Segmental Bone Defects Treated Using Recombinant Human Bone Morphogenetic Protein

*Niles D. Schwartz , B. Matthew Hicks

*Fort Wayne Medical Education Orthopaedic Division

Address for Correspondence

B. Matthew Hicks M.D,
7601 W. Jefferson Blvd, Fort Wayne, IN 46804,
Phone: (260) 436-8686
Fax: (260) 436-8326

Abstract

Introduction: Current treatment of segmental bone defects includes amputation, autograft, bone transport, free vascularized fibula, and acute shortening.  All have recognized significant complications and morbidity. Recombinant human bone morphogenetic proteins have been used successfully in lumbar fusion and acute open tibia fractures. The purpose of this study was to evaluate the union potential of recombinant human bone morphogenetic protein-2 (rhBMP-2) implanted on an absorbable collagen sponge (ACS) in human segmental bone defects.
Methods: We performed a retrospective analysis using rhBMP-2/ACS with bone graft substitutes (calcium sulfate or calcium phosphate) in treating 19 segmental bone defects in 18 patients. Etiology included acute trauma, post-trauma infection, or nonunion. There were 11 males and 7 females. There were 9 femur fractures, 6 tibial fractures, 2 clavicle fractures, 1 humerus fracture, and 1 ulnar fracture. Ten defects were 100% circumferential, while 9 were partial defects. Defect length averaged 4.75 cm, ranging from 1.5 to 8.0 cm. Open fractures occurred in 14 patients. Failure was determined as need for further surgical intervention or nonunion. A fracture was noted as healed by clinical use without pain and radiographic consolidation.
Results: Bony union occurred in 16 of 19 bone defects, with a union rate of 84%. Average time to union was 8.4 months (range 3.5 to 13.5 months). Failure was noted in 3 patients. Two of these patients were treated early on in the study with calcium sulfate in association with rhBMP-2/ACS and had premature resorption of the graft. The third failed patient had fixation failure at 6 weeks due to non-compliance. No infections were reported. No clinical reactions from the rhBMP-2 were reported.
Discussion and Conclusion: rhBMP-2 has the capability to heal critically sized bone defects in a variety of patients, with a success rate of 84% in our study. This can be done without the morbidity associated with auto-graft or many of the complications of other treatment. Treatment can also occur in a timely fashion given the severity of injury in some cases.

J.Orthopaedics 2006;3(2)e2

Introduction:

Management of segmental bone defects resulting from trauma can present the surgeon with a tremendous challenge. The impact on the patient is often significant as well, resulting in either limited function of the extremity or major risk and morbidity to many of those treated. The recommended treatment for defects less than 5 cm in length is rigid fixation and autogenous bone 1,2,3,4.  The disadvantages of using autograft bone include the blood loss associated with harvest and morbidity at the donor site 5,6,7,8.  For bony defects greater than 5 cm’s, historical options have included amputation, bone transport, or vascularized fibular transfers 9,10,11,12. All of these options have cited potentially significant morbidity associated with treatment.  Donor site morbidity of fibular graft site has been reported in 19% of cases 6 and fracture through the graft can occur in 25% of patients 7.

Recent literature suggests that recombinant human bone morphogenetic proteins (rhBMP) may be a viable alternative to autograft bone. With significant osteo-inductive effects 13,14, rhBMP-2 soaked onto an absorbable collagen sponge (rhBMP-2/ACS, INFUSE® Bone Graft, Medtronic Sofamor Danek, Memphis, TN) has already shown to be effective in spinal fusion 15. BMP has been shown to promoted bone formation in critical sized bone defects in several animal models 16,17,18,19, and has been used successfully as part of composite grafting for craniofacial reconstruction 20. Johnson et al reported on the use of human BMP extracts combined with autograft to treat six segmental defect patients; all patients developed solid union, with an average time to union of 4.7 months 21. Recently, rhBMP-2/ACS has also been approved by the FDA as an adjunct for the treatment of open tibia fractures 22.  The purpose of this study was to retrospectively review the union rate of critically sized segmental long bone defects using rhBMP-2 in combination with a bone substitute.

Material and Methods :

At our institution, we retrospectively reviewed the charts and radiographs of 19 patients (20 defects) who had been treated with recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge along with either calcium phosphate granules (MastergraftÒ, Medtronic) or calcium sulfate pellets (OsteosetÒ Wright Medical) in the treatment of segmental long bone defects.  The calcium phosphate granules were made of a composite of 15% hydroxyapatite (HA) and 85% beta-tricalcium phosphate (β-TCP). One patient died of unrelated causes and was not used in the results, leaving 19 defects in 18 patients.  Patient ages ranged from 16 to 71 with a mean of  41.  There were 11 males and 7 females.  Major comorbidities included rheumatoid arthritis, chronic steroid use, diabetes mellitus, obesity, alcoholism, COPD, and tobacco use (Table 1).

Table  1. Patient Information 

* Same patient with multiple defects
+ Gustillo-Anderson Classification
α Defect 4 Re-grafted

The defects were caused by trauma in 16, were post-infectious in 2, and one nonunion.  The defects were all in long bones and included 9 femurs, 6 tibias, 2 clavicles, 1 humerus, and 1 ulna.  Defect size was measured intra-operatively with or without contra-lateral comparison radiographs ranged from 1.5 to 8.0 cm, with a mean of 4.75 cm.  The cortical defects were 100% circumferential in 10 patients, while 9 patients involved loss between 50-99 %.  At initial trauma 14 of the defects had been open fractures.

All wounds that were open or were infected were treated with multiple irrigations and debridements, intravenous antibiotics as appropriate, and soft tissue coverage.  Delayed grafting then took place at a standard of 6 weeks if the wounds were clinically free of infection.  The procedures involved early internal fixation either with plates and screws or intramedullary rodding techniques as necessary. 

The technique of grafting involved rhBMP-2 soaked into an absorbable collagen sponge (used as a carrier for the BMP) for 20 minutes.  The next step was to then place the bone substitute on top of the sponge and roll it into what we called a ‘burrito’.  This was then placed into the defect.  Size was determined based on need.  Calcium phosphate was used in 16 defects, and calcium sulfate was used in 3.  The wounds were then closed in standard fashion.  Post-operative care involved cast immobilization and non-weight bearing where applicable. 

Union was determined by consolidation of the graft and formation of interlacing trabeculae.  Failure was determined by reabsorption of graft material, lack of progression, or fixation failure.  The patient charts were also evaluated as to clinical function of the extremity.

Results :

Radiographic evidence of union, which consisted of trabecular formation and consolidation of the fracture, occurred in 16 of 19 defects (84%).  Plain radiographs taken at routine intervals show maintenance of graft and progressive consolidation in the successful grafts, as shown in the example in  Figure 1.  There were 3 failures, which included resorption of the graft in 2 cases, and fixation failure in one patient.

         1a.                  1b.                      1c.
Figure 1 a-c.  a) Radiographs of post-traumatic segmental defect after wash out, internal fixation, and placement of antibiotic beads.  b) Radiographs 3 months after grafting technique showing interval consolidation.  c) Consolidation of defect at 10 months.

         2a.                     2b.                     2c.
Figure 2 a-c.  a) Initial injury post internal fixation and antibiotic bead placement.  b) Same injury 2 months post grafting technique.  c) Same injury 5 months post-grafting with reabsorbtion of the calcium sulfate graft material.

The average time to clinical union, which included radiographic union and clinical functional use of the extremity, was 8.4 months.  Union times ranged from 3.5 months up to 13.5 months.  There was no correlation between time to union and the defect size.  There was no correlation between those who abused tobacco and time to union.  None of the other comorbidities (Table 1) correlated with time to union.

Failure of the graft to unite occurred in 3 defects.    In the first case, the patient was treated for a grade III-B open tibia fracture and ipsilateral grade III-A supracondylar femur fracture.  He was treated with multiple I + D’s, intramedullary rodding and gracillis rotation flap for coverage for the tibia and internal fixation for the femur.  He then underwent delayed grafting with rhBMP-2/ACS and calcium sulfate at approximately 11 weeks post-injury for both defects.  At 5 months post-grafting, the tibial graft had reabsorbed and the gap remained.  He underwent repeat grafting (the second time with calcium phosphate and rhBMP-2/ACS) and healed at 9 months.

The second failure, shown in Figure 2, occurred in a 34 yo male with a grade III-A open supracondylar/intercondylar femur fracture.  He had early internal fixation along with multiple debridements and antibiotic beads.  At 7 weeks post-injury, he underwent grafting with rh-BMP-2/ACS along with calcium sulfate.  At 5 months post-injury, the graft had reabsorbed.

The 3rd failure involved a 28 yo female with a symptomatic clavicular non-union.  Approximately 6 weeks after grafting with BMP and tri-calcium phosphate, the internal fixation failed due to patient non-compliance.

Discussion :

As discussed, the difficulty of treating post-traumatic and post-infectious segmental bone defects continues to be a troublesome problem.  Clinicians continue to search for new ways of treatment given the frequent complications that ensue with current treatment regiments.  BMP bone grafting has the potential to be a valuable new option for segmental defects, and has already been shown useful in the treatment of spinal fusion, nonunion of difficult fractures, as well as in the treatment of open tibial fractures 15,22,23. 

Bone morphogenetic protein has been studied extensively in animals involving segmental defects.  Bostrom et al used a 2-cm ulnar defect model in rabbits to show dose dependent bone formation, showing union in all defects that were given the highest dosage 16.  Moreover, histological analysis demonstrated normal bone formation when using rhBMP-2/ACS.   Yasko et al also found dose related healing in a rat model 18.  Cook et al demonstrated 89% (25/28) union rate at 12 weeks in 2.5-cm canine ulnar segmental defects using rh-BMP-7 (OP-1).  Within the same time frame, the torsional strength of the new bone was rated at 65% of intact ulnas 17.  Sciadini and Johnson found healing comparable to auto graft when rhBMP-2/ACS was used in the same canine defect model 19.

Use of rhBMP in humans has to date involved spinal fusion, healing of tibial nonunion, and use in open tibial fractures.  A prospective, randomized trial involving patients with lumbar degenerative disc disease by Burkus et al compared the use of rhBMP-2/ACS vs iliac crest autograft in lumbar fusion, along with the use of lumbar cages.  They found a higher fusion rate (94.5 vs 88.7%) at 24 months in the group treated with BMP, along with shorter operative times, less blood loss, and similar clinical outcomes 15.  The control group had 8 adverse events related to the iliac crest bone donor site.  In a more recent trial, Govender et al evaluated the use and safety of rhBMP-2/ACS in a randomized, single blinded study involving open tibia fractures.  The patients were stratified according to severity, and either the standard procedure (involving local wound care with irrigation and debridement, and a static locked, reamed, IM nail) or the standard procedure along with the use of BMP at two different concentrations soaked on to the ACS carrier (1.5 mg/mL vs 0.75 mg/mL).   Results demonstrated a 44% reduction of the risk of secondary intervention in the group treated with 1.5 mg/mL rhBMP-2/ACS when compared with controls.  Healing rates of 58%  (BMP) vs 38% (standard treatment) were also observed at 12 months 22.  

Recently, Jones et al presented results from a small clinical trial involving rhBMP-2/ACS used as part of a staged bone grafting procedure.24 That study involved the treatment of 30 tibial fractures with traumatic bone loss of 1 to 5 cm in length.  Patients were randomized to receive iliac crest auto graft or allograft plus rhBMP-2/ACS.  The author concluded that rhBMP-2/ACS combined with allograft yielded similar healing to autogenous bone graft.   

In this study 2 out of the 3 patients treated with calcium sulfate and rhBMP-2/ACS experienced resorption of the graft material, resulting in failure.  It is theorized that the increased cellular activity induced by the rhBMP-2 led to the resorption.  The effect was not observed with the slower resorbing calcium phosphate granules. Surgeons should be cautious of using any fast resorbing material, such as a calcium sulfate, in the presence of a BMP product.  If the 3 calcium sulfate treated patients are removed from the analysis, then bony union occurred in 15 out of 16 defects (94%) treated with calcium phosphate and rhBMP-2/ACS.

We report here a retrospective review utilizing rhBMP-2/ACS combined with a bone substitute in segmental long bone defects with reasonable clinical results.  The rhBMP-2/ACS implant has been shown to be safe in humans and has excellent osteo-inductive effects.  We will continue to evaluate patients critically for the possible use of this technique.

Conclusion:

In summary, Metal-on-metal resurfaced hips with appropriate case selection can yield satisfactory results in the young and active patients with abnormal coxanatomy. This technique used in three patients with successful outcome and averted the need of structural graft augmentation.                                                                                              

Reference :

1. Dabezies EJ, Stewart WE, Goodman FG, Deffer PA. Management of segmental defects of the radius and ulna. J Trauma. 1971; 11:778-88.

2. Grace TG, Eversmann WW Jr. The management of segmental bone loss associated with forearm fractures. J Bone Joint Surg Am. 1980;62:1150-5.

3. Moroni A, Rollo G, Guzzardella M, Zinghi G. Surgical treatment of isolated forearm non-union with segmental bone loss. Injury. 1997;28:497-504.

4. Ring D, Allende C, Jafarnia K, Allende BT, Jupiter JB. Ununited Diaphyseal Forearm Fractures with Segmental Defects: Plate Fixation and Autogenous Cancellous Bone-Grafting. J Bone Joint Surg Am. 2004; 86:2440-2445.

5. Younger EM, Chapman MW. Morbidity at bone graft donor sites. J Orthop Trauma. 1989;3:192-5.

6. St John TA, Vaccaro AR, Sah AP, Schaefer M, Berta SC, Albert T, Hilibrand A. Physical and monetary costs associated with autogenous bone graft harvesting. Am J Orthop. 2003;32(1):18-23.

7. Ahlmann E, Patzakis M, Roidis N, Shepherd L, Holtom P. Comparison of anterior and posterior iliac crest bone grafts in terms of harvest-site morbidity and functional outcomes. J Bone Joint Surg Am. 2002;84-A(5):716-20.

8. Vail TP, Urbaniak JR. Donor-site morbidity with use of vascularized autogenous fibular grafts. J Bone Joint Surg Am. 1996;78:204-211.

9. Jupiter JB, Bour CJ, May JW. The Reconstruction of Defects in the Femoral Shaft with Vascularized Transfers of Fibular Bone. J Bone Joint Surg Am. 1987; 69: 365-374.

10. Heitann C, Erdmann D, Levin LS. Treatment of Segmental Defects of the Humerus with an Osteoseptocutaneous Fibular Transplant. J Bone Joint Surg Am 2002; 84: 2216-2223.

11. Song HR, Kale A, Park HB, et al. Comparison of Internal Bone Transport and vascularized Fibular Grafting for Femoral Bone Defects.  J Orthop Trauma. 2003; 17(3): 203-211.

12. Bowers KW, Edmonds JL, Girod DA, Jayaraman G, Chua CP, Toby EB. Osteocutaneous Radial Forearm Free Flaps: The Necessity of Internal Fixation of the Donor Site Defect to Prevent Pathologic Fracture. J Bone Joint Surg Am 2000; 82: 694.

13. Zagula H D, Buck DC, Brekke J, Wozney J M, Hollinger JO.  Bone formation with the use of rh BMP-2 (Recombinant Human Bone Morphogenic Protein).  J Bone Joint Surg Am 1997; 79A (12): 1778-1790.

14. Chang H, Jiang W, Phillips FM, et al. Osteogenic Activity of the Fourteen types of Human Bone Morpogenic Proteins (BMP’s). J Bone Joint Surg Am 2003; 85: 1544-1552.

15. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech. 2002; 15:337-49.

16. Bostrum M, Lane JM, Tumin E, et al. Use of Bone Morphogenic Protein-2 in the Rabbit ulnar Nonunion Model. Clin Orth. 1996; 1(327): 272-282.

17. Cook SD, Salkeld SL, Brinker MR, Wolfe MW, Rueger DC. Use of an Osteoinductive Biomaterial (rhOP-1) in Healing Large Segmental Bone Defects. J Orthop Trauma. 1998; 12(6): 407-417.

18. Yasko AW, Lane JM, Fellinger EJ, Rosen V, Wozney JM, Wang EA. The Healing of Segmental Bone Defects induced by Recombinant Human Bone Morphogenic Protein (rh-BMP-2). A Radiographic, Histological, and Biochemical Study in Rats. J Bone Joint Surg Am 1992; 74(5): 659-670.

19. 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;18:289-302.

20. Desilets CP, Merden CJ, Patterson AL, et al. Development of Synthetic Bone-Repair Materials for Craniofacial Reconstruction. J Craniofac Surg. 1990; 1: 150-153.

21. Johnson EE, Urist MR, Finerman GA. Repair of segmental defects of the tibia with cancellous bone grafts augmented with human bone morphogenetic protein. A preliminary report. Clin Orthop Relat Res. 1988

22. Govender S, Csimma C, Genant H K, 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 2002; 84: 2123 - 2134.

23. Friedlaender BE, Perry CR, Col JD, et al. Osteogenic Protein-1 (Bone Morphogenic Protein-7) in the Treatment of Tibial Nonunions. J Bone Joint Surg Am 2001; 83-A Supp 1: 151-158.

24. Jones AL, Bucholz RW, Bosse MJ, et al.  Prospective, randomized comparison of rhBMP-2/ACS in combination with allograft versus autogenous bone graft in healing diaphyseal tibial fractures with traumatic bone loss.  Trans Orthopaedic Trauma Association. Poster #17, 2004.

This is a peer reviewed paper 

Please cite as : Niles D. Schwartz: Segmental Bone Defects Treated Using Recombinant Human Bone Morphogenetic Protein

J.Orthopaedics 2006;3(2)e2

URL: http://www.jortho.org/2006/3/2/e2

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