Clinical UM Guideline

 

Subject: Recombinant Human Bone Morphogenetic Protein
Guideline #: CG-SURG-65 Publish Date:    12/27/2017
Status: New Last Review Date:    11/02/2017

Description

This document addresses the use of recombinant human bone morphogenetic protein (rhBMP) as an alternative to autologous bone graft in various orthopedic procedures.

Note: For information regarding bone growth stimulation, please see:

Note: For more information regarding the use of bone marrow aspirate concentrates, platelet derived growth factors, or mesenchymal stem cells please see:

Note: For more information regarding bone graft substitutes, please see:

Note: rhBMP-7, also known as OP-1, has been removed from the market in the U.S.

Clinical Indications

Medically Necessary:      

The use of recombinant human bone morphogenetic protein-2  including, but not limited to, InFUSE® bone graft is considered medically necessary for the following clinical situations:

Not Medically Necessary:

The use of recombinant human bone morphogenetic protein-2 is considered not medically necessary for conditions that do not meet the above criteria, including but not limited to:

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

CPT

 

20930

Allograft, morselized, or placement of osteopromotive material, for spine surgery only [when specified as recombinant human bone morphogenetic protein rhBMP-2]

20999

Unlisted procedure, musculoskeletal system, general [when specified as placement of recombinant human bone morphogenetic protein rhBMP-2 for tibial fracture]

 

 

ICD-10 Procedure

 

3E0U0GB

Introduction of recombinant bone morphogenetic protein into joints, open approach

3E0U3GB

Introduction of recombinant bone morphogenetic protein into joints, percutaneous approach

3E0V0GB

Introduction of recombinant bone morphogenetic protein into bones, open approach

3E0V3GB

Introduction of recombinant bone morphogenetic protein into bones, percutaneous approach

 

 

ICD-10 Diagnosis

 

 

All diagnoses

Discussion/General Information

Background

BMPs are members of the family of transforming growth factors.  At present, some 15 different BMPs have been identified, all with varying degrees of cartilage or bone inductive properties.  At the present time, only one rhBMP product, rhBMP-2 (marketed as InFUSE), is approved for use in the U.S. These products have been investigated as an alternative to bone autografting in a variety of clinical situations, including spinal fusions, internal fixation of fractures, treatment of bone defects, and reconstruction of maxillofacial conditions.  rhBMPs are delivered to the bone grafting site as part of a surgical procedure; a variety of carrier and delivery systems have been investigated.  Carrier systems, which are absorbed over time, function to maintain the concentration of the rhBMP at the treatment site, provide temporary scaffolding for osteogenesis and prevent extraneous bone formation.  Carrier systems have included inorganic material, synthetic polymer, natural polymers and bone allograft.  The rhBMP and carrier may be inserted via a delivery system, which may also function to provide mechanical support.  For interbody spinal fusion, delivery systems have included interbody fusion cages.  The carrier and delivery system are important variables in the clinical use of rhBMPs.  For example, different clinical applications will require different dosages of rhBMP with different carriers and delivery systems.  Therefore, the results of one clinical application cannot be extrapolated to others. 

Rationale

The following summarizes the results of controlled clinical trials involving the use of rhBMP-2 (InFUSE) for different indications.  It should be noted that the majority of trials were designed to show that the use of rhBMP is associated with bone fusion rates equivalent to autologous bone grafting.  The advantages of rhBMP are the elimination of a separate incision site and the associated pain and morbidity secondary to the harvesting of autologous bone graft, and the extension of autograft when it is limited or the replacement of autograft when none is available.

Spinal Fusion

Anterior Interbody Fusion of Lumbar Vertebrae (ALIF)

The pivotal clinical trial of rhBMP-2 as part of the U.S. Food and Drug Administration (FDA) approval process consisted of 279 individuals undergoing single-level lumbar fusion via an open anterior approach, who were randomized to receive either the LT (lumbar tapered)-Cage with rhBMP-2 or the same cage filled with iliac crest autograft (Bowden, 2002).  In a nonrandomized portion of the trial, an additional 136 individuals underwent a single-level laparoscopic lumbar interbody fusion with rhBMP-2.  There were no differences in fusion success rates, Oswestry Disability Index (ODI) scores or back pain between the randomized groups.  The group treated laparoscopically also had similar fusion rates.  The operative time and blood loss were significantly lower in those receiving the rhBMP-2, and obviously these individuals did not experience the pain and morbidity associated with the harvesting of autologous bone from the iliac crest.  The results were similar in a similarly designed trial of posterior lumbar interbody fusion (PLIF).  In addition, the group receiving rhBMP-2 had a hospital stay of 3.4 days compared to 5.1 days for the control group (Burkus, 2002).

A concurrent trial focused on the use of allograft bone dowels filled with rhBMP-2 on a collagen sponge.  A total of 46 individuals undergoing a single-level open anterior lumbar discectomy and interbody fusion were randomized to receive an allograft dowel filled with either rhBMP or autologous bone harvested from the iliac crest (Einhorn, 2003).  At 12 and 24 months, the investigational group showed higher rates of fusion and improved neurologic status of back and leg pain when compared with the control group.

A study by Carragee and colleagues in 2011 investigated the incidence of rhBMP-2 related retrograde ejaculation (RE) complications in a retrospective analysis of prospectively collected data in subjects undergoing ALIF with and without rhBMP-2.  The study involved 239 subjects undergoing ALIF, 65 receiving treatment with rhBMP-2 and 174 receiving standard care without rhBMP-2.  In the rhBMP-2 group, there were 5 RE events (7.2%) and only 1 in the control group (0.6%) (p=0.0025).  Only 3 of these subjects, 2 rhBMP-2 and 1 control subject, had resolution of RE at 1 year.  These findings reiterate concerns stated previously by other authors.  Caution should be taken when using this substance.

In 2014, Malham reported the results of a case series study involving the use of rhBMP-2 in ALIF procedures conducted by both a single vascular surgeon and a single spine surgeon in 131 subjects.  All subjects were treated with rhBMP-2 within a polyetherketone (PEEK) cage with instrumentation.  Additionally, of the 131 subjects treated, 86 underwent a standard ALIF and an additional 45 subjects underwent a hybrid ALIF with implantation of an artificial disc at L4-5.  The overall complication rate was reported to be 19.1%, with 13.0% experiencing minor complications.  Another 6.1% experienced major complications including pseudo-obstruction of the colon, pleural effusions, aspiration pneumonia, and DVT.  All complications resolved with conservative treatment.  One instance of retrograde ejaculation was reported (1.5%), and it failed to resolve completely at 12 months.  One subject who underwent artificial disc implantation required removal of the prosthesis followed by further fusion procedures.  The authors reported an overall fusion rate of 76.3% at 6 months, 92.4% at 9 months, and 96.9% at 12 months.  No differences in fusion rates were reported between the standard ALIF and hybrid groups.  Back and leg pain, as measured by visual analog scale, improved 57.2% and 61.8%, respectively.  There was a 54.3% improvement in the ODI.  While these results are promising, one issue that exists, beyond the lack of randomization and blinding, is that all surgical procedures in this study were done in a single center with the same surgeons.  It is unclear whether or not similar outcomes would be achieved in a population receiving care outside this specialized study setting.

At this time the vast majority of available studies address only instrumented anterior lumbar interbody fusion procedures.  The safety and efficacy of rhBMP use in uninstrumented procedures is not clear from the existing evidence.

Posterolateral Lumbar Intertransverse Fusion

The majority of posterior lumbar spinal fusion procedures performed today are posterolateral lumbar intertransverse fusions, which may also be known as a “TIF.”  The use of rhBMP-2 as an adjunct to posterolateral lumbar intertransverse fusion has been the subject of interest for some time, with several studies published on the issue.  A meta-analysis of the available literature concluded that the use of rhBMP-2, when compared to autologous iliac bone grafting, provides improved outcomes in achieving solid fusion and results in shorter hospital stays (Papakostidis, 2008).  A randomized controlled trial (RCT) published after the meta-analysis mentioned above included 102 individuals over the age of 60 undergoing instrumented posterolateral lumbar intertransverse fusion with rhBMP-2 (n=50) vs. iliac bone autograft (n=52) (Glassman, 2008).  The authors report that there were no significant differences between groups on the health-related quality of life questionnaire, but the rhBMP-2 group had significantly shorter operative times and average 2-year postoperative fusion rates were better in the rhBMP group (70.8% in the autograft group vs. 86.3% in the rhBMP group, p=0.03). 

A randomized controlled study by the same author evaluated the use of rhBMP-2 vs. iliac autograft in individuals who smoked and those who did not smoke undergoing posterolateral lumbar intertransverse fusion (Glassman, 2007a).  This study stratified the study population (n=148) into four groups: (1) smokers who received rhBMP-2 (n=21); (2) nonsmokers who received rhBMP-2 (n=55); (3) smokers who received autologous iliac crest bone graft (ICBG) (n=21); and (4) nonsmokers who received iliac autograft (n=5).  Successful fusion was reported in 95.2% of group 1 subjects, 100% of group 2 subjects, 76.2% of group 3 subjects, and 94% of group 4 subjects.  There was no significant difference between the smoker/rhBMP-2 and nonsmoker/rhBMP-2 groups (p=0.276) but there was a significant difference between fusion rates in the smoker/ICBG group versus the nonsmoker/ICBG group (p=0.042).  However, there was no significant difference in successful fusion rates at 2 years between smokers who received rhBMP-2 vs. smokers who received autograft (p=0.184).

Dimar and associates reported on the results of a randomized controlled trial of 98 individuals undergoing posterolateral lumbar intertransverse fusion, 45 of whom received ICBG and 53 who received rhBMP-2 (2006).  The authors reported that the rhBMP-2 group had significantly lower operative blood loss, shorter operative times, and higher fusion rate at 2 years when compared to the ICBG control group.  Several other small studies found similar results (Boden, 2002; Glassman, 2007b; Singh, 2006).

As with anterior lumbar interbody fusion procedures, the vast majority of available studies of posterolateral lumbar intertransverse fusion address only instrumented procedures.  The safety and efficacy of rhBMP use in uninstrumented procedures has not been demonstrated.

A report by Glassman and colleagues describes a retrospective case review of 1037 subjects who underwent posterolateral spine fusion using rhBMP-2 with an absorbable collagen sponge (ACS), with a focus on complication rates (2011).  They reported that medical and surgical complications were observed in 190 of 1037 subjects (18.3%), with 81 major complications (7.8%) and 110 minor complications (10.2%).  Neurologic complications were related to screw malposition in 6 subjects and epidural hematoma in 3 subjects.  New or more severe postoperative radicular symptoms were noted in 7 subjects (0.7%).  Psoas hematoma was identified by CT scan in 8 subjects (0.8%).  Complications directly related to rhBMP-2 were observed in at least 1 (0.1%) and in a worst case analysis, in as many as 6 subjects (0.6%).  The authors concluded that, “there were extremely few complications directly attributed to rhBMP-2/ACS, and the overall complication rates were consistent with established norms.”

Transforaminal Lumbar Interbody Fusion (TLIF) and Posterior Lumbar Interbody Fusion (PLIF)

There are currently only three studies published in the peer-reviewed literature describing the use of rhBMP-2 for transforaminal lumbar interbody fusion (TLIF) surgery.  The only controlled study involved 40 individuals, 19 who received iliac crest autograft and 21 who received rhBMP-2 allograft (Mummaneni, 2004).  Almost all of those in the rhBMP-2 group had radiographically confirmed solid fusion, with one incomplete fusion reported.  The autograft group had similar results, with one pseudoarthrosis occurring.  Fifty percent of autograft subjects reported significant pain at the donor site beyond 6 months.  No other significant differences were reported.  The largest study, by Potter and colleagues, included 100 individuals in a retrospective review (2005).  The overall fusion rate was reported to be 94%, with 81% reporting a greater than 50% decrease in symptoms.  Twenty individuals suffered minor complications, including transient radiculopathy (n=7), dural tear (n=6), and wound-related complications (n=5).  The last study, by Villavicencio and others, was a case series study with 74 individuals undergoing TLIF for degenerative disc disease (2005).  This study primarily was constructed to determine differences between open and mini-invasive procedures, and surgery at single and multiple levels.  The authors report full fusion in all individuals at 10 months, with no major complications.  Minor complications reported include neural injury (n=9), screw malposition (n=9), and CSF leak (n=3). 

The available literature addressing the use of rhBMP-2 for posterior lumbar interbody fusion (PLIF) procedures is limited to a few small case series (Joseph, 2007; Misel, 2009).  While neither of these studies reported ectopic bone formation or related complications, Wong and colleagues (2008) published a retrospective chart review of individuals referred to a tertiary spine institute with complications after surgery where rhBMP-2 had been used in an off-FDA label PLIF or TLIF application.  They described 5 cases of ectopic bone in the spinal canal with potential neurologic compromise.  The authors concluded that ectopic bone in the spinal canal associated with rhBMP-2 use in PLIF or TLIF may contribute to symptomatic neurologic findings in rare cases and that revision surgeries for this complication are difficult.  It should also be noted that an FDA trial of PLIF with rhBMP-2 was halted because of a high incidence (75%) of ectopic bone forming in the neural canal. 

Fusion of Cervical Vertebrae

There have been several published studies of rhBMP-2 as an alternative to autologous bone graft in fusion of the cervical spine (Baskin, 2003; Boakye, 2005; Butterman, 2008).  Baskin and colleagues used the carrier/delivery system consisting of machined fibular rings.  The trial consisted of 33 individuals undergoing single or two-level cervical discectomy and fusion who were randomized to receive fibular autograft rings filled either with rhBMP-2 or autologous bone graft.  Fusion was recorded in all individuals at 6 months after surgery, and the authors reported that the experimental group had statistically significant improvement in neck disability and arm pain scales.  Boakye retrospectively studied 24 individuals who underwent single, double or triple-level cervical spinal fusion augmented with rhBMP-2 with a follow-up of 12-16 months and radiographically documented fusion in all individuals.  Complications included transient laryngeal nerve injury, transient C-5 paresis, CSF leakage, and transient dysphagia.  A nonrandomized controlled trial has been reported by Butterman and colleagues (2008).  This study involved 66 individuals who underwent single, double or triple level cervical spinal fusion.  Of this population, 36 individuals received standard care with iliac crest autograft and 30 received treatment with rhBMP-2 allograft.  The authors reported no significant differences in outcomes based upon ODI scores, pain medication use, and neurological recovery.  Additionally, none of the allograft group had neck swelling presenting as dysphagia.  Only 14% of the autograft group was reported to have this complication. 

Hodges published the results of a case series study of 29 subjects undergoing posterior cervical fusion procedures (2011).  Subjects were followed for a minimum of 12 months, during which time no significant complications related to rhBMP-2 use were detected.  In contrast to the small study by Hodges, Williams and colleagues published the results of a retrospective study using data from the Scoliosis Research Society’s morbidity and mortality database from 2004-2007 (2011).  Of the 55,862 cases of spinal fusion in the database during the time frame evaluated, rhBMP-2 was used in 11,933 (22%) of cases.  Additionally, of the 5184 cases of anterior cervical fusion, rhBMP-2 was used in 674 (13%).  While the complication rate did not significantly differ between rhBMP-2 and non-BMP cases overall, in anterior cervical fusions complications were reported to be 5.8% in the rhBMP-2 group vs. 2.4% in the non-rhBMP-2 group (p<0.001).  Wound infections were more frequent in the rhBMP-2 group (2.1% vs. 0.4%, p<0.001).  In a multivariate analysis, only rhBMP-2 was found to be an independent predictor of complications for anterior cervical spinal fusion (p<0.001, odds ratio 1.6, 95% confidence interval [CI]). 

Dorward and others (2013) reported on a retrospective case series study of 57 subjects who underwent posterior cervical, occipitocervical, or cervicothoracic instrumented fusion augmented with rhBMP-2.  Mean follow-up was 37.7 ± 20.6 months.  Forty-eight participants (84.2%) had undergone previous cervical surgery, and 42.1% had a pre-existing nonunion.  Constructs spanned 5.6 ± 2.6 levels; 19.3% involved the occiput, while 61.4% crossed the cervicothoracic junction.  The observed fusion rate of rhBMP-2-augmented posterior cervical, occipitocervical, and cervicothoracic fusions was 89.5%.  Six participants (10.5%) experienced nonunion; only 2 required revision.  In each case of nonunion, instrumentation crossed the occipitocervical or cervicothoracic junction.  However, none of the analyzed variables was statistically associated with nonunion.  Fourteen participants (24.6%) suffered complications, with 7 requiring additional surgery.

In 2014, Goode and colleagues published the findings of an analysis of 61,937 cases of surgical fusion from the Thompson Reuters MarketScan Commercial Claims and Encounters Database 2010.  Included in the analysis were claims from individuals 18-64 years of age with 1 year of continuous insurance coverage who underwent a cervical fusion procedure between 2002 and 2009 in the U.S.  The use of rhBMP (either rhBMP-2 or rhBMP-7) in this population rose from 0.24% in 2002 to a high of 4.8% in 2007.  However, the use of rhBMP in cervical spinal fusion procedures later declined to 2% by 2009.  The use of rhBMP was reported to be strongly and independently associated with the number of comorbidities present in an individual (p<0.001).  Individuals receiving rhBMP, regardless of the surgical approach, were 29% more likely to experience complications in the first postoperative year (adjusted relative risk [aRR]=1.29).  The aRR of nervous system complications was 1.24 and 1.69 for surgical revisions.  Individuals receiving rhBMP had a 34% higher risk of 30-day readmission (aRR=1.34).  However, the only condition for which readmission was statistically higher for individuals who had received rhBMP was “dysphagia or edema” of the larynx (9.5% vs. 3.3%, p<0.01).  Additionally, readmission was on average 27.4% sooner among individuals receiving rhBMP.  Within the first postoperative year, individuals who had received rhBMP were also more likely to have received a cervical spine CT scan (aRR=1.30) or an epidural/block (aRR=1.29).  This study, using administrative claims data, suggests significant risks associated with the off-label use of rhBMP for primary cervical spine fusions.

In 2016, Arnold and others published the findings of a prospective case series study of 224 subjects who underwent anterior cervical discectomy and fusion (ACDF) with rhBMP-2.  Subjects were followed for 24 months post-operatively.  This population was compared to 486 historical controls that underwent ACDF with allograft alone.  Follow-up rate was similar in both groups (83% in the rhBMP group and 86% for controls).  The authors reported that the fusion rate at 24 months was significantly higher in the rhBMP group (99% vs. 87.2%, p=0.002).  However, at 24 months, the rate of heterotopic ossification was significantly higher in the rhBMP group (78.6% vs. 59.2%, p<0.001), and the mean length of heterotopic ossification was also significantly greater in the rhBMP group after adjusting for propensity score and corresponding preoperative dimensions (p=0.011 and 0.012, respectively). 

In 2017 two separate meta-analyses were published addressing the use of rhBMP in cervical fusion procedures (Liu, 2017; Zadegan, 2017).  The Lui study, a pooled analysis of 18 studies, concluded that use of rhBMP-2 was a significant risk factor in the development of post-operative dysphagia.  The Zadegan study, which involved pooled data from 4782 subjects, reported that most studies tended to show a significantly higher incidence of overall complication rate, dysphagia/dysphonia, cervical swelling, readmission, wound complications, neurologic complications, and ossification. They concluded that use of rhBMP yields a significantly higher fusion rate with similar patient-reported outcomes, yet increased risk of life-threatening complications.  They did not recommend the use of rhBMP in anterior cervical spinal fusion procedures.

In July 2008, the FDA issued a Public Health Notification regarding life-threatening complications resulting from the use of rhBMP as an adjunct to cervical spinal fusion procedures.  In this notification it is stated by the FDA, “Note that the safety and effectiveness of rhBMP in the cervical spine have not been demonstrated and these products are not approved by FDA for this use.”  They continue by stating that during the previous 4 years there have been 38 reports of complications related to such use, which were associated with “swelling of neck and throat tissue, which resulted in compression of the airway and/or neurological structures in the neck.  Some reports describe difficulty swallowing, breathing or speaking.”  These events required emergency interventions, and occurred mostly between 2 and 14 days post-operatively.  Interventions noted included respiratory support with intubation, anti-inflammatory medication, tracheotomy and, most commonly, second surgeries to drain the surgical site.  The most critical portion of the notice states:

Since the safety and effectiveness of rhBMP for treatment of cervical spine conditions has not been demonstrated, and in light of the serious adverse events described above, FDA recommends that practitioners either use approved alternative treatments or consider enrolling as investigators in approved clinical studies.

Fusion of Thoracic Vertebrae:

At this time, there are no clinical trials available describing the use of rhBMP during thoracic spinal fusion procedures.  Until evidence addressing this technique is available such use is considered not medically necessary.

Spinal Deformity:

rhBMP-2 has been proposed for use in the treatment of spinal deformities that require multiple level fusions and involvement of the sacrum.  At this time, few comparative studies have been published.  Maeda (2009) described a nonrandomized controlled trial involving 55 subjects who underwent fusion procedures for spinal deformities.  There were 32 subjects who received standard care with iliac bone graft vs. 23 who received treatment with rhBMP approved for compassionate use.  Of the 32 subjects in the control group, 9 (28.1%) developed a pseudarthrosis, while only 1 of 23 subjects (4.3%) in the rhBMP group developed a pseudarthrosis.  It was noted that there were significant differences between follow-up periods, with the rhBMP group having an average follow-up of 2.7 years vs. 4.9 years for the control group.  Mulconrey and others (2008) conducted a prospective, nonrandomized controlled study involving 98 subjects who underwent either anterior or posterior multi-level spinal fusion.  Group 1 included 47 subjects who underwent anterior fusion with rhBMP, group 2 included 43 subjects who received posterior fusion with local bone graft and bulking agent, and group 3 included 8 subjects who underwent posterior fusion with rhBMP.  The authors reported an overall fusion rate of 95% (group 1 -- 91%, group 2 -- 97%, group 3-- 100%).  Kim and others (2013) published the results of a nonrandomized controlled trial involving 63 consecutive subjects undergoing long fusion to the sacrum.  rhBMP was used to treat 31 subjects and 32 subjects received standard care with iliac bone graft.  Eight subjects in the rhBMP group underwent posterior fusion only, whereas 23 underwent combined anterior and posterior (A/P) fusion.  All 32 subjects in the control group had A/P fusion.  The rate of pseudarthrosis was 6.4% (2/31) in the rhBMP group vs. 28.1% (9/32) in the control group (p=0.04; odds ratio [OR]=5.67).  The fusion rates for the rhBMP group were 93.5% vs. 71.9% for the control group.  Oswestry Disability Indexes were similar between groups.  However, the rhBMP group demonstrated superior sum composite Scoliosis Research Society scores in pain, self-image and function domains (p=0.02).  Finally, Luhmann and colleagues (2004) enrolled 95 consecutive subjects who underwent: (1) anterior application of rhBMP-2 (n=46); (2) posterior application of rhBMP-2 (either as a stand-alone or with local bone graft only; n=41); or (3) compassionate-use posterior procedures (n=8).  The authors report that for group 1, operative levels were deemed fused in 89 of the 93 (96%) levels.  For group 2, solid fusion was assessed in 110 of the 118 (93%) operative levels.  For the group 3, the overall fusion rate was 100% (52 of 52 operative levels). 

Complications due to rhBMP-2 Use in Spinal Fusion Procedures

In mid-2013, two major meta-analyses were published based on individual subject data supplied by Medtronic, Inc. through Yale University Open Data Access (YODA) Project.  Two groups were selected by YODA in an open competition to synthesize evidence regarding the safety of rhBMP-2 (Fu, 2013; Simmonds, 2013).  The analyses used de-identified data from industry-sponsored RCTs of rhBMP-2 vs. iliac crest bone graft when used during spinal fusion surgery for degenerative disc disease and related conditions.  Additional data of similar populations from observational studies were also used for investigation of adverse events.

The meta-analysis conducted by the group led by Simmonds included subject-level data from 11 RCTs, regardless of spinal level or surgical approach.  Adverse event data was also collected from an additional 35 observational studies.  The authors reported that at 24 months, rhBMP-2 increased the rate of radiographic fusion by 12%, and improved mean scores on the ODI by 3.5%.  The improvement in ODI did not reach the previously defined threshold for a clinically significant effect.  Subjects who received rhBMP were reported to have a clearly higher incidence of leg and back pain in the immediate postoperative period.  This contrasts with the data for 3 months postoperatively, where recipients of rhBMP had less pain than subjects who had allograft treatment.  There was an almost two-fold increased risk of cancer reported in subjects treated with rhBMP-2.  However, due to the small number of events recorded, confidence intervals were large and definite conclusions could not be drawn.  The overall risk of cancer was low with either rhBMP or autograft procedures.  With regard to adverse events analysis from the observational studies, the risk of heterotopic bone formation, leg pain and radiculitis, retrograde ejaculation, and osteolysis were all more frequent in subjects receiving rhBMP during lumbar spinal fusion.  Among subjects undergoing cervical spine procedures, dysphagia was more common in rhBMP subjects.  The authors note that there was weak correlation between spinal fusion rates and reduction in pain scores.

The meta-analysis by Fu and colleagues included individual subject data from 13 RCTs and 31 cohort studies.  They found that rhBMP-2 and iliac bone crest autograft resulted in similar effectiveness outcomes for both lumbar and cervical fusion.  Also reported was that rhBMP-2 was associated with a non-significant increase in risk for urogenital problems, including retrograde ejaculation, when used for anterior lumbar interbody fusion.  This finding was based on sparse data which does not allow proper conclusions to be made.  When used for anterior cervical spine fusion, rhBMP-2 was associated with an increased risk for wound complications, dysphonia, and dysphagia.  An increased risk of cancer was found, but data were not sufficient to determine if risk was related to dose, and increased risk was no longer significant at 48 months.  Event rates were low, and the types of cancers recorded were heterogeneous.  Pain was more common shortly after surgery with rhBMP-2.  The information on adverse events in the published literature was found to be incomplete in comparison to the total amount of overall information available.  The authors concluded that the use of rhBMP-2 provides no additional advantage over autologous bone grafting and may be associated with significant risk of harm.  In their analysis on the quality of available data, they reported that there was significant reporting bias in the journal publications and they state, “Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and under-reporting.”

Overall, these studies report similar benefits to the use of rhBMP-2 and iliac bone autograft, with an uncertain risk of harm.  A number of unanswered questions remain.  The small benefits reported overall do not support the widespread use of rhBMP-2, but do leave the possibility that rhBMP-2 may lead to clinically significant improvements in selected subgroups, such as individuals with a high risk of fusion failure.  In addition, while there was a low adverse event rate overall, concerns remain about possible increased adverse event rates with rhBMP-2, including cancer. 

Several recent studies have also addressed this issue.  Mesfin and colleagues (2013) conducted a retrospective case series analysis of 52 consecutive subjects who received high-dose rhBMP-2 as part of spinal fusion surgery.  An average of 115 mg (range, 40 to 351 mg) of rhBMP-2 was used.  There were 265 primary and 237 revision procedures reported, and 261 were interbody fusions.  The average duration of follow-up was 42 months (range, 14 to 92 months).  Reported diagnoses included idiopathic scoliosis (41%), degenerative scoliosis (31%), fixed sagittal imbalance (18%), and other diagnoses (10%).  The rate of intraoperative complications was 8.2%.  Perioperative major surgical complications occurred at a rate of 11.6%, and the rate of perioperative major medical complications was 11.6%.  Minor medical complications occurred in 18.9% of the cases, and minor surgical complications occurred in 2.6%.  Logistic regression analysis and Pearson correlation did not identify a significant correlation between rhBMP-2 dosage and radiculopathy (r=20.006), seroma (r=20.003), or cancer (r=20.05).  Significant improvements in the ODI score (from a mean of 41 points to a mean of 26 points; p<0.001) and the total score from the Scoliosis Research Society Outcomes Instrument (SRS) (from a mean of 3.0 points to a mean of 3.7 points; p<0.001) were noted at the latest follow-up evaluation.  In contrast to these findings, Carragee and others (2013) published the results of a retrospective, nonrandomized controlled study involving the use of rhBMP-2 for lumbar spinal fusions.  High-dose rhBMP-2 was used in 239 subjects vs. autologous bone graft in 224 subjects.  At 2 years, with 86% follow-up, there were 15 new cancer events in 11 subjects in the rhBMP-2 group compared with 2 new cancer events in 2 subjects in the control group.  The incidence of new cancer events per 100 person-years was 3.37 (95% CI, 1.89 to 5.56) in the rhBMP-2 group at 2 years compared with 0.50 (95% CI, 0.06 to 1.80) in the control group.  The incidence rate ratio was 6.75 (95% CI, 1.57 to 60.83; p=0.0026) at 2 years.  Calculated in terms of the number of subjects with one or more cancer events 2 years after the surgery, the incidence rate per 100 person-years was 2.54 (95% CI, 1.27 to 4.54) in the rhBMP-2 group compared with 0.50 (95% CI, 0.06 to 1.82) in the control group at 2 years.  The incidence rate ratio was 5.04 (95% CI, 1.10 to 46.82; p=0.0194).  At 5 years, there was a 37% loss of follow-up, but a significantly greater incidence of cancer events was still observed in the rhBMP-2 group. 

Chrastil and others (2013) published a systematic review of the spectrum of complications reported in the literature after posterior interbody fusions of the lumbar spine augmented with rhBMP.  Seventeen articles were identified and reviewed that addressed the use and complications of rhBMP during PLIF and TLIF procedures.  The studies ranged from a level I prospective randomized trial to case reports of complications.  The authors reported appreciable rates of rhBMP-specific complications, including heterotopic ossification within the epidural space or neuroforamina, postoperative radiculitis, and endplate osteolysis with interbody device subsidence.  They conclude by stating, “High-quality clinical trials should be initiated to develop appropriate paradigms to maximize the safety and efficacy of rhBMP for posterior interbody fusions.”  In contrast to these reports, Lubelski and others (2013) conducted a retrospective case review of 547 subjects who underwent thoracolumbar and lumbar spine fusion with rhBMP.  Forty-one percent (41%) of subjects had undergone previous spine surgery.  Thirty-nine percent (39%) of subjects had a PLIF/TLIF, 29% underwent a PLF, and 20% an ALIF.  The authors reported no significant differences in the rate of complications in relation to historical controls.

Open Tibial Fractures

Govender and colleagues (2002) reported on the results of a trial that randomized 450 individuals with open tibial shaft fractures to receive initial irrigation and debridement followed by treatment with a locked intramedullary nail either alone or with additional rhBMP-2 on an absorbable collagen sponge placed over the fracture at the time of definitive wound closure.  The primary outcome measure was the proportion of individuals requiring secondary intervention due to delayed union or nonunion at 12 months.  A total of 58% of individuals treated with rhBMP-2 were healed compared with only 38% in the control group.  The rhBMP-2 group also had fewer hardware failures, fewer infections and showed faster wound healing.

Another large trial published by Swiontkowski and others in 2006 found significant benefits to the use of intra-medullary nail fixation augmented with rhBMP-impregnated collagen sponge when compared to intra-medullary nail fixation alone.  The study results found the rhBMP-treated group had fewer bone grafting procedures, fewer repeat interventions, and fewer infections at the 12-month follow-up visit. 

Closed Tibial Fractures

A study by Lyon (2013) evaluated the use of rhBMP-2 for the treatment of closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation in a randomized, double-blind controlled trial.  The study involved 369 subjects randomized in a 1:2:2:1 fashion to one of four groups: (1) standard of care, which consisted of definitive fracture fixation within 72 hours of injury with a locked intramedullary nail after reaming; (2) standard of care and injection with 1.0 mg/mL of rhBMP-2/calcium phosphate matrix (CPM); (3) standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; and (4) standard of care and injection with buffer/CPM.  The study was terminated after an interim analysis involving 180 subjects with 6 months of follow-up revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control group.  The authors concluded that in subjects with closed tibial fractures treated with reamed intramedullary nailing, the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone.

Additional Applications

There has been research interest in the following applications: management of early stages of osteonecrosis of the femoral head, as an adjunct to hip arthroplasty to restore bone defects in the acetabulum or femoral shaft, and as an adjunct to distraction osteogenesis (i.e., Iliazarov procedure).  Craniofacial applications have included periodontal defect regeneration, cleft palate repair, cranial defect repair, and restoration and maintenance of the alveolar dental ridge.  However, the literature regarding these applications consists of small case series; no controlled trials were identified. 

In late 2010, the Agency for Healthcare Research and Quality (AHRQ) published a report titled “Bone Morphogenetic Protein: The State of the Evidence of On-Label and Off-Label Use.”  This report assessed the available evidence addressing the use of rhBMPs.  Overall, the report concluded that the available data addressing the safety and efficacy of rhBMP-2 and rhBMP-7 for both on-label and off-label indications is moderate at best, and significant questions still exist regarding the benefits and drawbacks of its use in the clinical setting.

In 2012, Dodwell and colleagues published a brief report addressing the use of rhBMPs in children.  Using 2009 data from the Kid’s Inpatient Database, the authors report that of 8289 children who underwent spinal arthrodesis, rhBMP was used in 271 cases (n=9.2%).  Hospital complication rates and lengths of stay did not differ between individuals who received rhBMP and those who did not (p=0.29 and p=0.70, respectively).  However, it is well recognized that the vast majority of rhBMP-related complications occur well after discharge.  Unlike in adults, non-union is a rare occurrence following spinal fusion surgery in children.  Furthermore, current FDA approval language for InFUSE, for both open tibial fractures and degenerative disc disease, specifically states that this product is indicated for use only in skeletally mature individuals. 

Use of rhBMP in Pediatrics

In January 2015, the FDA published a safety communication regarding the use of use of bone graft substitutes containing recombinant proteins or synthetic peptides in individuals under age 18.  The use of rhBMP and rhBMP-containing products would fall under the scope of this document.  The main recommendations to health care providers in the communication include the following:

The FDA points out that these products are approved for use only in individuals over the age of 18 who have finished growing (skeletally mature) and are not approved for younger individuals who are still growing.  The use of these types of products have not been evaluated for their safety and effectiveness in individuals under 18 years of age, and use in this population may cause serious injuries.   This warning is based on the results of several large database-based studies and a small number of retrospective case series studies.

Overall, the available evidence in the peer-reviewed published literature addressing the use of rhBMP in skeletally immature individuals is limited.  Only a few studies look at the use of rhBMP in large populations younger than 18 years of age.  Two large studies looked at practice patterns of rhBMP use (Jain, 2013; Lam, 2014).  These studies utilized databases maintained by AHRQ (Agency for Healthcare Research and Quality) to describe the predictors of rhBMP use.  While they reported some conflicting results, they were in agreement that the use of rhBMP during pediatric spine surgery increased in the period between 2003 and 2009.  Additionally, they reported that the use of rhBMP increased with age and individuals with adolescent idiopathic scoliosis (AIS) were the least likely to receive treatment with rhBMP.  The highest were those with spondylolisthesis. 

The first of these studies was by Jain and colleagues who used the Nationwide Inpatient Sample (NIS) database to identify 4817 children, 18 years old or younger, who had undergone posterior and/or anterior spinal fusion procedures, using rhBMP.

The other study, by Lam and others, reported findings from the 2009 Kid’s Inpatient Database (KID).  A total of 9538 discharge records were identified for pediatric cases (up to 20 of age) that underwent spinal fusion surgery.  Of these, 1541 (10.8%) received rhBMP, with the majority (53.1%) being between 15 and 20 years old.  They reported that older age was a significant predictor of rhBMP use, with 72% of cases in which rhBMP was used being between 15 and 20 years of age compared with 50.8% in the group not receiving rhBMP. They also looked at the association of surgical approach and rhBMP use, with both the posterior occipitocervical and anterior lumbar approaches having increased odds ratio (OR) of rhBMP use compared with the posterior lumbar approach (OR=1.86; p=0.013 and OR=1.73; p<0.001, respectively).  The anterior cervical approach was found to have lower OR compared with the posterior lumbar approach (OR=0.25; p<0.001).  Contrary to what would be expected, the short- and mid-segment fusions were more likely to be associated with rhBMP use when compared to long-segment fusions (OR=1.42; p=0.016, and OR=1.44; p=0.005, respectively).  Revision for a failed prior fusion surgery was also highly associated with rhBMP use (OR=2.20; p<0.001).  Finally, the use of rhBMP had a significant association with a lower rate of transfusion (p<0.001).  No association was found between rhBMP use and length of stay.

In a report from Dodwell (2012), who also used data from the 2009 KID, it was reported that 8289 cases of pediatric spinal arthrodesis had occurred.  The use of rhBMP was reported in 711 of these cases (9.2%).  No significant differences in the estimated prevalence of complications were found between the rhBMP group and the non-rhBMP group (3.0% vs. 3.6%, respectively; p=0.39).  As was seen in the Lam study, they also reported that rhBMP use was associated with older age, lumbrosacral arthrodesis, and lower number of levels fused.  A lower use of rhBMP was associated with idiopathic scoliosis.

Using a proprietary database of orthopedic claims data from one of the largest private health insurers in the U.S., Rocque and others (2014) reported on the use of rhBMP and related complications.  They identified 4658 cases of pediatric spinal fusion between 2005 and 2011.  The use of rhBMP occurred in 1752 (37.6%) cases.  A higher percentage of females received treatment with rhBMP (39.4% vs. 34.2%, p=0.001).  Contrary to both Jain and Lam, no difference was found in rhBMP use between individuals age less than 10 years of age and those aged 10 to 19 (p=0.998).  Out of 4338 thoracolumbar fusions, 1714 used rhBMP (39.5%).  In comparison, rhBMP was only used in 14 (7.3%) of 193 reported cases of anterior cervical fusion.  Complications were reported in 172 of the 1752 rhBMP cases compared with 287  complications in 2906 non-rhBMP cases (p=0.948).  Of the complications in the rhBMP group, 38 (2.2%) were systemic, 27 (4.1%) were wound complications, 12 (0.86%) were central nervous system (CNS)-related, and 108 (6.2%) were categorized as “other complications.”  Finally, the rhBMP group had 24 (1.4%) reported reoperations vs. 40 (1.4%) in the non-rhBMP group.  This outcome study using administrative data was limited to 90 days.  The incidence of later onset complications was not measured.

Williams (2011) published the results of another large database-based study that provided data on outcomes and complications. They used data from the Scoliosis Research Society’s (SRS) morbidity and mortality database on all spinal fusion cases in individuals 20 years of age and younger submitted by members from 2004 through 2007.  The authors reported identifying 55,862 cases.  Of those, 11,933 (21%) involved the use of rhBMP.  The authors reported that degenerative spine disease and spondylolisthesis where highly associated with rhBMP use, compared to those with no rhBMP (p<0.001 for both).  Excluding cervical fusions, there were no significant differences between the rhBMP and non-rhBMP groups in terms of overall complications (8.5% vs. 8.4%), wound infections (2.3% vs. 2.4%), epidural hematomas/seromas (0.2% vs. 0.2%), or mortality (0.19% vs. 0.12%).  The authors identified 5148 cases of cervical fusion, with 674 (13%) involving the use of rhBMP.  They reported that use of rhBMP was associated with more overall complications (5.8% vs. 2.4%; p<0.001) and wound infections (2.1% vs. 0.4%; p<0.001) when compared to non-rhBMP cases.  No differences between groups was reported for the incidence of epidural hematoma/seroma (0.5% vs. 0.3%; p=0.3).  The rate of deep wound infection was significantly higher for subjects who had rhBMP used in thoraclolumbar fusions (1.1% vs. 0.2%; p<0.001).  For subjects who underwent interlaminar/facet fusions, the use of rhBMP was associated with a higher rate of epidural hematoma/seroma (0.5% vs. 0.7%; p=0.006).  As with previously discussed studies, increasing age was associated with increased use of rhBMP (p=0.006).

In addition to the above retrospective studies using administrative data, there are a small number of retrospective clinical studies evaluating the use of rhBMP in pediatric subjects undergoing various spinal fusion surgeries.  The largest of these involved 81 subjects, 18 years old and younger who received treatment with rhBMP during various orthopedic procedures.  The procedures reported included thoracic-lumbar-sacral spinal procedures (n=47), cervical spine procedures (n=5), femoral repair (n=7), tibial repair (n=21), and rib repair (n=1) (Oetgen, 2010).  Skeletal immaturity was confirmed in 53 (65.4%) subjects.  Mean follow-up was 22 months (range, 0.6-85 months), and 86% of subjects had greater than 1 year of follow-up.  Overall, 16 complications were reported in 91 surgical procedures evaluated, resulting in a complication rate of 17.5%.  No differences between the skeletally mature subjects and the non-skeletally mature subjects were found with regard to complication rates (25% vs. 17%; p=0.41).  There were 9 subjects who had multiple exposures to rhBMP, including 8 with 2 exposures and 1 with 3 exposures.  The complication rate in this subgroup was 27% (3 complications).  The complications reported include nine operative site problems (wound drainage, swelling and dehiscence), one enlargement of optic glioma, and six “others” (three deep infections, one compartment syndrome, one progressive myelopathy, and one dural fibrosis).

The next largest study involved 48 subjects, age 18 years and younger, who underwent dorsal occipitocervical fusions (Lindley, 2011).  Subjects were followed for an average of 53.2 months (range, 34-75 months).  The complications potentially related to rhBMP use included five cases of postoperative seroma formation (10.4%) and one case of ectopic bone formation (2.1%) noted at 15 months postoperatively. 

Three small retrospective case series involving between 11 and 19 subjects under the age of 20 years undergoing various spinal fusion procedures with rhBMP have been published (Abd-Al-Barar, 2011; Fahim, 2010; Gressot, 2014).

In summary, although the use of rhBMP for pediatric spine fusion has increased, this off-FDA label use of rhBMP involves significant risks, and the benefit-risk calculation is, at this time, strongly on the “risk” side.  While the North American Spine Society (NASS) does not currently support the routine use of rhBMP in skeletally immature individuals, it does advocate for its “compassionate use in very high risk children.”

Definitions

Anterior lumbar interbody fusion (ALIF): A spinal fusion surgery procedure where the surgeon approaches the surgical site through the abdominal cavity and the site of fusion is between the vertebral bodies; this is one of the most common approaches to spinal fusion.

Degenerative disc disease: A disease of a vertebral disc where the intervertebral disc breaks down, resulting in pain and disability.

Electrical bone growth stimulation: A medical device that uses an electric field or current to stimulate the growth of bone tissue.  These devices may be worn on the outside of the body or can be surgically implanted around the area requiring treatment.

Instrumented fusion: A fusion procedure involving the use of plates, screws, cages or rods to increase the stability of the joint during the healing process.

Intramedullary nail fixation (also known as IM nail fixation or intramedullary rod fixation): A surgical method of stabilizing a broken bone in order to prevent movement and promote proper healing.

Posterolateral intertransverse fusion of lumbar vertebrae (also known as TIF): A spinal fusion surgery procedure where the surgeon approaches the surgical site from the back and side, and the sites of fusion are the transverse processes.  This is one of the most common approaches to spinal fusion.

Posterior lumbar interbody fusion (PLIF): A spinal fusion surgery procedure where the surgeon approaches the surgical site from the back and the site of fusion is between the vertebral bodies.

Recombinant human bone morphogenic protein-2 (rhBMP-2, also known as InFUSE Bone Graft): A substance that may be used to stimulate the growth of bone; also known as dibotermin alfa.

Spinal fusion: A surgical procedure where two or more spinal vertebrae (spine bones) are surgically attached together.

Transforaminal lumbar interbody fusion (TLIF): A spinal fusion surgery procedure where the surgeon approaches the surgical site through the vertebral foramen and the site of fusion is between the vertebral bodies.

Transverse process: A bony protrusion on either side of the arch of a vertebra which functions as an anchor point and lever for attached muscles.

References

Peer Reviewed Publications:

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  67. Zadegan SA, Abedi A, Jazayeri SB, et al. Bone Morphogenetic Proteins in Anterior Cervical Fusion: A Systematic Review and Meta-Analysis. World Neurosurg. 2017; 104:752-787.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Agency for Healthcare Research and Quality. Bone Morphogenetic Protein: The State of the Evidence of On-Label and Off-Label Use. August 6, 2010. Available at: http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id75ta.pdf. Accessed on October 20, 2017.
  2. Garrison KR, Donell S, Ryder J, et al. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review. Health Technol Assess. 2007; 11(30):1-150, iii-iv.
  3. Garrison KR, Shemilt I, Donell S, et al. Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev. 2010;(6):CD006950.
  4. North American Spine Society. NASS coverage policy recommendations. Recombinant Human Bone Morphogenetic Protein (rhBMP-2). 2014. Available at: https://www.spine.org/PolicyPractice/CoverageRecommendations/AboutCoverageRecommendations.aspx. Accessed on April 28, 2017.
  5. U.S. Food and Drug Administration. FDA Public Health Notification: Life-threatening Complications Associated with Recombinant Human Bone Morphogenetic Protein in Cervical Spine Fusion. July 1, 2008.
  6. U.S. Food and Drug Administration. Approval letters for InFUSE. Available at:
  7. U.S. Food and Drug Administration. Use of bone graft substitutes containing recombinant proteins or synthetic peptides in patients under age 18 – FDA safety communication. January 21, 2015. Available at: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm431001.htm.  Accessed on October 20, 2017.
Websites for Additional Information
  1. American Academy of Orthopaedic Surgeons. Spinal Fusion. Available at: http://orthoinfo.aaos.org/topic.cfm?topic=A00348. Accessed on October 20, 2017.

Index

Dibotermin Alfa

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

New

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review. Initial document development. Moved content of SURG.00059 Recombinant Human Bone Morphogenetic Protein to new clinical utilization management guideline document with the same title.