|Year : 2020 | Volume
| Issue : 1 | Page : 54-60
Is bone morphogenetic protein 2 effective, safe and cost-efficient in nonunion surgery of long bones
Chun Hong Tang1, Shah Jehan1, Hemant K Sharma2
1 Department of Trauma and Orthopaedics, Hull University Teaching Hospitals, Hull, England, UK
2 Department of Trauma and Orthopaedics, Hull York Medical School, Hull University Teaching Hospitals, University of Hull, Hull, England, UK
|Date of Submission||01-Apr-2020|
|Date of Decision||21-Apr-2020|
|Date of Acceptance||22-Apr-2020|
|Date of Web Publication||30-Jun-2020|
Dr. Chun Hong Tang
Hull University Teaching Hospitals, Anlaby Road, Hull HU3 2JZ
Source of Support: None, Conflict of Interest: None
Background: The prevalence of fracture nonunion surgery is increasing in the general population with greater advancement in trauma surgery. Increasingly complex injuries involving the limbs are now amenable for limb preservation surgery, where in the past amputations would have been common place. Aims and Objectives: We carried out a literature review on the evidence available on the use of Bone Morphogenetic Protein 2 (BMP-2) for long bone nonunion surgery. Methods: This literature review was initially undertaken for a systematic review using PRISMA guidelines, however due to lack of high-quality published literature, we present a narrative review instead. The abstracts of the articles obtained on Medline and Embase database were scrutinised according to the inclusion and exclusion criterions. The primary endpoint was union rates, and secondary end points were time to union, re-operation and post op infection rates. Results: A total of 240 titles were obtained, and after review, 3 articles were selected for final analysis. There were no statistically significant differences noted between the primary and secondary endpoints in the autologous bone graft (ABG) group when compared against the BMP-2 with allograft group. An additional review of the literature suggests that BMP-2 is cost neutral to the healthcare system. Conclusion: Although no firm conclusions can be drawn due to lack of power, the trend suggests no significant difference in union rates between autograft or BMP-2 with allograft, with comparable results to each other in all measurable end-points.
Keywords: Autograft, bone morphogenetic protein 2, fracture, iliac crest graft, long bone fractures, nonunion surgery, nonunion surgery, synthetic grafts, trauma
|How to cite this article:|
Tang CH, Jehan S, Sharma HK. Is bone morphogenetic protein 2 effective, safe and cost-efficient in nonunion surgery of long bones. J Limb Lengthen Reconstr 2020;6:54-60
|How to cite this URL:|
Tang CH, Jehan S, Sharma HK. Is bone morphogenetic protein 2 effective, safe and cost-efficient in nonunion surgery of long bones. J Limb Lengthen Reconstr [serial online] 2020 [cited 2020 Sep 21];6:54-60. Available from: http://www.jlimblengthrecon.org/text.asp?2020/6/1/54/288572
| Introduction|| |
Fracture nonunion in long bones can cause to a patient's quality of life. The persistent pain experienced at the fracture site, results in muscle wasting, limited mobility, and loss of function. The prevalence of nonunions among long bones has been estimated to occur in up to 5%–10% of all fractures.
There have been multiple papers looking at the most effective methods to treat long bone nonunions. Kanakaris et al. published on the evidence available of using either autologous bone grafting or synthetic graft materials such as bone morphogenetic proteins (BMPs) at the sites of nonunions. They reported on a randomized trial by Friedlaender et al. in tibial aseptic nonunions, which established the safety and equivalent efficacy of BMP-7 when compared to autologous bone grafting.,
Autologous bone grafting is the gold standard, of which iliac crest grafts are the most common. It has the ideal combination of osteoconductive, osteoinductive, and osteogenic stem cells. However, its harvesting and use are associated with a degree of donor site morbidity and graft availability. A study by Hernigou et al. has shown that donor site morbidity had an overall major and minor complication rate of 5% and 13%, respectively. Major complications include donor defect hernias, vascular and sciatic nerve injuries, deep infections, deep hematomas, and iliac wing fractures. The minor complications involved were superficial infections, seromas, and hematomas. They concluded that bone marrow aspiration was as effective and had less complications than bone harvested from the iliac crest.
It is well accepted that with age, bone marrow is gradually and continuously replaced by fatty tissue, and therefore, the concentration of osteogenic cells decreases. This theory has been supported by Karampinos et al. looking at the composition of bone marrow in different healthy and pathological states using quantitative magnetic resonance imaging scans. Therefore, in the middle-aged to elderly population, alternative synthetic bone graft options should be considered as an adjunct intraoperatively.
The use of bone graft to enhance bony union is widely accepted, although its importance has been questioned by Moran et al. This group suggests that the ideal mechanical environment is more important than the use of biological substitutes to enhance union rates, though this is not universally accepted. Another school of thought believes that the biological environment is equally important, especially in atrophic nonunion. They reported union rates of 94.6% with bone grafting and 95% without it.
The interest in BMPs increased in the early 1990s, when the subtyping of recombinant human BMP was done. BMP, when attached to various carriers and scaffolds, can provide sufficient osteoinductive and osteoconductive properties, to stimulate bone healing at fracture sites. In addition, it has limited susceptibility to graft versus host immunological responses when compared against the use of allograft.
BMPs are a variant of multifunctional growth factors that belong to the transforming growth factor-β group. BMPs were first identified by Urist et al. in 1965, although the proteins responsible for bone formation were not discovered till the purification and sequencing of BMP-3 (osteogenin) and the cloning of BMP-2 and BMP-4 in 1988 by Wozney et al., Since then, around 20 different subtypes of BMP have been discovered.
The most common BMPs used in the market in the last few years were both the BMP-2 (InductOs, Medtronic Biopharma BV, The Netherlands) and BMP-7 (OP-1, Olympus Biotech, USA). However, BMP-7 was subsequently withdrawn from the market following on a business decision made by its parent company. As a result, BMP-2 is the only remaining clinically available BMP graft that is available to surgeons. Its use within open fractures and spinal surgery has been licensed and established for a few years but is currently only available as an off-label product for use in long bone nonunion surgery.
The aim of this study is to undertake a review of efficacy of BMP-2 in long bone nonunions and its potential complications.
| Methods|| |
The systematic review was undertaken using PRISMA guidelines as per [Figure 1]. Two independent reviewers (CHT and SJ) performed the search using PubMed and Embase using the following keywords: bone morphogenetic protein 2, BMP-2, long bone, nonunion surgery, nonunion surgery, complications, healing and revision surgery. The search was limited to the English language from 1960 to the present.
The initial search produced 240 titles. Both authors then reviewed these titles and abstracts to select the articles where BMP-2 was specifically used. We limited our search to include only BMP-2 as BMP-7 is no longer clinically relevant, as described above. Of the 240 titles reviewed, 21 abstracts were assessed as being eligible and their full articles were obtained for review. These articles were reviewed independently and three studies were selected for final analysis (Flier et al., Tressler et al., and Takemoto et al.).
The primary endpoint for the study was union rates. The secondary endpoints were the time to union of fractures, reoperation rates, and incidence of postoperative infections and cost-effectiveness.
The inclusion criteria were as follows:
- Studies in which BMP-2 was used for established long bone (femur, tibia, humerus, radius, and ulna) fracture nonunion
- Studies where BMP-2 was compared directly against autologous bone graft (ABG).
The studies were excluded on the basis of the following criteria:
- Animal studies
- Nonclinical studies
- Studies where BMP-2 was used for primary fractures
- Studies where BMP-2 was used for arthrodesis rather than fracture nonunion
- Studies where BMP-2 was used in bones of the extremities (hand and feet)
- Studies where BMP-2 was used in congenital cases, for example, congenital pseudoarthrosis of tibia
- Case series with <10 cases.
A review of the three studies selected was performed. The Cochrane RevMan v5.3 (Cochrane Community, London, United Kingdom) was used for statistical analysis.
| Results|| |
All three studies were cohort studies. There were two retrospective studies (Flierl and Tressler et al.) and one prospective (Takemoto et al.) study. There were a total of 339 patients in all three studies. There were 183 females and 156 males. The age range was 31–63 years, with an average age of 48 years. The average follow-up time was 17 months (3–34 months).
Overall, there were no statistically significant differences noted between the primary and secondary endpoints in the ABG group when compared against the BMP-2 group.
The study by Flierl et al. involved a total of 182 patients across 2 level 1 trauma centers in the United States of America. This was a heterogeneous study with four different treatment arms in their study. Nonunion was defined as a fracture that was not completely healed at 9 months. The four cohorts of bone grafts used in this study were autograft alone, allograft alone, allograft, and autograft in combination and BMP-2 with or without allograft. When this last group was considered, there were 23 patients in total; 6 received BMP-2 alone while 17 had BMP-2 with allograft. The long bones included were the femur, tibia, and humerus. Both septic and aseptic nonunions were included in this study. The minimum follow-up time in this study was 12 months.
Their primary outcome in this study was time to union, with secondary outcomes of postoperative infection, revision surgery, and revision bone grafting. They found that the time to union in patients who had received autologous bone grafting (198 days, 95% confidence interval [CI]: 172–255 days) compared to the BMP-2 group (217 days, 95% CI: 158–277 days) was not significantly different. When their secondary outcomes of surgical revision rates and the need for further revision with bone grafting was considered, the autograft group had a significantly reduced rate for both (17.1% and 8.6%), when compared against the BMP-2 group (26.1% and 17.4%) (P < 0.01 for autograft vs. all other cohorts).
The incidence of postoperative infection was higher in the BMP-2 group (17.4%) versus the autograft group (12.4%). This was not statistically significant between the two groups. Interestingly, when further stratified by superficial versus deep infection, however, the autograft had a higher superficial infection rate (ABG: 4.8% vs. BMP-2: 0%), whereas the BMP-2 group had a higher deep infection rate (ABG: 7.6% vs. BMP-2: 17.4%). Neither of these subanalysis results was significant.
They concluded that autograft was the most efficacious bone grafting adjunct for long bone nonunion surgery. They highlighted potential safety concerns of the use of BMP and allograft and highlighted the increasing use of the Reamer-Irrigator-Aspirator (RIA) system as an alternative to iliac crest bone harvesting.
The next study by Tressler et al. compared a total of 89 patients with 93 established long bone (femur, tibia, and humerus) nonunions. Nonunion was defined as lack of bridging callus formation in 3 out of 4 cortices radiographically at 6 months or no display of progression of healing over a 3-month period. Patients with active infection at the nonunion site were excluded. The two arms in this study were autograft only (iliac crest grafting, 74 patients) and BMP-2 with the addition of allograft cancellous bone chips (19 patients). Patients were followed up for a mean of 30 months.
They did not find any significant difference between the union rates of ABGs against BMP-2 (ABG: 85% vs. BMP-2: 68%). This was further confirmed on logistic regression analysis in their study. They also secondarily did not find any difference in the incidence of postoperative infections between the two groups (ABG: 16.2% vs. BMP-2: 5.3%). They, however, did find a significant difference in favor of BMP-2 in terms of shorter operative times and subsequently less intraoperative blood loss. They also performed subanalysis of multiple variables that can affect the prevalence of nonunion that is not part of the scope of this review.
They concluded that, although autologous bone grafting remains the gold standard, BMP-2 might offer a suitable alternative, particularly when it reduces overall operative blood loss and time.
The final study by Takemoto et al. compared augmenting ABG with BMP-2 versus ABG alone. ABG was obtained from the iliac crest. They compared a total of 118 patients with nonunions, 68 had received both BMP-2 and ABG, while 50 received ABGs alone. Patients with active infection at the nonunion site were excluded. Patients were followed up prospectively at 3-, 6-, and 12-month intervals.
They found that there was no difference between either group in terms of union rates (ABG: 96% vs. BMP-2: 98.5%) or its time to union (ABG: 5.4 months vs. BMP-2: 6.6 months). They, therefore, concluded that the addition of BMP-2 did not have the desired synergistic effect on healing of long bone nonunions.
Surgical complications also did not differ between the treatment groups. The reoperation rate, however, was slightly higher for the BMP-2 group versus the autograft group (BMP-2: 16.2 vs. ABG: 8%), although this was not statistically significant. They postulated this to be due to the slightly slower healing rate observed in the BMP-2 group. They concluded that BMP-2, however, is a safe adjuvant to autograft. However, they estimated the cost of BMP-2 to be approximately USD$3500 per application and concluded that its high cost may not necessarily be warranted in each case.
Analysis of the above studies showed that the odds of achieving union [Figure 2] were less for the BMP-2 group (odds ratio [OR] = 0.54), although the group difference was not statistically significant (95% CI [0.24–1.20]). The time to fracture union was 32 days less in the ABG group, and this difference was of borderline significance (95% CI [−0.11–64.47]) [Figure 3].
|Figure 2: The overall union rates between autologous bone graft and bone morphogenetic protein-2 groups|
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|Figure 3: The overall time to union between the autologous bone graft and bone morphogenetic protein-2 groups|
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The odds of re-operation, however [Figure 4], were greater in the BMP-2 group (OR = 1.94), although this was not statistically significant (95% CI [0.88–4.27]). There was a slight reduction in postoperative infection rates [Figure 5] within the BMP-2 group, although the odds ratio of 0.83 is not statistically significant, and the two studies included in this analysis, in fact, show odds ratios in different directions.
|Figure 4: Overall re-operation rates between the autologous bone graft and bone morphogenetic protein-2 groups|
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|Figure 5: Overall postoperative infection rates between the autologous bone graft and bone morphogenetic protein-2 groups|
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| Discussion|| |
BMPs are known to signal their cellular effects through the serine/threonine kinase receptors. BMPs act to increase the rate of transcription and/or stabilizing the mRNA and, therefore, upregulate the gene expression in osteoblastic cells and promote their specific phenotypic expression.,
Recent therapeutic applications of synthetic BMPs have been observed in bone defects, nonunion surgery, spinal fusion, and also root canal surgery. The osteoinductive capacity of BMP-2 has been demonstrated in preclinical models and evaluated in multiple clinical trials.,,,,,,
Since the publication in 2002 of the “rhBMP-2 Evaluation in Surgery for Tibial Trauma” study by Govender et al., which found BMP-2 to be safe and significantly superior to the standard of care in accelerating fracture and wound healing, and the subsequent approval by the both the United Kingdom's National Institute for Clinical Excellence and the United States Food and Drug Administration (FDA) for the use of BMP-2 for spinal surgery and open fractures, there has been great interest in the use of this particular synthetic substance within the domain of nonunion surgery. Subsequent literature reviews have demonstrated that though BMP-2 has equivalent union rates and outcomes, the costs and complications of its application versus autograft harvesting are something that needs further research. This explains why BMP-2 is still not an approved product by the FDA for use in nonunion surgery. The lack of high-quality published literature, therefore, necessitates further research to understand and identify the true effect of BMP-2 on bone healing.
Desai et al. also showed a mean and median time to union of 27.6 and 21 weeks (193 and 147 days), respectively, in recalcitrant nonunions of the tibia. This was a retrospective case series study of nine patients, which was not included in our study due to our exclusion criteria. All patients in their study received a combination of ABGs and BMPs. They did not make a comparison between groups. However, they concluded that ABGs in addition to BMP stimulates bone production and consolidation, which correlated with the results by Takemoto et al. as above.,
We looked into the literature available to compare the costs and morbidity associated with BMP-2 when compared against autograft, particularly iliac crest graft harvest. These studies are primarily done within the domains of spinal surgery. We opined that these findings can be used as a guide in nonunion surgery as well, albeit with limitations.
A study by Polly et al. concluded that over 2 years, the initial cost of BMP-2 may be offset by the reduction in costs of other outpatient services rendered. This conclusion was further analyzed by Glassman et al. by comparing both the direct and indirect costs of the BMP-2 versus iliac crest harvest, in addition to performing an in-depth economic analysis of the two treatment methods. They found that mean operating theater time was significantly shorter in the BMP-2 group, although the estimated difference in mean blood loss was not different between the groups. This was further supported by Tressler et al. and Haws et al.,
In addition, when the total costs of all inpatient and outpatient services rendered were calculated at the 3-month perioperative period, they found the costs for the BMP2 group to be lower than the iliac crest group, USD$33,860 versus USD$37,227 respectively. This was postulated to be due to the disproportionately higher number of people requiring inpatient rehabilitation and outpatient facilities in the iliac crest group. They, therefore, discussed that though the mean hospital cost difference of USD$3599 was less than the unit costs of BMP2 itself, which was USD$5000 in their unit, the main cost saving associated with the use of BMP-2 and allograft, was the less frequent requirement for both inpatient and outpatient rehabilitation services. Their findings, therefore, lend credence to Polly et al.'s conclusion, which found similar cost savings over a 2-year period,.
The additional morbidity of iliac crest harvest has also been studied by multiple studies. The quoted complication rate of iliac crest harvest ranges from 9.4% to 49%.,,, A study by Kim et al. prospectively analyzed the rate of postoperative pain postiliac crest harvest for spinal surgery at different timelines and found a relatively high rate of persistent symptoms at 12 months, especially in terms of harvest site pain (16.5%) and numbness (29.1%). They discussed that the degree of functional disability reported by patients also appears to be higher than previously quoted.
These donor site complications can, however, be negated by the use of the RIA systems, which harvest autologous graft from within the intramedullary canal. A study by Schmidaier et al. showed elevated levels of multiple growth factors and BMP-2 in the reaming debris as compared to iliac crest curettings. Porter et al. also identified the potential for RIA aspirate for bone healing beyond that provided by filtered osseous particles. However, more studies will be required to directly comparein vivo use of bone grafts harvested from RIA versus iliac crest before any definitive conclusions can be made.
The morbidity of harvesting ABGs should also be balanced against the potential risks and subsequent need for revision surgery when using synthetic BMP-2. In our review, we have noted that although the postoperative infection rates were noted to be higher overall in the BMP-2 group, when both studies were analyzed in detail, we have found that both authors (Flierl et al. and Tressler et al.) have mentioned that there were no significant differences in the incidence of postoperative infection between the groups. In fact, both studies contrasted the other in terms of postoperative infection rates between the groups [Figure 5]. Takemoto et al. went on to postulate that the reason the BMP-2 group had a higher re-operation rate was due to the slower healing rates noted in this group. They, however, did not offer any further explanation as to why healing would be expected to be slower in this group.
A review by Carlisle and Fischgrund into the use of BMP in spinal fusion reported an inherent risk of inducing antibody formation with the use of BMP and, therefore, cautioned its use in pregnant women. They also mentioned that with the risk of angiogenesis and the promotion of cell differentiation, its use in the presence of a local tumor is cautioned for fear of its carcinogenic effects. Multiple studies have also shown the risk of heterotrophic ossification and bone overgrowth at sites of BMP application, though this is not unanimous in allin vivo cases.,
A limitation of our study is that it is at best a Level III evidential study as it incorporates one prospective and two retrospective cohort studies as part of our narrative review. There are no Level I or II studies comparing the efficacy between autograft and BMP-2 in long bone nonunions.
Therefore, we have chosen to only review studies that made a direct comparison between autograft and BMP-2. We have included studies that pooled both autograft/allograft and BMP-2 in the same group as comparison, to increase the power of our study, which we accept, introduces heterogeneity into the results.
In addition to that, we have also limited our literature review to that within the English language, therefore, any similar publications but in a different language may have been missed out by our review. We are also limited further by the heterogeneity and bias that are present in each and between studies and accept that this could have an impact on the results and conclusions of our review. For example, all three of the included studies reported a case mix of both atrophic and hypertrophic nonunions without specifying the degree of gap at the fracture site or the amount of bone graft used in each case.
The lack of any statistical differences in all of our endpoints also weakens this study somewhat, although that could be explained by the small overall numbers and hence lack of power in the overall analysis. A power analysis set at 80%, with an odds ratio 0.54 for union rates and an event rate of 205/277, would require 377 participants in each arm for an adequately powered randomized control study.
| Conclusion|| |
Due to the lack of good-quality published literature, no firm conclusions can be drawn. Within the literature available, BMP-2 with allograft, however, appears to be as effective and safe as autograft, with fewer complications associated with ABG harvesting.
An economic analysis of BMP-2 against iliac crest graft in spinal surgery concluded that the use of BMP-2 was cost neutral when the prevention of pain and complications associated with iliac crest harvest was included.
BMP-2 may be a logical adjuvant in nonunion surgery for middle-aged and elderly patients, where quality of harvested ABGs is not the best. BMP-2 also eliminates the complications and morbidity associated with ABG harvesting.
A multicenter randomized control trial for long bone nonunion would be justified to measure the true effect of BMP-2.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]