Introduction
Bone morphogenetic proteins (BMP) are multi-functional growth factors that belong to the transforming growth factor beta (TGF-beta) superfamily, they were introduced in the medical scenario to promote bone healing with the proposal of less morbidity compared to the usual methods of bone graft harvest; it is the only bone inducer with level I of clinical evidence. The Food and Drug Administration (FDA) approved its use in July of 2002 for anterior approaches of lumbar spine fusion procedures.
The spinal fusion is a tool for the treatment ofdegenerative, traumatic, neoplastic and infectious conditions of the spine, it can be achieved with interbody fusion, posterior or posterolateral fusion and circumferencial fusion. The most used examples of BMP’s are recombinant human BMP-2 (rhBMP-2 is approved for anterior lumbar interbody fusions – ALIF) and recombinant human BMP-7 (rhBMP-7 has received a humanitarian device exemption for revision posterolateral lumbar fusion operation).
Implants containing BMP’s are promising to its safety and it is as effective as iliac crest bone graft (ICBG). Adopting the use of it brings high costs and it has safety concerns with reported complication specifics to its use, including osteolysis, ectopic bone formation, radiculitis, cervical soft tissue swelling and pseudoarthrosis.
Nowadays the greatest use ofBMP is for offlabel treatments as an adjunt to allograft or autograft bone – often replacing the use of ICBG in mandibular reconstruction, unspecific oral and maxillofacial facial surgeries, cervical spine fusion, pseudoarthrosis fusion. But it is still in the need of further investigation related to its collateral effects. Pseudoarthrosis occur when the fusion attempt fails, a solid fusion is not achieved, or there is motion across the segment leading to it, and it can be clinically symptomatic as pain, deformity, neurocompression or hardware failure. There are two types: hypertrophic/hypercascular and atrophic/avascular, the last one is applicable osteoinductive treatment with BMP. This review intends to correlate and clarify the use of BMP’s and its bias on pseudoarthrosis, when it is a correction or cause factor.
Methods
A qualitative systematic review of articles about the use of Bone Morphogenetic Protein in Pseudarthrosis was developed on a basis of preselected data. It was performed a search of literature from the online database BVS and SCOPUS from January 2006 to November 2015. The search was focused from the following terms: (1) ‘Pseudarthrosis’ {Medical Subject Headings } [MeSH term]; and (2) ‘Bone Morphogenetic Proteins’ {Medical Subject Headings } [MeSH term], these terms were chosen to define our central matter ofthe paper and all articles were evaluated with rigor to proper sampling.
The analysis of the articles follows predefined eligibility criteria. We adopt the following inclusion criteria: (1) original articles with full text online access; (2) From the relevant source titles: ‘Spine’, ‘Injury’, ‘Spine Journal’, ‘Journal of Bone and Joint Surgery Series A’, ‘Journal ofNeurosurgery Spine’ and ‘Journal of Orthopaedic Research’; (3) Observational, experimental or quasi-experimental studies; (4) Writings in English only; (5) Studies which focus on the use ofBMP in pseudarthrosis.
Exclusion criteria were: (1) other projects, such as case reports, case series, literature review and comments, (2) The non-original studies, including editorials, comments, prefaces, brief comments and letter to the editor; (3) Productions that did not accomplish the proposed theme; and (4) the articles in which the objective of the study did not matched the theme purposed by the systematic review in question. We found applicable 85 articles that, when screened, resulted in 24 articles that met the criteria of evidence and were included in this review (Table 1). Discussion
Bone morphogenetic and osteogenetic proteins are mul-tifunctional growth factors that belong to the transforminggrowth factor-b superfamily. Although osteogenetic proteinsare primarily considered osteogenic factors, further inves-tigations have shown that these proteins are also essentialfor embryogenesis and organogenesis, and that they havepleiotropic roles in cell growth, differentiation, migration,and apoptosis. The most used examples of BMP’s are rhBMP-2 (approved for anterior lumbar interbody fusions – ALIF) andrhBMP-7 (has received a humanitarian device exemptionapproval for repair of lumbar pseudarthrosis).
By July of 2002, the FDA approved the use of rhBMP-2 combined with a biologic carrier ofcollagen (bovine type I collagen) as a substitute for single level ALIF.1,2,4–6 According to Nadyala et al.7 the rhBMPs are currently the most effective osteobiologic agents to increase the rate of arthrodesis but are often used as an off label application. Mulconrey et al.1 describes sustainable results of success, by multiple centers, demonstrating to be superior to ICBG for ALIF. Its use had a rapidly increasing in the United States, despite the initial high costs.5
The study ofKlimo et al.8 has demonstrated that the fusion process using rhBMP-2 is a dynamic one, with osteolysis dominating the initial phase, leading to end-plate resorption and consequently loss of some of the disk space height and sagittal alignment that was achieved with surgery. The rhBMP-7 has been documented as a potential treatment alternative for different diseases, including bone disease, stroke, inflammatory bowel disease, prostate cancer, and chronic renal disease.9 More explicitly, rhBMP-7 plays an important role in bone formation by inducing differentiation of pluripotent mesenchymal cells into active osteoblasts, Furlan et al.9 concludes that it can induce a stable, mature, posterolateral spinal fusion mass more rapidly than an autologous bone graft, and the resulting fusion mass may be biomechanically stiffer in the early stages (up to 3 months) of healing.
BMP had a 98% vs. ICBG 76% of fusion rate, once been extended its use to off label posterior spinal fusion, anterior/posterior cervical fusion. To Mulconrey et al.1 at a single level research of 2 years, BMP demonstrate a superior posterolateral spinal fusion rate (88%) than ICBG (73%). Those patients had decreased blood loss, shorter length of surgery and shorter hospital stay.1,10 According to Hoffmann et al.5 rhBMP-2 is more effective with a reduction in radiographic nonunion compared with BMP-7, demineralized bone matrix, and activated growth factor.
It must be evaluated all the variables in the spinal fusion, the detrimental factors to fusion are medical comorbidities, tobacco use, preoperative pseudarthrosis, preoperative laminectomy, age, increasing number of surgical levels. Others are osteoporosis, minimal local bone graft, previous and long fusion.1 Failures have been attributed to poor vascularity of a scarred fusion bed and persistence of systemic inhibitors, such as nicotine.11 To Furlan et al.9 the population at risk for a spinal nonunion are patients with connective tissue disorders, individuals with a history of major diseases that could adversely affect bone healing, patients receiving medications that negatively affect bone healing, patients with a history of previous nonunion fusions, and/or patients with limited availability or poor quality of autogenous bone graft
Singh et al.4 and Hsu et al.12 emphasizes that applying BMP is not without risk, the FDA in 2008 issued a public health warning to its use in cervical spine fusion alerting to wound complications, dysphonia, dysphagia and ectopic bone formation. In the lumbar spine, reports have demonstrated radiculitis, pseudarthrosis, seroma/hematoma formation, and heterotopic ossification with rhBMP-2 use. Apprehension about its pro-oncogenic potential has limited its use in the pediatric population, although this trend may be changing.2,5,12 Both Singh et al.4 and Hoffmann et al.5 groups theorizes that the lack of postoperative dead space in Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIFs) surgery may lead to an inflammatory state because of the high concentration of BMP-2, resulting in edema and seroma, theoretically inducing radiculitis, vertebral osteolysis and neuroforaminal bone growth.4,5
Pyogenic vertebral osteomyelitis is one of less common complications after spinal fusion, present late or in patients with multiple medical morbidities such as diabetes, HIV or rheumatoid conditions; the use of BMPs to correct this hostile environment of pyogenic infection it is proven effective managed by circumferential instrumented fusion in combination with antibiotics, according to Allen et al.13 it has good evidence of bony fusion, no infection recurrence and the patients had clinical improvement.
Hoffmann et al.5 affirms that there is no significant authentic immunologic antibody response to rhBMP-2 or type I bovine collagen, and the reexposure does not lead to a symptomatic antibody formation according to serology testing.
Pseudoarthrosis occur when the fusion attempt fails, a solid fusion is not achieved, or there is motion across the segment leading to it, and it can be clinically symptomatic as pain, deformity, neurocompression or hardware failure. The risks factors are: osteoporosis, cervical kyphotic deformity, revision fusion surgery, multilevel surgery, or a history ofsmoking.10 Adogwa et al.14 suggests that revision surgery of lumbar arthrodesis for symptomatic pseudarthrosis is a viable treatment that improves low-back pain, disability and quality of life. Pseudarthrosis after spine fusion leads to poor clinical outcomes and a significant cost to patients and the healthcare system.12
The study of Lu et al.10 says it is interesting to note that a majority (63%) of the allograft cohort patients who exhibited pseudarthrosis were smokers, whereas all the patients who were in the BMP group had a solid fusion regardless of smoking status. The use of rhBMP-2 appears to reduce the risk of pseudarthrosis, but this benefit is most pronounced in patients treated with 4-level anterior cervical discectomy fusion (ACDF) who are smokers.
Pseudoarthrosis is one of the most common complications after long adult spinal fusion to the sacrum and typically occurs at the thoracolumbar and lumbosacral junctions.15 Is a major limitation of multilevel anterior cervical fusion, traditional techniques have a 20% of patients who develop pseudarthrosis, one strategy used to help decrease the rate of it is to have posterior instrumentation to increase the rigidity of the construct, however it adds morbidity by increase the time of surgery. Frenkel et al.16 demonstrate that BMP usage in anterior cervical approach has almost 100% rate of solid arthrodesis regardless of level, but its study does not have statistical significance.
According to Singh et al.4 6.8% of patients who underwent a MIS-TLIF procedure were identified as having pseudarthrosis, they all were clinically symptomatic and underwent a revision arthrodesis – a contralateral MIS-TLIF. Patients with revision surgery because of pseudarthrosis are younger than those who did not have a revision ( p < .001), it is a group of patients with a high prevalence of smokers compared with the ones who did not need revision (41.3% vs. 26.7%, p < .054). The need for review procedure for those patients costs an average of $20,267 (American dollars) of hospital direct costs and physician charges.
Pseudarthrosis at L5–S1 is one of the most common complications of long fusions to the sacrum in adult deformity surgery. Strategies for decreasing it include interbody fusion, use of BMP-2 at the lumbosacral junction, and the use of sacro-pelvic fixation, individually or in combination.17 The repair in the lumbar spine presents a challenging surgical problem with high failure rates been reported, resulting from poor vascularity in a scarred fusion bed, inadequate posterior bony surface area, loss of sagittal alignment, and exposure to adverse systemic factors such as nicotine. Higher fusion rates were noted with rhBMP-7 than autograft in this setting (82% vs. 42%) in those cases. Another potential bone graft alternative that has been extensively studied is rhBMP-2, demonstrated by Lawrence et al.18 to overcome the inhibitory effects of nicotine in a model of primary spinal fusion and appears to be an effective alternative in its preclinical model for a scenario with innumerous risk factors for pseudarthrosis repair.
Future studies should be conducted to elucidate the underlying control over the observed gene expression involved in pseudarthrosis, the expression of certain osteogenic and angiogenic genes that have been previously demonstrated to be inhibited by nicotine. For the White et al.11 model it had up-regulation in the implantation of osteogenic protein-1 at the pseudarthrosis site. Gene expression data supported the hypothesis that the discrepancy in fusion success may be due to osteogenic protein-1’s ability to up-regulate osteogenic and angiogenic cytokines required for fusion, and, thus, overcome nicotine’s inhibition of local gene expression.
According to Mulconrey et al.1 rhBMP-2 has the ability to create solid fusion in the presence of negative variables and in multilevel spinal fusion, eliminating the necessity for iliac crest bone graft, to Hoffmann et al.5 non-union rates in lumbar spine fusion with rhBMP-2 are low, a high dosage (>12 mg) is associated with higher chance of postoperative seroma and infection requiring invasive intervention, such as reutilization of it.
Frenkel et al.16 indicates that cervical fusion approach with BMP its possible without increase in complication rates if using lower doses of BMP, following the safety concern of the FDA notification, any multilevel anterior cervical procedure, even without BMP, can lead to dysphagia and airway problems. Although according to Lu et al.10 the use of rhBMP-2 in patients undergoing 2-level ACDF significantly increases the severity of dysphagia, without affecting the overall incidence of it. MIS-TLIFs showed neural compromise by a case series evaluated,1 although rhBMP-2 is effective for arthrodesis in the unilateral MIS-TLIF the complication ofthis off-label usage are present – neuroforaminal bone growth, osteolysis and pseudarthrosis.4
Kim et al.15 confirms that BMP is superior to ICBG in achieving fusion in long constructs in adult deformity surgery. The rate of pseudarthrosis was significantly higher in the ICBG group than BMP group, the concentration and dosage of rhBMP-2 used seems to have an effect on the rate of fusion and pseudarthrosis rate because no patient receiving more than 5 mg per level had apparent or detected pseudarthrosis (n = 20/20).
To Buttermann19 (2008) BMP seems to have greater indication in patients having three- or greater-level ACDF, patients who are undergoing revision, patients who have morbid obesity or diabetics and are at risk ofbone graft site complications, and patients who have osteoporosis in which the iliac-crest bone graft itself may be subject to collapse or exhibits a risk of subsidence.
Veillete and McKee6 agree that for lumbar spine fusion the use of BMP showed an increased fusion rate, with a decrease of revision procedures in the same period, but it has no correlation with decrease in the use of ICBG and the use of BMP correlates with substantial increase in hospital chargers. It may question financial justification. Kim et al.15 justify that for long fusions to the sacrum BMP use significantly decreases pseudarthrosis rates in this patient population when compared with ICBG alone. Which corroborates with Annis et al.17 study where the use of low dose of BMP-2 at the L5–S1 level in combination with sacro-pelvic fixation achieved satisfactory fusion rates in adult deformity surgery.
Currently, most of the burden of the increased costs is borne by the hospitals and surgeon providers. However, over the long term, the costs may be similar and have yet to be determined conclusively.19 The future market for BMP-2 in lumbar fusion surgery will depend on the clinical significance of increased fusion in the context of possible side effects and cost considerations, as well as the potential arrival of newer and safer fusion-promoting agents.20 To Frenkel et al.16 the BMP-group has a faster fusion progress in a 3-month follow-up than in non-BMP group.
The efficacy of TLIF with BMP is supported in the large series with long-term follow-up of Crandal et al.21 Reliable fusion and improved outcomes can be expected in adults undergoing TLIF for deformity, spondylolisthesis, and degenerative disease. Most complications occurred in patients with deformity.
Furlan et al.9 results suggest that the use of rhBMP-7 is safe and may contribute to high fusion rates, as demonstrated by radiographs, reduced levels of disability, and improved quality of life in patients considered to be at a high risk for developing a nonunion after spinal reconstructive surgery. At Theologis et al.22 study shows no difference in outcomes between autogenous iliac crest, allogeneic bone graft, and bone substitutes in primary posterior spine fusion with instrumentation in idiopathic scoliosis. This study contributes to the growing body of evidence that rhBMP-7 is safe for surgical use in the clinical arena. The use of an rhBMP-7 implant may be a contributing factor to the elevated rate of radiographic fusion, improved quality of life, and reduced degree of disability after spinal fusion that was observed in its group of patients at a high risk for developing pseudarthrosis. It does not confer additional benefit when bone fusion is likely to occur in a normal fashion; however, in patients with one or more risk factors for impaired bone healing, the adjuvant use of it may negate these effects, allowing adequate bone fusion to occur.
Crandall et al.23 five-year follow-up after TLIF with BMP, confirms effective arthrodesis in short and long fusions, both primary and revision surgeries. Most complications occurred in deformity patients, the BMP-related ones (seroma, ectopic bone) were rare. Even with very low dose BMP used in the study of Mannion et al.20 complications related to BMP usage were not avoided completely, it was observed asymptomatic heterotopic ossification and two cases of perineural cyst formation, one of whom required revision. Hoffmann et al.5 points out the need of additional research to determine dose dependency and genetic predisposition to react to BMPs, such as over (ectopic bone and seroma) or underreaction (nonunion). Final remarks Our review shows that the use of BMPs is effective and secure compared to ICGB, but depending of the location of usage (cervical spine, lumbar spine or sacrum) and the medical status of the patient (presence of comorbidities, tobacco usage) its more probable to exhibit complications, such as neuroforaminal bone growth, osteolysis, pseudarthrosis, seroma, hematoma. This data determine that the usage of BMPs must be an agreement between patient and physician, an informed decision discussing the benefits and risks of BMP for each case. Conflicts of interest The authors declare no conflicts of interest.
