INFUSE BONE GRAFT PRECLINICAL AND CLINICAL EVIDENCE: TRAUMA BONE GRAFTING (SPINE AND ORTHOPAEDIC)

STUDIES AND EVIDENCE: TRAUMA PROCEDURES

Recombinant human bone morphogenetic protein-2 (rhBMP-2) has become one of the most extensively researched biologic agents that are commercially available. With more than a decade of approved market use, Infuse Bone Graft is safe and effective in fusing bone for indicated use in an open tibia fracture.

  • Clinical studies
    Review information on the three human clinical trials that determined the effective dosing volume of rhBMP-2, found reduced secondary interventions, reduced rate of nonunion, decreased rate of infection in severe fractures and the healing results associated with Infuse Bone Graft.
  • Case studies
    See examples of the healing capacity of Infuse Bone Graft for tibial fractures by comparing before and after radiographs from the case studies.
  • Preclinical data*
    Before clinical studies were conducted, the effects of rhBMP-2 were studied in animals. These studies tested different types of bones, and also evaluated how nicotine and steroids affect bone formation facilitated by rhBMP-2.

In the Summary of Safety and Effectiveness Data, you can find complete information about the Indications of Use, Contraindications, Warnings and Precautions, Device Description, Adverse Events, Summary of Preclinical Testing and Summary of Clinical Testing.


CLINICAL STUDIES

Human clinical studies of Infuse Bone Graft have evaluated the effectiveness of recombinant human bone morphogenetic protein-2 (rhBMP-2) in healing open tibial fractures. The studies determined the effective dose of rhBMP-2 to be applied to the absorbable collagen sponge (ACS), its success rate in reducing the number of fracture nonunions, and it's healing effect on surrounding soft tissues.

HUMAN CLINICAL TRIALS DETERMINE EFFECTIVE CONCENTRATION OF rhBMP-2

Three dose-ranging clinical studies have been conducted to identify the effective therapeutic concentration of rhBMP-2/ACS for tibial fractures. This is measured as quantity of rhBMP-2 per unit volume of ACS.

Both the concentration of rhBMP-2 and the length of time that rhBMP-2 is present at the implant site are positively correlated with the rate of bone formation, the amount of bone formed, and the density of the resulting bone. From these studies the 1.50 mg/ml rhBMP-2/ACS concentration (Infuse Bone Graft) was found to be clinically effective.

STUDY

DESIGN

DRUG

RESULTS

Riedel et al.1

Prospective, observational n=12

0.43 mg/ml rhBMP-2/ACS(IM nan or external fixation used)

Study provided important safety data on rhBMP-2/ACS in trauma and information for the design of larger clinical studies.

Bucholz et al.2

Prospective, randomized n=60

IM nail alone
IM nail + 0.75 mg/ml rhBMP-2/ACS
IM nail + 1.50 mg/ml rhBMP-2/ACS

There was a trend toward fewer secondary interventions for delayed union in the rhBMP-2/ACS treatment groups; this trend was not statistically significant.

Govender et al.3

Prospective, randomized n=450

IM nail alone
IM nail + 0.75 mg/ml BMP-2/ACS
IM nail + 1.50 mg/ml rhBMP-2/ACS

Study established clinical safety and efficacy of rhBMP-2/ACS at 1.50 mg/ml in open tibia fractures. which resulted in FDA approval of Infuse Bone Graft (See results graphs).

Treatment included irrigation and debridement, wound management, and IM nail fixation.

PATIENTS TREATED WITH INFUSE BONE GRAFT VERSUS CONTROL4

Secondary Intervention

41% Reduction (p=0.001)

Nonunion

29% Reduction (p=0.0075)

Infection (Grade Ill A&B)

44% Reduction (p=0.0377)

Infuse Bone Graft Combats the Many Challenges of Open Tibial Fractures

The results of the clinical trials indicate that Infuse Bone Graft:

Infuse Bone Graft significantly reduced secondary interventions.

Infuse Bone Graft significantly reduced secondary interventions.



  • Significantly (p<0.001) reduced secondary interventions by 41%
    • The number of invasive procedures was reduced by 59%.3
    • Delayed union was higher in the control group (26%) when compared to the Infuse Bone Graft group (17%.)1
Infuse Bone Graft significantly reduced nonunion.

Infuse Bone Graft significantly reduced nonunion.



  • Significantly (p<0.0075) reduced rate of nonunion by 29%
    • Successful union is measured by fracture union and the absence of secondary intervention.
    • Of the study patients, 62.4% achieved clinical success vs. 46.7% for control.1
Infuse Bone Graft decreased the rate of infection in severe fractures by 44%.

Infuse Bone Graft significantly decreased the rate of infection in severe fractures.



  • Significantly (p<0.0377) decreased rate of infection in severe fractures by 44%
    • Reduced infection among Grade IIIA and IIIB open fractures1

More Patients Healed

More patients were considered healed (fracture consolidation) at every time point measured in this study when they received Infuse Bone Graft as compared to the control. The difference was significant (p<0.01) from the 14- to 52-week time points.

Infuse Bone Graft healed soft tissue at 6 weeks in more patients compared to the control.

Infuse Bone Graft healed soft tissue at 6 weeks in more patients compared to the control.

Soft Tissue Wound Healing at 6 Weeks

More patients with healed soft tissue at 6 weeks received Infuse Bone Graft as compared to the control. The difference was significant (p=0.001). It is thought that Infuse Bone Graft stimulates the bone forming cells to release other growth factors that may promote angiogenesis and soft tissue healing.5

Infuse Bone Graft healed more soft tissue at 6 weeks in more patients than the control group.

Soft tissue wound healing at 6 weeks was 22% higher (p=0.0010) in the Infuse Bone Graft group compared to the control.

Case Studies4

These case studies demonstrate the effectiveness of Infuse Bone Graft on healing open tibial fractures. These patients received Infuse Bone Graft in the pivotal trial that was conducted to achieve the trauma approval by the U.S. Food and Drug Administration.

Healing Capacity

Before and after radiographs of study patients illustrate the healing capacity of Infuse Bone Graft.

Healed at 14 weeks

Healed at 14 weeks — Patient #9:

  • 26 years old, male
  • Motorcycle accident
  • Right tibia
  • Type—IIIA
Healed at 20 weeks

Healed at 20 weeks—Patient #32:

  • 29 years old, male
  • Motorcycle accident
  • Left tibia
  • Type—IIIB
Healed at 26 weeks

Healed at 26 weeks — Patient #43:

  • 21 years old, male
  • Motor vehicle accident
  • Smoker
  • Right tibia
  • Type—IIIA

PRECLINICAL DATA*4 

Before the clinical studies, the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) were studied in animals. These studies demonstrate the effectiveness of rhBMP-2 in various challenging environments. Absorbable collagen sponges (ACS) with rhBMP-2 were studied in a variety of bone healing models and environments. These models examined the performance of rhBMP-2 in different fracture sites, in addition to comparisons between animals that were exposed to nicotine and steroids.*

Animal Fracture Models

Animal studies have demonstrated that rhBMP-2 application on an ACS can accelerate healing in rabbit and goat long bone fracture models.

Goat tibiae treated with rhBMP-2 improved torsional toughness.

 

Radiographic, biomechanical, and histologic evaluation of the impacted bone indicates that it is appropriate for the anatomic site where it forms, and functions biologically and biomechanically as native bone.

Treatment with rhBMP-2 resulted in large callus formation in a rabbit ostomy model.

In addition, the rhBMP-2/ACS-impacted bone can repair itself following fracture, in a manner indistinguishable from native bone.

STUDY

MODEL

RESULTS

Bouxsein et al.6

Rabbit ulna n=72

The calluses in rhBMP-2-treated ulnae were 20 – 60% larger than controls. Biomechanical properties were restored more quickly in rabbits treated with rhBMP-2. By 4 weeks, biomechanical properties were equivalent to intact ulnae, whereas controls only achieved 45% of the biomechanical strength of intact controls.

Welch et al.7

Goat tibia n=16

rhBMP-2/ACS used as an onlay resulted in increased callus size and maturity, as assessed radiographically and histologically. Fractures wrapped with rhBMP-2/ACS had increased torsional toughness.

Wozney et al.4

Rabbit ulna n=24

Histologically there was no treatment effect on morphology of the growth plates.

Wozney et al.4

Rabbit ulna n=49

Osteotomy repair of bone that had been induced by rhBMP-2/ACS. Defects in bone induced by rhBMP-2/ACS healed by a process similar to that seen in normal native bone.

 

Animal Segmental Defect Models

Animal studies have demonstrated that rhBMP-2/ACS can induce bone and repair large, segmental, critical-sized defects in:

  • Rat femora
  • Rabbit radii
  • Rabbit ulnae
  • Canine radii
  • Non-human primate radii

The induced bone biologically and structurally integrates with the pre-existing bone, and remodels physiologically, i.e., consistent with the biomechanical forces placed on it.

STUDY

MODEL

RESULTS

Yasko et al.8

Rat femur n=45

rhBMP-2 dose-response-related healing of critical-sized defects measured by radiographic and histologic criteria.

Bostrom et al.9

Rabbit ulna n=50

No defects implanted with only the ACS achieved union. High dose rhBMP-2/ACS healed 100% of the defects. Histology demonstrated bone formation with abundant normal-appearing osteoid.

Hollinger et al.10

Rabbit radius n=32

Control groups had significantly less new bone than rhBMP-2/ACS. rhBMP-2/ACS had radiopaque bridging by 8 weeks.

Wozney et al.8

Rabbit radius n=32

No deleterious effects on radiocarpal joint observed when rhBMP-2/ACS placed in a distal radius defect connected to joint cavity.

Zabka et al.11

Canine femoral allograft incorporation n=21

Augmentation of the allograft-host bone junctions with rhBMP-2/ACS resulted in a stronger and more complete union than with autograft.

Sciadini et al.4,12

Canine radius n=27

Defects treated with rhBMP-2/ACS healed at 12 weeks. Biomechanical strength of limbs treated with rhBMP-2 was greater than or equal to autograft-treated defects.

Seeherman et al.8

Non-human primate radius or ulna n=6

rhBMP-2/ACS induced bone by 4 weeks. Compression of ACS limited the amount of bone induction observed within the defect.

 

Comparison of rhBMP-2 and rhBMP-713

Infuse Bone Graft outperformed both OP-1 Implant and autologous bone graft in a canine.

 

An independent animal study was conducted comparing Infuse Bone Graft to OP-1® Implant (rhBMP-7). The study evaluated the concentrations of the two commercially available products in a canine ulnar segmental defect model as compared to autologous bone graft. Samples were observed using radiographic methods and at 12 weeks they were examined for histologic healing and mechanical strength. Results from this animal study suggest that Infuse Bone Graft outperformed both OP-1 Implant and autologous bone graft in a canine.

Effect of nicotine and steroids on rhBMP-2/ACS bone induction

In animal studies, rhBMP-2/ACS induced bone and fracture repair in the presence of several agents that compromise bone metabolism (e.g., nicotine and corticosteroids).

Rabbit nicotine model14

In a rabbit ulnar fracture model, rhBMP-2/ACS induced bone formation despite systemic administration of nicotine. Nicotine did not influence the rate of fracture repair.

rhBMP-2/ACS induced bone formation despite systemic administration of nicotine.

The rhBMP-2/ACS enhanced the biomechanical properties and callus formation in all groups. These images show medullary canal remodeling in rhBMP-2/ACS treated osteotomy in a nicotine-treated rabbit. Oc = Osteoclast.

Medullary canal remodeling in rhBMP-2 ACS treated osteotomy in a nicotine-treated rabbit.

Rabbit steroid model15

Histologic analysis showed that treatment with rhBMP-2/ACS enhanced the healing of osteotomies. At both 6 and 8 weeks, the osteotomies treated with rhBMP-2/ACS were fully bridged, suggesting that rhBMP-2/ACS overcomes the bone inhibiting effects of steroids.

Osteotomies treated with rhBMP-2/ACS were fully bridged, suggesting rhBMP-2 overcomes inhibiting effects of steroids.

Rat nicotine model4

In the rat ectopic model, rhBMP-2/ACS demonstrated the ability to form bone in the presence of nicotine.

Bone forms in the presence of nicotine

Rat steroid model4

Results show that prednisolone can inhibit bone formation, but rats treated with rhBMP-2/ACS exhibited similar bone formation in saline and prednisolone groups. This demonstrates that rhBMP-2/ACS can overcome prednisolone inhibition in rat models.

RhBMP-2/ACS induced bone formation in prednisolone groups.

TIBIA TRAUMA INDICATIONS

BRIEF SUMMARY OF INDICATIONS, CONTRAINDICATIONS, AND WARNINGS FOR:
INFUSE™ BONE GRAFT

Infuse Bone Graft is indicated for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after appropriate wound management. Infuse Bone Graft must be applied within 14 days after the initial fracture. Prospective patients should be skeletally mature.

Infuse Bone Graft consists of two components – recombinant human Bone Morphogenetic Protein-2 solution and a carrier/scaffold for the bone morphogenetic protein solution and resulting bone. These components must be used as a system. The bone morphogenetic protein solution component must not be used without the carrier/scaffold component or with a carrier/scaffold component different from the one described in this document.

Infuse Bone Graft is contraindicated for patients with a known hypersensitivity to recombinant human Bone Morphogenetic Protein-2, bovine Type I collagen or to other components of the formulation and should not be used in the vicinity of a resected or extant tumor, in patients with an active malignancy or patients undergoing treatment for a malignancy. Infuse Bone Graft should also not be used in patients who are skeletally immature, in patients with an inadequate neurovascular status, in patients with compartment syndrome of the affected limb, in pregnant women, or in patients with an active infection at the operative site.

There are no adequate and well controlled studies in human pregnant women. In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies that are capable of crossing the placenta. Women of child bearing potential should be warned by their surgeon of potential risk to a fetus and informed of other possible orthopedic treatments. The safety and effectiveness of this device has not been established in nursing mothers. Women of child-bearing potential should be advised to not become pregnant for one year following treatment with this device.

Please see the package insert for the complete list of indications, warnings, precautions, adverse events, clinical results, and other important medical information.

CAUTION: Federal (USA) law restricts this device to sale by or on the order of a physician with appropriate training or experience.


*

Animal studies are not necessarily indicative of human clinical outcome.


1

Riedel GE, Valentin-Opran A. Clinical evaluation of rhBMP-2/ACS in orthopedic trauma: a progress report. Orthopedics. 1999;22(7):663-5.

2

Bucholz et al. A dose finding study of rhBMP-2/ACS in open tibia shaft fractures requiring surgical management. Genetics Institute Protocol C9612-11. IDE G940150. Final Study Report August 2, 1999. Data on file.

3

Govender S, Csimma C, Genant HK, Valentin-Opran A (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. 2002;84-A(12):2123-34.

4

Summary of Safety and Effectiveness (SS&E) Data, INFUSE® Bone Graft, PMA p000054, April 30, 2004, http://www.accessdata.fda.gov/cdrh_docs/pdf/P000054b.pdf; data on file.

5

Deckers MM, van Bezooijen RL, van der Horst G, Hoogendam J, van Der Bent C, Papapoulos SE, Lowik CW. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology. 2002 Apr; 143(4): 1545-53.

6

Bouxsein ML, Turek TJ, Blake CA, D’Augusta D, Li X, Stevens M, Seeherman HJ, Wozney JM. Recombinant human Bone Morphogenetic Protein-2 accelerates healing in a rabbit ulnar osteotomy model. J Bone Joint Surg Am. 2001;83-A(8):1219-30.

7

Welch RD, Jones AL, Bucholz RW, Reinert CM, Tjia JS, Pierce WA, Wozney JM, Li XJ. Effect of recombinant human Bone Morphogenetic Protein-2 on fracture healing in a goat tibial fracture model. J Bone Miner Res. 1998;13(9):1483-90.

8

Yasko AW, Lane JM, Fellinger EJ, Rosen V, Wozney JM, Wang EA. The healing of segmental bone defects, induced by recombinant human Bone Morphogenetic Protein-2 (rhBMP-2). A radiographic, histological, and biomechanical study in rats. J Bone Joint Surg Am. 1992;74(5):659-670.

9

Bostrom M, Lane JM, Tomin E, Browne M, Berberian W, Turek T, Smith J, Wozney J, Schildhauer T. Use of Bone Morphogenetic Protein-2 in the rabbit ulnar nonunion model. Clin Orthop Relat Res. 1996;327:272-282.

10

Hollinger JO, Schmitt JM, Buck DC, Shannon R, Joh SP, Zegzula HD, Wozney J. Recombinant human Bone Morphogenetic Protein-2 and collagen for bone regeneration. J Biomed Mater Res. 1998;43:356-364.

11

Zabka AG, Pluhar GE, Edwards RB 3rd, Manley PA, Hayashi K, Heiner JP, Kalscheur VL, Seeherman HJ, Markel. Histomorphometric description of allograft bone remodeling and union in a canine segmental femoral defect model: a comparison of rhBMP-2, cancellous bone graft, and absorbable collagen sponge. J Orthop Res. 2001;19(2):318-27.

12

Sciadini MF, Johnson KD. Evaluation of recombinant human Bone Morphogenetic Protein-2 as a bone-graft substitute in a canine segmental defect model. J Orthop Res. 2000;18(2):289-302.

13

Cook SD, Salkeld SL, Patron LP, Christakis P. "In-Vivo Comparison of BMP-2 (Infuse) and BMP-7 (OP-1 Implant)" Paper No. 351, 72nd Annual Meeting of American Academy of Orthopaedic Surgeons, Feb 2005.

14

Ammirati KM, Blake CA, Luppen CA, Seeherman HJ, Wozney JM, Bouxsein M. Effect of rhBMP-2 on fracture healing in nicotine treated rabbits. Trans Orthop Res Soc. 2000;1053.

15

Luppen CA, Blake CA, Ammirati KM, Stevens ML, Seeherman HJ, Wozney JM, Bouxsein ML. Recombinant human Bone Morphogenetic Protein-2 enhances osteotomy healing in glucocorticoid-treated rabbits. J Bone Miner Res. 2002;17(2):301-10.