Bone Morphogenetic Protein and Carrier and Delivery Systems

Bone morphogenetic proteins are members of the transforming growth factors family. At present, some 20 bone morphogenetic proteins 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 provide mechanical support.

Applications

The carrier and delivery system are important variables in the clinical use of rhBMPs, and different clinical applications (eg, long-bone nonunion, 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), while rhBMP in a collagen sponge with bone dowels or interbody cages are used for interbody spinal fusion. Also, interbody fusion of the lumbar spine can be approached from an anterior (anterior lumbar interbody fusion), lateral, or posterior direction (posterior lumbar interbody fusion or transforaminal lumbar interbody fusion; see Appendix). Surgical procedures may include decompression of the spinal canal and insertion of pedicle screws and rods to increase the stability of the spine.

Posterior approaches (posterior lumbar interbody fusion, transforaminal lumbar interbody fusion) allow decompression (via laminotomies and facetectomies) for treatment of spinal canal pathology (eg, spinal stenosis, lateral recess and foraminal stenosis, synovial cysts, hypertrophic ligamentum flavum) along with spine stabilization. Such approaches are differentiated from instrumented or noninstrumented posterolateral fusion, which involves the transverse processes. Due to the proximity of these procedures to the spinal canal, risks associated with ectopic bone formation are increased (eg, radiculopathies). Increased risk of bone resorption around rhBMP 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 (see summary of key approvals in Table 1). 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.^1, 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 U. S.

Table 1. rhBMP Products and Associated Carrier and Delivery Systems Approved by FDA

Systems	Manufacturer	Approved	PMA No.
INFUSE™ Bone Graft Alternative to autogenous bone graft for sinus augmentations For localized alveolar ridge augmentations in extraction socket defects	Medtronic	03/07	P050053
INFUSE™ Bone Graft Expanded indication for spinal fusion procedures in skeletally mature patients with degenerative disc disease at 1 level from L4 to S1 Expanded indication for acute, open tibial shaft fractures stabilized with nail fixation		10/09	P050053/S012
INFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device Indicated for spinal fusion procedures in skeletally mature patients with degenerative disc disease at 1 level from L4 to S1 Up to grade 1 spondylolisthesis at involved level Implantation via anterior open or anterior laparoscopic approach	Medtronic Sofamor Danek USAa	07/02	P000058
INFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device Extension of device use from L2 to S1 May be used with retrolisthesis		07/04	P000058/S002
INFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device Indicated for acute, open tibial shaft fractures stabilized with nail fixation Alternative to autogenous bone graft for sinus augmentations For localized alveolar ridge augmentations in extraction socket defects		10/09	P000058/S033
INFUSE™ Bone Graft/Medtronic Interbody Fusion Device(Marketing name change) Expanded indication for 2 additional interbody fusion devices Perimeter Interbody Fusion Device implanted via retroperitoneal ALIF L2 to S1 or OLIF L5 to S1 Clydesdale Spinal System implanted via OLIF at single level from L2-S5		12/15	P000058/S059
INFUSE™ Bone Graft/Medtronic Interbody Fusion Device Expanded indication for 2 additional interbody fusion devices: Divergence-L Anterior/Oblique Lumbar Fusion System Pivox™ Oblique Lateral Spinal System		09/17	P000058/S065

ALIF: anterior lumbar interbody fusion; FDA: Food and Drug Administration; OLI: oblique lateral interbody fusion; PMA: premarket approval; rhBMP: recombinant human bone morphogenetic protein; S: supplement.
^aMedtronic is the manufacturer for all of the INFUSE™ bone graft and carrier systems.

Related Policies

• Ultrasound Accelerated Fracture Healing Device (Policy #008 in the Treatment Section)
• Recombinant and Autologous Platelet-Derived Growth Factors as a Treatment of Wound Healing and Other Non-Orthopedic Conditions (Policy #004 in the Treatment Section)
• Electrical Bone Growth Stimulation of the Appendicular Skeleton (Policy #010 in the Treatment Section)
• Electrical Stimulation of the Spine as an Adjunct to Spinal Fusion Procedures (Policy #154 in the Treatment Section)
• Lumbar Spinal Fusion (Policy #073 in the Surgery Section)

To access guidelines that apply to members enrolled in plans that HAVE elected the Program, please visit www.evicore.com/HorizonSpineSurgery.

For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)


1. Use of recombinant human bone morphogenetic protein-2 (rhBMP-2; Infuse®) is considered medically necessary in skeletally mature patients:

• For anterior lumbar interbody fusion procedures when use of autograft is not feasible.
• For instrumented posterolateral intertransverse spinal fusion procedures when use of autograft is not feasible.
• For the treatment of acute, open fracture of the tibial shaft, when use of autograft is not feasible.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

When this policy was created, RCTs supported the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in the treatment of anterior interbody spinal fusion when used with a tapered cage and in the treatment of open tibial fractures.^2, A randomized study reported by Govender et al (2002) supported the use of recombinant human bone morphogenetic protein-7 (rhBMP-7) in the treatment of recalcitrant nonunions of the long bones.^3, It should be noted that most of these trials were designed to show that use of recombinant human bone morphogenetic protein (rhBMP) was equivalent (not superior) to autologous bone grafting. The proposed advantage of rhBMP is the elimination of a separate incision site to harvest autologous bone graft and the associated pain and morbidity. However, Howard et al (2011) raised questions about the magnitude of pain observed with iliac crest bone graft harvesting.^4, In this study, 112 patients who had an instrumented posterolateral lumbar fusion at 1 or 2 levels were seen at a tertiary spine center for a routine postoperative visit. Iliac crest bone graft was harvested in 53 (47.3%) patients through the midline incision used for lumbar fusion, and rhBMP-2 was used in 59 (52.7%) patients with no graft harvest. An independent investigator, not directly involved in patient care and was unaware of the type of bone graft used in the fusion, examined each patient for tenderness over the surgical site as well as the left and right posterior iliac crest. At a mean follow-up of 41 months (range, 6-211 months), there was no significant difference between the groups in the proportion of patients complaining of tenderness over either iliac crest (mean pain score, 3.8 vs 3.6 on a 10-point scale). While 54% of patients complained of tenderness over 1 or both iliac crests, only 10 (9%) of 112 patients had pain over the crest from which the graft was harvested (mean pain score, 4.4).

Lumbar Spinal Fusion
Clinical Context and Therapy Purpose

The purpose of rhBMP is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as allograft bone or synthetic bone substitute, in patients with who are undergoing anterior or posterolateral lumbar spinal fusion and in whom autograft is not feasible.

The question addressed in this policy is: Does the use of bone morphogenetic protein improve the net health outcome in individuals who are undergoing spinal fusion when an autograft is not feasible?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with who are undergoing anterior or posterolateral lumbar spinal fusion and in whom autograft is not feasible.

Interventions

The therapy being considered is rhBMP. Two rhBMPs have been extensively studied: rhBMP-2, applied with an absorbable collagen sponge (Infuse™), and rhBMP-7, applied in putty (OP-1®). These protein products have been investigated as alternatives to bone autografting.

Patients with who are undergoing anterior or posterolateral lumbar spinal fusion and in whom autograft is not feasible are actively managed by neurosurgeons, orthopedic surgeons, physical therapists and primary care providers in an outpatient clinical setting.

Comparators

Comparators of interest include allograft bone or synthetic bone substitute. Allograft bone is obtained from a donor for use in grafting procedures, such as a spine fusion surgery. The donor bone graft acts as a temporary calcium deposit on which a patient's own bone eventually grows and replaces in the bone-fusing process called "creeping substitution." This is managed by an orthopedic surgeon and primary care providers in an inpatient surgical setting.

Outcomes

The general outcomes of interest are symptoms, morbid events, functional outcomes, and treatment-related morbidity. Negative outcomes of interest the potential for heterotopic bone formation, leg pain/radiculitis and, osteolysis.

The existing literature evaluating rhBMP as a treatment for patients who are undergoing anterior or posterolateral lumbar spinal fusion and in whom autograft is not feasible has varying lengths of follow-up. At least one year of follow-up is desirable to adequately evaluate outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
2. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
3. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
4. Studies with duplicative or overlapping populations were excluded.

Two meta-analyses^5,6, assessing the effectiveness and harms of rhBMP-2 in spine fusion were published following a 2011 U.S. Senate investigation^7, of industry influence on the INFUSE™ clinical studies and a systematic review by Carragee et al (2011)^8, of emerging safety concerns with rhBMP-2. The systematic review by Carragee et al (2011) compared conclusions about safety and efficacy from the 13 published rhBMP-2 industry-sponsored trials with available 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 (overestimation of harm) in the reporting of iliac crest donor site pain. Comparison between the published studies and the FDA documents revealed internal inconsistencies and adverse events not reported in the published articles.

Both meta-analyses assessed individual patient-level data, published and unpublished, provided by the manufacturer through the Yale University Open Data Access Project. One meta-analysis was conducted by Simmonds et al (2013) and the other by Fu et al (2013).

Simmonds et al (2013) included patient-level data from 12 RCTs (n=1408 patients), regardless of spinal level or surgical approach, and adverse event data from an additional 35 observational studies.^5, Use of rhBMP-2 increased the rate of radiographic fusion by 12% compared with iliac crest bone graft, with substantial heterogeneity across trials. A small improvement in the Oswestry Disability Index score (3.5 percentage points) fell below the previously defined threshold for a clinically significant effect. Reviewers also found a small improvement in back pain (1 point on a 20-point scale) and 36-Item Short-Form Health Survey Physical Component Summary score (1.9 percentage points). There was no significant difference between groups for leg pain. There was a potential for bias in the pain and functional outcomes because outcomes were patient-reported and patients were not blinded to the treatment received. Overall, the increase in successful fusion rate at up to 24 months did not appear to be associated with a clinically significant reduction in pain.

The systematic review by Fu et al (2013) included individual patient-level data from 13 RCTs (n=1981 patients) and 31 cohort studies.^6, Reviewers found moderate evidence of no consistent differences between rhBMP-2 and iliac crest bone graft in overall success, fusion rates, or other effectiveness measures for anterior lumbar interbody fusion or posterolateral fusion. A small RCT and three cohort studies revealed no difference in effectiveness outcomes between rhBMP and iliac crest bone graft for anterior cervical fusion. Reporting in the originally published trials was found to be biased with the publications selecting analyses and results that favored rhBMP over iliac crest bone graft.

Both meta-analyses suggested that cancer risk might be increased with rhBMP-2, although the number of events was low and there was heterogeneity in the types of cancer. In the Simmonds et al (2013) trial, the combined analysis revealed a relative risk (RR) of 1.84 (95% confidence interval, 0.81 to 4.16) for cancer in the bone morphogenetic protein group but this increased rate was not statistically significant. Fu et al (2013) performed a combined analysis of cancer incidence at 24 and 48 months posttreatment. At 24 months, there was a statistically significant increase in cancer for the bone morphogenetic protein group (RR=3.45; 95% confidence interval, 1.98 to 6.0); at 48 months, the increase was not statistically significant (RR=1.82; 95% confidence interval, 0.84 to 3.95).

Other adverse events were increased for the bone morphogenetic protein group. Simmonds et al (2013) found a higher incidence of early back and leg pain with rhBMP-2. The individual publications consistently reported higher rates of heterotopic bone formation, leg pain/radiculitis, osteolysis, and dysphagia but combined analysis for these outcomes was not performed. Fu et al (2013) reported that rhBMP-2 was associated with a statistically nonsignificant increase in the risk for urogenital problems when used for anterior lumbar fusion and an increase in the risk for wound complications and dysphagia when used for anterior cervical spine fusion. Fu et al (2013) also noted that the data on adverse events in the published literature was incomplete compared with the total amount of data available.

A systematic review and meta-analysis assessing the safety and efficacy of bone substitutes in lumbar spinal fusion was published by Feng et al (2019).^9, The study identified 27 RCTs involving 2488 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 (2020).^10, 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 Oswestry 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 (2019) conducted a meta-analysis of bone morphogenetic protein-2 vs iliac crest bone graft for posterolateral fusion of the lumbar spine.^11, 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 Oswestry 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.

Off-Label Use of Bone Morphogenetic Protein in Lumbar Spinal Fusion

Off-label use of bone morphogenetic protein can include multiple levels and dosages greater than the FDA approved dose of rhBMP-2 for single-level fusion. Carragee et al (2013) assessed cancer risk after high-dose rhBMP-2 (40 mg) using publicly available data from the pivotal, multicenter RCT of AMPLIFY™ (n=463).^12, The study found an increase in the incidence of cancer, a reduction in the time to first cancer, and a greater number of patients with multiple cancers. For example, at 2 years, there were 15 new cancer events in 11 patients in the rhBMP-2 group compared with 2 new cancer events in 2 patients treated with autogenous bone graft (incidence rate ratio, 6.75). When calculated in terms of the number of patients with 1 or more cancer events 2 years after surgery, the incidence rate per 100 person years was 2.54 in the rhBMP-2 group and 0.50 in the control group (incidence rate ratio, 5.04). The mean time to development of cancer was 17.5 months after use of rhBMP-2 and 31.8 months in the controls. Three patients, all in the rhBMP-2 group, developed multiple new cancers.

Zadegan et al (2017) conducted a systematic review and meta-analysis investigating the off-label uses of rhBMP.^13, 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 (2018) investigated the effectiveness and safety of using rhBMP-2 in transforaminal lumbar interbody fusions.^14, 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 (bone morphogenetic protein group) and 104 patients were treated with bone grafting (non-bone morphogenetic protein group. Results were similar between groups; fusion rates were 92.7% and 92.3% for bone morphogenetic protein and non-bone morphogenetic protein patients, respectively. Seven patients in the bone morphogenetic protein group and two patients in the non-bone morphogenetic protein group experienced radiculitis. Seroma was observed in two patients in the bone morphogenetic protein group; it was not observed in any patients in the non-bone morphogenetic protein 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.

Retrospective analyses of data from Medicare^15, and from a commercial insurer database^16, failed to confirm a higher risk of cancer in rhBMP-2 patients. 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.^17,

Section Summary: Lumbar Spinal Fusion

The evidence on the effectiveness and potential harms of rhBMP-2 and rhBMP-7 in spinal fusion consists of RCTs, systematic reviews, meta-analyses, and observational studies. The fusion rates with the use of rhBMP are comparable to bone autograft. There is evidence that specific complication rates are higher with rhBMP.

Tibial Fractures and Nonunions
Clinical Context and Therapy Purpose

The purpose of rhBMP is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as plate or intramedullary nail, in patients who are undergoing surgery for acute tibial shaft fracture and in whom autograft is not feasible.

The question addressed in this policy is: Does the use of bone morphogenetic protein improve the net health outcome in individuals who are undergoing surgery for acute tibial shaft fracture when an autograft is not feasible?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals who are undergoing surgery for acute tibial shaft fracture and in whom autograft is not feasible.

Interventions

The therapy being considered is rhBMP. Two rhBMPs have been extensively studied: rhBMP-2, applied with an absorbable collagen sponge (Infuse™), and rhBMP-7, applied in putty (OP-1®). These protein products have been investigated as alternatives to bone autografting in internal fixation of fractures.

Patients who are undergoing surgery for acute tibial shaft fracture and in whom autograft is not feasible are actively managed by orthopedic surgeons. or general surgeons.

Comparators

Comparators of interest include plate or intramedullary nail. An intramedullary rod, also known as an intramedullary nail or inter-locking nail or Küntscher nail (without proximal or distal fixation), is a metal rod forced into the medullary cavity of a bone. Intramedullary nails have long been used to treat fractures of long bones of the body. This is managed by orthopedic surgeons and primary care providers in an outpatient clinical setting.

Outcomes

The general outcomes of interest are symptoms, morbid events, functional outcomes, and treatment-related morbidity.

The existing literature evaluating rhBMP as a treatment for patients who are undergoing surgery for acute tibial shaft fracture and in whom autograft is not feasible has varying lengths of follow-up. At least six months of follow-up is desirable to adequately evaluate outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
2. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
3. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
4. Studies with duplicative or overlapping populations were excluded.

Dai et al (2015) published a meta-analysis on rhBMP for the healing of acute tibial fractures (4 RCTs; n=868 patients) and nonunions (4 RCTs; n=245 patients).^18, For acute tibial fractures, three RCTs were conducted with rhBMP-2 and one with rhBMP-7. All included studies were conducted over a decade ago. Use of rhBMP was associated with a higher rate of union (RR=1.16) and a lower rate of revision (RR=0.68) than controls (3 trials with soft-tissue management, 1 with intramedullary nail plus autograft). There was no significant difference between the bone morphogenetic protein and control groups for hardware failure or infection. For tibial fracture nonunions, three trials used rhBMP-7 and the fourth trial did not state which formulation. The RR was nearly 1 (0.98), and there was no significant difference between the bone morphogenetic protein and intramedullary nail plus autograft groups in the rates of revision or infection. Interpreting these results is difficult given the variations in control groups and formulations of rhBMP used, one of which is no longer marketed in the U.S.

A Cochrane review by Garrison et al (2010) evaluated the comparative effectiveness and costs of rhBMP for healing of acute fractures and nonunions vs standard of care.^19, The literature search was conducted to 2008; 11 RCTs (total n=976 participants) and 4 economic evaluations selected for inclusion. The times to fracture healing were comparable between the rhBMP and control groups. There was some evidence for faster healing rates, mainly for open tibial fractures without secondary procedures (RR=1.19). Three trials indicated that fewer secondary procedures were required for acute fractures treated with rhBMP (RR=0.65). Reviewers concluded that limited evidence suggested rhBMP may be more effective than standard of care for acute tibial fracture healing; however, the efficacy of rhBMP for treating nonunion remains uncertain (RR=1.02).

Randomized Controlled Trials

Lyon et al (2013) reported on a manufacturer-funded, randomized, double-blind trial of injectable rhBMP-2 in a calcium phosphate matrix for closed tibial diaphyseal fractures.^20, The trial 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 study termination due to futility.

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.^21, 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.

Section Summary: Tibial Fractures and Nonunions

The evidence for the use of rhBMP in long-bone fractures and nonunions consists of RCTs, systematic reviews, and meta-analyses. Two systematic reviews have concluded that rhBMP can reduce reoperations rates compared with soft-tissue management with or without intramedullary nailing. An RCT evaluating patients with open tibia fractures with critical size defects concluded that there was not enough evidence to support equivalence between iliac crest bone graft and rhBMP-2 for radiographic union.

Miscellaneous Surgical Procedures
Clinical Context and Therapy Purpose

The purpose of rhBMP is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as autograft plus allograft bone, in patients who are undergoing other surgical procedures (eg, oral and maxillofacial, hip arthroplasty, distraction osteogenesis).

The question addressed in this policy is: Does the use of bone morphogenetic protein improve the net health outcome in individuals who are undergoing surgery for miscellaneous conditions such as oral and maxillofacial fracture when an autograft is not feasible?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals who are undergoing other surgical procedures (eg, oral and maxillofacial, hip arthroplasty, distraction osteogenesis).

Interventions

The therapy being considered is rhBMP. Two rhBMPs have been extensively studied: rhBMP-2, applied with an absorbable collagen sponge (Infuse™), and rhBMP-7, applied in putty (OP-1®). These protein products have been investigated as alternatives to bone autografting in a variety of surgical procedures such as treatment of bone defects, and reconstruction of maxillofacial conditions.

Patients who are undergoing other surgical procedures (eg, oral and maxillofacial, hip arthroplasty, distraction osteogenesis) are actively managed by orthopedic surgeons and oral and maxillofacial surgeons.

Comparators

Comparators of interest include autograft bone or synthetic bone substitute. Oral sensory loss may be associated with autograft bone harvest in maxillofacial procedures.

Outcomes

The general outcomes of interest are symptoms, morbid events, functional outcomes, and treatment-related morbidity.

The existing literature evaluating rhBMP as a treatment for patients who are undergoing other surgical procedures (eg, oral and maxillofacial, hip arthroplasty, distraction osteogenesis) has varying lengths of follow-up. At least one year of follow-up is desirable to adequately evaluate outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
2. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
3. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
4. Studies with duplicative or overlapping populations were excluded.

• The strength of the body of evidence on clinical outcomes is moderate that rhBMP-2 does not provide an advantage in prosthesis implantation and functional loading compared with autograft plus allograft bone.
• There is moderate evidence that oral sensory loss associated with autograft bone harvest can be avoided by use of rhBMP-2.

Additional Applications

Limited research has evaluated the use of rhBMP for 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 (ie, Ilizarov procedure).^24,25, The literature on these applications consists of small case series; no controlled trials have been identified.

Section Summary: Other Surgical Procedures

There is little evidence supporting the use of rhBMP in surgical procedures or interventions other than spinal fusion and acute long fractures. Conclusions cannot be drawn on the utility of rhBMP for other surgical indications.

Summary of Evidence

For individuals who are undergoing anterior or posterolateral lumbar spinal fusion and in whom autograft is not feasible who receive rhBMP, the evidence includes randomized controlled trials, systematic reviews, and meta-analyses. Relevant outcomes are symptoms, morbid events, functional outcomes, and treatment-related morbidity. In 2013, 2 systematic reviews of rhBMP-2 trials using manufacturer-provided individual patient-level data were published. Overall, these reviews found little to no benefit of rhBMP-2 over iliac crest bone graft for all patients undergoing spinal fusion, with an uncertain risk of harm. The small benefits reported do not support the widespread use of rhBMP-2 as an alternative to iliac crest autograft. However, the studies do establish that rhBMP-2 has efficacy in promoting bone fusion and will improve outcomes for patients for whom use of iliac crest bone graft is not feasible. The overall adverse event rate was low, though concerns remain about increased adverse event rates with rhBMP-2, including cancer. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are undergoing surgery for acute tibial shaft fracture and in whom autograft is not feasible who receive rhBMP, the evidence includes randomized controlled trials and systematic reviews of the randomized controlled trials. Relevant outcomes are symptoms, morbid events, functional outcomes, and treatment-related morbidity. Two systematic reviews have concluded that rhBMP can reduce reoperations rates compared with soft-tissue management with or without intramedullary nailing. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals undergoing other surgical procedures (eg, oral and maxillofacial, hip arthroplasty, distraction osteogenesis) who receive rhBMP, the evidence includes a health technology assessment, systematic review, and small case series. Relevant outcomes are symptoms, morbid events, functional outcomes, and treatment-related morbidity. The evidence does not permit conclusions about the effect of rhBMP for craniomaxillofacial surgery or tibial shaft fracture nonunion. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
American Association of Neurological Surgeons et al

Joint guidelines on lumbar spinal fusion from the American Association of Neurological Surgeons and the Congress of Neurological Surgeons (2014) were updated.^26, Both groups gave a grade B recommendation (multiple level II studies) for the use of recombinant human bone morphogenetic protein-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 recombinant human bone morphogenetic protein-2 as an option for posterior lumbar interbody fusion and transforaminal lumbar interbody fusion, posterolateral fusion in patients older than 60 years, and as a graft extender for either instrumented or noninstrumented posterolateral fusions. The societies also gave a grade C recommendation (based on multiple level IV and V studies) that the use of recombinant human bone morphogenetic protein-2 as a graft option has been associated with a unique constellation of complications of which surgeons should be aware when considering this graft extender/substitute.

North American Spine Society

In 2014, the North American Spine Society (NASS) issued coverage policy recommendations outlining the clinical indications for the adjunct use of rhBMP-2 in spinal fusion surgeries based on the strength of the available evidence (level I to level IV).^27, NASS recommends adjunct use of rhBMP-2 in spinal fusion surgeries for the following clinical scenarios and qualifying criteria, as appropriate:

1. "Stand-Alone Anterior Lumbar Interbody Fusion: in all patient groups except males with a strong reproductive priority"
2. "Posterolateral Lumbar Fusion: in all patients at high risk for nonunion with autogenous bone graft or in those with inadequate or poor quality autogenous bone available"
3. "Posterior Lumbar Interbody Fusion and transforaminal lumbar interbody fusion in patients at high risk for nonunion with autogenous bone graft or in those with inadequate or poor quality autogenous bone available"
4. "Posterior Cervical or Thoracic Fusions"
a. "in pediatric patients at very high risk for fusion failure (eg, neuromuscular scoliosis, occipitocervical pathology)"
b. "in adult patients at high risk for nonunion, for example, revision surgery"
5. "Anterior Cervical Fusion: in patients at high risk for nonunion, for example, revision surgery"

1. "Routine anterior and posterior cervical fusion procedures"
2. "Single level posterior/posterolateral fusions in healthy adults"
3. "Routine pediatric spine fusion procedures (eg, adolescent idiopathic scoliosis)"

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 2.

Table 2. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT00984672	Evaluation of Radiculitis Following Use of Bone Morphogenetic Protein-2 for Interbody Arthrodesis in Spinal Surgery	103	Dec 2020 (ongoing)
NCT02718131a	A Study of INFUSE Bone Graft (BMP-2) in the Treatment of Tibial Pseudarthrosis in Neurofibromatosis Type 1 (NF1)	54	Dec 2021 (ongoing)
NCT02924571	Prospective, Blinded, Non-randomized Study of Thoracolumbar Spinal Fusion Graft Efficacy: Bone Marrow Aspirate Concentrate and Allograft Versus Recombinant Bone Morphogenetic Protein-2 (BMP)	30	Jan 2022 (recruiting)
NCT04073563a	Prospective, Randomized, Controlled, Blinded Pivotal Study In Subjects Undergoing A Transforaminal Lumbar Interbody Fusion At One Or Two Levels Using Infuse™ Bone Graft and The Capstone™ Spinal System With Posterior Supplemental Fixation For The Treatment Of Symptomatic Degenerative Disease Of The Lumbosacral Spine	1017	Jun 2025 (recruiting)
Unpublished
NCT01308996a	A Prospective, Open Label, Randomized, Multicenter, Controlled Clinical Study of INFUSE® Bone Graft Used as an Alternative to Autogenous Bone Graft for Vertical Alveolar Ridge Augmentation	0	Sep 2017 (withdrawn)

NCT: national clinical trial; BMP: bone morphogenetic protein.
^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Bone Morphogenetic Protein
Bone Graft Substitute
Bone Morphogenic Proteins
BMP (Bone Morphogenic Proteins)
InFUSE Bone Graft
OP-1 Bone Graft
Osteogenic Protein 1
Recombinant Human Bone Morphogenic Protein (rhBMP)
rhBMP (Recombinant Human Bone Morphogenic Protein)

References:
1. Schultz DG, Center for Devices and Radiological Health, Food and Drug Administration (FDA). 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 20, 2020.

2. U.S. Food and Drug Administration (FDA). Summary of Safety and Effectiveness: InFUSE Bone Graft/LT-Cage Lumbar Tapered Fusion Device [P000058]. 2002; https://www.accessdata.fda.gov/cdrh_docs/pdf/P000058b.pdf. Accessed February 20, 2020.

3. Govender S, Csimma C, Genant HK, et al. 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. Dec 2002;84-A(12):2123-2134. PMID 12473698

4. Howard JM, Glassman SD, Carreon LY. Posterior iliac crest pain after posterolateral fusion with or without iliac crest graft harvest. Spine J. Jun 2011;11(6):534-537. PMID 20947439

5. Simmonds MC, Brown JV, Heirs MK, et al. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med. Jun 18 2013;158(12):877-889. PMID 23778905

6. Fu R, Selph S, McDonagh M, et al. Effectiveness and harms of recombinant human bone morphogenetic protein- 2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med. Jun 18 2013;158(12):890-902. PMID 23778906

7. United States Senate Finance Committee. Staff report on Medtronic's influence on INFUSE clinical studies. Int J Occup Environ Health. Apr-Jun 2013;19(2):67-76. PMID 23684264

8. Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. Jun 2011;11(6):471-491. PMID 21729796

9. Feng JT, Yang XG, Wang F et al. 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

10. Liu S, Wang Y, Liang Z et al. 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

11. Mariscal G, Nunez JH, Barrios C et al. 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

12. Carragee EJ, Chu G, Rohatgi R, et al. Cancer risk after use of recombinant bone morphogenetic protein-2 for spinal arthrodesis. J Bone Joint Surg Am. Sep 4 2013;95(17):1537-1545. PMID 24005193

13. Zadegan SA, Abedi A, Jazayeri SB, et al. Bone morphogenetic proteins in anterior cervical fusion: a systematic review and meta-analysis. World Neurosurg. Aug 2017;104:752-787. PMID 28315798

14. Khan TR, Pearce KR, McAnany SJ, et al. Comparison of transforaminal lumbar interbody fusion outcomes in patients receiving rhBMP-2 versus autograft. Spine J. Mar 2018;18(3):439-446. PMID 28822825

15. Cooper GS, Kou TD. Risk of cancer after lumbar fusion surgery with recombinant human bone morphogenic protein-2 (rh-BMP-2). Spine. 2013 Oct;38(21). PMID 23883824

16. Cooper GS, Kou TD. 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

17. Dettori JR, Chapman JR, DeVine JG et al. 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

18. Dai J, Li L, Jiang C, et al. Bone morphogenetic protein for the healing of tibial fracture: a meta-analysis of randomized controlled trials. PLoS One. Oct 2015;10(10):e0141670. PMID 26509264

19. Garrison KR, Shemilt I, Donell S, et al. Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev. Jun 16 2010(6):CD006950. PMID 20556771

20. Lyon T, Scheele W, Bhandari M, et al. 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

21. Cannada LK, Tornetta P, Obremskey WT et al. 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

22. Ratko TA, Belinson SE, Samson DJ, et al. Bone Morphogenetic Protein: The State of the Evidence of On-Label and Off-Label Use (AHRQ Technology Assessment Report). Rockville, MD: Agency for Healthcare Research and Quality; 2010.

23. Ramly EP, Alfonso AR, Kantar RS et al. 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

24. Valentin-Opran A, Wozney J, Csimma C, et al. Clinical evaluation of recombinant human bone morphogenetic protein-2. Clin Orthop Relat Res. Feb 2002;395:110-120. PMID 11937870

25. Einhorn TA. Clinical applications of recombinant human BMPs: early experience and future development. J Bone Joint Surg Am. 2003;85-A(Suppl 3):82-88. PMID 12925614

26. Kaiser MG, Groff MW, Watters WC, 3rd, et al. 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. Jul 2014;21(1):106-132. PMID 24980593

27. North American Spine Society (NASS). NASS Coverage Policy Recommendations: Recombinant Human Bone Morphogenetic Protein (rhBMP-2). 2014. https://www.spine.org/Product-Details?productid=%7B9567DDCC-4EC7-E411-9CA5-005056AF031E%7D. Accessed February 20, 2020.

20930
20999