The results of this study demonstrate that rhOP-l is a clinically safe osteogenic implant and is associated with substantial clinical and radiographic success when used in conjunction with intramedullary rod fixation for the treatment of tibial nonunions. Furthermore, these rates of success were comparable with those achieved with autograft, when evaluated at 9 and 24 months following surgery.
Tibial nonunions were chosen for this study because of their relatively high frequency, substantial morbidity, and challenging treatment requirements26,34
. The incidence of fractures in the United States exceeds six million each year, of which approximately 25% involve long bones and more than one-third of these (more than 580,000 cases) are injuries of the tibia and fibula. Collectively, fractures result in greater than 3.5 million visits to emergency rooms and nearly 11 million outpatient visits on an annual basis. The socioeconomic impact of fractures further includes approximately 146 million restricted activity days, more than 36 million lost work days, more than 7.3 million lost school days, and nearly 6.5 million patient days each year.
Many prior clinical studies have been designed to evaluate treatment alternatives for tibial nonunions1,4,8,19,21,34
, but this is the first of a prospective, randomized, and partially blinded nature to assess a BMP or other osteogenic molecule. In these previous studies, there has been a lack of uniformity in the definition of nonunion and often a lack of rigor in terms of assessment criteria, particularly radiographic analysis33
As is true of other studies, radiographic analysis in the present circumstance raises important issues regarding the assessment of fracture repair. It is, for example, difficult to maintain “blinding” of the radiologists with respect to autograft, which is mineralized from the outset, when compared with the radiolucent nature of OP-1 and its collagen matrix. On the other hand, without the benefit of history and time frame since surgery for each set of radiographs, it becomes problematic to separate the presence of pre-existing mineral of bone autograft from induced new bone. Similarly, standardized plain radiographic views that adequately and reproducibly demonstrate the entire bone gaps of irregular fracture configurations, partially obscured by their associated internal fixation, are impractical if not impossible. In the final analysis, radiographic interpretation is subjective. The establishment of outcome criteria, such as the definitive time following treatment used for analysis and the percent of the circumferential gap (or number of cortices) that must be bridged to confer success, represent arbitrary decisions. Indeed, in clinical practice, the physician combines historical, clinical, and radiographic information to arrive at a conclusion regarding the status of fracture healing or outcome. It is this comprehensive perspective, as reported in the present study, that supports the conclusion of substantial clinical efficacy of OP-1 in the treatment of tibial nonunions, comparable with that achieved with the use of autogenous bone.
It is also important to keep in mind that OP-1 (BMP-7) is not a new molecule. Rather, this protein structure has been highly conserved in phylogeny since the introduction of the skeleton over 400,000,000 years ago. The availability of this molecule, in recombinant form, for the purpose of enhancing osseous repair is novel.
OP-1 has been evaluated extensively in preclinical studies in critical-sized defects of rabbit, canine, sheep, and nonhuman primates9-13,18
. In each circumstance, OP-1 was associated with a high degree of success, comparable in frequency and completeness of repair with that seen with bone autograft. Importantly, all new bone induced by any bone graft material or osteogenic molecule, including OP-1, is of autogenous origin, and this bone continues to remodel in the same manner as is normal for the particular skeletal site and its biomechanical environment.
Geesink and colleagues17
recently reported the first experience with rhOP-1 in humans. In the study, gaps were created in the fibula during high tibial osteotomy for degenerative disease of the knee. These segmental defects did not heal when implanted with the type I collagen carrier alone but repaired completely in five of six patients in whom the OP-1 implant was placed in this gap.
At present, there are several alternatives to bone autografts. The choices include allogeneic bone processed fresh, deep-frozen, or freeze-dried and sometimes demineralized to varying degrees, as well as a variety of synthetic hydroxyapatite, tricalcium phosphate, and other ceramic preparations of a primarily osteoconductive nature2,5,16
. Autogenous bone remains the standard to which other choices must be compared, reflecting its relatively high osteogenic potential and, by definition, its biocompatibility. Autograft has drawbacks, however, such as the need for an additional operative site with its associated perioperative morbidity (e.g., pain, potential infection, blood loss, and fracture)35
, and limits exist with respect to the size, shape, and quantity of bone autograft available. Donor site morbidity is eliminated with the use of allografts and synthetics, but the intrinsic osteoinductive capacity of these materials is absent or less than that of autograft. Biomechanical properties of these substances also vary, depending on the method of preparation, the structural characteristics of the product, or both25
. Allografts are extremely safe in terms of disease transmission when acquired and processed according to established guidelines, but the remote possibility of contamination by clinically significant microorganisms remains15
The incidence of postoperative osteomyelitis at the nonunion site was significantly greater in the autograft-treated group (3% in patients implanted with OP-1 compared with 21% receiving autograft, p = 0.002). The reason or reasons for this difference were not addressed by this study, but a similar high rate of infection at the fracture site was reported by Chapman and colleagues6
. This group compared autograft with a collagen-calcium phosphate graft material in the treatment of fresh fractures of long bones, and the autograft recipients had a significantly higher infection rate (13.0 compared with 4.9%, p = 0.008).
OP-1 in recombinant form and combined with a type-1 bovine bone-derived collagen offers the advantages of a highly inductive molecule, with an excellent safety profile and the lack of donor site morbidity. It has little intrinsic biomechanical strength, but OP-1 can be combined with other implants to achieve stability when necessary. Like all bone graft materials, OP-1 requires a healthy host bed, capable of providing the vascularity and cell populations necessary for osseous regeneration and repair. As such, OP-1 in an appropriate matrix provides a unique profile of clinical, biological, and biomechanical characteristics, which should be carefully considered by physicians and patients when making choices among available bone graft and graft substitutes used in the treatment of tibial nonunions. The efficacy of OP-1 in other formulations and clinical circumstances requiring an osteogenic stimulus, including various fracture sites, spinal arthodesis, total joint arthroplasty, and maxillofacial indications, is currently being explored.