| Coverage Policy Manual | |
| Policy #: | 2004030 |
| Category: | Surgery |
| Initiated: | July 2004 |
| Last Review: | December 2023 |
|
|
|
|||||||||||
| Bone Morphogenetic Protein | |
|
|
|
| Description: |
Bone morphogenetic proteins (BMP) are members of the transforming growth factors family At present, some 20 different BMPs have been identified, all with varying degrees of tissue-stimulating properties.
The recombinant human bone morphogenetic proteins (RhBMPs) are delivered to the bone grafting site as part of a surgical procedure; a variety of carrier and delivery systems has been investigated. Carrier systems, which are absorbed over time, 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.
The carrier and delivery system are important variables in the clinical use of rhBMPs, and different clinical applications, such as long-bone nonunion, or interbody or intertransverse fusion, have been evaluated with different carriers and delivery systems. For example, rhBMP putty with pedicle and screw devices are used for instrumented intertransverse fusion (posterolateral fusion; PLF), while rhBMP in a collagen sponge with bone dowels or interbody cages are used for interbody spinal fusion. In addition, interbody fusion of the lumbar spine can be approached from an anterior (anterior lumbar interbody fusion; ALIF), lateral (XLIF), or posterior direction (PLIF or TLIF). Surgical procedures may include decompression of the spinal canal and insertion of pedicle screws and rods to increase stability of the spine.
Posterior approaches (PLIF and TLIF) allow decompression (via laminotomies and facetectomies) for treatment of spinal canal pathology (e.g., spinal stenosis, lateral recess and foraminal stenosis, synovial cysts, hypertrophic ligamentum flavum) along with stabilization of the spine and are differentiated from instrumented or non-instrumented posterolateral intertransverse fusion, which involves the transverse processes alone. Due to the proximity of these procedures to the spinal canal, risks associated with ectopic bone formation are increased (e.g., radiculopathies). Increased risk of bone resorption around BMP grafts, heterotopic bone formation, epidural cyst formation, and seromas has also been postulated.
Regulatory Status
The INFUSE Bone Graft product (Medtronic) consists of rhBMP-2 on an absorbable collagen sponge carrier; it is used in conjunction with several carrier and delivery systems. The INFUSE line of products has been approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process. FDA product code: NEK.
In 2008, the FDA issued a public health notification on life-threatening complications associated with rhBMP in cervical spine fusion, based on reports of complications with use of rhBMP in cervical spine fusion (Schultz, 2008). Complications were associated with swelling of neck and throat tissue, which resulted in compression of the airway and/or neurologic structures in the neck. Some reports described difficulty swallowing, breathing, or speaking. Severe dysphagia following cervical spine fusion using rhBMP products has also been reported in the literature. As stated in the public health notification, the safety and efficacy of rhBMP in the cervical spine have not been demonstrated. These products are not approved by the FDA for this use.
In 2011, Medtronic received a “nonapprovable letter” from the FDA for AMPLIFY™. The AMPLIFY rhBMP-2 Matrix uses a higher dose of rhBMP (2.0 mg/mL) with a compression-resistant carrier.
OP-1 Putty (Stryker Biotech), which consists of rhBMP-7 and bovine collagen and carboxymethylcellulose, forms a paste or putty when reconstituted with saline. OP-1 Putty was initially approved by the FDA through the humanitarian device exemption process (H020008) for 2 indications:
“OP-1 Implant is indicated for use as an alternative to autograft in recalcitrant long-bone nonunions where use of autograft is unfeasible and alternative treatments have failed.”
FDA product code: MPW.
“OP-1 Putty is indicated for use as an alternative to autograft in compromised patients requiring revision posterolateral (intertransverse) lumbar spinal fusion, for whom autologous bone and bone marrow harvest are not feasible or are not expected to promote fusion. Examples of compromising factors include osteoporosis, smoking and diabetes.”
FDA product code: MPY.
Stryker Biotech sought the FDA permission to expand the use of OP-1 Putty to include uninstrumented posterolateral lumbar spinal fusion for the treatment of lumbar spondylolisthesis. In 2009, the FDA Advisory Committee voted against the expanded approval. Olympus Biotech (a subsidiary of Olympus Corp.) acquired OP-1 assets in 2010. In 2014, Olympus closed Olympus Biotech operations in the United States and discontinued domestic sales of Olympus Biotech products. The rhBMP-7 product is no longer marketed in the United States.
Recombinant Human Bone Morphogenetic Protein Products and Associated Carrier and Delivery Systems Approved by U.S. Food and Drug Administration
INFUSE™ Bone Graft, manufactured by Medtronic, received approval 3/07 (P050053):
INFUSE™ Bone Graft received approval 10/09 (P050053/S012):
INFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device, manufactured by Medtronic Sofamor Danek USA, received approval 7/02 (P000058):
INFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device received approval 7/04 (P000058/S002):
INFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device received approval 10/09 (P000058/S033)
INFUSE™ Bone Graft/Medtronic Interbody Fusion Device (Marketing name change) received approval 12/15 (P000058/S059):
INFUSE™ Bone Graft/Medtronic Interbody Fusion Device received approval 9/17 (P000058/S065)
Coding
There is no specific CPT or HCPCS code for bone morphogenetic protein. In 2011, CPT code 20930 was revised to include BMP-type materials used in spine surgery:
20930: Allograft, morselized, or placement of osteopromotive material, for spine surgery only (List separately in addition to code for primary procedure).
In the setting of spinal fusion, bone morphogenetic proteins may be used primarily as an alternative to autologous bone grafting. Since harvesting of autologous bone graft is coded separately from the fusion procedure (i.e., CPT codes 20936-20938), when bone morphogenetic protein is used as an alternative to the bone graft, these codes should no longer be reported. In contrast, the CPT code for treating tibial fracture nonunions with autograft (i.e., CPT code 27724) includes the harvesting component, and, therefore, when bone morphogenetic protein is used as an alternative in this setting, presumably the associated physician’s work would be decreased, since no autologous harvest is required. Finally, for treatment of acute, open tibial fractures, bone morphogenetic protein is not used as an alternative to autologous bone graft, but in addition to standard treatment with an intramedullary nail.
|
|
|
|
|
Policy/ Coverage: |
Effective January 2017
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Use of recombinant Bone Morphogenetic Protein-2 (InFUSE) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Bone Morphogenetic Protein (rhBMP-2) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications, including but not limited to:
For contracts without Primary Coverage Criteria, Bone Morphogenetic Protein (rhBMP-2) is considered investigational for all other indications, including but not limited to:
Investigational services are an exclusion in the member benefit certificate of coverage.
Cages used for implantation for non-covered uses will not be covered.
Effective Prior to January 2017
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Use of recombinant Bone Morphogenetic Protein-2 (InFUSE) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
Use of recombinant human bone morphogenetic protein-7 (OP-1) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Bone Morphogenetic Protein (rhBMP-2 or rhBMP-7) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications, including but not limited to:
For contracts without Primary Coverage Criteria, Bone Morphogenetic Protein (rhBMP-2 or rhBMP-7) is considered investigational for all other indications, including but not limited to:
Investigational services are an exclusion in the member benefit certificate of coverage.
Cages used for implantation for non-covered uses will not be covered.
Effective September 2009- August 2010
Use of recombinant Bone Morphogenetic Protein-2 (InFUSE) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
Use of recombinant human bone morphogenetic protein-7 (OP-1) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
Bone Morphogenetic Protein (rhBMP-2 or rhBMP-7) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications, including but not limited to:
For contracts without Primary Coverage Criteria, Bone Morphogenetic Protein (rhBMP-2 or rhBMP-7) is considered investigational for all other indications, including but not limited to:
Investigational services are an exclusion in the member benefit certificate of coverage.
Cages used for implantation for non-covered uses will not be covered.
Effective July 2004 - August 2009
Bone morphogenetic protein may be used:
Bone morphogenetic protein is not covered based on benefit certificate primary coverage criteria when used as, but not limited to,:
Primary Coverage Criteria requires that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria, Bone morphogenetic protein is considered investigational when used as, but not limited to:
Investigational services are a contract exclusion in the member's certificate of coverage.
|
|
|
|
| Rationale: |
This policy was initially developed in July 2004 following the FDA approval of rhBMP-2 (InFUSE) and the FDA Humanitarian Device Exemption approval of rhBMP-7 (OP-1 Implant). The policy was later archived and is currently being reactivated following a literature search through November 2009.
At the time this policy was created, randomized clinical trials supported the use of rhBMP-2 in the treatment of interbody spinal fusion when used in conjunction with a tapered cage, and also in the treatment of open tibial fractures (Govender, 2002) (FDA Summary). In addition, a randomized study supported the use of rhBMP-7 in the treatment of recalcitrant nonunions of the long bones (FDA Summary). There were inadequate data to document efficacy in other clinical applications. Specifically, approval by the U.S. Food and Drug Administration (FDA) through the Humanitarian Device Exemption of rhBM-7 in the treatment of revision posterolateral spinal fusion was based on a small trial of 48 patients (Johnsson, 2002). While the largest clinical trials and randomized studies demonstrated that rhBMP can be an alternative to an autologous bone graft for interbody spinal fusion, treatment of tibial fractures, and fracture nonunions, these results could not be extrapolated to other clinical indications for autologous bone graft because of the variable of the carrier and delivery systems. Use of these devices as part of a posterior interbody lumbar fusion was an off-label indication.
The results of the MEDLINE database search through November 2009 are summarized as follows, according to the categories of Spinal Fusion, Long-Bone Fractures and Nonunions and Additional Applications.
Spinal Fusion
Anterior Lumbar Fusion
The pivotal clinical trial of InFUSE (rhBMP-2) as part of the FDA approval process consisted of 279 patients undergoing single-level lumbar fusion via an open anterior approach who were randomized to receive either the LT (i.e., lumbar tapered)-cage with rhBMP-2 or the same cage filled with iliac crest autograft. In a non-randomized portion of the trial, an additional 136 patients underwent a single-level laparoscopic lumbar interbody fusion with rhBMP-2. There were no differences in fusion success rates, Oswestry disability index, 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 rhBMP-2, and these patients did not have to experience the pain and morbidity associated with the harvesting of autologous bone from the iliac crest. The results were comparable in 2 similarly designed trials of posterior lumbar interbody fusion (Sandhu, 2003) (Haid, 2004). In one trial, the group receiving rhBMP-2 had a hospital stay of 3.4 days compared to 5.1 days for the control group (Sandhu, 2003).
A report by Burkus et al in 2002 focused on the use of allograft bone dowels filled with rhBMP-2 on a collagen sponge (Burkus, 2002). A total of 46 patients 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. At 12 and 24 months, the investigational group showed higher rates of fusion and improved neurologic status and back and leg pain when compared with the control group. In 2005, Burkus and colleagues reported on rhBMP delivered with a threaded cortical allograft dowel (Burkus, 2005), a continuation of their 2002 study. This study included 131 patients undergoing anterior interbody fusion who were randomized to receive rhBMP on a threaded allograft or conventional fusion using autologous bone graft. Fusion rates were superior in the rhBMP group as well as the subjective outcomes of pain and disability.
Additional studies published in 2005 reported on the outcomes of patients undergoing multiple levels of fusion with rhBMP-2. For example, Luhmann and colleagues reported on a case series of 70 patients undergoing multilevel fusions with both anterior and posterior surgical approaches (Luhmann, 2005). The fusion rate was 93%–100%, depending on the type of surgery, similar to that reported in the pivotal trials of the InFUSE product.
Posterior Lumbar Fusion
In 2005, Villavicencio and colleagues reported on the use of rhBMP-2 for transforaminal interbody spinal fusion in a consecutive case series of 74 patients, where some patients underwent multiple fusions and others underwent a minimally invasive approach in which the rhBMP was delivered on an absorbable collagen sponge (Villavicencio, 2005). The authors did not identify any differences in short-term outcomes, and concluded that the use of an absorbable collagen sponge as a carrier permits a minimally invasive approach.
The 2009 literature update identified some small case series of rhBMP-2 on a collagen sponge for interbody fusion using a posterolateral approach. Neurologic impairment from ectopic bone in the lumbar canal following this off-label use of rhBMP-2 was reported (Wong, 2008). Five patients had been referred to a tertiary spine institute with complications following use of rhBMP-2 for posterior lumbar interbody fusion and transforaminal lumbar interbody fusion. Retrospective review was performed for patient demographics, operating room notes from the index rhBMP surgery, imaging studies, and current clinical status. The authors concluded from their review that ectopic bone in the spinal canal associated with posterolateral rhBMP-2 application may in rare cases contribute to symptomatic neurologic findings requiring difficult revision surgery.
In 2006, Dimar and colleagues reported an FDA-approved investigational protocol that compared rhBMP-2 (bovine collagen and tricalcium hydroxyapatite compression resistant matrix) with iliac crest autograft for single-level lumbar degenerative disease with instrumented (pedicle screw/rod) posterolateral fusion (Dimar, 2006). Similar improvements were observed in the 2 groups for back pain (score change from16.4 to 9.0 and from 16.1 to 9.5) and leg pain (score change from 14.2 to 8.5 and from 14.5 to 9.3) at 24-month follow-up. Solid fusion was observed by blinded observers in 48 of 53 (91%) of the rhBMP-2 patients and 33 of 45 (73%) of the autograft patients. This study is limited by loss to follow-up; only 65% (98/150) of the patients enrolled in the randomized trial were available for 24-month follow-up. These investigators also reported a retrospective subgroup analysis based on smoking status (Glassman, 2007). Of 148 radiographs reviewed, successful fusion was seen in 20 of 21 smokers (95%) in the BMP-2 group and 16 of 21 smokers (76%) in the autograft group.
In 2008, Glassman and colleagues reported instrumented posterolateral intertransverse fusion using rhBMP-2 with an absorbable collagen sponge (InFUSE) compared with iliac crest autograft in patients older than 60 years of age (Glassman, 2008). A total of 106 patients with a diagnosis of disc pathology, spondylolisthesis, stenosis, deformity, instability, post-decompression revision, or adjacent level fusion were randomized to rhBMP-2 (n = 50) or autograft (n = 52). All patients underwent decompression and instrumented lumbar fusion; none of the patients had an interbody fusion. Two-year follow-up in 100 patients showed similar improvements for the two groups in the Oswestry disability index, SF-36, and back pain and leg pain scores. Four patients in the rhBMP-2 group and 11 in the autograft group had additional surgical procedures during the 2-year follow-up. In the rhBMP group, the 4 additional surgeries (1 each) were for wound infection, adjacent compression fracture, nonunion, and adjacent level degeneration. The 11 additional procedures in the autograft group were due to wound infection (n = 2), nonunion (n = 5), and (1 each) reposition of the pedicle screw, late screw removal, pain pump insertion, and adjacent level degeneration. Two-year postoperative computed tomography (CT) scans showed an average CT grade that was higher in the rhBMP-2 group (4.3) than the autograft group (3.8). Blinded analysis of fusion rate based on bridging bone (CT grades 4 and 5) was 86% in the rhBMP-2 group and 71% in the autograft group.
Efficacy of rhBMP-2 for the treatment of multilevel adult spinal deformity was investigated in a prospective, single center, non-blinded radiographic analysis for anterior and posterior intertransverse (off-label) fusion with 98 patients (308 levels) with a mean age of 51.4 years (Mulconrey, 2008). For all groups the posterior instrumentation consisted of bilateral pedicle screw/rod constructs with 5.5-mm stainless steel rods. Routine radiographic and clinical follow-up was performed at 6 weeks, 3 months, 6 months, 1 year, and 2 years, with a minimum radiographic follow-up of 2 years. Anterior spinal fusion was performed in 47 patients (109 levels) with rhBMP-2 (8–12 mg/level) placed on an absorbable collagen sponge within a titanium mesh cage. The anterior reconstructions were in the distal lumbar spine and were protected with posterior instrumented fusion. Two surgeons not involved in the operative procedure independently reviewed and graded each fusion level. At a mean 2.5 years of follow-up, fusion was observed in 91% of the levels (average 2.3 levels per patient). Posterolateral intertransverse fusion was performed in 43 patients (156 levels) with rhBMP-2 (19.8 mg/level) applied to the posterolateral spine with local bone graft and extender. At a mean 2.6 years of follow-up, 97% of the levels (average 3.6 levels per patient) were graded as fused. A third group was composed of 8 patients (43 levels) who received FDA-approved posterolateral “compassionate use” surgeries on the basis of multiple prior fusion failures with past harvesting of iliac bone. Five of these patients had preoperative pseudarthrosis. High-dose rhBMP (40 mg/level) without any autogenous bone resulted in a 100% fusion rate with a mean number of levels fused of 5.4 per patients. The average fusion rate with rhBMP-2 for the 3 groups was 95% of levels, and the overall pseudarthrosis rate after multilevel spinal deformity fusion was 5% (13 levels).
Dimar and colleagues reported on a randomized controlled trial of 463 patients undergoing instrumented single-level posterolateral arthrodesis (Dimar,2009). Patients were randomized to either receive rhBMP-2 or an autogenous bone graft. Mean operative times and blood loss were both less than in the group that received rhBMP-2. At 24 months, 96% of the rhBMP-2 group evidenced fusion compared with only 89% in the iliac crest bone-graft group. With clinical outcomes similar in both groups and persistent donor-site pain being reported in 60% of the iliac crest bone-graft patients at 24 months, the off-label use of rhBMP-2 for posterolateral spinal fusion meets primary coverage criteria of effectiveness in improving health outcomes.
Non-instrumented posterolateral intertransverse process fusion is another common type of spinal fusion procedure as a treatment of spondylolithesis, but with distinct mechanical and biologic demands compared to instrumented interbody or intertransverse fusion, and thus requires a distinct approach to carrier/delivery systems. At the time this policy was created, preclinical studies indicated that a carrier sponge was inadequate, and the structural support of an interbody back cage (i.e., the delivery system) was not available for this setting. Boden and colleagues investigated rhBMP-2 in this clinical situation (Boden, 2002). In this study, the carrier system consisted of hydroxyapatite and tricalcium phosphate. One randomized study was identified that focused on the use of rh-BMP-7 for posterolateral lumbar fusion (Johnsson, 2002). The delivery system for rh-BMP-7 consisted of bovine collagen mixed with saline, creating a paste that was applied to the decorticated surface. The trial included 20 patients who were randomized to receive rh-BMP-7 or autologous bone. There were no significant differences in fusion outcomes between the two groups.
Subsequently, rhBMP-7 (OP-1) in a putty carrier (i.e., OP-1 Putty) received FDA approval through the Humanitarian Device Exemption as an alternative to autologous bone graft in “compromised” patients undergoing revision of a prior fusion. Compromised patients include those with osteoporosis, those who smoke, and those with diabetes. The data presented to the FDA are provided in “Summary of Safety and Probable Benefit” and consist of a randomized trial of 48 patients with single-level degenerative lumbar spondylolisthesis and spinal stenosis who underwent treatment with rhBMP-7 alone, in combination with an autograft, or autograft alone. The data were reported only for those receiving rhBMP-7 alone or autograft alone, constituting 24 and 12 patients, respectively. The summary provided minimal details regarding the compromised nature of these patients, stating only that 7 of the 24 patients receiving rhBMP-7 alone had compromising factors. In addition, unlike the labeled indication, which limits the use of this product to those undergoing revision surgery, patients in this trial were undergoing primary fusion. Effectiveness was based on radiographic success and improvement in the Oswestry Disability Index. The clinical and radiographic success rate was superior in those receiving rhBMP-7. The FDA summary concludes: “Based on a pilot clinical study, OP-1 Putty has demonstrated probable benefit as an alternative to autograft in patients who required a primary uninstrumented fusion for the treatment of degenerative spondylolithesis. While these data cannot be extrapolated directly to the expected performance of OP-Putty in revision posterolateral spinal fusions in the compromised population, there is reason to believe that OP-Putty could have a probable benefit in this population. When revision of a failed fusion is required, most patients are limited to either living with pain and altered function or repeating the original procedure with additional autologous bone, which may result in depletion of the bone stock and further risk to the patient. Allograft bone and bone graft substitutes are not considered feasible alternative to autografts in revision surgery due to their lack of osteogenic potential. For certain patients, for example those with implanted leads, bone growth stimulators would not be considered as feasible options. The preclinical and clinical data suggest that it is reasonable to conclude that the probable benefit to health from using the device for the target population outweighs the risk of illness or injury, taking into account the probable risks and benefits or currently available alternative treatments.”
In 2008, Vaccaro and colleagues published an FDA trial on use of OP-1 (rhBMP-7) in patients with symptomatic degenerative spondylolisthesis and spinal stenosis (Vaccaro, 2008). None of the patients had undergone previous lumbar surgery, and all had failed at least 6 months of nonoperative treatment (including physical therapy, lumbar epidural injections, anti-inflammatory medications, and activity modifications). Excluded were patients with current or history of smoking, morbid obesity, or a known sensitivity to collagen. After enrollment, 335 patients were randomized in a 2:1 ratio to receive OP-1 Putty or iliac crest autograft; 295 were treated (208 OP-1 and 87 autograft). Following treatment, patients were fitted with a lumbosacral orthosis and instructed to wear the brace when out of bed for 3 months. Follow-up visits were scheduled at 6 weeks, and 3, 6, 9, 12, and 24 months after surgery. Patients who were still alive and had not been categorized as a retreatment failure were invited to participate in the 36+ month follow-up. About 70% of patients from both groups were available at the 36+ month follow-up, which was reported to be 80% of the eligible patients (i.e., not failures and still alive). The number of treatment failures prior to 24 months was not reported. The primary endpoint at 24 months, as designed for FDA submission, was a composite measure of a 20% improvement in the Oswestry Disability Index, absence of serious adverse events, absence of a decrease in neurologic status, and radiographic fusion success. Overall success at 24 months did not achieve non-inferiority, due primarily to a decrease in bridging bone in the OP-1 Putty group (62%) compared with the autograft group (83%), as evaluated by radiologists who were blinded to the treatment condition. The 36+ month Modified Overall Success composite outcome was found to be similar between the two treatment groups, having replaced the measure of radiological success with simple presence of bone on CT scan. The percentage of patients showing a greater than 20% improvement on the Oswestry Disability Index was 69% for OP-1 and 77% for autograft. These scores were not significantly different. A visual analogue scale (VAS) score for donor site pain in the autograft patient group averaged 2.1 of 10 at 6 weeks, 1.6 at 12 months, 1.2 at 24 months and 1.1 at 36 months. Following review of the study results, an FDA panel voted 6-1 against expanding the indications for OP-1. This study supports the FDA’s Humanitarian Device Exemption for use of OP-1 in compromised patients requiring revision posterolateral intertransverse lumbar spinal fusion, for whom autologous bone and bone marrow harvest are not feasible or are not expect to promote fusion, but results are insufficient to support use of OP-1 Putty (rhBMP-7) in primary posterolateral intertransverse lumbar spinal fusion when autograft is feasible.
A retrospective analysis described posterolateral fusion without instrumentation using rhBMP-2 and morselized autologous spinous process elements (Hamilton, 2008). The study included 55 patients (mean of 68 years of age) who were moderately to severely disabled; 44 (80%) were diagnosed with degenerative spondylolisthesis with disabling pain and radiculopathy. Fusion was performed in all patients to prevent instability after significant medial facet joint resection. At an average 6 months after surgery (range, 3–36 months), 80% of patients showed significant fusion. Two patients (4%) showed no fusion. Follow-up evaluation by telephone or mail was conducted on 47 patients (85%) using an SF-12 Health Survey and a Modified Oswestry Low Back Pain Disability Questionnaire. Patients were asked to recall both their pre- and postoperative low back pain and their overall health status. Prior to surgery, 11 patients were bed bound and 30 experienced very severe pain that impacted all aspects of daily living and work. At an average of 34 months of follow-up (range, 29–36 months), no patients were bedridden, 1 reported very severe pain, 12 reported moderate to severe pain, and 34 reported none to minimal pain. Prospective controlled studies are needed to evaluate rhBMP-2 on an absorbable collagen sponge for posterolateral intertransverse fusion without instrumentation.
Fusion of Cervical Vertebrae
rhBMP-2 has been used as an alternative to autologous bone graft in fusion of the cervical spine. In 1 study the carrier/delivery system consisted of machined fibular rings (McKay, 2002). The trial consisted of 33 patients undergoing single or 2-level discectomy and fusion who were randomized to receive fibular rings filled either with rhBMP-2 or autologous bone graft. Fusion was recorded in all patients at 6 months after surgery. Another study (with 77 consecutive patients undergoing either cervical or lumbar interbody fusion) found greater end plate resorption and subsidence following treatment with rhBMP-2 (49% of levels) in comparison with allograft/demineralized bone matrix (6% of levels) (Vaidya, 2007).
There have been reports of adverse events with rhBMP in cervical fusion. Vaidya et al reported that use of rhBMP-2 for cervical interbody fusion (22 consecutive patients) resulted in greater swelling (8 vs. 6 mm) and dysphagia (65% vs. 22%) at up to 6 weeks after surgery in comparison with 24 consecutive patients treated with demineralized bone matrix (Vaidya, 2007).
In July 2008, the FDA issued a public health notification regarding life-threatening complications associated with recombinant human bone morphogenetic protein in cervical spine fusion. The FDA recommended that practitioners either use approved alternative treatments or consider enrolling as investigators in approved clinical studies.
Long-Bone Fractures and Nonunions
Open Tibial Fractures
Govender and colleagues reported on the results of a trial that randomized 450 patients 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 a absorbable collagen sponge placed over the fracture at the time of definitive wound closure (Govender, 2002). The primary outcome measure was the proportion of patients requiring secondary intervention due to delayed union or nonunion at 12 months. A total of 58% of patients 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.
A subgroup analysis from combined European (n = 450) and American (n = 60) multicenter trials assessed the interaction of rhBMP-2 and reaming in the treatment of type-III open tibial fractures (Swiontkowski, 2006). From the total group of patients (n = 131) who presented with a type-III open tibial fracture, the BMP-2 treated group was found to have fewer bone grafting procedures, fewer secondary interventions, and a lower rate of infection compared with intramedullary nail fixation alone. However, examination of the subgroup treated with reamed intramedullary nailing (n = 113; BMP-2 = 65 control = 48) revealed no significant differences between the two groups. The uneven distribution of intramedullary preparation between the groups raises questions about the relative contribution of reaming to the overall results.
Kuklo and colleagues published a case series on the use of rhBMP-2 for the treatment of tibial fractures in injured soldiers (Kuklo, 2008). This report was later retracted and the author was accused of falsifying data (Scott, 2009). The use of rhBMP for this indication is controversial and there is a lack of scientific evidence that it’s use for the treatment of open tibial fractures is safe and effective.
Fracture Nonunions
rhBMP-7 has received FDA approval through the Humanitarian Device Exemption process as an alternative to bone autograft in the recalcitrant long bone nonunions, and the data presented to the FDA have been published in the medical literature (Friedlaender, 2001). The study included 122 skeletally mature patients with 124 tibial nonunions. Each patient was treated by intramedullary rod fixation, either accompanied by rh-BMP-7 or fresh bone autograft. The rhBMP-7 was applied as a paste to the fracture ends. At 9 months after the procedure, 81% of the rhBMP treated nonunions and 84% of the control group reported clinical success compared to a radiologic success of 75% and 84%, respectively. Because both treatment groups received an intramedullary rod, this study was not designed to determine if either the rhBMP-7 or autologous grafting improved outcomes compared to the intramedullary rod fixation alone. However, about half of the patients had undergone a prior fusion attempt with an intramedullary rod, and from 30%–40% had undergone a prior autograft. In its Summary of Safety and Probable Benefit, the FDA concluded: “…the OP-1 implant has demonstrated probable benefit as an alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed, thus providing patients with a treatment for nonunion where the alternative is either amputation or no treatment. This should allow the patients to regain some mobility and may decrease their pain on ambulation.”
A randomized trial and a multicenter registry from Europe (Ekrol, 2008) (Kanakaris, 2008). Ekrol et al randomized 30 patients undergoing corrective osteotomy for symptomatic malunion after distal radial fractures to receive either rhBMP-7 or autogenous bone graft harvested from the ipsilateral iliac crest (Ekrol, 2008). The first 10 patients (4 rhBMP-7 and 6 autogenous bone grafts) were treated with non-bridging external fixation, the next 20 with internal fixation with a dorsal pi-plate to improve stability. All patients who had been treated with autogenous bone graft had complete filling of the metaphyseal defect with healing at an average of 7 weeks. The 14 patients treated with rhBMP-7 exhibited slower (13–18 weeks) and incomplete healing. Two of the 4 patients treated with external fixation and rhBMP-7 developed excessive osteolysis around the osteotomy site, resulting in loss of the corrected position and non-union of the osteotomy. Of the 10 patients treated with internal fixation with a dorsal pi-plate, 5 healed at the volar cortex with a dorsal defect remaining at 1 year. Two of the 10 developed non-union. The authors concluded that rhBMP-7 does not confer the same stability as bone graft and heals at a slower rate than autogenous bone graft.
Results from 68 consecutive cases of rhBMP-7 for tibial non-unions (minimum follow-up of 12 months) were reported from 6 orthopedic centers in Europe using a specialized rhBMP data registry (Kanakaris, 2008). The median time between the initial injury and treatment with rhBMP-7 was 23 months (range, 9 to 317). In 24 cases (35%), previous treatment with autologous bone graft had been unsuccessful. In 25 cases (14 of which had previously been treated with rhBMP-7), rhBMP-7 was combined with autologous bone graft. Thus, 37% of the 68 patients received both rhBMP-7 and autologous bone graft. At a mean 21-month follow-up (range, 12–30 months), the union rate was reported to be 90%, with a median time to union of 6.5 months (range, 3–15 months). The number of patients who were lost to follow-up before 12 months was not reported, and no comparison was conducted with use of autologous bone graft alone. No systemic allergic reactions or adverse effects were observed and/or reported.
In October 2009, allegations of fraud were made against Stryker Biotech and its top management regarding their marketing practices of the OP-1 Implant and OP-1 Putty for use in long bones and in the spine. The devices were approved through the FDA Humanitarian Device Exemption process with the restriction that the device could only treat a condition that affected fewer than 4,000 patients and could not be sold for profit.
There is a lack of scientific evidence that the use of rhBMP-7 (OP-1) for the treatment of long-bone nonunion improves health outcomes compared to autologous bone graft and does not meet primary coverage criteria of effectiveness.
Additional Applications
There has been research interest in the following applications: management of early stages of osteonecrosis of the vascular 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., Ilizarov procedure) (Valentin-Opran, 2002) (Einhorn, 2003). Craniofacial applications have included periodontal defect regeneration, cleft palate repair, cranial defect repair, restoration, and maintenance of the alveolar dental ridge. However, the literature regarding these applications consists of small case series; no controlled trials were identified.
There continues to be interest in BMP for oral maxillofacial procedures. For example, Boyne and colleagues reported on a phase II trial of 48 patients who were undergoing staged maxillary sinus floor augmentation (Boyne, 2005). Patients were assigned to two different dosages of BMP delivered on an absorbable collagen sponge or to bone grafting. Mean increases in alveolar ridge were similar in all three groups, permitting the endosseous dental implantation.
2010 Update
In 2009, Agarwal and colleagues published a meta-analysis of osteoinductive bone graft (stimulate new bone formation) substitutes for lumbar fusion in patients with degenerative disc disease (Agarwal, 2009). The interventions examined were BMP-2, BMP-7, demineralized bone matrix, and platelet gel. Seventeen studies (1342 patients) met the inclusion criteria, including 9 randomized controlled trials and 5 prospective controlled trials. Procedures included anterior lumbar interbody fusion (ALIF; 5 studies), posterolateral or posterior lumbar interbody fusion (PLF/PLIF; 11 studies) and anterior-posterior lumbar fusion (1 study). Four studies used rhBMP-2 for posterior fusion, which is not currently an FDA-approved indication. BMPs were combined with an osteoconductive material (scaffolding to support bone growth) in 9 of the 17 studies, and the comparison group was autologous iliac crest bone graft in all but 2 of the 17 studies. Meta-analysis of the 3 randomized controlled trials that compared BMP-7 with autologous bone graft showed no significant improvement in radiographic nonunion or Oswestry Disability Index. Meta-analysis of the 6 randomized controlled trials that compared BMP-2 with autologous bone graft showed a decrease in the risk of radiographic nonunion with BMP-2 following either ALIF or PLF/PLIF at 12-24 months. When the radiographic results were corrected for publication bias, the effect of BMP-2 remained clinically significant. It was calculated that 8 patients would be needed to treat to avoid one radiographic nonunion. Four randomized controlled trials on BMP-2 reported dichotomous data from the Oswestry Disability Index. The Oswestry Disability Index was not significantly improved by BMP-2 at 12-24 months follow-up, however, there was a trend toward benefit and the studies were not powered to detect differences in clinical outcomes. Results were mixed regarding operating time, blood loss, and length of hospital stay.
Mroz and colleagues published a 2010 systematic review of complications related to use of BMP (Mroz, 2010). The most commonly reported complications associated with BMP use in spine surgery include resorption/osteolysis, extradiscal/ectopic/heterotopic bone formation, graft subsidence, graft or cage migration, and elevated antibody response, and hematoma. The reported rate of BMP-related complications is highly variable (ranging from 0% to 100%) and there is a lack of data on rates of complications without BMP for comparative purposes. However, given the potential complications related to the use of BMP-2 in ventral cervical spine surgery, its use was not recommended. Data were considered insufficient to validate the use of BMP-2 for posterior cervical or thoracic fusion, and the potential complications related to the use of BMP-2 in posterior lumbar Interbody fusion raised concerns regarding it routine use in this application.
Chen and colleagues reported 4 cases of delayed symptomatic ectopic bone formation after minimally invasive transforaminal lumbar interbody fusion, in which bone fusion was augmented with BMP-2 applied to an absorbable collagen sponge (Chen, 2010). A 2010 systematic review of complications related to use of BMP in spine surgery indicates considerable uncertainty regarding the rate of complications following off-label (e.g., posterior and transforaminal) use in the lumbar spine (Mroz, 2010).
A 2010 Cochrane review evaluated the effectiveness and costs of BMP on fracture healing in acute fractures and nonunions compared with standards of care (Garrison, 2010). The literature was searched to October 2008, and 11 randomized controlled trials (976 participants) and 4 economic evaluations were included in the review. The times to fracture healing were comparable between the BMP and control groups. There was some evidence for increased healing rates, mainly for open tibial fractures without secondary procedures (risk ratio of 1.19). Three trials indicated that fewer secondary procedures were required for acute fractures treated with BMP (risk ratio of 0.65). The authors concluded that limited evidence suggests that BMP may be more effective than standard of care for acute tibial fracture healing, however, the use of BMP for treating nonunion remains unclear (risk ratio of 1.02). Limited evidence suggested that the direct medical costs associated with BMP could be offset by faster healing and reduced time off work for patients with the most severe open tibia fractures. The authors noted that there was a high level of industry involvement and a high risk of bias in the evidence. A limitation of this review is that the authors did not distinguish results obtained from BMP-2 versus BMP-7.
The use of rhBMP either has not been shown to be as beneficial as the established alternative (iliac crest autograft) and/or evidence is insufficient to permit conclusions concerning the effect of rhBMP for posterior or transforaminal interbody spinal fusion (because of safety concerns related to ectopic bone formation in the spinal canal) and treatment of non-instrumented posterolateral intertransverse spinal fusion when autograft is feasible and expected to promote fusion. Changes will be made to the coverage statement in regards to these two indications. The literature review did not identify any randomized controlled trials that would prompt any other changes to the coverage statement.
September 2010 Update
The August 2010 AHRQ Technology Assessment Report was reviewed. The assessment concluded the off-label use of rhBMP2 for acute open tibial fractures “enhances healing and reduces the need for invasive second procedures. This conclusion was based on the findings of one RCT (Govender, 2002) which compared two doses of rhBMP2 versus standard of care. The RCT is supported by a smaller unpublished RCT with an identical design. The coverage statement for rhBMP2 will be expanded to include the treatment of acute, open fractures of the tibial shaft.
2012 Update
A literature search was conducted through September 2012. There was no new literature identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
Spinal Fusion
In 2011, Carragee and colleagues published a systematic review of emerging safety concerns with rhBMP-2 (Caragee, 2011). The review compared conclusions regarding safety and efficacy from the 13 published rhBMP-2 industry-sponsored trials with available U.S. Food and Drug Administration (FDA) data summaries, subsequent studies, and databases. Evaluation of the original trials suggested methodologic bias against the control group in the study design (discarding local bone graft and failure to prepare facets for arthrodesis) and potential bias (overestimating of harm) in the reporting of iliac crest donor site pain. In addition, even though there were no rhBMP-2-associated adverse events reported in the original 13 trials (0 events in 780 patients), comparison between the published studies and FDA documents revealed internal inconsistencies and adverse events that were not reported in the published articles. Based on the FDA data and subsequent studies, the systematic review estimated that adverse events with use of rhBMP-2 ranged from 10% to 50%, depending on the approach to spinal fusion.
Posterior Interbody Fusion or Transforaminal Interbody Fusion of Lumbar Vertebrae
In 2011, Mannion and colleagues reported fusion and adverse event rates following use of low-dose rhBMP-2 (1.4 mg) with local bone graft in a series of 30 patients who underwent minimally invasive posterior or TLIF (Mannion, 2011). Computed tomography (CT) scan showed complete fusion in 33 of 36 spinal levels at the first postoperative scan (mean of 7.1 months). There was one case of nonunion at 12 months, with vertebral body osteolysis and cage subsidence into the end plate. In addition, despite very low dose rhBMP-2, there were 2 cases (6.7%) of asymptomatic heterotopic ossification in the neural foramen and 2 cases (6.7%) of inflammatory perineural cyst formation, one of which was symptomatic and required revision. Another retrospective review of 23 patients who had a complete set of CT scans after TLIF found the incidence of osteolysis in the adjacent vertebral bodies to be 54% at 3-6 months and 41% at 1-2 years (Helgeson, 2011).
Fusion of Cervical Vertebrae
Stachniak and colleagues retrospectively reviewed the incidence of prevertebral soft tissue swelling and dysphagia in 30 patients who underwent multi-level anterior cervical discectomy and fusion with rhBMP-2 (0.6 mg/level) (Stachniak, 2011). Most patients were treated with a standardized dexamethasone taper postoperatively to reduce clinical complications. Soft tissue swelling was assessed by an independent radiologist using cervical spine radiographs on postoperative day 1 and at 2, 6, and 10 weeks and 6 months after surgery. Soft tissue swelling peaked at 2 weeks and decreased to near preoperative levels by 6 months. At 2 weeks, the Cervical Spine Research Society Swallowing-Quality of Life tool showed 19% of patients frequently choking on food, 4.8% frequently choking when drinking, and 47.6% with frequent food sticking in the throat. By 6 months, 0% had frequent choking on food, 6.7% had frequent difficulty drinking, and 6.7% had frequent food sticking in the throat. No patients required reoperation or hospitalization for soft tissue swelling. The Neck Disability Index, neck pain, and arm pain scores all improved progressively over 6 months. Incidence of fusion, measured by cervical CT scans, was 95% at 6 months and 100% at 9 months. A number of questions were raised by this report, including what is the appropriate dose of rhBMP-2, whether the rhBMP-2-soaked sponges should be contained solely within the grafts, whether the grafts should be vented or unvented, and whether tissue glue should be used in conjunction with rhBMP-2 to shield the tissue. Financial support for this study was received from Medtronic Spinal and Biologics.
Complications, including seroma formation and heterotopic bone formation, have also been reported with use of rhBMP-2 in pediatric craniocervical arthrodesis (Lindley, 2011). In a retrospective review of 48 pediatric patients who underwent dorsal occipitocervical fusion, there were 6 complications (12.5%). Two of the 5 patients who developed postoperative seroma required emergency reoperation for symptoms suggesting brainstem compression and obstructive hydrocephalus. A sixth patient required reoperation for heterotopic bone formation causing cervicomedullary compression. The authors conclude that use of rhBMP during occipitocervical fusion in this population can create life-threatening complications and should be avoided whenever possible.
Open Tibial Fractures
In a 2011 study, Aro and colleagues found no significant benefit of rhBMP-2 on the rate of healing in open tibial fractures treated with reamed nail fixation (Aro, 2011). A total of 277 patients were randomized to standard of care (SOC) consisting of reamed intramedullary nail fixation and routine soft tissue management or SOC plus an absorbable collagen sponge implant containing rhBMP-2. The fractured tibia and the surrounding tissues were assessed at 6, 10, 13, 16, 20, 24, 32, 41, and 52 weeks in this single-blind study. The primary efficacy outcome was the proportion of subjects with a healed fracture at 13 and 20 weeks by intent-to-treat analysis, and a 20% difference in healing rates was considered to be clinically meaningful. At week 13, the proportions of patients with a healed fracture were 60% for rhBMP-2 and 48% for SOC (p=0.054). At week 20, the proportions of patients with a healed fracture were 68% and 67% for rhBMP-2 and SOC, respectively. Twelve percent of the subjects in each group underwent secondary procedures. Infection was seen in 27 (19%) of the patients in the rhBMP-2 group and 15 (11%) in the SOC group (p=0.065). Deep infections involving bone were more common in the rhBMP-2 group (9% vs. 2%). There was also a higher rate of serious adverse events (requiring hospitalization) in the rhBMP-2 group (3% vs. 0%) due primarily to the difference in infections. The adverse event incidence (i.e., hardware failures, peripheral edema, heterotopic ossification, and pain) was otherwise similar between the treatment groups.
Oral and Maxillofacial Procedures
A 2011 systematic review of rhBMP-2 for reconstruction of the alveolar cleft identified 3 studies with a total of 49 patients that compared rhBMP-2 with Iliac crest bone grafting (ICBG) and had radiographic quantification of bone in the reconstructed cleft (van Hout, 2011). One small randomized controlled trial (n=16) reconstructed the alveolar clefts in children with mixed dentition and found comparable bone quantity (difference of 5.8%) but lower bone height (10.2 mm vs. 13.9 mm) for patients treated with rhBMP-2 compared to ICBG. Local postoperative swelling was observed in 37.5% of the rhBMP-2 group, while significant donor site pain was reported in 87.5% of patients in the control group. In another small randomized controlled trial in skeletally mature patients (n=21), bone quantity (95% vs. 63%) and bone height (85% vs. 70%) were superior following use of rhBMP-2. The control group showed significant donor site pain, more wound healing problems and a longer hospital stay. The third study included in the review was a retrospective analysis with only 2 children in the control group.
Use of rhBMP-2 delivered by hydrogel was associated with severe swelling when used in children with cleft lip and palate (Neovius, 2012). A low rhBMP-2 concentration (50 mcg/mL) did not induce bone formation in the first 2 patients randomized to rhBMP-2. The study was terminated when treatment of the next 2 patients with a higher dose of rhBMP-2 (250 mcg/mL) resulted in severe gingival swelling.
Through April 30, 2011, the FDA’s Manufacturer and User Facility Device Experience (MAUDE) received 83 reports of adverse events involving rhBMP-2 in oral and maxillofacial operations (Woo, 2012). rhBMP-2 was used off-label in 66.3% of these cases and included reconstruction of the mandible after fracture or cancer and alveolar cleft repair. The most frequently reported adverse events were local edema/pain, surgical site infections/wound complications, and graft failure.
Overall, the evidence does not support a health benefit of rhBMP in oral and maxillofacial procedures.
Ongoing Clinical Trials
A search of the online site clinicaltrials.gov in September 2012 identified several ongoing studies. Of particular interest is an industry-sponsored Phase II randomized controlled dose-finding study of intra-articular BMP-7 for osteoarthritis of the knee (NCT01111045). The study lists an enrollment of 355 subjects and is described as completed as of January 2012. As of September 2012, no publications from this study have been identified.
NCT00984672 is a prospective observational study of radiculitis following use of rhBMP-2 in spinal fusion. The study will evaluate the incidence of this complication and use postoperative imaging studies to help determine whether bony overgrowth occurs adjacent to the effected spinal nerves. The study has an estimated enrollment of 240 patients with completion in February 2013.
2013 Update
A search of the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
2014 Update
A literature search conducted through October 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2014, Lyon et al reported a manufacturer-funded randomized double-blind trial of injectable rhBMP-2 in a calcium phosphate matrix for closed tibial diaphyseal fractures (Lyon, 2013). The study had a target enrollment of 600 patients but was stopped after interim analysis with 387 patients enrolled. Addition of the injectable rhBMP-2 paste to the standard of reamed intramedullary nail fixation did not shorten the time to fracture healing, resulting in the study termination due to futility.
Guidelines on lumbar spinal fusion from the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons were updated in 2014 (Kaiser, 2014). AANS/CNS gave a Grade B recommendation (multiple level II studies) for the use of rhBMP-2 as a substitute for autologous iliac crest bone for anterior lumbar interbody fusion and single-level posterolateral instrumented fusion. Grade C recommendations were made for rhBMP-2 as an option for PLIF and TLIF , posterolateral fusion in patients older than 60 years, and as a graft extender for either instrumented or noninstrumented posterolateral fusions. AANS/CNS also gave a Grade C recommendation (based on multiple level IV and V studies) that the use of rhBMP-2 as a graft option has been associated with a unique constellation of complications of which the surgeon should be aware when considering the use of this graft extender/substitute.
2016 Update
A literature search conducted through September 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Long-Bone Fractures and Nonunions
Dai and colleagues published a meta-analysis on rhBMP for the healing of acute tibial fractures (4 RCTs, 868 patients) and non-unions (4 RCTs, 245 patients) (Dai, 2015). For acute tibial fractures, 3 RCTs were conducted with rhBMP-2 and 1 with rhBMP-7. All of the included studies were conducted over a decade ago. rhBMP was associated with a higher rate of union (RR=1.16) and a lower rate of revision (RR=0.68) compared with controls (3 trials with soft-tissue management and 1 with intramedullary nail [IM] plus autograft). There was no significant difference between the BMP and control groups for hardware failure or infection. For tibial fracture non-unions, 3 trials used rhBMP-7 and the 4th trial did not state which formulation. The RR=0.98, and there was no significant difference between the BMP and IM plus autograft groups in the rate of revision or infection. Interpretation of these results is limited by the different control groups and different formulations of rhBMP, one of which is no longer marketed in the U.S.
2017 Update
A literature search conducted through October 2017 did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
A literature search was conducted through October 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
LUMBAR SPINAL FUSION
Systematic Reviews
Zadegan et al conducted a systematic review and meta-analysis investigating the off-label uses of rhBMP (Zadegan, 2017) Reviewers evaluated the evidence for rhBMP-2 and rhBMP-7 in anterior cervical spine fusions. A literature search returned 18 articles (total N=4782 patients). Reviewers specifically assessed rhBMP for fusion rates, adverse events and complication rates. The fusion rate was higher in rhBMP than in alternative treatments such as bone grafting. However, serious complications (eg, cervical swelling, dysphagia/dysphonia, ossification) occurred more frequently in rhBMP procedures than in any other treatment alternative.
Observational Studies
In a retrospective cohort study, Khan et al investigated the effectiveness and safety of using rhBMP-2 in transforaminal lumbar interbody fusions (Khan, 2018). The authors compared rhBMP-2 with bone autograft by reviewing data on 191 patients undergoing anteroposterior instrumented spinal fusion with transforaminal lumbar interbody fusion from 1997 to 2014 at a single institution. Patients were separated into 2 treatment groups: 83 patients were treated with rhBMP-2 (BMP group) and 104 patients were treated with bone grafting (non-BMP group. Results were similar between groups; fusion rates were 92.7% and 92.3% for BMP and non-BMP patients, respectively. Seven patients in the BMP group and 2 patients in the non-BMP group experienced radiculitis. Seroma was observed in 2 patients in the BMP group; it was not observed in any patients in the non-BMP group. Given these very small differences, the authors concluded that rhBMP-2 is a comparable treatment option to bone grafting in transforaminal lumbar interbody fusion procedures.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A systematic review and meta-analysis assessing the safety and efficacy of bone substitutes in lumbar spinal fusion was published by Feng et al (Feng, 2019). The study identified 27 RCTs involving 2,488 patients utilizing various bone grafts for lumbar arthrodesis. Use of rhBMP-2 provided the highest fusion rate and was found to be significantly superior to iliac crest bone graft (OR 0.21; 95% CI, 0.11 to 0.36; p<0.001), autograft local bone (OR 0.18; 95% CI, 0.04 to 0.78); p=0.022), and allograft (OR 0.13; 95% CI, 0.03 to 0.60; p=0.009). However, both iliac crest bone graft and rhBMP-2 demonstrated an increased incidence of adverse events.
A systematic review and meta-analysis of bone morphogenetic protein vs autologous iliac crest bone graft in lumbar fusion was reported by Liu et al (Liu, 2020). A total of 20 RCTs involving 2,185 patients were identified. A higher fusion success rate (OR 3.79; 95% CI, 1.88 to 7.63; p=0.0002; I2 = 58%), enhanced improvement in Oswetry disability index scores (mean difference 1.54; 95% CI, 0.18 to 2.89; p=0.03), and a lower re-operation rate (OR 0.59; 95% CI, 0.43 to 0.80; p=0.0007) was demonstrated in the rhBMP group. No statistically significant difference in the incidence of adverse events was reported between rhBMP and iliac crest bone graft (OR 0.91; 95% CI, 0.70 to 1.18; p=0.47).
Mariscal et al conducted a meta-analysis of bone morphogenetic protein-2 vs iliac crest bone graft for posterolateral fusion of the lumbar spine (Mariscal, 2020). Six RCTs evaluating 908 patients (446 bone morphogenetic protein-2; 462 iliac crest bone graft) were identified. The fusion success rate was significantly higher at 86% vs 60% at 6 months (n=687; OR 3.75; 95% CI, 2.58 to 5.44; p<0.00001; I2=86%) and 88% vs 80% at 12 months (n=448; OR 1.76; 95% CI, 1.06 to 2.92; p=0.03; I2=43%) in the bone morphogenetic protein vs iliac crest bone graft groups. Moderate to high statistical heterogeneity was determined. Administration of osteoinductive materials (bone morphogenetic protein-2 or iliac crest bone graft) used variable vehicles, doses, and concentrations. Surgery time (p<0.00001; I2=83%) and hospitalization duration (p=0.003; I2=78%) were both found to be significantly longer in the iliac crest bone graft group. Differences in quality of life measures including Oswetry disability index, 36 - Item Short Form health Survey, and Back Pain Score were not significantly different between the two groups. No significant differences in adverse events (eg, respiratory effects, infection, malignancy, and additional surgical procedures) were noted between groups except for the non-unions subgroup (OR 0.28; 95% CI, 0.11 to 0.68; p=0.005; I2=0%) which demonstrated a higher incidence of adverse events with iliac crest bone graft.
Retrospective analyses of data from Medicare and from a commercial insurer database failed to confirm a higher risk of cancer in rhBMP-2 patients (Cooper, 2013; Cooper, 2018). The results probably reflect decreased off-label use and indicate that, in doses and vehicles approved for lumbar surgery, cancer risk is negligible. Long-term follow-up data from patients treated with elective spinal fusion continue to reveal no increased risk of cancer with the use of rhBMP (Dettori, 2019).
The Major Extremity Trauma Research Consortium (2019) published the results of a multicenter RCT comparing rhBMP-2 and absorbable collagen sponge (INFUSE™ Bone Graft) against iliac crest bone graft for the treatment of open tibia fractures with critical size defects (Cannada, 2019). The study enrolled 30 adult patients with Type II, IIIA, or IIIB open tibia fractures and bone defects treated with an intramedullary nail and critical size defects 1-5 cm in length and at least 50% circumference on orthogonal radiograph. Patients with bone defects exceeding the size of one large INFUSE™ kit were excluded. Sixteen patients were randomized to rhBMP-2 and 14 patients were randomized to iliac crest bone graft. The primary outcome measure was radiographic union within 52 weeks without the need for a secondary intervention as assessed by a panel of experienced orthopedic trauma surgeons blinded to patient treatment assignment. Secondary outcome measures included clinical healing, patient-reported measures, and major complications. Union data was available for 23 patients at 52 weeks; 7/12 (58.3%) in the rhBMP-2 group achieved radiographic union compared to 9/11 (81.8%) in the iliac crest bone graft group (mean difference -0.23; 90% CI, -0.55 to 0.10). Patients in the rhBMP-2 also exhibited lower rates of clinical healing at 52 weeks (27% vs 54%), poorer mean Short Musculoskeletal Function assessment scores, and experienced more major complications (5 vs 3). The authors concluded that there was not enough evidence to conclude that iliac crest bone graft and rhBMP-2 are equivalent for radiographic union in patients with open tibial fractures. Target enrollment in this study was not met due to low incidence of eligible bone defects in the civilian trauma population. After 5 years, trial enrollment was discontinued.
Ramly et al published a systematic review assessing the safety and efficacy of rhBMP-2 in craniofacial surgery (Ramly, 2019). A total of 17 RCTs were identified evaluating the use of rhBMP-2 in the maxillary sinus, alveolar ridge, alveolar cleft, or for cranial defect reconstruction. Study follow-up durations were variable (range, 3-36 months) and outcome assessments were based on clinical exam, radiology, and/or histology. There was also wide variation in concentrations, carriers, and controls. Five RCTs evaluating rhBMP-2 in maxillary sinus floor augmentation were identified. Two RCTs comparing rhBMP-2 to bone graft controls found the control group to be superior. Three RCTs comparing rhBMP-2 to xenografts reported variable outcomes. Seven RCTs evaluated rhBMP-2 in alveolar ridge augmentation. Three studies found no significant difference vs control whereas four studies favored rhBMP-2 over various controls. Only 1 of 4 RCTs comparing rhBMP-2 to iliac crest bone graft in alveolar cleft reconstruction favored rhBMP-2, and reflected the only trial in this subgroup that enrolled skeletally mature patients. The authors concluded that the safety profile of rhBMP-2 and the quality of evidence supporting its use in craniofacial surgery is still in development.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In the premarket approval application for rhBMP-2 (INFUSE® Bone Graft) as an alternative to autogenous bone graft for sinus augmentation, and for localized alveolar ridge augmentations for defects associated with extraction sockets, data from 5 clinical studies were submitted (3 for sinus floor augmentation and 2 for extraction socket augmentation) (FDA, 2007). All 5 studies had a similar protocol with the treatment course consisting of study device implantation followed by an osteoinduction phase, dental implant placement followed by an osseointegration phase, and prosthesis placement (functional loading) followed by functional restoration. A total of 312 patients were enrolled across the 5 studies with varying rhBMP-2 doses and control groups utilized. In the pivotal sinus augmentation study, results revealed that 79% (95% CI, 68.5%-87.3%) of patients in the rhBMP-2 group successfully received dental implants without additional augmentation, received a prosthesis, and maintained functional loading for at least 6 months. The success rate at 6 months post-loading in the autogenous bone graft group was higher by 11.8% (95% CI, 0.8%-22.8%); however, the graft group had a significantly increased rate of adverse events as compared to rhBMP-2. The FDA concluded that the "benefits (despite success rates being lower than that reported for bone graft) outweigh the risks." With regard to the clinical data for extraction socket augmentation, the functional loading success rate for rhBMP-2 ranged from 48% to 66% across all postoperative evaluation time points; however, the patient population was too small to determine statistical significance. Similarly to the sinus augmentation data, fewer adverse events were noted with rhBMP-2 as compared to the autogenous bone graft group, which may offset any concerns regarding reduced effectiveness.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Wu et al conducted a meta-analysis of bone morphogenetic protein-2 versus iliac crest bone graft for posterolateral fusion of the lumbar spine (Wu, 2021). Fourteen RCTs including 1516 patients (789 bone morphogenetic protein-2; 727 iliac crest bone graft) were identified. Patients who received bone morphogenetic protein-2 had a significantly higher fusion rate, lower surgery time, lower additional surgical procedures, and higher Oswestry Disability Index compared to patients who received iliac crest bone graft. No significant difference was found between bone morphogenetic protein-2 and iliac crest bone graft in non-union rates, hospitalization days, and adverse events.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.
|
|
|
|
| CPT/HCPCS: | |
|
|
|
| References: |
FDA Summary of Safety and Probable Benefit.(2004) OP-1 Putty. www.fda.gov/cdrh/pdf2/H020008b.pdf Agarwal R, Williams K, Umscheid CA et al.(2009) Osteoinductive bone graft substitutes for lumbar fusion: a systematic review. J Neurosurg Spine 2009; 11(6):729-40. Armstrong, David.(2008) “Medtronic Says Device For Spine Faces Probe.” 19 November 2008: Vol. CCLII No. 120. Aro HT, Govender S, Patel AD et al.(2011) Recombinant human bone morphogenetic protein-2: a randomized trial in open tibial fractures treated with reamed nail fixation. J Bone Joint Surg Am 2011; 93(9):801-8. Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center.(2010) Bone Morphogenetic Protein: The state of the evidence of on-label and off-label use. Technology Assessment Report. AHRQ Technology Assessment Program. Boden SD, Kang J, Sandhu H et al.(2002) Use of recombinant human bone morphogenetic protein-2 to achieve posterolateral lumbar spine fusion in humans: a prospective, randomized clinical pilot trial: 2002 Volvo Award in clinical studies. Spine 2002; 27(23):2662-73. Bone Morphogenetic Protein (Infuse Bone Graft) The Medical Letter. 2009;51(1327/1328):99-100. Boyne PJ, Lilly LC, Marx RE et al.(2005) De novo bone induction by recombinant human bone morphogenetic protein-2 (rhBMP-2) in maxillary sinus floor augmentation. J Oral Maxillofac Surg 2005; 63(12):1693-7. Burkus Jk, Gornet MF, Dickman CA, et al.(2002) Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech. 2002 Oct;15(5):337-49. Burkus JK, Sandhu HS, Gornet MF et al.(2005) Use of rhBMP-2 in combination with structural cortical allografts: clinical and radiographic outcomes in anterior lumbar spinal surgery. Spine 2005; 30(17 suppl):S110-7. Burkus JK, Transfeldt EE, Kitchel SH et al.(2004) Posterior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cases. Spine 2002; 27(21):2396-408. Burkus JK, Transfeldt EE, Kitchel SH, et al.(2002) Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002 Nov 1;27(21):2396-408. Cahill K, Chi J, et al.(2009) Prevalence, Complications, and Hospital Charges Associated with Use of Bone-Morphogenetic Proteins in Spinal Fusion Procedures JAMA, Vol. 302, No. 1 pp 58-66 Cannada LK, Tornetta P, Obremskey WT et al.(2019) A Randomized Controlled Trial Comparing rhBMP-2/Absorbable Collagen Sponge Versus Autograft for the Treatment of Tibia Fractures With Critical Size Defects. J Orthop Trauma. 2019 Aug;33(8). PMID 31022069 Carragee EJ, Hurwitz EL, Weiner BK.(2011) A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J 2011; 11(6):471-91. Chen NF, Smith ZA, Stiner E et al.(2010) Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion. J Neurosurg Spine 2010; 12(1):40-6. Cooper GS, Kou TD.(2013) Risk of cancer after lumbar fusion surgery with recombinant human bone morphogenic protein-2 (rh-BMP-2). Spine. 2013 Oct;38(21). PMID 23883824 Cooper GS, Kou TD.(2018) Risk of Cancer Following Lumbar Fusion Surgery With Recombinant Human Bone Morphogenic Protein-2 (rhBMP-2): An Analysis Using a Commercially Insured Patient Population. Int J Spine Surg. 2018 Apr;12(2). PMID 30276083 Dai J, Li L, Jiang C, et al.(2015) Bone Morphogenetic Protein for the Healing of Tibial Fracture: A Meta-Analysis of Randomized Controlled Trials. PLoS One. 2015;10(10):e0141670. PMID 26509264 Dettori JR, Chapman JR, DeVine JG et al.(2019) Longer follow-up continues to reveal no increased risk of cancer with the use of recombinant human bone morphogenetic protein in spine fusion. Spine J. 2019 Oct;19(10). PMID 31108234 Dimar JR 2nd, Glassman SD, Burkus JK, et al.(2009) Clinical and radiographic analysis of an optimized rhBMP-2 formulation as an autograft replacement in posterolateral lumbar spine arthrodesis. J Bone Joint Surg Am. 2009 Jun;91(6):1377-86. Dimar JR, 2nd, Glassman SD, Burkus JK et al.(2009) Clinical and radiographic analysis of an optimized rhBMP-2 formulation as an autograft replacement in posterolateral lumbar spine arthrodesis. J Bone Joint Surg Am 2009; 91(6):1377-86. Dimar JR, Glassman SD, Burkus KJ et al.(2006) Clinical outcomes and fusion success at 2 years of single-level instrumented posterolateral fusions with recombinant human bone morphogenetic protein-2/compression resistant matrix versus iliac crest bone graft. Spine 2006; 31(22):2534-9. Einhorn TA.(2003) Clinical applications of recombinant human BMPs: early experience and future development. J Bone Joint Surg Am 2003; 85-A(suppl 3):82-8. Ekrol I, Hajducka C, Court-Brown C et al.(2008) A comparison of RhBMP-7 (OP-1) and autogenous graft for metaphyseal defects after osteotomy of the distal radius. Injury 2008; 39(suppl 2):S73-82. FDA Summary of Safety and Effectiveness. InFUSE Bone Graft/LT-Cage Lumbar Tapered Fusion Device. FDA 2003. www.fda.gov/cdrh/pdf/PO00058b,pdf. FDA Summary of Safety and Probable Benefit..(2001) OP-1 Implant. www.fda.gov/cdrh/pdf/ho10002b.pdf. Feng JT, Yang XG, Wang F et al.(2019) Efficacy and safety of bone substitutes in lumbar spinal fusion: a systematic review and network meta-analysis of randomized controlled trials. Eur Spine J. 2019 Dec. PMID 31872300 Friedlaender GE, Perry CR, Cole JD et al.(2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 2001; 83-A suppl 1(pt. 2):S151-8. Garrison KR, Shemilt I, Donell S et al.(2010) Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev 2010; (6):CD006950. Glassman SD, Carreon LY, Djurasovic M et al.(2008) RhBMP-2 versus iliac crest bone graft for lumbar spine fusion: a randomized, controlled trial in patients over sixty years of age. Spine 2008; 33(26):2843-9. Glassman SD, Dimar JR 3rd, Burkus K et al.(2007) The efficacy of rhBMP-2 for posterolateral lumbar fusion in smokers. Spine 2007; 32(15):1693-8. Govender S, Csimma C, Genant HK et al.(2002) BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 2002; 84-A(12):2123-34. Hamilton DK, Jones-Quaidoo SM, Sansur C et al.(2008) Outcomes of bone morphogenetic protein-2 in mature adults: posterolateral non-instrument-assisted lumbar decompression and fusion. Surg Neurol 2008; 69(5):457-61. Helgeson MD, Lehman RA, Jr., Patzkowski JC et al.(2011) Adjacent vertebral body osteolysis with bone morphogenetic protein use in transforaminal lumbar interbody fusion. Spine J 2011; 11(6):507-10. Johnsson R, Stromqvist B, Aspenberg P.(2002) Randomized radiostereometric study comparing osteogenic protein-1 (BMP-7) and autograft bone in human noninstrumented posterolateral lumbar fusion: 2002 Volvo Award in clinical studies. Spine 2002; 27(23):2654-61. Kaiser MG, Groff MW, Watters WC, 3rd, et al.(2014) Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 16: bone graft extenders and substitutes as an adjunct for lumbar fusion. J Neurosurg Spine. 2014; 21(1):106-32. http://thejns.org/toc/spi/21/1. Accessed October 6, 2014. Kanakaris NK, Calori GM, Verdonk R et al.(2008) Application of BMP-7 to tibial non-unions: a 3-year multicenter experience. Injury 2008; 39(suppl 2):S83-90. Khan TR, Pearce KR, McAnany SJ, et al.(2018) Comparison of transforaminal lumbar interbody fusion outcomes in patients receiving rhBMP-2 versus autograft. Spine J. Mar 2018;18(3):439-446. PMID 28822825 Kuklo TR, Groth AT, Anderson RC.(2008) Recombinant human bone morphogenetic protein-2 for grade III open segmental tibial fractures from combat injuries in Iraq. J Bone Joint Surg [Br]. 2008;90-B:1068-72. Lindley TE, Dahdaleh NS, Menezes AH et al.(2011) Complications associated with recombinant human bone morphogenetic protein use in pediatric craniocervical arthrodesis. J Neurosurg Pediatr 2011; 7(5):468-74. Liu S, Wang Y, Liang Z et al.(2020) Comparative Clinical Effectiveness and Safety of Bone Morphogenetic Protein Versus Autologous Iliac Crest Bone Graft in Lumbar Fusion: a meta-analysis and systematic review. Spine. 2020 Jan. PMID 31923133 Lyon T, Scheele W, Bhandari M, et al.(2013) Efficacy and safety of recombinant human bone morphogenetic protein-2/calcium phosphate matrix for closed tibial diaphyseal fracture: a double-blind, randomized, controlled phase-II/III trial. J Bone Joint Surg Am. Dec 4 2013;95(23):2088-2096. PMID 24306695 Mannion RJ, Nowitzke AM, Wood MJ.(2011) Promoting fusion in minimally invasive lumbar interbody stabilization with low-dose bone morphogenic protein-2-but what is the cost? Spine J 2011; 11(6):527-33. Mariscal G, Nunez JH, Barrios C et al.(2020) A meta-analysis of bone morphogenetic protein-2 versus iliac crest bone graft for the posterolateral fusion of the lumbar spine. J. Bone Miner. Metab. 2020 Jan;38(1). PMID 31292724 McKay B, Sandhu HS.(2002) Use of recombinant human bone morphogenetic protein-2 in spinal fusion applications. Spine 2002; 27(16 suppl 1):S66-85. Meier, Barry.(2009) “Medtronic Gets Subpoena Regarding Disputed Study.” The New York Times. 24 June 2009. Mroz TE, Wang JC, Hashimoto R et al.(2010) Complications related to osteobiologics use in spine surgery: a systematic review. Spine (Phila Pa 1976) 2010; 35(9 Suppl):S86-104. Mulconrey DS, Bridwell KH, Flynn J et al.(2008) Bone morphogenetic protein (RhBMP-2) as a substitute for iliac crest bone graft in multilevel adult spinal deformity surgery: minimum two-year evaluation of fusion. Spine 2008; 33(20):2153-9. Neovius E, Lemberger M, Docherty Skogh A et al.(2012) Alveolar bone healing accompanied by severe swelling in cleft children treated with bone morphogenetic protein-2 delivered by hydrogel. J Plast Reconstr Aesthet Surg 2012 [Epub ahead of print]. Papakostidis C, Kontakis G, Bhandari M et al.(2008) Efficacy of autologous iliac crest bone graft and bone morphogenetic proteins for posterolateral fusion of lumbar spine: a meta-analysis of the results. Spine 2008; 33(19):E680-92. Ramly EP, Alfonso AR, Kantar RS et al.(2019) Safety and Efficacy of Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) in Craniofacial Surgery. Plast Reconstr Surg Glob Open. 2019 Aug;7(8). PMID 31592029 Sandhu HS.(2003) Bone morphogenetic proteins and spinal surgery. Spine 2003; 28(15 suppl):S64-73. Schultz DG, Center for Devices and Radiological Health, Food and Drug Administration (FDA).(2008) FDA Public Health Notification: Life-threatening Complications Associated with Recombinant Human Bone Morphogenetic Protein in Cervical Spine Fusion [letter]. 2008 July 1; https://wayback.archive-it.org/7993/20170111190511/http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ucm062000.htm. Accessed February 19, 2021. Scott J.(2009) Withrawal of paper. J Bone Joint Surg [Br]. 2009;91-B:285-286. Stachniak JB, Diebner JD, Brunk ES et al.(2011) Analysis of prevertebral soft-tissue swelling and dysphagia in multilevel anterior cervical discectomy and fusion with recombinant human bone morphogenetic protein-2 in patients at risk for pseudarthrosis. J Neurosurg Spine 2011; 14(2):244-9. Swiontkowski MF, Aro HT, Donell S et al.(2006) Recombinant human bone morphogenetic protein-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am 2006; 88(6):1258-65. U.S. Food and Drug Administration (FDA).(2007) Infuse Bone Graft. Summary of safety and effectiveness data. March 2007. https://www.accessdata.fda.gov/cdrh_docs/pdf5/P050053B.pdf. Accessed March 7, 2021. Vaccaro AR, Whang PG, Patel T et al.(2008) The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study. Spine J 2008; 8(3):457-65. Vaidya R, Carp J, Sethi A et al.(2007) Complications of anterior cervical discectomy and fusion using recombinant human bone morphogenetic protein-2. Eur Spine J 2007; 16(8):1257-65. Vaidya R, Weir R, Sethi A et al.(2007) Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence. J Bone Joint Surg Br 2007; 89(3):342-5. Valentin-Opran A, Wozney J, Csimma C et al.(2002) Clinical evaluation of recombinant human bone morphogenetic protein-2. Clin Orthop 2002; 395:110-20. van Hout WM, Mink van der Molen AB, Breugem CC et al.(2011) Reconstruction of the alveolar cleft: can growth factor-aided tissue engineering replace autologous bone grafting? A literature review and systematic review of results obtained with bone morphogenetic protein-2. Clin Oral Investig 2011; 15(3):297-303. Villavicencio AT, Burneikiene S, Nelson EL et al.(2005) Safety of transforaminal lumbar interbody fusion and intervertebral recombinant human bone morphogenetic protein-2. J Neurosurg Spine 2005; 3(6):436-43. Wong DA, Kumar A, Jatana S et al.(2008) Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine J 2008; 8(6):1011-8. Woo EJ.(2012) Adverse events reported after the use of recombinant human bone morphogenetic protein 2. J Oral Maxillofac Surg 2012; 70(4):765-7. Wu Z, Zhou B, Chen L, et al.(2021) Bone morphogenetic protein-2 against iliac crest bone graft for the posterolateral fusion of the lumbar spine: A meta-analysis. Int J Clin Pract. Apr 2021; 75(4): e13911. PMID 33277737 Zadegan SA, Abedi A, Jazayeri SB, et al.(2017) Bone morphogenetic proteins in anterior cervical fusion: a systematic review and meta-analysis. World Neurosurg. Aug 2017;104:752-787. PMID 28315798 |
|
|
|
|
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |
|