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World J Orthop. Mar 18, 2015; 6(2): 269-277
Published online Mar 18, 2015. doi: 10.5312/wjo.v6.i2.269
Use of demineralized bone matrix in the extremities
Georgios I Drosos, Panagiotis Touzopoulos, Athanasios Ververidis, Konstantinos Tilkeridis, Konstantinos Kazakos, Department of Orthopaedic Surgery, Medical School, Democritus University of Thrace, University General Hospital of Alexandroupolis, 68100 Alexandroupolis, Greece
Author contributions: Drosos GI and Touzopoulos P contributed to conception and design of the study; Drosos GI, Touzopoulos P and Ververidis A contributed to acquisition, analysis and interpretation of data; Drosos GI, Touzopoulos P and Tilkeridis K contributed to drafting the article; Drosos GI, Ververidis A, Kazakos K and Tilkeridis K contributed to revising the article; all the authors read and approved the final manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Georgios I Drosos, MD, PhD, Assistant Professor of Orthopaedics, Department of Orthopaedic Surgery, Medical School, Democritus University of Thrace, University General Hospital of Alexandroupolis, 68100 Alexandroupolis, Greece. drosos@otenet.gr
Telephone: +30-694-4380694 Fax: +30-255-1030339
Received: April 29, 2014
Peer-review started: April 30, 2014
First decision: June 27, 2014
Revised: July 7, 2014
Accepted: October 14, 2014
Article in press: October 16, 2014
Published online: March 18, 2015

Abstract

Autologous bone graft is considered as the gold standard for all indications for bone grafting procedures but the limited availability and complications in donor site resulted in seeking other options like allografts and bone graft substitutes. Demineralized bone matrix (DBM) is an allograft product with no quantity limitation. It is an osteoconductive material with osteoinductive capabilities, which vary among different products, depending on donor characteristics and differences in processing of the bone. The purpose of the present review is to provide a critical review of the existing literature concerning the use of DBM products in various procedures in the extremities. Clinical studies describing the use of DBM alone or in combination with other grafting material are available for only a few commercial products. The Level of Evidence of these studies and the resulting Grades of Recommendation are very low. In conclusion, further clinical studies of higher quality are required in order to improve the Recommendation Grades for or against the use of DBM products in bone grafting procedures.

Key Words: Bone, Grafting, Allograft, Demineralized bone matrix, Non-union

Core tip: Demineralized bone matrix (DBM) is an allograft product that was found to be safe as an option of bone grafting. As far as its effectiveness is concerned, and according to the existing literature: (1) there is a good evidence for its use in bone cysts combined with autologous marrow aspirate; (2) in fracture nonunion and filling the defects after tumor surgery DBM used alone or combined with other grafting material are supported by a lower quality studies; and (3) there is insufficient evidence to make a treatment recommendation for DBM use in fracture treatment of other applications. Furthermore, according to the existing literature there are results of clinical use of only a few DBM products and thus the recommendation concerning the DBM use should probably also be referred to these specific products and not to any DBM product.



INTRODUCTION

In recent years, the requirements for bone grafting have increased, due to the increasing number of procedures, in orthopaedic, oral and maxillofacial surgery[1]. Autologous bone is considered the ideal graft for any indication providing the best osteogenic, osteoinductive and osteoconductive potential of all grafts, with no immunological rejection[2-5]. Allograft materials and graft substitutes have been developed to avoid limitations of autologous graft, like limited availability and donor site morbidity[6-12].

Demineralized bone matrix (DBM) is an osteoconductive and osteoinductive allograft product, but no osteogenic capacity because of its processing[13-18]. The osteoinductive capacity of DBM can be affected by storage, demineralization process, washing procedure, sterilization method and vary from donor to donor resulting in differences between and within products[19-25]. DBM has no immunological rejection as the antigenic surface structure of the bone is destroyed during demineralization by acid[26], but, on the other hand, it is known that a host immune response can be induced by allogeneic bone[27-30], despite its processing Nevertheless, to the best of our knowledge, there are no studies concerning the possible immunogenicity and its influence on the bone formation for the different DBM products.

Since DBM was found to be effective and safe as an option of bone grafting, it has been used to induce bone formation in various procedures.

The aim of this study is to present a critical review of the existing literature concerning the use of DBM products, alone or as a composite graft, in various procedures requiring bone grafting in the extremities.

The key words “demineralized bone matrix”, and “DBM”, were used for a MEDLINE search and results were restricted to clinical trials in the English language. Clinical studies of use of DBM in spinal fusion were excluded.

Clinical studies were evaluated using the levels of evidence rating for clinical studies[31] and grades of recommendation are based on this evaluation[32] as follows: (1) Grade-A recommendations: Consistent level-I studies; (2) Grade-B recommendations: Consistent level-II or III studies; (3) Grade-C recommendations: Level-IV or V evidence, or conflicting evidence; and (4) Grade-I recommendations: Insufficient evidence to make a treatment recommendation. Twenty one clinical studies were selected for this review. These studies were analysed and described by category of use (Table 1).

Table 1 Clinical studies of demineralized bone matrix use in extremities.
Ref.DesignDiagnosis/proceduresType of graftMain outcomesLevel of evidence
Clinical studies of DBM used in fractures
Lindsey et al[33]Prospective, randomized pilot studyPatients treated for long bone fracturesDBM (Grafton®) + bone marrow n = 10 Iliac crest autograft n = 8Full bone formation in 90% with DBM + marrow and 75% with autograft at 12/12 Totally 100% healed with DBM + marrow and 63% heal with autograftII
Cheung et al[34]Retrospective comparative studyPeriarticular fractures (n = 28)Allograft conductive cancellous chips + DBM Grafton® (n = 13) Allograft conductive cancellous chips + DBM Orthoblast (n = 15)Healing on the first graft attempt without complications DBM Grafton®: 69% DBM Orthoblast: 100%III
Bibbo et al[35]Retrospective comparative studyPatients treated for displaced intra-articular calcaneal fracturesDBM + CaSO4 + vancomycin n = 33 Control group n = 11Union in 8.2 wk with graft, while 10.4 wk in control group P < 0.05 Wound problems in 15% in graft groupIII
Clinical studies of DBM used in nonunions
Hierholzer et al[36]Retrospective consecutive cohort studyPatients with an aseptic, atrophic delayed union or nonunion of a humeral shaft fracture were treated with ORIF and graftAutologous iliac crest bone graft n = 45 DBM (Grafton®) n = 33Union in 100% with autologous graft vs 97% in DBM group Union in 4.5 mo with autologous graft vs 4.2 mo in DBM group 44% of the autologous graft group had donor site morbidityIII
Wilkins et al[37]Prospective clinical studyPatients with stiff nonunions of long bones (n = 66)Percutaneous use of a mixture of autologous bone marrow and allograft DBM (AlloMatrix)61 of 69 patients with stiff nonunion went on to union in an average of 8.1 mo; 7 more healed after a second procedureIV
Wilkins et al[39]Retrospective clinical studyPatients undergoing surgical intervention for removal of benign tumors (n = 41) or treatement of nonunions in multiple bone types (n = 35)AlloMatrix Injectable Putty38 of 41 patients with benign tumors healed within an average of 4.8 mo, and 30 of 35 patients with nonunion went on to union in an average of 3.5 moIV
Ziran et al[38]Consecutive patientsPatients required bone grafting for atrophic/avascular nonunionsAlloMatrix + morselized cancellous allograft chips (1:1 ratio) n = 4151% developed postoperative drainage, 34% developed deep infection, 32% required surgical interventionIV
Clinical studies of DBM used in bone cysts
Park et al[40]Retrospective comparative studyCalcaneal unicameral cysts were treated with graftLyophilized irradiated CAB + bone marrow n = 13 DBM + bone marrow n = 10Complete healing in 9/13 in CAB group vs 5/9 in DBM group Healed with defect in 4/13 in CAB group and 3/9 in DBM group No infections or pathologic fractures during 48/12 follow upIII
Di Bella et al[41]Retrospective comparative study184 patients treated for unicameral bone cysts with cortical erosionMultiple injection of corticosteroid Single injection of DBM + bone marrow concentrate38% healed with steroids at 48/12 and 71% healed with DBM + BMC at 20/12 Failure rate after 1 steroid injection was 63% vs 24% with DBM + BMCIII
Rougraff et al[42]Consecutive patientsActive unicameral bone cyst (n = 23)Trephination and percutaneous injection of a mixture of demineralized bone matrix (Grafton) and autologous bone marrowHealing on the first graft attempt: 78%IV
Kanellopoulos et al[43]Consecutive patientsActive unicameral bone cyst (n = 19)Combination of percutaneous reaming, injection of a mixture of allogenic DBM (AlloMatrix) and autologous bone marrowHealing on the first graft attempt: 89.5%IV
Hass et al[44]Retrospective case seriesTreatment of juvenile bone cysts at all sites with DBMJuvenile bone cysts packed with DBM (n = 9)Totally osteodense images after an average of 8 mo, with no other significant changes in 2 yr follow-upIV
Sung et al[45]Retrospective comparative studyPatients, younger than 20, treated for humeral and femoral unicameral bone cystsCorticosteroid injection n = 94, curretage + bone graft n = 39, Steroids + DBM + bone marrow aspirate n = 34Failure rate was 84% with steroids, 64% with curretage and 50% with SDB P < 0.001. Retreatment in 76% with steroids, 63% with curretage and 71% with SDBIII
Clinical studies of DBM used in tumor surgery
Kim et al[46]Retrospective comparative studyBony defects after tumor surgery of various bone tumorsICS n = 28 DBM n = 28ICS and DBM success rate = 85.7% (24/28) and 88.9% (24/27) P < 0.05 Average healing time for ICS and DBM was 17.3 wk and 14.9 wk P < 0.05III
Wilkins et al[39]Retrospective clinical studyPatients undergoing surgical intervention for removal of benign tumors (n = 41) or treatment of nonunions in multiple bone types (n = 35)AlloMatrix injectable putty38 of 41 patients with benign tumors healed within an average of 4.8 mo, and 30 of 35 patients with nonunion went on to union in an average of 3.5 moIV
Clinical studies of DBM used in various long bone applications
Dallari et al[47]Prospective, randomized control trialHigh tibial osteotomy for genu varusDBSint® (Mg-hydroxyapatite + DBM) n = 9 SINTlife®n = 13 Lyophilised bone chips n = 96/52 DBSint® showed higher osseointegration rate than lyophilized bone chips (P < 0.01) 52/52 DBSint® was demonstrated as effective and safe as SINTlife® and bone chipsII
Hatzokos et al[48]Retrospective comparative studyPatients were managed with bone transport for the treatment of a tibial bone defect, with 3 types of docking procedures (n = 43)Group A: closed compression Group B: autologous iliac graft Group C: BMC + DBMHealing time was significantly longer in the compression group as compared with the BMC + DBM P < 0.05, no significant difference among the groups in terms of complication ratesIII
Wilkins et al[49]Prospective clinical studyPatients requiring bone grafting procedures (n = 50)Combination product of bioassayed DBM (AlloGro®) and calcium sulfate pelletsHealing rate of 98% within an average period of 11.8 wkIV
Clinical studies of DBM used in osteonecrosis of femoral head
Feng et al[50]Retrospective comparative studyTreatment of large osteonecrotic lesions of the femoral head with graftOsteoSet®2 DBM + free vasculated fibular graft n = 2, Free vasculated fibular graft + autologous cancellous bone n = 24Improvement in the mean Harris hip score was noted in both groups P < 0.001, no significant differences in Harris hip score and clinical outcomes between groupsIII
Clinical studies of DBM used in acetabular revision
Etienne et al[51]Retrospective clinical studyAcetabular revision surgery (n = 20)Acetabular reconstruction using a mixture of DBM (ALLOMATRIX™ C Bone Putty) and cancellous allograft chipsSuccessful graft incorporation in 18 of 20 patients (90%)IV
Clinical studies of DBM used in fusion
Thordarson et al[52]Retrospective Comparative StudyComplex ankle or hindfoot fusion with commercially available DBM formulations that did or did not contain crushed cancellous allograft bone (n = 63)Grafton® + allograft cancellous bone chips n = 37 Orthoblast + allograft cancellous bone chips n = 26Clinical and radiological fusion In DBM Grafton: 86% In DBM Orthoblast: 92%III
USE OF DBM IN FRACTURES

One level II[33] and two level III[34,35] comparative studies concerning the use of DBM in long bone fractures have been published. In the level II study the DBM combined with bone marrow aspirate was used in diaphyseal long bone fractures. In the first level III study the DBM combined with allograft cancellous chips was used in patients with periarticular fractures when in the second the DBM with calcium sulfate and vancomycin was used in displaced intra-articular calcaneal fractures.

Lindsey et al[33], in a prospective randomized pilot study, compared the results in patients with diaphyseal long bone fractures treated with either DBM Grafton® (Osteotech, Eatontown, NJ, United States) combined with aspirated bone marrow or autologous iliac crest bone graft alone. In 12 mo follow up, 90% of the patients who received DBM and aspirated bone marrow achieved full bone formation vs 75% of the autologous graft group. Additionally, finally healing rate was 100% in DBM group and 63% in the autograft group. Results suggest that the use of DBM with aspirated bone marrow is comparable with the use of autologous graft, in treatment of long bone fractures.

In a retrospective study, Cheung et al[34], compared Grafton® (Osteotech, Eatontown, NJ, United States) with Orthoblast (Gensci, Irvine, CA, United States) in the treatment of periarticular fractures in 28 patients. In both groups allograft cancellous chips were used in combination with the DBM. Bone union was achieved with no complications in 100% with Grafton® and in 69% in Orthoblast. Authors suggest the combination of allograft cancellous chips with Grafton® could be an alternative to autologous grafting for these fractures.

Bibbo et al[35] studied retrospectively bone healing and complications in 44 patients with displaced intra-articular calcaneal fractures with bone defect treated with open reduction and internal fixation. DBM with calcium sulfate (AlloMatrix™, Wright Medical, Arlington, TN) and vancomycin used in 33 patients and no grafting in 11 patients. The mean union time in the combined graft group was of 8.2 wk and of 10.2 wk in the control group. There were wound problems in 5 of 33 patients in DBM group (two minor and three serious wound problems), but in mean follow up time of 22 mo, no evidence of osteomyelitis were demonstrated.

USE OF DBM IN NON-UNIONS

One level III and three level IV studies concerning the use of DBM in non-unions were found. The level III study is a comparative study between DBM and autologous iliac crest bone graft in humeral delayed and non-unions[36]. The level IV studies report the results[37,38] and the complications[38] of the DBM use in bone non-unions.

Hierholzer et al[36], reported the results after open reduction, internal fixation and bone grafting in ninety-eight patient with non-union or delayed union of humeral shaft fractures. No significant difference was found between Grafton® DBM and autologous iliac crest bone graft. The union rate in Grafton® group was 97% with a mean healing time of 4.2 mo while in the autologous graft group the union rate was 100% with a mean healing time of 4.5 mo. However, in the autologous grafting group donor site morbidity was 44%.

Wilkins et al[37] treated 66 patients with non-unions of long bone fractures by percutaneous application of DBM (AlloMatrix™) and autologous bone marrow. Union rate was 88% at an average of 8.1 mo after surgery. Authors suggested that this method of treating nonunions is as successful as iliac crest autologous bone grafting, with additional benefits of reduced cost, decreased morbidity of donor site and shorter hospital stay.

In a retrospective clinical study, Wilkins et al[39] used AlloMatrix™ putty in 35 patients with non-union in various bones and in 41 patients after surgical treatment of benign tumors. Union rate for the non-union group was 85.7% in a mean time of 3.5 mo while the heling rate in the tumor group was 92.7% in an average of 4.8 mo.

In the other hand, Ziran et al[38], in a series of 41 consecutive patients, who required bone grafting for atrophic/avascular nonunions, presented the complications associated with the use of a specific graft (AlloMatrix™). Patients were monitored for healing and adverse effects, (local or systemic reactions, wound problems, infection). Of the 41 patients, 13 had drainage which required surgical intervention, and 14 patients developed deep infection of the surgical area, of whom 11 patients required surgical treatment. Authors suggest that the use of that type of graft resulted in an unaccepted rate of complications, compared to the complication rate of the use of allograft in literature.

USE OF DBM IN BONE CYSTS

Over the last years DMB becomes more and more popular for the treatment of bone cysts. Several studies present good results of the use of DBM in bone cysts, proving high healing and low complication rate. There are two level III[40,41] and two level IV[42,43] studies, which present the use of DBM and autologous bone marrow in treatment of active unicameral bone cysts, one level IV[44] study with the use of DBM in juvenile bone cysts and one level III[45] study with use of DBM combined with autologous bone marrow and steroids in bone cysts.

Park et al[40] compared retrospectively the efficacy of percutaneous local injection of lyophilized chips of allogeneic bone and autogenous bone marrow, vs demineralized bone powder (Injecta bone TR, Modumedi Ltd., Daegu, Republic of Korea) and autogenous bone marrow, in 23 calcaneal unicameral cysts. Patients were followed up for an average of four years. Complete healing was achieved in 9 out of 13 cysts treated with chip allogeneic bone and in 5 out of 10 cysts treated with demineralized bone powder. Four of the first group and three of the DBM group healed with a defect, while the other two of the DBM group, classified as persistent cysts. During follow up there was no sign of infection or pathologic fractures.

Di Bella et al[41], in a retrospective comparative study of 184 patients with unicameral bone cysts and cortical erosion, compared the outcomes of multiple injections of costricosteroids vs single injection of DBM (Musculoskeletal Tissue Bank of the Rizzoli Orthopaedic Institute) and bone marrow concentrate. Minimum follow up of both groups was 12 mo. After first injection, authors observed a healing rate of 21% in the steroids group vs 58% in the DBM and bone marrow concentrate group. Multiple injections of steroids followed in the steroid group. Finally 38% healed with corticosteroids when 71% healed with DBM and bone marrow mixture. There was no difference of fracture rates between the two groups. Authors concluded that treating unicameral bone cysts with a single injection of a mixture of DBM and bone marrow concentrate appears to provide high healing rate, and better outcomes when compared with percutaneous corticosteroid injections.

Rougraff et al[42] applied percutaneously autologous bone marrow combined with DBM (Grafton®) in 23 patients with bone cysts. The healing rate was 78% in a mean time of 50 mo, while in 5 patients a second procedure was required. No pathologic fracture was reported.

In another series of 19 children, Kanellopoulos et al[43], used a combination of percutaneous reaming and an injection of a mixture of DBM (AlloMatrix™) and autologous bone marrow, in the treatment of active unicameral bone cysts. During a mean follow up time of 28 mo, authors reported a healing rate after the first graft attempt, up to 89.5%, while two patients required second surgical intervention. Authors reported no pathologic fracture or other complication.

Hass et al[44], treated 9 children with bone cysts (juvenile cysts) with Grafton® packing after curettage of the cyst. Complete healing was achieved in all patients, with totally osteodense radiographic images after an average time of 8 mo. There was only one significant complication in a child, who sustained a pathologic distal tibial fracture five months post-operatively. There were no other significant changes in two years follow up.

In a retrospective comparative study of 167, younger than 20 years old, patients, Sung et al[45], presented the failure rates of three surgical managements of humeral and femoral unicameral bone cysts. One therapeutic strategy was the use of corticosteroid injection in 94 patients, the second was curettage of the cyst and use of bone graft in 39 patients and the third was a combination of injection of steroids, DBM (Grafton® gel) and bone marrow aspirate in 34 patients. Mean follow up was 7.3 years and outcomes included treatment failure, defined clinically as pathologic fracture or need for retreatment, and complications. After one treatment, 84% of cysts treated with steroids had failed while, 64% of the curettage group failed and only 50% of the third group with the steroids, DBM and bone marrow mix didn’t healed. For unicameral bone cysts requiring retreatment, 76% retreated with steroids had failed vs 63% with curettage and 71% with mix composite. Authors concluded that the use of steroids with DBM and bone marrow aspirate is a reasonable first surgical treatment of unicameral bone cysts in young patients.

USE OF DBM IN TUMOR SURGERY

There are at least two studies[39,46], presenting the use of DBM in defects due to surgical intervention of bone tumors. One level IV study presents the use of an injectable type of graft, which is DBM and calcium sulfate, in bone tumor surgery. The other level III study investigates the use of DBM in defects after removal various bone tumors.

Recently, Kim et al[46] investigated, retrospectively, the efficacy of injectable calcium sulfate and DBM in bone defects after tumor surgery of various bone tumors. 56 patients, who were surgically treated for bone tumors, randomly allocated in two groups. 28 patients treated with injectable calcium sulfate, while the other 28 with DBM graft (Orthoblast II, Integra OrthoBiologics Inc., Irvine, CA, United States). Radiologic and clinical outcomes compared between groups. One case with early pathologic fracture in DBM groups has been excluded from the study, so the reference value of this group was 27 patients. Results showed successful healing in 24 out of 28 patients, in an average of 17.3 wk with injectable calcium sulfate vs 24 out of 27 patients, in an average of 14.9 wk with DBM graft. Authors concluded that both grafts appear to be comparable and effective in the treatment of bone defects following tumor surgery.

Wilkins et al[39] analysed retrospectively a series of 41 patients with benign tumors treated with removal of the lesion and use of AlloMatrix™ Injectable Putty for grafting. In the same study, 35 patients with nonunions in multiple bone types, treated with the same graft, as mentioned above. Bone healing was observed at an average of 4.8 mo in 38 out of 41 patients in the tumor group. Complications developed in 12 patients, in both groups, including infection in two patients, continued sterile wound drainage in five patients, refracture in two cases, hardware failure in one case, one postoperative neuroma formation, and one case of decreased range of joint motion. A recurrence of the tumor occurred in three patients. In this study, AlloMatrix™ Injectable Putty used as bone void filler in bone defects after tumor surgery. Authors believed that the use of DBM shows results equal to those reported with autograft.

DBM IN VARIOUS LONG BONE APPLICATIONS

In a prospective randomized control trial, Dallari et al[47] investigated the bone healing ability of DBSint®, which is a biomimetic composite, obtained by mixing SINTlife® (Fin-Ceramica SpA, Faenza, Italy) and human DBM, produced in authors Institute Bone Bank (Rizzoli Orthopaedic Institute, Bologna, Italy), vs a Mg-hydroxyapatite graft (SINTlife®) and lyophilized bone chips, in high tibial osteotomies for genu varus. Nine patients randomly received DBSint®, 13 patients SINTlife®, and nine patients received allograft lyophilized bone chips, as a control group. Radiological, clinical and histomorphological outcomes were evaluated. At six-weeks follow-up, DBSint® showed a higher osseointegration rate in comparison with lyophilised bone chips. while, at the same time, histomorphometry of computed tomography guided bone biopsies showed that a good osteogenetic potential was demonstrated with DBSint®, as well as with SINTlife® and the control group. At final follow-up of 1 year, all patients had relief from knee pain and improvement of walking ability. The Knee Society Functional Score was significantly different between groups, but all recorded values were in normal range. The study concluded that DBSint® was demonstrated as effective and safe as SINTlife® and lyophilized bone chips, within the limits of the study.

Hatzokos et al[48], evaluated the use of different grafts in the docking site in patients who managed with bone transport for treatment of a tibial defect. All 43 patients were divided into three groups according to the “docking site procedure” used. In group A, closed compression was applied, in group B surgical debridement of the docking site followed by the application of autologous iliac bone graft, and in group C, debridement followed by the application of bone marrow concentrate and DBM (Grafton Putty DBM OST Development SA, Clermont-Ferrand, France). Docking site consolidation was assessed both radiographically and clinically. Healing time was significantly longer in the first group treated only with closed compression, compared with DBM group, while there was no difference between the grafting groups. There was no significant difference in complication rates between the different groups. Authors concluded that the application of DBM and autologous bone marrow concentrate is equivalent to autologous bone graft in management of docking site during distraction osteogenesis, proving that it is an effective and safe treatment option.

In a prospective clinical study, Wilkins et al[49] reported that a mixture of calcium sulphate pellets and DBM (AlloGro®). In this level IV study, 50 patients underwent bone grafting for a variety of diagnosis including benign bone lesions (n = 35), non-union of long bones (n = 11), osteomyelitis (n = 3), and one patient for acute fracture. Results showed high efficacy of grafting, since 49 out of 50 patients healed in an average of 11.8 wk. The complication rate was very low, with a re-infection in one patient, and a recurrence of a bone cyst in another patient. According to the authors this mixture of calcium sulphate pellets and AlloGro® DBM was safe with no graft-related complications and effective for bone regeneration.

USE OF DBM IN OSTEONECROSIS OF FEMORAL HEAD

In a level III study, Feng et al[50] studied the safety and efficacy of a type of DBM (OsteoSet®) in treatment of patients with large osteonecrotic lesions of the femoral head. In a retrospective study the authors compared 24 patients that underwent free vascularized fibular grafting and OsteoSet® with 24 patients who underwent fibular grafting and autologous cancellous bone grafting. There was no significant difference in clinical outcomes, Harris Hip Score or complication rates between the two groups. The authors concluded that in patients with femoral head osteonecrosis treated with free vasculated fibular grafting, harvesting autologous bone can be avoided using the equally effective OsteoSet® DBM.

USE OF DBM IN ACETABULAR REVISION

Etienne et al[51] in a level IV retrospective study reported the results after bone grafting for bone loss in acetabulum revision surgery in 20 patients. The authors used allograft cancellous bone mixed with DBM (Allomatrix™). Successful graft incorporation was found in 90% of the patients in a mean follow-up of 27 mo.

USE OF DBM IN FUSION

There is one level III study, of Thordarson et al[52], comparing two different DBM products used in 63 patients with ankle or foot fusions. In 37 patients Grafton® putty was used, and in the rest 26 patients Orthoblast used to enhance fusion. All patients followed-up, clinically and radiographically to fusion or non-union time, with a minimum follow-up of 1 year. The Grafton group succeeded a fusion rate of 86%, while the Orthoblast group healing rate reached 92%. Authors concluded there was no significant difference between union rates of those two grafts.

CONCLUSION

Although there is an able number of studies in the literature, examining the use of DBM products either alone or in combination with other grafting materials, in several applications in extremity operations, there is little information concerning the true efficacy of most of these products.

There are very few studies that examine the true efficacy of specific DBM products alone as a graft. In the other hand there are a lot of studies, which examined the use of DBM in combination with osteogenic grafts such as bone marrow, with osteoconductive bone-void filler such as calcium sulphate, and other allografts like cancellous chips.

It is also obvious that from a big variety of available DBM in the market, there are clinical studies available for only a few commercial products. Although information from clinical data is limited, pre-clinical studies have shown that there are differences between the different products concerning their osteoconductive and osteoinductive characteristics. Therefore, our recommendations should probably also be referred to the specific products as well as to the levels of the available studies.

INDICATIONS AND RECOMMENDATIONS
Use of DBM in fractures

According to the existing literature there is insufficient evidence to make a treatment recommendation (grade-I recommendations).

There is only (1) one Level II[33] comparative study where the DBM combined with bone marrow aspirate was used in diaphyseal long bone fractures; (2) one Level III study[34] where the DBM combined with allograft cancellous chips was used in patients with periarticular fractures; and (3) one Level III[35] study where the DBM with calcium sulfate and vancomycin was used in displaced intra-articular calcaneal fractures.

Use of DBM in nonunions

Four studies (one Level III[36] and three Level IV studies[37-39]) concerning the use of DBM in non-unions were found (grade-C recommendations).

Although there is a comparative study between DBM and autologous iliac crest bone graft in humeral delayed and non-unions[36] (level III study) this is the only comparative study.

Use of DBM in bone cysts

There are four studies (two Level III[40,41] and two Level IV[42,43] studies), presenting the use of DBM and autologous bone marrow in treatment of active unicameral bone cysts, one level III[45] study with use of DBM combined with autologous bone marrow and steroids and one level IV[44] study with the use of DBM alone.

Therefore it is suggested that the use of DBM and autologous bone marrow in treatment of active unicameral bone cyst is a good option (grade-B recommendations).

Use of DBM in tumor surgery

There is only one retrospective comparative (Level III) study[46] between injectable calcium sulfate and DBM and one level IV study presenting the results of an injectable DBM (grade-C recommendations).

DBM in various applications

There is insufficient evidence to make a treatment recommendation (grade-I recommendations) as there is only one available study for the following procedures: (1) High tibial osteotomy for genu varus[47] (level II study); (2) Docking site procedure in bone transport for the treatment of a tibial bone defect (level III study)[48]; (3) Various bone grafting procedures (level IV study)[49]; (4) Treatment of large osteonecrotic lesions of the femoral head with graft (level III study)[50]; (5) Acetabular revision surgery (level IV study)[51]; and (6) Complex ankle or hindfoot fusion (level III study)[52].

In conclusion, further clinical studies of higher level of Evidence are required in order to improve the Recommendation Grades for or against the use of DBM products (alone or combined with other grafting material) in bone grafting procedures.

Footnotes

P- Reviewer: Decker S S- Editor: Tian YL L- Editor: A E- Editor: Liu SQ

References
1.  Dinopoulos H, Dimitriou R, Giannoudis PV. Bone graft substitutes: What are the options? Surgeon. 2012;10:230-239.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 52]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
2.  Khan SN, Tomin E, Lane JM. Clinical applications of bone graft substitutes. Orthop Clin North Am. 2000;31:389-398.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 126]  [Cited by in F6Publishing: 126]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
3.  Berven S, Tay BK, Kleinstueck FS, Bradford DS. Clinical applications of bone graft substitutes in spine surgery: consideration of mineralized and demineralized preparations and growth factor supplementation. Eur Spine J. 2001;10 Suppl 2:S169-S177.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 37]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
4.  Keating JF, McQueen MM. Substitutes for autologous bone graft in orthopaedic trauma. J Bone Joint Surg Br. 2001;83:3-8.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 131]  [Cited by in F6Publishing: 145]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
5.  Finkemeier CG. Bone-grafting and bone-graft substitutes. J Bone Joint Surg Am. 2002;84-A:454-464.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Kurz LT, Garfin SR, Booth RE. Harvesting autogenous iliac bone grafts. A review of complications and techniques. Spine (Phila Pa 1976). 1989;14:1324-1331.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Fernyhough JC, Schimandle JJ, Weigel MC, Edwards CC, Levine AM. Chronic donor site pain complicating bone graft harvesting from the posterior iliac crest for spinal fusion. Spine (Phila Pa 1976). 1992;17:1474-1480.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Habal MB, Reddi AH. Bone grafts and bone induction substitutes. Clin Plast Surg. 1994;21:525-542.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Arrington ED, Smith WJ, Chambers HG, Bucknell AL, Davino NA. Complications of iliac crest bone graft harvesting. Clin Orthop Relat Res. 1996;300-309.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1108]  [Cited by in F6Publishing: 1021]  [Article Influence: 36.5]  [Reference Citation Analysis (0)]
10.  Sandhu HS, Grewal HS, Parvataneni H. Bone grafting for spinal fusion. Orthop Clin North Am. 1999;30:685-698.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 142]  [Cited by in F6Publishing: 109]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
11.  Niedhart C, Pingsmann A, Jürgens C, Marr A, Blatt R, Niethard FU. [Complications after harvesting of autologous bone from the ventral and dorsal iliac crest - a prospective, controlled study]. Z Orthop Ihre Grenzgeb. 2003;141:481-486.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 18]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
12.  Dimitriou R, Mataliotakis GI, Angoules AG, Kanakaris NK, Giannoudis PV. Complications following autologous bone graft harvesting from the iliac crest and using the RIA: a systematic review. Injury. 2011;42 Suppl 2:S3-15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 531]  [Cited by in F6Publishing: 522]  [Article Influence: 40.2]  [Reference Citation Analysis (0)]
13.  Urist MR. Bone: formation by autoinduction. Science. 1965;150:893-899.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4079]  [Cited by in F6Publishing: 3611]  [Article Influence: 61.2]  [Reference Citation Analysis (0)]
14.  Buring K, Urist MR. Effects of ionizing radiation on the bone induction principle in the matrix of bone implants. Clin Orthop Relat Res. 1967;55:225-234.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Dubuc FL, Urist MR. The accessibility of the bone induction principle in surface-decalcified bone implants. Clin Orthop Relat Res. 1967;55:217-223.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Urist MR, Silverman BF, Büring K, Dubuc FL, Rosenberg JM. The bone induction principle. Clin Orthop Relat Res. 1967;53:243-283.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 434]  [Cited by in F6Publishing: 435]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
17.  Eriksson C. Surface energies and the bone induction principle. J Biomed Mater Res. 1985;19:833-849.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 14]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
18.  Jones CB. Biological basis of fracture healing. J Orthop Trauma. 2005;19:S1-S3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 8]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
19.  Han B, Tang B, Nimni ME. Quantitative and sensitive in vitro assay for osteoinductive activity of demineralized bone matrix. J Orthop Res. 2003;21:648-654.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 85]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
20.  Oakes DA, Lee CC, Lieberman JR. An evaluation of human demineralized bone matrices in a rat femoral defect model. Clin Orthop Relat Res. 2003;281-290.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 56]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
21.  Takikawa S, Bauer TW, Kambic H, Togawa D. Comparative evaluation of the osteoinductivity of two formulations of human demineralized bone matrix. J Biomed Mater Res A. 2003;65:37-42.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 54]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
22.  Peterson B, Whang PG, Iglesias R, Wang JC, Lieberman JR. Osteoinductivity of commercially available demineralized bone matrix. Preparations in a spine fusion model. J Bone Joint Surg Am. 2004;86-A:2243-2250.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Lee YP, Jo M, Luna M, Chien B, Lieberman JR, Wang JC. The efficacy of different commercially available demineralized bone matrix substances in an athymic rat model. J Spinal Disord Tech. 2005;18:439-444.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 64]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
24.  Bae HW, Zhao L, Kanim LE, Wong P, Delamarter RB, Dawson EG. Intervariability and intravariability of bone morphogenetic proteins in commercially available demineralized bone matrix products. Spine (Phila Pa 1976). 2006;31:1299-1306; discussion 1307-1308.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Wildemann B, Kadow-Romacker A, Haas NP, Schmidmaier G. Quantification of various growth factors in different demineralized bone matrix preparations. J Biomed Mater Res A. 2007;81:437-442.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 117]  [Cited by in F6Publishing: 125]  [Article Influence: 7.4]  [Reference Citation Analysis (0)]
26.  Tuli SM, Singh AD. The osteoninductive property of decalcified bone matrix. An experimental study. J Bone Joint Surg Br. 1978;60:116-123.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Bos GD, Goldberg VM, Zika JM, Heiple KG, Powell AE. Immune responses of rats to frozen bone allografts. J Bone Joint Surg Am. 1983;65:239-246.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Friedlaender GE. Immune responses to osteochondral allografts. Current knowledge and future directions. Clin Orthop Relat Res. 1983;58-68.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Horowitz MC, Friedlaender GE. Immunologic aspects of bone transplantation. A rationale for future studies. Orthop Clin North Am. 1987;18:227-233.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Friedlaender GE, Horowitz MC. Immune responses to osteochondral allografts: nature and significance. Orthopedics. 1992;15:1171-1175.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Wright JG, Swiontkowski MF, Heckman JD. Introducing levels of evidence to the journal. J Bone Joint Surg Am. 2003;85:1-3.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Wright JG, Einhorn TA, Heckman JD. Grades of recommendation. J Bone Joint Surg Am. 2005;87:1909-1910.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 91]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
33.  Lindsey RW, Wood GW, Sadasivian KK, Stubbs HA, Block JE. Grafting long bone fractures with demineralized bone matrix putty enriched with bone marrow: pilot findings. Orthopedics. 2006;29:939-941.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Cheung S, Westerheide K, Ziran B. Efficacy of contained metaphyseal and periarticular defects treated with two different demineralized bone matrix allografts. Int Orthop. 2003;27:56-59.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Bibbo C, Patel DV. The effect of demineralized bone matrix-calcium sulfate with vancomycin on calcaneal fracture healing and infection rates: a prospective study. Foot Ankle Int. 2006;27:487-493.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Hierholzer C, Sama D, Toro JB, Peterson M, Helfet DL. Plate fixation of ununited humeral shaft fractures: effect of type of bone graft on healing. J Bone Joint Surg Am. 2006;88:1442-1447.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 86]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
37.  Wilkins RM, Chimenti BT, Rifkin RM. Percutaneous treatment of long bone nonunions: the use of autologous bone marrow and allograft bone matrix. Orthopedics. 2003;26:s549-s554.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Ziran BH, Smith WR, Morgan SJ. Use of calcium-based demineralized bone matrix/allograft for nonunions and posttraumatic reconstruction of the appendicular skeleton: preliminary results and complications. J Trauma. 2007;63:1324-1328.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 39]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
39.  Wilkins RM, Kelly CM. The effect of allomatrix injectable putty on the outcome of long bone applications. Orthopedics. 2003;26:s567-s570.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Park IH, Micic ID, Jeon IH. A study of 23 unicameral bone cysts of the calcaneus: open chip allogeneic bone graft versus percutaneous injection of bone powder with autogenous bone marrow. Foot Ankle Int. 2008;29:164-170.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 35]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
41.  Di Bella C, Dozza B, Frisoni T, Cevolani L, Donati D. Injection of demineralized bone matrix with bone marrow concentrate improves healing in unicameral bone cyst. Clin Orthop Relat Res. 2010;468:3047-3055.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 42]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
42.  Rougraff BT, Kling TJ. Treatment of active unicameral bone cysts with percutaneous injection of demineralized bone matrix and autogenous bone marrow. J Bone Joint Surg Am. 2002;84-A:921-929.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Kanellopoulos AD, Yiannakopoulos CK, Soucacos PN. Percutaneous reaming of simple bone cysts in children followed by injection of demineralized bone matrix and autologous bone marrow. J Pediatr Orthop. 2005;25:671-675.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 29]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
44.  Hass HJ, Krause H, Kroker S, Wagemann W. Implantation of human demineralized bone matrix (DBM) for the treatment of juvenile bone cysts. Oper Orthop Traumatol. 2006;18:19-33.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Sung AD, Anderson ME, Zurakowski D, Hornicek FJ, Gebhardt MC. Unicameral bone cyst: a retrospective study of three surgical treatments. Clin Orthop Relat Res. 2008;466:2519-2526.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 60]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
46.  Kim JH, Oh JH, Han I, Kim HS, Chung SW. Grafting using injectable calcium sulfate in bone tumor surgery: comparison with demineralized bone matrix-based grafting. Clin Orthop Surg. 2011;3:191-201.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
47.  Dallari D, Savarino L, Albisinni U, Fornasari P, Ferruzzi A, Baldini N, Giannini S. A prospective, randomised, controlled trial using a Mg-hydroxyapatite - demineralized bone matrix nanocomposite in tibial osteotomy. Biomaterials. 2012;33:72-79.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 35]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
48.  Hatzokos I, Stavridis SI, Iosifidou E, Karataglis D, Christodoulou A. Autologous bone marrow grafting combined with demineralized bone matrix improves consolidation of docking site after distraction osteogenesis. J Bone Joint Surg Am. 2011;93:671-678.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 53]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
49.  Wilkins RM, Kelly CM, Giusti DE. Bioassayed demineralized bone matrix and calcium sulfate: use in bone-grafting procedures. Ann Chir Gynaecol. 1999;88:180-185.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Feng Y, Wang S, Jin D, Sheng J, Chen S, Cheng X, Zhang C. Free vascularised fibular grafting with OsteoSet®2 demineralised bone matrix versus autograft for large osteonecrotic lesions of the femoral head. Int Orthop. 2011;35:475-481.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 15]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
51.  Etienne G, Ragland PS, Mont MA. Use of cancellous bone chips and demineralized bone matrix in the treatment of acetabular osteolysis: preliminary 2-year follow-up. Orthopedics. 2004;27:s123-s126.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Thordarson DB, Kuehn S. Use of demineralized bone matrix in ankle/hindfoot fusion. Foot Ankle Int. 2003;24:557-560.  [PubMed]  [DOI]  [Cited in This Article: ]