Commentary on “Does recombinant human bone morphogenetic protein-2 (rhBMP-2) use in adult spinal deformity increase complications and are complications associated with location of rhBMP-2 use?”
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Controversy surrounds the indications for use of bone morphogenetic protein-2 (BMP-2) in spine surgery, with its use FDA-approved only for anterior lumbar interbody fusion using threaded cylindrical cages. However, the majority of BMP-2 is used off-label.
Recently published meta-analyses of industry sponsored IDE trials reported a small but significant increase in fusion rates associated with BMP-2 compared to iliac crest bone graft (ICBG) but no clinically significant improvement in patient reported outcome
measures at two years.1,2 These studies encompassed a wide variety of applications, including anterior and posterior cervical and lumbar fusions, with some studies
evaluating transforaminal and posterior lumbar interbody fusion as well. Given the lack of clinical benefit and the possibility of increased rates of complications such as post-
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operative pain, wound complications, retrograde ejaculation, swelling in the anterior cervical spine, osteolysis and subsidence, ectopic bone formation, and cancer, there
seems to be no evidence-based reason to use BMP-2 in straightforward degenerative cases involving fusion of one or two levels.3 Missing from the industry sponsored trials
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were studies evaluating BMP-2 use in long thoracolumbar fusions for adult deformity, a challenging fusion environment for which BMP-2 might be well-suited. Kim et al. recently published a cohort series comparing fusion rates and clinical outcomes between adult deformity patients treated with BMP-2 and ICBG and reported significantly higher fusion rates and better clinical outcomes for the BMP-2 patients, without any clear
increase in complication rate.4 As such, there is interest in data evaluating the use of BMP-2 in adult deformity surgery. The authors of the current study have performed a multicenter, prospective cohort study including 279 patients to evaluate complications associated with BMP-2 use in adult
EP TE D
deformity surgery, defined as fusion of at least four levels in the setting of coronal or sagittal plane deformity. This was an observational study, meaning that the surgeons
determined who was to receive BMP-2 versus ICBG, what type of surgery to perform, and what dose of BMP-2 to use. Not surprisingly, the BMP-2 and ICBG groups were
markedly different at baseline, with the BMP-2 group having an increased comorbidity
burden, a higher proportion of smokers, a greater magnitude of scoliosis, and undergoing a greater number of osteotomies, interbody fusions, and anterior-posterior fusions. The ICBG group was more likely to undergo a pedicle subtraction osteotomy. The authors
reported a complication rate that was approximately twice as high for the BMP-2 patients compared to the ICBG patients, though this was driven primarily by minor complications
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occurring within the first three months. The re-operation rate was approximately 50%
higher in the ICBG group. Based on their results, the authors concluded that BMP-2 was not associated with major complications, neurological complications or wound-related complications.
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Overall complication rates tend to be determined by two factors—the definition of a complication and the thoroughness of the surveillance for complications. In looking at the authors’ complications list, wound problems and neurological deficits are the only complications they evaluated that are ostensibly related to BMP-2. They did not evaluate acute post-operative pain or radiculitis, retrograde ejaculation, ectopic bone formation,
osteolysis and subsidence, or cancer, so no conclusions can be made about the association between BMP-2 and most of the complications that others have linked to its use. The increased rate of complications within the first three months observed in this paper is probably better explained by the higher comorbidity burden and greater magnitude of
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surgery in the BMP-2 group. While the authors performed a multivariate analysis, they did not perform a comparison between the complication rate for the BMP-2 and ICBG
groups controlled for baseline differences and differences in the magnitude of surgery.
Additionally, while the rates of the potentially relevant complications—namely wound
problems and neurological complications—were substantially higher in the BMP-2 group (i.e. five-fold increase in wound complications and two-fold increase in infection and neurological complications), these differences were not statistically significant. The
absolute numbers of these complications were quite low, with 5 wound dehiscences, 13 deep infections, 5 superficial infections, and 3 seromas/hematomas, indicating that the
study was markedly underpowered to compare rates of these complications. Despite the
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study including 279 patients, this demonstrates how massive numbers of patients are
required to compare rates of low frequency events like infection.5 While this paper does not allow one to make definitive conclusions about the association between BMP-2 and complications in adult deformity surgery, papers like this one are a good first step
A
towards understanding BMP-2 use in this application. It seems unlikely any clear answers about the association between BMP-2 and complications will emerge until a BMP-2 registry with appropriate surveillance for complications is created, and it seems unlikely that this will occur anytime soon. In the meantime, we look forward to the authors’ upcoming papers describing clinical outcomes and fusion rates in this cohort.
REFERENCES 1.
Fu R, Selph S, McDonagh M, et al. Effectiveness and harms of recombinant
human bone morphogenetic protein-2 in spine fusion: a systematic review and metaanalysis. Annals of internal medicine 2013;158:890-902. Simmonds MC, Brown JV, Heirs MK, et al. Safety and effectiveness of
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2.
recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Annals of internal medicine 2013;158:877-89. 3.
Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human
bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and
lessons learned. The spine journal : official journal of the North American Spine Society 2011;11:471-91. 4.
Kim HJ, Buchowski JM, Zebala LP, Dickson DD, Koester L, Bridwell KH.
RhBMP-2 is superior to iliac crest bone graft for long fusions to the sacrum in adult spinal deformity: 4- to 14-year follow-up. Spine 2013;38:1209-15.
Mirza SK. Folly of FDA-approval studies for bone morphogenetic protein. The
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5.
A
spine journal : official journal of the North American Spine Society 2011;11:495-9.
EP TE D
Controversy surrounds the indications for use of bone morphogenetic protein-2 (BMP-2) in spine surgery, with its use FDA-approved only for anterior lumbar interbody fusion using threaded cylindrical cages. However, the majority of BMP-2 is used off-label.
Recently published meta-analyses of industry sponsored IDE trials reported a small but significant increase in fusion rates associated with BMP-2 compared to iliac crest bone graft (ICBG) but no clinically significant improvement in patient reported outcome
measures at two years.1,2 These studies encompassed a wide variety of applications, including anterior and posterior cervical and lumbar fusions, with some studies
evaluating transforaminal and posterior lumbar interbody fusion as well. Given the lack of clinical benefit and the possibility of increased rates of complications such as post-
C C
operative pain, wound complications, retrograde ejaculation, swelling in the anterior cervical spine, osteolysis and subsidence, ectopic bone formation, and cancer, there
seems to be no evidence-based reason to use BMP-2 in straightforward degenerative cases involving fusion of one or two levels.3 Missing from the industry sponsored trials
A
were studies evaluating BMP-2 use in long thoracolumbar fusions for adult deformity, a challenging fusion environment for which BMP-2 might be well-suited. Kim et al. recently published a cohort series comparing fusion rates and clinical outcomes between adult deformity patients treated with BMP-2 and ICBG and reported significantly higher fusion rates and better clinical outcomes for the BMP-2 patients, without any clear
increase in complication rate.4 As such, there is interest in data evaluating the use of BMP-2 in adult deformity surgery. The authors of the current study have performed a multicenter, prospective cohort study including 279 patients to evaluate complications associated with BMP-2 use in adult
EP TE D
deformity surgery, defined as fusion of at least four levels in the setting of coronal or sagittal plane deformity. This was an observational study, meaning that the surgeons
determined who was to receive BMP-2 versus ICBG, what type of surgery to perform, and what dose of BMP-2 to use. Not surprisingly, the BMP-2 and ICBG groups were
markedly different at baseline, with the BMP-2 group having an increased comorbidity
burden, a higher proportion of smokers, a greater magnitude of scoliosis, and undergoing a greater number of osteotomies, interbody fusions, and anterior-posterior fusions. The ICBG group was more likely to undergo a pedicle subtraction osteotomy. The authors
reported a complication rate that was approximately twice as high for the BMP-2 patients compared to the ICBG patients, though this was driven primarily by minor complications
C C
occurring within the first three months. The re-operation rate was approximately 50%
higher in the ICBG group. Based on their results, the authors concluded that BMP-2 was not associated with major complications, neurological complications or wound-related complications.
A
Overall complication rates tend to be determined by two factors—the definition of a complication and the thoroughness of the surveillance for complications. In looking at the authors’ complications list, wound problems and neurological deficits are the only complications they evaluated that are ostensibly related to BMP-2. They did not evaluate acute post-operative pain or radiculitis, retrograde ejaculation, ectopic bone formation,
osteolysis and subsidence, or cancer, so no conclusions can be made about the association between BMP-2 and most of the complications that others have linked to its use. The increased rate of complications within the first three months observed in this paper is probably better explained by the higher comorbidity burden and greater magnitude of
EP TE D
surgery in the BMP-2 group. While the authors performed a multivariate analysis, they did not perform a comparison between the complication rate for the BMP-2 and ICBG
groups controlled for baseline differences and differences in the magnitude of surgery.
Additionally, while the rates of the potentially relevant complications—namely wound
problems and neurological complications—were substantially higher in the BMP-2 group (i.e. five-fold increase in wound complications and two-fold increase in infection and neurological complications), these differences were not statistically significant. The
absolute numbers of these complications were quite low, with 5 wound dehiscences, 13 deep infections, 5 superficial infections, and 3 seromas/hematomas, indicating that the
study was markedly underpowered to compare rates of these complications. Despite the
C C
study including 279 patients, this demonstrates how massive numbers of patients are
required to compare rates of low frequency events like infection.5 While this paper does not allow one to make definitive conclusions about the association between BMP-2 and complications in adult deformity surgery, papers like this one are a good first step
A
towards understanding BMP-2 use in this application. It seems unlikely any clear answers about the association between BMP-2 and complications will emerge until a BMP-2 registry with appropriate surveillance for complications is created, and it seems unlikely that this will occur anytime soon. In the meantime, we look forward to the authors’ upcoming papers describing clinical outcomes and fusion rates in this cohort.
REFERENCES 1.
Fu R, Selph S, McDonagh M, et al. Effectiveness and harms of recombinant
human bone morphogenetic protein-2 in spine fusion: a systematic review and metaanalysis. Annals of internal medicine 2013;158:890-902. Simmonds MC, Brown JV, Heirs MK, et al. Safety and effectiveness of
EP TE D
2.
recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Annals of internal medicine 2013;158:877-89. 3.
Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human
bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and
lessons learned. The spine journal : official journal of the North American Spine Society 2011;11:471-91. 4.
Kim HJ, Buchowski JM, Zebala LP, Dickson DD, Koester L, Bridwell KH.
RhBMP-2 is superior to iliac crest bone graft for long fusions to the sacrum in adult spinal deformity: 4- to 14-year follow-up. Spine 2013;38:1209-15.
Mirza SK. Folly of FDA-approval studies for bone morphogenetic protein. The
C C
5.
A
spine journal : official journal of the North American Spine Society 2011;11:495-9.
