Review Article
Complications with the u of bone morphogenetic protein 2(BMP-2)in
spine surgery
Chadi A.Tannoury,MD a ,Howard S.An,MD b ,*
a
Boston University Medical Center,720Harrison Ave.,D2N,Boston,MA 02118,USA
b
Department of Orthopaedic Surgery,Rush University Medical Center,1611West Harrison St.Suite 300,Chicago,IL 60612,USA
Received 14August 2012;revid 16July 2013;accepted 23August 2013
Abstract
BACKGROUND CONTEXT:Recombinant human bone morphogenetic protein 2(rhBMP-2)is a very potent osteogenic growth factor that has been ud successfully in various spine fusions,ob-viating the need for autologous iliac crest bone graft harvest and therefore avoiding the associated morbidities.
PURPOSE:In the past few years,a tremendous increa in rhBMP-2usage was noted,and con-cerns regarding costs,benefits,and safety issues were raid by many.The goal of this work was to provide a comprehensive review of the adver events and complications associated with u of rhBMP-2.
STUDY DESIGN:Literature review.
METHODS:This is a review of the current literature on the reported adver events,complica-tions,and concerns associated with rhBMP-2u.
RESULTS:This article discuss the wide spectrum of adver outcomes related to rhBMP-2u in the lumbar and the cervical spine;retrograde ejaculation,antibodies formation,postoperative radiculitis,postoperative nerve root injury,ectopic bone formation,vertebral osteolysis/edema,dys-phagia and neck swelling,hematoma formation,interbody graft lucency,and wound healing com-plications are reviewed.Cost-related concerns,dosage considerations,carrier types,and theoretical ca
rcinogenesis concerns were also prented.
CONCLUSIONS:Despite the excellent spinal fusion rates promoted by this powerful molecule,the increasingly reported adver outcomes associated with bone morphogenetic protein usage have created real concerns.This article will provide the reader with a good understanding of the reported complications associated with rhBMP-2u and ultimately help recognize its safety spectrum and limits for better clinical application.Ó2014Elvier Inc.All rights rerved.
Keywords:
Bone morphogenetic protein;rhBMP-2;Complications;Osteolysis;Ectopic bone;Spine;Fusion;Radiculitis;Retrograde ejaculation
Introduction
In 1965,Marshall Urist discovered the bone morphoge-netic protein (BMP)[1],a class of growth factors belonging to the transforming growth factor-b family [2].Numerous types of BMP molecules have been discovered;however,few have been involved in osteoblast differentiation and bone development [3].
Recombinant human bone morphogenetic protein 2(rhBMP-2)(InFUSE;Medtronic Sofamor Danek,Mem-phis,TN,USA)is a commercially available form and cur-rently approved by the U.S.Food and Drug Administration (FDA)for u in the anterior lumbar interbody fusion (ALIF)within a titanium tapered cage [4,5].
FDA device/drug status:Approved (INFUSE ÒBone Graft-P050053).Author disclosures:CAT:Nothing to disclo.HSA:Royalties:U&I Inc.(About D/year,Paid directly to institution/employer);Stock Owner-ship:U&I Inc.(D shares,Paid directly to institution/employer),Spinal Kinteics (B shares,Paid directly to institution/employer),Advanced Bio-logics Inc.(B shares,Paid directly to institution/employer),Medysy Inc.(B shares,Paid directly to institution/employer);Endowments:Rush University Medical Center (D/year,Paid directly to institution/employer);Grants:Spinalcyte Inc.(F,Paid directly to institution/employer).
The disclosure key can be found on the Table of Contents and at .
*Corresponding author.Department of Orthopaedic Surgery,Rush University Medical Center,1611West Harrison St.Suite 300,Chicago,IL 60612,USA.
E-mail address : (H.S.An)1529-9430/$-e front matter Ó2014Elvier Inc.All ri
欧洲的良心ghts rerved.
数九寒冬/10.1016/j.spinee.2013.08.060
The Spine Journal 14(2014)
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Multiple studies on ALIFs by Burkus ported ex-cellent fusion rates,decread operative time,lower blood loss,and shorter hospital stay with the u of rhBMP-2 compared with autologous iliac crest bone graft(ICBG) [4–6].
幼儿新年祝福语Besides its application in ALIF,all other us of rhBMP-2are considered off label[4,6–10].
A meta-analysis looked at the benefits of rhBMP-2in promoting posterolateral fusion.The authors reported sig-nificantly lower rates of fusion failures,shorter hospitaliza-tion,and less blood loss with the u of BMP-2compared with autologous ICBG[11].
Even in smokers,Glassman reported the superiority of BMP-2(95%)over autologous ICBG(76%)in promoting solid posterolateral lumbar fusion at a single level,after2 years follow-up[12].
Similarly,other investigators reported95%to100%suc-cessful arthrodesis with the u of BMP-2in posterior lum-bar interbody fusion(PLIF)[7,8,13].
Additionally,the role of BMP-2in promoting arthrode-sis,as a substitute for ICBG in patients with multilevel spi-nal deformity,was investigated by Mulconrey et al.At 2-year follow-up,the investigators
concluded that the u of rhBMP-2eliminated the necessity for ICBG and yielded an excellent fusion rate[14].
Recent systematic reviews questioned the effectiveness and advantages of BMP-2over ICBG as previously re-ported by the industry-sponsored trials.Reviews and inves-tigations from the Yale University Open Data ba Project, the Medtronic internal reports,the FDA reports,and a thor-ough literature arch concluded that there are no clear ad-vantages of BMP-2u in spine fusion over bone graft,and even more rious adver events were found to be associ-ated with BMP-2u;therefore,clear indications for BMP-2u and its safety were precluded[15,16].
Trends in usage and cost-related concerns
Cahill in2009retrospectively looked at patients who underwent spinal fusion between2002and2006and noted that the nationwide u of BMP has incread from0.69% of all fusions in2002to24.89%in2006.With this tremen-dous increa in BMP usage,adver events start being noted and reported.Additionally,with usage of BMP-2, greater inpatient hospital charges were noted across all cat-egories of fusion ranging from11%to41%with greatest percentage increa en for anterior cervical fusions,de-spite same length of hospital admission[17].
Similarly,Mulconrey reported incread costs with the amount of BMP ud per level and per number of levels fud[14].
However,Ackerman reported the results of an economic evaluation of BMP versus autogenous ICBG in single-level anterior spine fusion and found that from a payer’s perspec-tive the upfront price of BMP is likely to be entirely offt by reductions in the u of other medical resources(ie,pain clinics,rehabilitation rvices,physical therapy,and so on) and preventing pain and complications associated with iliac crest harvest as well as reduction of the costs associated with fusion failures[18].
A more recent investigation by Glassman reported that while the index hospitalization ems to be of higher cost with utilization of BMP-2versus ICBG,the patients who receive BMP-2will have a net saving by decread pay-ment for inpatient rehabilitation and decread hospital re-imburment,physician costs,and other outpatient rvices [19].
Complications of rhBMP-2u in lumbar spine surgery
The u of BMP-2in the lumbar spine has raid some concerns and safety issues as adver events start being documented adver events were start being documented.
Antibodies formation
Bone morphogenetic protein is a foreign immunogenic molecule that stimulates the formation of antibodies[21]. Reactions to BMP on re-exposures may theoretically occur locally at the level of the wound or as a systemic respon. Despite this theoretical concern,unpublished data by Car-reon prented at the22nd annual meeting of the North American Spine Society reported no clinical evidence of pernicious conquences with re-exposure to BMP(L.Car-reon and associates,unpublished data prented at the22nd Annual Meeting of the North American Spine Society, 2007).Additionally,despite detectable antibody titers in expod subjects,no clinical quelae have been reported in the literature[21,22].
Postoperative radiculitis
Development of vere postoperative radiculitis is another reported adver event with the u of BMP,particularly in PLIF and transforaminal interbody fusion(TLIF)[23].The inflammatory properties of BMP em to result in new post-operative radicular symptoms without structural neural com-pression.Formation of ectopic bone in the neural foramen, and/or in proximity to the nerve root sleeve is also thought to be implicated in the genesis of radiculitis[24].
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Mindea reported BMP-related postoperative radiculitis in11.4%of patients who underwent TLIF through a mini-mally invasive exposure[23].
Similarly,Sanfilippo in a retrospective design,noted a significant increa in the risk of developing postoperative radiculitis following transforaminal lumbar interbody fu-sion when BMP-2was ud(nine in39patients)as com-pared with using autogenous ICBG(one in29patients). In tho patients,rhBMP-2–related radiculitis symptoms developed1to4days after surgery,persisted more than6 months,and lasted13.4months on average.Also,female gender was found to be an independent risk factor and yields a risk ratio of5.2compared with male counterparts (J Sanfilippo an
d associates,unpublished data prented at the22nd Annual Meeting of the North American Spine Society,2007).
The u of DuraSeal Xact Sealant System(Confluent Surgical,Waltham,MA,USA)has been anecdotally sug-gested to minimize the relea of BMP-2in the vicinity of the nerve root and potentially help reducing the develop-ment postoperative radiculitis.In a retrospective review of TLIF cas,Rihn ported reduction of postoperative radiculitis when thin layers of hydrogel alant(Duraal; Confluent Surgical Inc.,Waltham,MA,USA)were applied at the annulotomy sites;they suggested that Duraal appli-cation helped containing rhBMP-2and reduced the inci-dence of postoperative rhBMP-2–related radiculitis[24]. Postoperative nerve injury
New or worning of a pre-existing neurologic deficit were also reported in patients who underwent minimally in-vasive TLIFs with rhBMP-2at one and two levels.All neu-rologic complications occurred in thefirst cas treated percutaneously and therefore the authors suggested the at-tribution of nerve injury to the surgical learning curve rather than a direct effect of BMP u[8].Postoperative nerve root compression has also been noted with the u of rhBMP-2.Bilateral epidural cyst formation was reported by Muchow et al.and prented as progressive radicular pain following a TLIF with rhBMP-2u in a27-year-old man.The postoperative leg symptoms resolved completely following excision of
the compressive mass and the his-topathology of the operative specimen revealed woven and osteoid bone surrounded by an inflammatoryfibrovas-cular tissue.[25].Similarly,Owens ported evidence of neurocompressive romas(four cas)and epidural hematoma(one ca)formation in a ries of204patients undergoing TLIF with rhBMP-2,which all required surgi-cal decompression[26].
Ectopic bone formation
Joph in2007conducted an obrvational study with prospective computed tomography analysis and reported higher incidence of heterotopic bone formation(20.8%)in the epidural and foraminal spaces with the u of BMP-2,compared with no BMP-2u(8.3%),in posterior minimal access interbody(PLIF and TLIF)fusions.How-ever,the authors reported no clinical quelae associated with thefindings[27].
Similarly,a more recent European study reported5.5% incidence of asymptomatic ectopic bone formation after the u of low do(1.4mg/level)BMP-2in minimally in-vasive TLIF and PLIF.The authors also noted two cas out of36to have developed perineural cyst,and one of them required revision of the interbody cage[28].
In an obrvational cohort study,Wong et al.identified and reportedfive cas of ectopic bone in the s
pinal canal with potential neurologic compromi.Revision surgeries in the instances were very difficult[29].致命顺从
Although the clinical significance of BMP-2–related ec-topic bone formation is still debatable and largely un-known,certain theories implicate the roles of excessive bleeding,the prence of surgical hematoma,and the u of hemostatic agents(eg,Gelfoam;Pfizer,New York,NY, USA)as carriers for rhBMP-2and are implicated in its dis-mination to the nearby soft tissues,promoting ectopic bone formation.Certain measures to minimize the forma-tion of heterotopic bones have been anecdotally reported, and the include placement of rhBMP-2anterior to and within the interbody cage in the anterior column and u of DuraSeal Sealant System(Confluent Surgical,Waltham, MA,USA)in the posterior interbody fusion techniques. Vertebral osteolysis and/or edema
Despite the robust fusion mass promoted by BMP-2, vertebral osteolysis and bone resorption were reported in a ries of patients who underwent TLIF supplemented with BMP-2.McClellan noted the prence of osteolysis in69%of the operated levels,and bad on the size and ex-tent of vertebral involvement,the osteolysis was catego-rized as mild,moderate,and vere[30].
Similarly,Lewandrowski et al.looked at68TLIF cas performed using cages and BMP-2for the diagn
osis of de-generative spondylolisthesis,and they reportedfive cas of vertebral osteolysis developed within4months after sur-gery.Patients with osteolysis reported worning back pain with variable radiculopathy that started as early as4weeks and as late as3months after the index surgery.In allfive patients,osteolytic defectsfilled in spontaneously and symptoms typically resolved within3months of non-operative care[31].
In addition to osteolysis,risks of subsidence and graft migration are to be considered.A systematic review by Mroz ported a mean incidence of44%bone resorp-tion,25%graft subsidence,and27%cage migration for lumbar interbody fusion surgeries performed with rhBMP-2u.However,no long-term detrimental effects were reported,and reoperations were rare[32].
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Retrograde ejaculation
In addition to the concerning reports by FDA,a study by Carragee pared the incidence of RE after ALIF in patients with and without rhBMP-2u;the authors noted five RE events(7.2%)in the rhBMP-2group and one (0.6%)in the control group[33].
Similarly,a retrospective analysis by Comer -pared the incidence of RE in male subjects undergoing ALIF with and without BMP-2.They noted that exposure to rhBMP-2was associated with higher RE(6.3%vs.
0.9%in control)and urinary retention(9.7%vs.4.6%in control).They also found that the prence of prostatic hy-pertrophy dia at baline incread the risk of RE in subjects expod to BMP-2[34].
On the other hand,a recent retrospective cohort by Lind-ley et al.looked at the incidence of RE following anterior lumbar surgery with disc replacement versus fusion with the u of rhBMP-2.Postoperative RE occurred in7.4% of ALIF/rhBMP-2group compared with9.8%in the disc replacement group.The investigators reported no signifi-cant difference between the two groups and suggested that RE complication may be related to the retroperitoneal ap-proach rather than the u of rhBMP-2[35].
Moreover,a recent prospective study by Tepper et al.in-vestigated the incidence of RE after ALIF with and without the u of rhBMP-2.Retrograde ejaculation was diagnod bad on quantitative men analysis,urine analysis,and qualitative standardized questionnaire.The incidence of RE was found to 超星学习通网页
be similar whether ALIF was performed with or without rhBMP-2u(9.5%vs.10%,respectively)[36]. Complications of rhBMP-2u in cervical spine surgery
Systematic reviews looked at the complications associ-ated with the u of rhBMP-2in the cervical spine and re-ported43%mean of osteolysis and graft subsidence.Also, dysphagia and soft-tissue swelling with respiratory difficul-ties occurred with a mean ranging between5.8%and17% [17,32].
At the2005annual North American Spine Society meet-ing,numerous studies looked at the adver events en with BMP-2u in anterior cervical decompression and fu-sion(ACDF).The investigators reported2-to10-fold in-crea in dysphagia and dyspnea compared with control groups[37].In another study prented at the2006annual North American Spine Society meeting,Naraghi reported threefold increa in risk of swallowing difficulties with high-do BMP-2(2–4.2mg/patient)compared with low do(0.5–1.5mg/patient)(Naraghi et al.,unpublished data prented at the21st Annual Meeting of the North Ameri-can Spine Society,2006).
Therefore,in July1,2008,FDA issued warning regard-ing off label u of rhBMP-2in the cervical spine[38].Dysphagia and neck swelling
In a review of hospital nationwide inpatient sample,Ca-hill found after performing an univariate analy
sis with mul-tivariable adjustment that the u of rhBMP-2in anterior cervical fusion procedures was associated with a higher rate of complication occurrence,especially in the form of dys-phagia(odds ratio 1.63)and wound issues(odds ratio 1.67).On the other hand,there were no incread compli-cations with BMP u in posterior cervical fusion[17].
The occurrence of neck swelling and dysphagia follow-ing ACDF as found in50%of patients who received rhBMP-2/allograft compared with14%of patients who re-ceived ICBG.Severe dysphagia occurred in5%of patients requiring feeding tube placement.Symptoms also emed proportional to the number of operated levels and incread rhBMP-2dosage[39,40].
Hematoma formation
Shields ported hematoma formation in9.9%of patients treated with ACDF and high-do rhBMP-2.One study has reported that2%of patients required reoperation and hematoma evacuation[40,41].
Lucency,vertebral edema,and osteolysis
满天星的花语和寓意Vaidya et al.studied the fusion levels in patients treated with ACDF with and without rhBMP-2.They r
eported33% of fusion levels exhibiting early lucency and subsidence compared with none in the allograft/demineralized bone matrix group[42].
End plate resorption was also noted in almost all patients who received rhBMP-2,disc space subsidence noted in 40.5%,and cage migration noted in 4.3%of patients [43,44].
Complications in posterior cervical fusion with BMP Investigations by Crawford ported similar com-plication rate with or without rhBMP-2u in posterior cer-vical fusion.However,greater,yet not statistically significant,wound complication rate was noted in the rhBMP-2group[45].
Asymptomatic heterotopic ossification was also noted in almost7%of patients who had posterior cervical arthrode-sis with rhOP-1[46].
On the other hand,Anderson ported two cas of neurologic decline occurring5to14days following poste-rior cervical laminectomy and instrumented fusion with rhBMP-2.Both patients developed moderate-to-large ro-ma with vere cord compression necessitating surgical de-compression.The authors postulated the implication of rhBMP-2as a potential cau of the roma formation and subquently cord compression and neurologic com-promi in patients undergoing posterior cervical laminec-tomy and fusion[47].
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Dosage considerations
The approved human concentration of1.5mg/mL,ini-
tially ud in human clinical trials,was bad on nonhuman
primate data[22].Currently,three sizes of the InFUSE
Bone Graft component are available:small kit2.8mL,me-
dium kit5.6mL,and large kit8mL with solution concen-
tration of1.5mg/mL.
The do-dependent effect of BMP-2has been recently
re-investigated in an in vivo rat model with femoral g-
mental defect.The results of this study established a low
sub-therapeutic BMP-2concentration range(5–10m g/mL
or total absolute do0.375–0.75m g of BMP-2)with no ad-
equate fusion potentials,a mid-range therapeutic BMP-2
concentration(30m g/mL or total do of 2.25m g of
BMP-2)with adequate fusion capacity without adver
events,and a high supra-therapeutic BMP-2concentration
range(above150m g/mL or more than total do of11.25 m g of BMP-2)with adequate bony fusion capacity yet with risks of inducing cyst-like bony defectsfilled with adipo
tissue.Additionally,local tissue inflammatory changes and
exudates were noted with4mg/mL BMP-2u.The overall
results of this study were consistent with previous reports
and reproduced the side effects of high BMP-2concentra-
tions approaching the typical human1500m g/mL beyond
which bone healing is no longer improved and rather lower
bone quality may develop due to abnormal cystic adipo
tissue formation contributing to lower mechanical proper-
ties[48].
Additional reports form Medtronic(Medtronic Sofa-
mor)with regard to AMPLIFY,a higher2.0mg/mL
concentration BMP-2product intended for posterolat-
eral lumbar fusion,suggested that the concentration
and relea rate of rhBMP-2,rather than the do,
are the key elements for local bone induction
[49,50].However,due to theoretical concerns of repro-
ductive toxicology,carcinogenesis,and relative safety
of BMP-2compared with ICBG FDA denied the u
of AMPLIFY.
Carcinogenesis concerns
Many clinical and basic science investigations looked at
the potential carcinogenic effect of BMP-2.
In certain tumors,the expressions of many BMP surface
receptors were found to be highly expresd[51–53].How-
ever,preclinical safety data regarding rhBMP-2effects on
human cancerous cell proliferation revealed no significant
mutagenic conquence[54,55].
Mines spectively studied patients(O66
years)who underwent lumbar spinal fusion surgery with
and without rhBMP-2u.Risk of subquent pancreat-
ic cancer development was assd,and they reported
no associated incread risk with exposure to BMP-2
[56].
Zhang et al.investigated the BMP-2effect on the prolif-eration of malignant human gastric epithelial cells,and an inhibitory activity was reported[57].
On the other hand,Jin et al.investigated the effects of BMP-2on the proliferation and differentiation of breast cancer cells.The cancerous cells,once treated with rhBMP-2,exhibited molecular and cytoskel
青春只有一次etal changes promoting their migration and invasion capacities[58].
In a similar study,Wang et al.looked at the effects of BMP-2on breast cancer cells and found that BMP-2indu-ces the expression of certain estrogen receptors in the can-cerous cells and ultimately alters the tumor resistance to endocrine therapy[59].
An in vivo analysis also reported that human oral cell carcinoma,when treated with BMP-2,became more locally aggressive and acquired wor survival capacities[60].
In2010,FDA reported a notably and alarming incread cancer rates(fourfold)with3.8%new malignancies(9/239) reported among patients in the Amplify group compared with only0.89%noted in the control group at24months [49].Further follow-up at60months cancer rates incread in both groups;however,remained higher in the Amplify group(5%vs.1.8%for the control group).
On the other hand,Thawani ducted a system-atic review on the association between u of BMPs and the promotion of cancer formation or metastatic spread. No definitive association was found;however,the authors recommended that BMPs u should be contraindicated in patients with cancers requiring spinal fusion[61].
Similarly,a recent literature review was conducted to examine the role of BMP-2in various cancers(prostate, lung,breast,and so on).Of the412identified studies, 43(46%,19in vitro,8human,16animal)reported a pro-malignancy effect of rhBMP-2,whereas12(13%, 7in vitro,2human,4animal)reported a tumor-suppressing effect of BMP-2,and38(41%,16in vitro, 19human,3animal)did not study the effect of exogenous BMP-2on cancers.Only one human study supported the tumor-suppressing effect of BMP-2as do-dependent, and two studies showed no do dependence for pro-malignancy effect of BMP-2.Animal studies showed con-flicting data as well.Most significantly,no available study demonstrated the role of BMP-2in the genesis of de novo cancers[62].
抗疫感谢信More recently,the Yale University Open Data Access Project team carried an independent analysis on safety,ef-fectiveness,and harms of rhBMP-2in spine fusion[15,16]. Data from the Medtronic(Minneapolis,MN,USA)and the Maverick trials[4,63,64]reported new cas of cancer identified in recipients of rhBMP-2(incidence20/694)dur-ing an extended follow-up period.Although the reported absolute risk for cancer is as low as3%,the rhBMP-2recip-ient group developed nearly twice the number of new can-cer cas noted in the ICBG recipient group(8/608).This obrved increa in the cancer incidence,while absolutely low and uncertain,remains a real concern for the
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