACBG (Figure 8).
Operative time Two papers were included in this study. Meta analysis showed that OR = -3.64, 95% CI (-7.35, 0.06), I2 = 93%, P=0.05. The results showed that there was significant difference between BMP-2 and ICBG in the operative time (Figure 9).
Length of hospital stay Two papers were included in this hospital study. Meta analysis showed that OR = -1.97, 95% CI (-2.41，-1.53), I2 = 98%, P<0.00001. The results showed that there was significant difference between BMP-2 and ICBG in the length of hospital stay (Figure 10).
Discussion Alveolar cleft is a kind of maxillary deformity in patients with cleft lip and palate. There are several main problems in the sequential treatment of cleft lip and palate: impaired eruption of primary or permanent teeth on the affected side, affecting chewing and facial appearance; oronasal fistula, affecting the patient's pronunciation and oral hygiene; alveolar bone defect on the affected side causes the alar base to lose bone support and present collapse deformity. Alveolar cleft can affect 1/3 of the patient's facial morphology14. Normal alveolar bone has active remodeling ability in the whole life process. As long as there is appropriate mechanical tension and functional stimulation, it will promote bone growth. This biological characteristic means that as long as bone tissue similar to alveolar bone is implanted, the teeth can erupt normally, have normal function and maintain normal facial shape. Since the first report of alveolar cleft bone regeneration in 197215, it has been used to improve the quality of life for cleft patients. This surgical procedure offers several clinical advantages, such as improved oral hygiene16, nasal support17, closure of oronasal fistula15, et al. ICBG obtained from the anterior iliac bone remains the most widely used and the benchmark against which other graft materials are evaluated18-20. However, some therapeutic disadvantages remain unresolved, such as the surgical invasion of donor sites, limited donor tissue, and severe absorption of grafted bone21. Therefore, non-autologous bone substitutes have been sought. Since Urist
22
first
reported that bone morphogenetic proteins (BMPs) could promote differentiation of pluripotential cells into cartilage- and bone-forming cells and therefore were pivotal for bone regeneration, BMPs have attracted much attention in the field of osseous regeneration. Recombinant technology has led to the cloning and expressing of human BMPs in quantities suitable for therapeutic applications in preclinical studies 23
.BMP-2 is a low-molecular-weight glycoprotein, which is the strongest factor in the
family of bone morphogenetic proteins. It is the strongest bone formation stimulus among all known growth factors. It can induce osteogenic precursor cells to differentiate into bone and chondrocyte. It also plays an important role in the growth
and development of bone and teeth and the repair of bone defects24-26. The use of BMP-2 in oral and maxillofacial surgeries has been investigated widely, including its use in the repair of large jaw defects and premaxillary clefts27, 28. After pooling the findings of relevant studies, moderate synthesized evidence was found that the amount of new bone formation with BMP-2 bound to ACS is similar to that of ICBG when used for cleft repair
9, 29
. Compared to the use of ICBG for alveolar cleft bone
graft, the rhBMP-2 grafting offers an opportunity to avoid the risk of infection of the donor site and reduce the surgical stress for patients. In this study, the effects of BMP-2 and ICBG on ACBG were systematically evaluated by Meta-analysis. To evaluate whether BMP-2 can achieve the same effect as ICBG. This study systematically analyzed the bone grafting effect of BMP-2 and ICBG from nine aspects: filling rate of alveolar cleft in bone graft, volume, height and density of bone graft area, failure rate after bone graft, infection rate after bone graft, incidence of oronasal fistula, operative time and length of hospital stay. The results showed that BMP-2 and ICBG had no significant statistical difference in filling rate of alveolar cleft bone graft, volume and density of bone graft area, failure rate after bone graft and incidence of oronasal fistula after bone graft. There were significant statistical differences in height of bone graft area, infection rate, operative time and length of hospital stay after bone graft. BMP-2 had better height, lower infection rate, less operative time and shorter of hospital stay than ICBG. This study also has some limitations. The number of references and samples included is relatively small, and it may not be possible to carry out bias analysis, subgroup analysis and so on, which may affect the reliability of the meta-analysis results. The literature included in this Meat analysis is published literature, which cannot exclude negative knots and unpublished literature is not included in this study. The specific research methods included in the literature are different, which may affect the heterogeneity of this meta-analysis. To sum up, from the existing literature, BMP-2 and ICBG have no significant difference in ACBG effect; BMP-2 has more advantages in ACBG area height, postoperative infection rate, operative time and length of hospital stay. Due to the
limitation of the quantity and quality of the literature, more studies are needed to verify the above conclusions.
Conflicts of interest None of the listed authors have conflicts of interest or any disclosures.
Funding Funding for this project was provided by Natural Science foundation of Shandong Province (ZR2015HM022).
References 1. Sales PHH, Oliveira-Neto OB, Torres TS, de Lima FJC. Effectiveness of dental implants placed in bone graft area of cleft Patients. Int J Oral Maxillofac Surg 2019. 2. Liang F, Leland H, Jedrzejewski B, et al. Alternatives to Autologous Bone Graft in Alveolar Cleft Reconstruction: The State of Alveolar Tissue Engineering. J Craniofac Surg 2018: 29: 584-93. 3. Liu XL, Shi B, Zheng Q, Li CH. Alveolar Bone Grafting and Cleft Lip and Palate: A Review. Plast Reconstr Surg 2017: 140: 359e-60e. 4. Saaiq M, Ashraf B. Modifying "Pico" Question into "Picos" Model for More Robust and Reproducible Presentation of the Methodology Employed in A Scientific Study. World J Plast Surg 2017: 6: 390-92. 5. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010: 25: 603-5. 6. Herford AS, Boyne PJ, Rawson R, Williams RP. Bone morphogenetic protein-induced repair of the premaxillary cleft. J Oral Maxillofac Surg 2007: 65: 2136-41. 7. Canan LW, Jr., da Silva Freitas R, Alonso N, et al. Human bone morphogenetic protein-2 use for maxillary reconstruction in cleft lip and palate patients. J Craniofac Surg 2012: 23: 1627-33. 8. Dickinson BP, Ashley RK, Wasson KL, et al. Reduced morbidity and improved healing with bone morphogenic protein-2 in older patients with alveolar cleft defects. Plast Reconstr Surg 2008: 121: 209-17. 9. Alonso N, Tanikawa DY, Freitas Rda S, et al. Evaluation of maxillary alveolar reconstruction using a resorbable collagen sponge with recombinant human bone morphogenetic protein-2 in cleft lip and palate patients. Tissue Eng Part C Methods 2010: 16: 1183-9. 10. Francis CS, Mobin SS, Lypka MA, et al. rhBMP-2 with a demineralized bone matrix scaffold versus autologous iliac crest bone graft for alveolar cleft reconstruction. Plast Reconstr Surg 2013: 131: 1107-15. 11. Balaji SM. Use of recombinant human Bone Morphogenetic Protein (rhBMP-2) in reconstruction of maxillary alveolar clefts. J Maxillofac Oral Surg 2009: 8: 211-7. 12. She XM, Zhang Q, Tian K, Yang L, Xiong GF. [Clinical study of bone-inducing active materials in repairing alveolar cleft]. Hua Xi Kou Qiang Yi Xue Za Zhi 2010:28: 391-4. 13. Xia JS. Feasibility and reliability of repairing alveolar cleft bone defect with bone-inducing active materials. [J Clin Rehabil Tis Eng Res] 19 2015:19:7619-23. 14. Weissler EH, Taub PJ. Reply: Alveolar Bone Grafting and Cleft Lip and Palate: A Review. Plast Reconstr Surg 2017: 140: 360e. 15. Boyne PJ, Sands NR. Secondary bone grafting of residual alveolar and palatal clefts. J Oral Surg 1972;30:87-92. 16. Tai CC, Sutherland IS, McFadden L. Prospective analysis of secondary alveolar bone grafting using computed tomography. J Oral Maxillofac Surg 2000;58:1241-9; discussion 1250. 17. Turvey TA, Vig K, Moriarty J, Hoke J. Delayed bone grafting in the cleft maxilla and palate: a retrospective multidisciplinary analysis. Am J Orthod 1984;86:244-56. 18. Cohen M, Figueroa AA, Haviv Y, Schafer ME, Aduss H. Iliac versus cranial bone for secondary grafting of residual alveolar clefts. Plast Reconstr Surg. 1991;87:423–427; discussion 428.
19. Jia YL, Fu MK, Ma L. Long-term outcome of secondary alveolar bone grafting in patients with various types of cleft. Br J Oral Maxillofac Surg. 2006;44:308–312. 20. Horswell BB, Henderson JM. Secondary osteoplasty of the alveolar cleft defect. J Oral Maxillofac Surg. 2003;61:1082–1090. 21. Swan MC, Goodacre TE. Morbidity at the iliac crest donor site following bone grafting of the cleft alveolus. Br J Oral Maxillofac Surg 2006;44:129-33. 22. Urist MR. Bone: formation by autoinduction. Science. 1965;150:893–899. 23. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kritz RW, Hewick RM. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242:1528–1534. 24. Pan W, Wu C, Yang Z, et al. Secondary Alveolar Bone Grafting and Iliac Cancellous Bone Harvesting for Patients With Alveolar Cleft. J Craniofac Surg 2016: 27: 883-91. 25. Bessa PC, Casal M, Reis RL. Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery). J Tissue Eng Regen Med 2008: 2: 81-96. 26. Cicciu M, Herford AS, Cicciu D, Tandon R, Maiorana C. Recombinant human bone morphogenetic protein-2 promote and stabilize hard and soft tissue healing for large mandibular new bone reconstruction defects. J Craniofac Surg 2014: 25: 860-2. 27. Balaji SM. Use of recombinant human bone morphogenetic protein (rhBMP-2) in reconstruction of maxillary alveolar clefts. J Max-illofac Oral Surg 2009;8:211–7. 28. Dickinson BP, Ashley RK, Wasson KL, O’Hara C, Gabbay J, Heller JB, Bradley JP. Reduced morbidity and improved healing with bone morphogenic protein-2 in older patients with alveolar cleft defects. Plast Reconstr Surg 2008;121:209–17. 29. Canan Jr LW, Silva Freitas RD, Alonso N, Tanikawa DY, Rocha DL, Coelho JC. Human bone morphogenetic protein-2 use for maxillary reconstruction in cleft lip and palate patients. J Craniofac Surg 2012;23:1627–33.
Figure Legend
Fig 1 Flow chart of literature screening
Fig 2 Meta-analysis of bone graft filling rate
Fig 3 Meta-analysis of bone graft volume
Fig 4 Meta-analysis of bone graft height
Fig 5 Meta- analysis of bone graft density
Fig 6 Meta-analysis of failure rate in bone graft area
Fig 7 Meta-analysis of infection rate after bone grafting
Fig 8 Meta-analysis of the rate of oronasal fistula after bone grafting
Fig 9 Figure 9. Meta-analysis of operative time after bone graftiing
Fig 10 Meta-analysis of length of hospital stay after bone grafting
Author
Year
experimental
control group
Outcome
NOS
group Herford AS et al.
Canan Jr et al.
2007
2012
BMP-2/ACS
ICBG
Bone graft filling rate,
(n=10)
（n=2）
Volume of bone graft area
BMP-2/ACS
ICBG
Bone graft filling rate,
(n=6)
（n=6）
Volume of bone graft area,
6
7
Height of bone graft area, Failure rate of bone graft Dickinson BP et al.
Alonso N et al.
2008
2010
BMP-2/ACS
ICBG
Failure rate of bone graft
7
(n=9)
（n=12）
BMP-2/ACS
ICBG
Bone
6
(n=8)
（n=8）
rate ,Volume of bone graft
graft
filling
area, Height of bone graft area Francis et al.
2013
BMP-2/DBM
ICBG
Failure rate of bone graft,
(n=36)
（n=19）
infection rate, Incidence of
7
oronasal fistula Balaji SM
Hammoudeh JA et
2009
2017
al. She X et al.
Wang SM et al.
2010
2011
BMP-2/ACS
ICBG
Bone graft filling rate
7
(n=30)
（n=30）
BMP-2/ACS
ICBG
Failure rate of bone graft,
7
(n=228)
（n=242）
infection rate
BMP-2/DBB
ICBG
Failure rate of bone graft
6
(n=12)
（n=15）
BMP-2/β-TCP
ICBG
Failure rate of bone graft,
6
(n=12)
（n=32）
Bone graft filling rate
Table 1 Includes the basic features of the literature
Outcomes of Bone Morphogenetic Protein-2 and iliac cancellous bone transplantation on alveolar cleft bone grafting: A Meta-Analysis Wen-lin Xiao , Kai-ning Jia , Guo Yu , Ning Zhao PII: DOI: Reference:
S1748-6815(20)30031-0 https://doi.org/10.1016/j.bjps.2020.01.011 PRAS 6398
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received date: Accepted date:
26 May 2019 15 January 2020
Please cite this article as: Wen-lin Xiao , Kai-ning Jia , Guo Yu , Ning Zhao , Outcomes of Bone Morphogenetic Protein-2 and iliac cancellous bone transplantation on alveolar cleft bone grafting: A Meta-Analysis, Journal of Plastic, Reconstructive & Aesthetic Surgery (2020), doi: https://doi.org/10.1016/j.bjps.2020.01.011
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.
Review
Outcomes of Bone Morphogenetic Protein-2 and iliac cancellous bone
transplantation
on
alveolar
cleft
bone
grafting:
A
Meta-Analysis
Wen-lin Xiao*, Kai-ning Jia, Guo Yu, Ning Zhao
Department of Stomatology, the Affiliated Hospital of Qingdao University, Qingdao 266003, China
*Address correspondence to: Professor, Wen-lin Xiao, Department of Stomatology, the Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, China. E-mail: [email protected]
Abstract Background: To systematically evaluate the effect of bone morphogenetic protein-2 (BMP-2) and iliac cancellous bone graft (ICBG) on alveolar cleft bone grafting (ACBG) in cleft lip and palate. Method: Online databases were searched for case-control studies related to the application of BMP-2 and ICBG in ACBG. Result: Meta-analysis showed that the filling rate (OR = 4.1, 95% CI (0.06, 2.63), the volume of bone graft area (OR=-0.42, 95% CI (-1.44, 0.60), the height of bone graft area (OR=-21.38, 95% CI (-23.00, -19.76), the density of bone graft area (OR = 0.43, 95% CI (-0.79, 1.64), the failure rate of bone graft (OR = 0.02, 95% CI (-0.03, 0.06), infection after operation, the rate (OR = 0.20, 95% CI (0.05, 0.73)) and the incidence of postoperative oronasal fistula (OR = 4.1, 95% CI (0.06, 2.63)) were no significant statistical difference for the effect of BMP-2 and ICBG in ACBG. There were obvious statistical differences in operative time (OR = -3.64, 95% CI (-7.35, 0.06)) and the length of hospital stay (OR = -1.97, 95% CI (-2.41，-1.53)). Conclusion: The meta-analysis shows that there is no significant difference between BMP-2 and ICBG in filling rate, volume, density, failure rate and the occurrence of oronasal fistula after ACBG. There were significant differences between BMP-2 and ICBG in the operation time and hospitalization time of ACBG. Compared with ICBG bone graft, BMP-2 has more advantages in ACBG area height remained, postoperative infection rate, the operative time and the length of hospital stay.
Key Words BMP-2; iliac cancellous bone; bone graft; meta-analysis; case-control study
Introduction The treatment of cleft alveolar process is a very important part in the sequential treatment of cleft lip and palate. Only through good bone grafting can we lay a good foundation for the follow-up orthodontic treatment and denture restoration. The bone source of alveolar cleft bone graft is mostly iliac bone, because iliac bone has abundant cancellous bone. Transplanted cancellous bone can respond to the moving teeth, and has strong anti-infective ability. The method of bone extraction is simple and the wound is concealed. However, autogenous bone transplantation also has many problems, such as trauma, pain, skin scar, limb movement limitation and so on. Autogenous bone mass cannot meet the needs of surgery because of the bone mass in donor site, wider fissures or bilateral alveolar cleft, etc 1, 2. In recent years, BMP-2 has become an artificial material to repair alveolar cleft instead of autogenous bone, and has become a research hotspot 3. However, BMP-2 and autologous ICBG did not systematically evaluate the effect of ACBG. Therefore, this study systematically analyzed the effects of BMP-2 and ICBG after ACBG using Meta-analysis method. Information and methods Literature retrieval strategies The meta-analysis was conducted according to the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines. According to the principle of PICOS4 the search strategies of this study were extracted: P, alveolar cleft patients; I, BMP-2; C, IBCG; O: ACBG effect; S, case-control study. According to PICOS principle, the search terms are alveolar cleft, BMP-2, IBCG. By searching PubMed, The Cochrane Library, Embase, Google Scholar, Ovid, Springer, Elsevier, Chinese National Knowledge Infrastructure, and the Chinese Biomedical Database, the relevant literature published before November 2018 was searched.
Inclusion and exclusion criteria Inclusion criteria: Alveolar cleft bone graft patients, no other unrelated control, IBCG,
BMP-2 case-control study, language unlimited. Exclusion criteria: duplicate documents with the same data, the original data cannot be obtained or the full text of the literature cannot be obtained. The inclusion and exclusion of literature should be carried out independently by two researchers. When the two researchers fail to reach a consensus conclusion, the two sides should discuss and solve the problem first. If they fail to reach a consensus conclusion, the third party should discuss and decide. Data collection Data collection and two researchers used "two-person independent extraction method" to extract data. At the same time, the basic characteristics of the included literature were extracted, including the author of the literature, the year of publication, the sample size of the experimental group and the control group, and the outcome indicators.
Quality assessment Two researchers independently assessed the literature risk according to the Newcastle-Ottawa scale5. This scale includes three categories and eight items: the selection of study population (case determination, case representation, control selection, control determination), inter-group comparability, measurement of exposure factors (determination of exposure factors, determination of exposure factors by the same method in case group and control group, ineffective response rate). Among the categories of "selection" and "exposure", a quality item of a study was rated at most one point, and the category of "comparability" was rated at most two points. Articles with 6 or more points are generally considered to be of high quality.
Statistical analysis Meta-analysis of data was carried out using Review Manager 5.3 software.
Results Literature search results
216 literatures were preliminarily retrieved and 9 literatures6-13 were finally included after screening step by step. The process and results of literature screening are shown in Figure 1. Basic characteristics and bias risk assessment results included in the literature The basic characteristics of the literature and the results of bias risk assessment are shown in Table 1. Table 1 shows that the NOS scores of the included studies are higher than 6 points, indicating that the quality of the included studies is higher. Meta-analysis results Bone graft filling rate Four articles were included in this study. Meta-analysis showed that OR=-0.05, 95% CI (-2.13, 0.96), I2=56%, P=0.90, which showed good heterogeneity. BMP-2 and ICBG had no significant difference in filling rate of alveolar cleft bone (Figure 2).
Volume of bone graft area The meta-analysis showed that OR=-0.42, 95% CI (-1.44, 0.60), I2=50%, P=0.42. The results showed that there was no significant difference between BMP-2 and ICBG in the volume of alveolar cleft bone graft area (Figure 3).
Height of bone graft area Two papers were included in this study. Meta-analysis showed that OR=-21.38, 95% CI (-23.009, -19.76), I2=80%, P_0.00001. The results showed that BMP-2 was significantly different from ICBG in the height of alveolar cleft bone graft area, and BMP-2 was a protective factor (Figure 4).
Density of bone graft area Two papers were included in this study. Meta analysis showed that OR = 0.43, 95% CI (-0.79, -1.64), I2 = 70%, P_0.49. The results showed that BMP-2 and ICBG had no significant difference in the density of alveolar cleft bone graft area (Figure 5).
Failure rate of bone graft Five papers were included in this study. Meta analysis showed that OR = 0.02, 95% CI (-0.03, 0.06), I2 = 0%, P 0.50. The results showed that there was no significant difference between BMP-2 and ICBG in the failure rate of alveolar cleft bone graft area (Figure 6).
Infection rate after bone grafting Two papers were included in this study. Meta analysis showed that OR = 0.20, 95% CI (0.05, 0.73), I2 = 0%, P_0.01. The results showed that there was a significant difference between BMP-2 and ICBG in the infection rate of alveolar cleft bone graft area after operation, which indicated that BMP-2 was a protective factor to reduce the infection rate after bone graft (Figure 7).
Oral and nasal fistula after bone grafting Two papers were included in this study. Meta analysis showed that OR = 0.41, 95% CI (0.06, 2.633), I 2 = 13%, P 0.35. The results showed that there was no significant difference between BMP-2 and ICBG in the situation of oronasal fistula after ACBG (Figure 8).
Operative time Two papers were included in this study. Meta analysis showed that OR = -3.64, 95% CI (-7.35, 0.06), I2 = 93%, P=0.05. The results showed that there was significant difference between BMP-2 and ICBG in the operative time (Figure 9).
Length of hospital stay Two papers were included in this hospital study. Meta analysis showed that OR = -1.97, 95% CI (-2.41，-1.53), I2 = 98%, P<0.00001. The results showed that there was significant difference between BMP-2 and ICBG in the length of hospital stay (Figure 10).
Discussion Alveolar cleft is a kind of maxillary deformity in patients with cleft lip and palate. There are several main problems in the sequential treatment of cleft lip and palate: impaired eruption of primary or permanent teeth on the affected side, affecting chewing and facial appearance; oronasal fistula, affecting the patient's pronunciation and oral hygiene; alveolar bone defect on the affected side causes the alar base to lose bone support and present collapse deformity. Alveolar cleft can affect 1/3 of the patient's facial morphology14. Normal alveolar bone has active remodeling ability in the whole life process. As long as there is appropriate mechanical tension and functional stimulation, it will promote bone growth. This biological characteristic means that as long as bone tissue similar to alveolar bone is implanted, the teeth can erupt normally, have normal function and maintain normal facial shape. Since the first report of alveolar cleft bone regeneration in 197215, it has been used to improve the quality of life for cleft patients. This surgical procedure offers several clinical advantages, such as improved oral hygiene16, nasal support17, closure of oronasal fistula15, et al. ICBG obtained from the anterior iliac bone remains the most widely used and the benchmark against which other graft materials are evaluated18-20. However, some therapeutic disadvantages remain unresolved, such as the surgical invasion of donor sites, limited donor tissue, and severe absorption of grafted bone21. Therefore, non-autologous bone substitutes have been sought. Since Urist
22
first
reported that bone morphogenetic proteins (BMPs) could promote differentiation of pluripotential cells into cartilage- and bone-forming cells and therefore were pivotal for bone regeneration, BMPs have attracted much attention in the field of osseous regeneration. Recombinant technology has led to the cloning and expressing of human BMPs in quantities suitable for therapeutic applications in preclinical studies 23
.BMP-2 is a low-molecular-weight glycoprotein, which is the strongest factor in the
family of bone morphogenetic proteins. It is the strongest bone formation stimulus among all known growth factors. It can induce osteogenic precursor cells to differentiate into bone and chondrocyte. It also plays an important role in the growth
and development of bone and teeth and the repair of bone defects24-26. The use of BMP-2 in oral and maxillofacial surgeries has been investigated widely, including its use in the repair of large jaw defects and premaxillary clefts27, 28. After pooling the findings of relevant studies, moderate synthesized evidence was found that the amount of new bone formation with BMP-2 bound to ACS is similar to that of ICBG when used for cleft repair
9, 29
. Compared to the use of ICBG for alveolar cleft bone
graft, the rhBMP-2 grafting offers an opportunity to avoid the risk of infection of the donor site and reduce the surgical stress for patients. In this study, the effects of BMP-2 and ICBG on ACBG were systematically evaluated by Meta-analysis. To evaluate whether BMP-2 can achieve the same effect as ICBG. This study systematically analyzed the bone grafting effect of BMP-2 and ICBG from nine aspects: filling rate of alveolar cleft in bone graft, volume, height and density of bone graft area, failure rate after bone graft, infection rate after bone graft, incidence of oronasal fistula, operative time and length of hospital stay. The results showed that BMP-2 and ICBG had no significant statistical difference in filling rate of alveolar cleft bone graft, volume and density of bone graft area, failure rate after bone graft and incidence of oronasal fistula after bone graft. There were significant statistical differences in height of bone graft area, infection rate, operative time and length of hospital stay after bone graft. BMP-2 had better height, lower infection rate, less operative time and shorter of hospital stay than ICBG. This study also has some limitations. The number of references and samples included is relatively small, and it may not be possible to carry out bias analysis, subgroup analysis and so on, which may affect the reliability of the meta-analysis results. The literature included in this Meat analysis is published literature, which cannot exclude negative knots and unpublished literature is not included in this study. The specific research methods included in the literature are different, which may affect the heterogeneity of this meta-analysis. To sum up, from the existing literature, BMP-2 and ICBG have no significant difference in ACBG effect; BMP-2 has more advantages in ACBG area height, postoperative infection rate, operative time and length of hospital stay. Due to the
limitation of the quantity and quality of the literature, more studies are needed to verify the above conclusions.
Conflicts of interest None of the listed authors have conflicts of interest or any disclosures.
Funding Funding for this project was provided by Natural Science foundation of Shandong Province (ZR2015HM022).
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19. Jia YL, Fu MK, Ma L. Long-term outcome of secondary alveolar bone grafting in patients with various types of cleft. Br J Oral Maxillofac Surg. 2006;44:308–312. 20. Horswell BB, Henderson JM. Secondary osteoplasty of the alveolar cleft defect. J Oral Maxillofac Surg. 2003;61:1082–1090. 21. Swan MC, Goodacre TE. Morbidity at the iliac crest donor site following bone grafting of the cleft alveolus. Br J Oral Maxillofac Surg 2006;44:129-33. 22. Urist MR. Bone: formation by autoinduction. Science. 1965;150:893–899. 23. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kritz RW, Hewick RM. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242:1528–1534. 24. Pan W, Wu C, Yang Z, et al. Secondary Alveolar Bone Grafting and Iliac Cancellous Bone Harvesting for Patients With Alveolar Cleft. J Craniofac Surg 2016: 27: 883-91. 25. Bessa PC, Casal M, Reis RL. Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery). J Tissue Eng Regen Med 2008: 2: 81-96. 26. Cicciu M, Herford AS, Cicciu D, Tandon R, Maiorana C. Recombinant human bone morphogenetic protein-2 promote and stabilize hard and soft tissue healing for large mandibular new bone reconstruction defects. J Craniofac Surg 2014: 25: 860-2. 27. Balaji SM. Use of recombinant human bone morphogenetic protein (rhBMP-2) in reconstruction of maxillary alveolar clefts. J Max-illofac Oral Surg 2009;8:211–7. 28. Dickinson BP, Ashley RK, Wasson KL, O’Hara C, Gabbay J, Heller JB, Bradley JP. Reduced morbidity and improved healing with bone morphogenic protein-2 in older patients with alveolar cleft defects. Plast Reconstr Surg 2008;121:209–17. 29. Canan Jr LW, Silva Freitas RD, Alonso N, Tanikawa DY, Rocha DL, Coelho JC. Human bone morphogenetic protein-2 use for maxillary reconstruction in cleft lip and palate patients. J Craniofac Surg 2012;23:1627–33.
Figure Legend
Fig 1 Flow chart of literature screening
Fig 2 Meta-analysis of bone graft filling rate
Fig 3 Meta-analysis of bone graft volume
Fig 4 Meta-analysis of bone graft height
Fig 5 Meta- analysis of bone graft density
Fig 6 Meta-analysis of failure rate in bone graft area
Fig 7 Meta-analysis of infection rate after bone grafting
Fig 8 Meta-analysis of the rate of oronasal fistula after bone grafting
Fig 9 Figure 9. Meta-analysis of operative time after bone graftiing
Fig 10 Meta-analysis of length of hospital stay after bone grafting
Author
Year
experimental
control group
Outcome
NOS
group Herford AS et al.
Canan Jr et al.
2007
2012
BMP-2/ACS
ICBG
Bone graft filling rate,
(n=10)
（n=2）
Volume of bone graft area
BMP-2/ACS
ICBG
Bone graft filling rate,
(n=6)
（n=6）
Volume of bone graft area,
6
7
Height of bone graft area, Failure rate of bone graft Dickinson BP et al.
Alonso N et al.
2008
2010
BMP-2/ACS
ICBG
Failure rate of bone graft
7
(n=9)
（n=12）
BMP-2/ACS
ICBG
Bone
6
(n=8)
（n=8）
rate ,Volume of bone graft
graft
filling
area, Height of bone graft area Francis et al.
2013
BMP-2/DBM
ICBG
Failure rate of bone graft,
(n=36)
（n=19）
infection rate, Incidence of
7
oronasal fistula Balaji SM
Hammoudeh JA et
2009
2017
al. She X et al.
Wang SM et al.
2010
2011
BMP-2/ACS
ICBG
Bone graft filling rate
7
(n=30)
（n=30）
BMP-2/ACS
ICBG
Failure rate of bone graft,
7
(n=228)
（n=242）
infection rate
BMP-2/DBB
ICBG
Failure rate of bone graft
6
(n=12)
（n=15）
BMP-2/β-TCP
ICBG
Failure rate of bone graft,
6
(n=12)
（n=32）
Bone graft filling rate
Table 1 Includes the basic features of the literature