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Osteogenic protein-1 (bone morphogenic protein-7) combined with various adjuncts in the treatment of humeral diaphyseal nonunions.

Abstract

A prospective study was conducted to determine the efficacy of using recombinant BMP-7 (rhOP-1) as an adjuvant in the treatment of diaphyseal humeral nonunions. Twenty-three consecutive patients with atrophic humeral diaphyseal nonunions were treated at seven separate institutions. All nonunions were fixed with either a compression plate or an intramedullary nail in conjunction with various bone grafting techniques. Recombinant OP-1 was delivered to the fracture site in a Type I collagen carrier at the time of fixation. All fractures went on to eventual union. There were no serious complications and no adverse reactions to the rhOP-1 implant. Our study suggests that rhOP-1 may be a safe and effective adjuvant for the treatment of humeral diaphyseal nonunions.

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Fractures of the humeral shaft are a major source of morbidity, comprising about 3% of all fractures. (1,2) While the vast majority of these fractures will unite with closed treatment, surgical fixation may be warranted in certain cases. (3) Nonunion of the humeral diaphysis occurs after 3% to 12% of fractures, (4,5) and can be a debilitating condition that leaves the patient with severe pain and leads to stiffness of both the shoulder and elbow joints. In the rare event of a humeral shaft nonunion, compression plate fixation or intramedullary nailing combined with bone grafting of defects or atrophic nonunions results in a 95% healing rate. (6) While these results have been good, there is significant donor site morbidity associated with the harvest of autogenous iliac crest bone graft.

In the past decade, a considerable amount of effort has been directed toward identifying biologic osteoinductive agents to aid in the healing of osseous fractures. Specifically, studies into bone specific differentiation of local tissue have highlighted the role of the bone morphogenic proteins (BMP). (7,8) Multiple animal studies have shown that recombinant BMP-7 combined with a collagen carrier can induce both heterotopic bone formation at various sites as well as aid in the healing of significant bone defects. (9-14) Human studies have also shown the benefits of using recombinant BMP-7 (osteogenic protein-1) in the treatment of tibial nonunions and bone defects. (15,16) This study was performed to determine the efficacy of using recombinant BMP-7 as an adjuvant in the treatment of diaphyseal humeral nonunions.

Materials and Methods

Twenty-three consecutive patients with 23 humeral non-unions were enrolled in an industry sponsored (Stryker Biotech, Hopkinton, MA) clinical study under a Food and Drug Administration (FDA) approved Investigational Device Exemption (IDE) in which they were assigned to treatment with recombinant OP-1 (rhOP-1). Each patient had a humeral nonunion based on a 1988 FDA guidance document definition requiring nine months duration of the nonunited fracture with no evidence of progressive healing over the previous three months. (17) Patients who, in the judgment of their treating orthopaedic surgeon, were candidates for internal fixation alone, had a hypertrophic nonunion, or had a clinically apparent infection at the fracture site were excluded from this study.

All patients were treated between March, 2002, and July, 2003, at one of seven medical centers in the United States after institutional review board approval had been obtained at the local healthcare facility and with the patient's informed consent. Once a diagnosis of nonunion had been established, all of the patients underwent plate and screw or intramedullary nail fixation in conjunction with either allograft or autograft bone grafting or demineralized bone matrix (DBM). In addition patients were treated with rhOP-1 contained within a Type I collagen matrix implant.

Each sterile unit of the rhOP-1 implant (Stryker Biotech, Hopkinton, MA) contained 3.5 milligrams of the rhOP-1 mixed with one gram of Type 1 bovine bone-derived collagen (the total reconstituted volume was approximately four milliliters per unit). Each patient was dosed with one unit of the rhOP-1 implant in addition to the bone graft.

Clinical diagnosis of union was determined by the absence of pain at the fracture site, no motion at fracture site on manual three-point stressing in the sagittal and coronal planes, and functional recovery of range of motion with the involved extremity. The primary end-point of the study was the nine-month visit. Standard radiographs were obtained in the anteroposterior and lateral projections. Patients were assessed for radiographic healing by the treating surgeon and an independent examiner. Radiographic healing required bridging of three out of four cortices on anteroposterior and lateral views.

All preoperative and postoperative adverse events were reported and classified as non-serious or serious according to the International Conference of Harmonization (ICH) Guideline for Good Clinical Practice. (18) Serious adverse events included any untoward medical occurrence temporally related to the use of rhOP-1 implant that resulted in death, was life-threatening, required inpatient hospitalization or prolonged current hospitalization, or resulted in significant or persistent disability. (18) Non-serious adverse events are any untoward medical occurrence that did not fulfill the definition of a serious adverse event.

Results

Twenty-three patients (23 nonunions) were enrolled into the study. There were nine males and fourteen females with an age range of 21 to 87 years (mean: 56.6 years). Eight patients were smokers and three patients were chronic alcoholics; no patient in the study had diabetes mellitus. The average patient weight was 76 kg (range: 55.5 to 108.6 kg). All but two of the fractures were closed, with thirteen occurring in the right upper extremity and ten on the left. Eleven of the fractures occurred in the proximal third of the shaft, five in the middle third, five in the distal third, and two were segmental. Sixteen of the fractures resulted from low-velocity falls, three from high-energy falls from a height, three from motor vehicle accidents, two from blunt trauma, and two from penetrating trauma. There was an average of 1.3 surgical procedures (range: 0 to 3) conducted prior to the index procedure of the nonunion. One of the patients with a nonunion had been previously diagnosed with an infection.

Twenty-one of the nonunions were repaired with a plate and screws. Two of the nonunions were fixed with an intramedullary nail. In addition to the standardized dose of rhOP-1, patients were treated with various types of bone graft and other osteoinductive agents. Four patients were treated with iliac crest bone graft alone, one with DBM alone, and 18 were treated with a combination of autograft, allograft cancellous chips, platelet concentrate gel, or DBM. No patients were treated with allograft bone or platelet concentrate gel alone. Patient characteristics and specific treatments are outlined in Table 1.

All fractures went on to eventual union. The mean time from repair to union was 144.3 days (range: 69 to 356 days). Because of the lack of standardization with regards to adjunctive bone graft or bone graft substitutes used, no comparison of healing time after application of rhOP-1 could be made.

There were four perioperative adverse events encountered in three treated patients. Three of the perioperative adverse events were serious and one was non-serious. Serious perioperative adverse events include two radial nerve palsies (one of which eventually resolved) and one brachialis muscle contracture. One patient developed a superficial cellulitis that was the lone non-serious perioperative adverse event. There were four late serious adverse events encountered at follow-up. The patient with the brachialis contracture developed severe elbow stiffness and declined further surgical intervention. One patient developed a superficial wound infection and was treated medically with a short course of intravenous antibiotics. Heterotopic ossification developed near the shoulder in one patient resulting in pain and limitations in range of motion. Finally, one patient developed a late ulnar nerve palsy.

Discussion

Recently, a considerable amount of research has been conducted to identify specific biologic agents that can be used in the treatment of difficult fractures and nonunions. Previous reports on the use of rhOP-1 in the treatment of nonunions have been encouraging. Friedlander and colleagues reported their results in a prospective multi-center study comparing the use of autogenous iliac crest bone grafting to rhOP-1 in conjunction with a reamed intramedullary nail for treatment of tibial diaphyseal nonunions.16 They reported comparable radiographic and clinical results in the rhOP-1 group without the donor site morbidity associated with harvesting of iliac crest bone graft. Geesink and associates showed that rhOP-1 in conjunction with a collagen carrier led to the healing of five out of six fibular defects encountered after high tibial osteotomy.15 None of the fibular defects treated with only the collagen carrier went on to heal. In our current study, all of the diaphyseal humeral nonunions went on to heal and there was a low rate of complications.

Currently, humeral shaft nonunions are repaired with surgical fixation. Classically, hypertrophic nonunions have been treated with compression plating only, while atrophic nonunions may require bone graft. In 1937, Campbell reported a 94% healing rate in humeral nonunions treated with plating and autogenous bone grafting. (19) Rosen reported a 95% union rate in nonunions treated with operative fixation.6 He used autogenous iliac crest bone graft in atrophic cases and in nonunions with bone defects. Other investigators have found similar success in treating humeral nonunions. (20-22) Specifically, Ring reported bony union in 14 of 15 patients with atrophic nonunions containing bony defects treated with plating and autogenous bone grafting. (22) While these results are excellent, they rely on a separate surgical procedure to obtain the graft, which carries inherit risks including pain, infection, hematoma, and residual sensory loss. (23,24) In our current study, union occurred in all 11 patients who did not have autogenous iliac crest bone grafting.

There are a few potential weaknesses of our study design that are worth mentioning. The first weakness is the potential for detection bias when assessing the radiographs for union. To minimize the detection bias, all of the films were reviewed by an independent examiner. Another weakness of the study was the varied use of alternate bone graft and bone graft substitutes. It is unclear what the role of these adjuncts had in the healing potential of the nonunions treated in this group of patients.

Our results, in conjunction with other recent literature, support the use of rhOP-1 for treating non-unions in conjunction with conventional plating or intramedullary nailing techniques. Currently, the cost of a single 3.5 mg dose of rhOP-1 is $5,000. The benefit of avoiding potential complications associated with the harvest of autogenous iliac crest bone graft, however, cannot be overstated. While allogenic bone grafts avoid donor site morbidity and provide an osteoconductive framework, they lack the osteoinductive properties associated with autogenous bone graft. We believe that hypertrophic nonunions of the humeral shaft should continue to be treated with compression plating alone; while atrophic nonunions can be treated with rhOP-1 and allogenic bone graft material instead of using an autogenous bone graft. While the rhOP-1 can provide osteogenic properties, the osteoconductive allogenic bone graft can act as a scaffold for new bone formation.

Conclusion

Previous experience has shown the strong osteoinductive properties of rhOP-1 with a good safety profile; however, further research is required to more clearly define the indications and optimum matrix for delivery of the agent. While the routine use of rhOP-1 in the treatment of hypertrophic nonunions may not be warranted, it should be considered, in conjunction with allogenic bone grafting, for the treatment of atrophic and recalcitrant nonunions of the humeral diaphysis.

References

(1.) Adams JC: Outlines of Fractures. Edinburgh: E. & S. Livingstone, 1968.

(2.) Christensen S: Humeral shaft fractures, operative and conservative treatment. Acta Chir Scand 1967;133(6):455-60.

(3.) Schatzker J: Fractures of the humerus. In: Schatzker J, Tile M (eds): The Rationale for Operative Fracture Care (2nd ed). Berlin: Springer-Verlag, 1996, pp. 83-94.

(4.) Sarmiento A, Zagorski JB, Zych GA, Latta LL, Capps CA: Functional bracing for the treatment of fractures of the humeral diaphysis. J Bone Joint Surg Am 2000;82:478-86.

(5.) Pennsylvania Orthopaedic Society, Scientific Research Committee: Fresh midshaft fractures of the humerus in adults: Evaluation of treatment in Pennsylvania during 1952-1956. Pa Med J 1959;62:848-850.

(6.) Rosen H: The treatment of nonunions and pseudarthroses of the humeral shaft. Orthop Clin North Am 1990 Oct;21(4):725-42.

(7.) Sampath TK, Reddi AH: Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. Proc Natl Acad Sci USA 1981;78:7599-603.

(8.) Urist MR, Strates BS: Bone morphogenetic protein. J Dent Res 1971;50:1392-1406.

(9.) Salkeld SL, Patron LP, Barrack RL, Cook SD: The effect of osteogenic protein-1 on the healing of segmental bone defects treated with autograft or allograft bone. J Bone Joint Surg Am 2001;83(6):803-16.

(10.) Cook SD, Baffes GC, Wolfe MW, Sampath TK, Rueger DC: Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. Clin Orthop 1994;301:302-12.

(11.) Cook SD, Dalton JE, Tan EH, Whitecloud TS 3rd, Rueger DC: In vivo evaluation of recombinant human osteogenic protein (rhOP-1) implants as a bone graft substitute for spinal fusions. Spine 1994;19:1655-63.

(12.) Cook SD, Rueger DC: Osteogenic protein-1: Biology and applications. Clin Orthop 1996;324:29-38.

(13.) Cook SD, Wolfe MW, Salkeld SL, Rueger DC: Effect of recombinant humanosteogenic protein-1 on healing of segmental defects in nonhuman primates. J Bone Joint Surg Am 1995;77:734-50.

(14.) Cunningham BW, Kanayama M, Parker LM, Weis JC, Sefter JC, Fedder IL, McAfee PC: Osteogenic protein versus autologous interbody arthodesis in sheep thoracic spine: A comparative endoscopic study using the Bagby and Kuslich interbody fusion device. Spine 1999;24:509-18.

(15.) Geesink RG, Hoefnagels NH, Bulstra SK: Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect. J Bone Joint Surg Br 1999;81:710-18.

(16.) FriedlaEnder GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S: Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 2001;83(S1):S151-8.

(17.) Guidance Document for the Preparation of Investigational Device Exemptions and Pre-market Approval Applications for Bone Growth Stimulator Devices. Rockville, Maryland, United States Food and Drug Administration, 1988.

(18.) International Conference of Harmonization (ICH) Guideline for Good Clinical Practice. FDA Federal Registrer; Vol. 62, No. 90, May 9, 1997, pages 25691-25709.

(19.) Campbell WC: Ununited fractures of the shaft of the humerus. Ann Surg 1937;105:135-49.

(20.) Barquet A, Fernandez A, Luvizio J, Masliah R: A combined therapeutic protocol for aseptic nonunion of the humeral shaft: A report of 25 cases. J Trauma 1989;29:95-100.

(21.) McKee MD: Management of humeral nonunions after the failure of locking intramedullary nails. J Orthop Trauma 1996;10(7):492-9.

(22.) Ring D, Jupiter JB, Quintero J, Sanders RA, Marti RK: Atrophic ununited diaphyseal fractures of the humerus with a bony defect: Treatment by wave-plate osteosynthesis. J Bone Joint Surg Br 2000;82(6):867-71.

(23.) DeOrio JK, Farber DC: Morbidity associated with anterior iliac crest bone grafting in foot and ankle surgery. Foot Ankle Int 2005;26(2):147-51.

(24.) 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(5):716-20.

Matthew R. Bong, M.D., Edward L. Capla, M.D., and Kenneth A. Egol, M.D., are in the NYU-HJD Department of Orthopaedic Surgery, Hospital for Joint Diseases New York, New York. Anthony T. Sorkin, M.D., is with Rockford Orthopaedic Associates, Rockford, Illinois. Michael Distefano, M.D., is in private practice in Hackensack, New Jersey. Rosemary Buckle, M.D., is at Orthopaedic Associates, Houston, Texas. Robert W. Chandler, M.D., is at the Kerlan-Jobe Orthopaedic Clinic, Los Angeles, California. Kenneth J. Koval, M.D., is in the Department of Orthopaedic Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

Correspondence: Kenneth J. Koval, M.D., Dartmouth-Hitchcock Medical Center, Department of Orthopaedic Surgery, One Medical Center Drive, Lebanon, New Hampshire 03756-0001.

This research was conducted as a trial sponsored by Stryker Biotech Inc., Hopkinton, Massachusetts.
Table 1 Patient Demographics

 Fracture
 Type and
Sex Age Location Fixation Graft Types

M 87 CL-PRO Plate CC, SYMPH, STIM
M 38 CL-DIST Plate DBM, CC
F 60 CL-MID Plate ICBG, CC
F 68 CL-DIST Plate ICBG, CC, STIM
F 70 CL-MID Plate ICBG, CC, DBM, STIM
F 61 CL-PRO Plate DBM, CC, STIM
F 44 CL-PRO Plate DBM, CC
F 80 CL-PRO Plate DBM, ICBG, CC
F 30 CL-SEG Plate ICBG, CC, STIM
M 71 CL-PRO Plate DBM, ICBG, CC
M 21 OP-PRO Plate ICBG, CC
F 49 CL-DIST Plate DBM, CC
M 56 OP-DIST Plate ICBG
F 43 CL-MID Plate ICBG
M 44 CL-PRO Plate ICBG
F 63 CL-PRO IM Rod DBM, CC
F 31 CL-MID Plate None
M 52 CL-PRO Plate DBM, CC
F 58 CL-PRO IM Rod DBM, CC
F 75 CL-PRO Plate DBM
M 86 CL-DIST Plate ICBG
M 39 CL-MID Plate ICBG, CC
F 76 CL-SEG Plate DBM, CC

CL-Closed, OP-Open, PRO-Proximal, MID-Midshaft, DIST Distal,
SEG-Segmental, CC-Allogenic cancellous bone chips, STIM-Implantable
bone stimulator, DBM-Demineralized bone graft, ICBG-Iliac crest
bone graft, SYMPH-Symphony platelet concentrate (Depuy, Warsaw, IN)
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Article Details
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Author:Bong, Matthew R.; Capla, Edward L.; Egol, Kenneth A.; Sorkin, Anthony T.; Distefano, Michael; Buckle
Publication:Bulletin of the NYU Hospital for Joint Diseases
Date:Jun 22, 2005
Words:2837
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