Abstract
Background: The role of bone morphogenetic proteins
(BMPs) in osseous repair has been demonstrated in numerous animal
models. Recombinant human osteogenic protein-1 (rhOP-1 or BMP-7)
has now been produced and was evaluated in a clinical trial conducted
under a Food and Drug Administration approved Investigational Device
Exemption to establish both the safety and efficacy of this BMP in
the treatment of tibial nonunions. The study also compared the clinical
and radiographic results with this osteogenic molecule and those
achieved with fresh autogenous bone.
Materials and Methods: One hundred and twenty-two
patients (with 124 tibial nonunions) were enrolled in a controlled,
prospective, randomized, partially blinded, multi-center clinical
trial between February, 1992, and August, 1996, and were followed
at frequent intervals over 24 months. Each patient was treated by insertion
of an intramedullary rod, accompanied by rhOP-1 in a type I collagen
carrier or by fresh bone autograft. Assessment criteria included
the severity of pain at the fracture site, the ability to walk with full
weight-bearing, the need for surgical re-treatment of the nonunion
during the course of this study, plain radiographic evaluation of
healing, and physician satisfaction with the clinical course. In addition,
adverse events were recorded, and sera were screened for antibodies
to OP-1 and type-I collagen at each outpatient visit.
Results: At 9 months following the operative procedures (the
primary end-point of this study), 81% of the OP-1-treated
nonunions (n = 63) and 85% of those receiving
autogenous bone (n = 61) were judged by clinical criteria
to have been treated successfully (p = 0.524). By radiographic
criteria, at this same time point, 75% of those in the
OP-1-treated group and 84% of the autograft-treated patients
had healed fractures (p = 0.218). These clinical results
continued at similar levels of success throughout 2 years of observation,
and there was no statistically significant difference in outcome
between the two groups of patients at this point (p = 0.939).
All patients experienced adverse events. Forty-four percent of patients
in each treatment group had serious events, none of which were related
to their bone grafts. More than 20% of patients treated
with autografts had chronic donor site pain following the procedure.
Conclusions: rhOP-1 (BMP-7), implanted with a type
I collagen carrier, was a safe and effective treatment for tibial nonunions.
This molecule provided clinical and radiographic results comparable
with those achieved with bone autograft, without donor site morbidity.
Despite the remarkable intrinsic capacity of bone to regenerate
and undergo repair, numerous musculoskeletal disorders require or
benefit from the addition of an osteoinductive stimulus, traditionally in
the form of autogenous bone graft. One such challenging clinical
condition is nonunion of the tibia.
The estimated incidence of long bone fractures in the United
States is nearly 1,500,000 per year26.
A relatively small percentage of these injuries proceed to nonunion,
while considerably more result in delayed healing8.
The majority of long bone nonunions occur in the tibia, and they
are responsible for substantial morbidity in the form of pain, loss
of function, and interference with personal and vocational productivity?7,26. Tibial nonunions are
particularly recalcitrant to treatment, and consequently many alternative approaches
to elicit their healing have been suggested. These options include
various forms of skeletal fixation, with or without supplemental bone
graft, usually autogenous in nature34.
Additional treatment considerations include physical modalities,
such as electrical stimulation1,4or
the use of ultrasound19. Each
approach offers advantages and disadvantages. None of these methods,
however, has provided a rapid and uniformly reliable method of treatment
to manage the pain, lost function, or morbidity associated with
these injuries. Indeed, some morbidity may be attributed to the
selected modality of treatment, such as pain at the bone graft donor
site35, pin track or surgically
introduced infection, and muscle atrophy or joint stiffness secondary
to immobilization.
In recent years, our knowledge of bone repair and regeneration,
at both the cellular and molecular levels, has greatly improved5,23. This is particularly true with
respect to the molecular signals responsible for regulating the
recruitment, differentiation, and activity of macromolecules responsible
for the bone remodeling cycle. Observations by Urist and Strates31,32 and later by Sampath and Reddi29predicted and then demonstrated
the properties and effects of the bone morphogenetic proteins (BMPs). Along
with other members of the transforming growth factor-beta (TGF-b)
superfamily and related growth and differentiation factors (GDFs),
these molecules are directly involved in the processes of fracture
repair and bone graft incorporation3,11,22,27,
28,30.
Human osteogenic protein-1 (OP-1 or BMP-7) has been cloned and
reproduced with recombinant technology (rhOP-1)24 and,
when combined with a collagen carrier, has been shown to induce
new bone formation in heterotopic sites as well as repair skeletal
defects in a wide variety of animal models9-13,18.
These extensive preclinical studies have also supported the safety
of OP-1. On the basis of this biological success and safety profile,
a prospective, randomized, partially blinded clinical trial was accomplished
in which patients with established tibial nonunions were treated
with intramedullary fixation and implantation at the fracture site
of OP-1 in a collagen carrier or by bone autograft.
The Study Population
One hundred and twenty-two patients with 124 tibial nonunions
(one patient had bilateral tibial nonunions and one patient had
two nonunited fractures in the same tibia) were enrolled in a clinical
study, under a Food and Drug Administration (FDA) approved Investigational
Device Exemption (IDE), in which they were randomly assigned to
one of two treatment groups (OP-1 or bone autograft). Each patient
had a tibial nonunion, as based on a 1988 FDA guidance document
definition requiring 9 months duration of the nonunited fracture
with no evidence of progressive healing over the previous 3 months14. Patients who, in the judgment of
their treating orthopaedic surgeon, were candidates for internal fixation
alone (generally reaming and an intramedullary rod), were excluded,
as were patients with clinically apparent infection at the fracture
site. Other contraindications to inclusion in this study are listed
in Table I.
All patients were treated between February, 1992, and August,
1996, at one of 17 medical centers in the United States, after institutional
review board approval had been obtained at the local health care facility
and with the patient’s informed consent. In each case,
the involved orthopaedic surgeon had determined that the patient
would best be treated by internal fixation and required a supplemental
bone graft. Consequently, all 122 patients enrolled in this study
underwent intramedullary (IM) rod fixation (the type of rod and
the decision to lock the device were left to the discretion of each
surgeon). A new rod was inserted at this time in more than 90% of fractures
in each group (90.5%, 57 of 63 fractures in the OP-1-treated
group, and 91.8%, 56 of 61 fractures in the autograft-treated
group). In the remaining fractures, a previously inserted IM rod was
left in place. One-half of the patients (61 patients with 63 tibial
nonunions) were randomly assigned to receive an implant at the fracture
site with OP-1 in a type I collagen carrier, and the other half
(61 patients with 61 tibial nonunions) received bone autograft in
a similar manner. Surgeons were aware of the treatment group to
which each patient was assigned after the random selection process.
OP-1 Implant
The rhOP-1 implant was supplied by Stryker Biotech (Hopkinton,
Massachusetts). Each sterile package (or unit) contained 3.5 milligrams
of the rhOP-1 mixed with 1 gram of type I bovine bone-derived collagen
(the total reconstituted volume was approximately 4 milliliters
per unit). The volume of fracture gap present at the time of surgery (following
debridement) determined the amount of rhOP-1 used in each patient,
to a maximum of two units.
Methods of Clinical Assessment
Clinical assessment included the presence of pain at the fracture
site (none, mild, moderate, or severe) and the ability to bear weight
(none, partial, or full) on the involved extremity. These criteria
were evaluated at 1, 2, 3, 6, 9, 12, and 24 months following surgery,
and the primary end-point of the study was the 9-month visit. Clinical
success was defined as full weight-bearing, less than severe pain
at the fracture site on weight-bearing, and no further surgical
intervention for the purpose of enhancing fracture repair (i.e.,
re-treatment). The operating surgeon’s level of
satisfaction with the healing process at this same time interval
was also recorded. In addition, the time of the surgical procedure,
estimated blood loss, and hospital length of stay were noted. For
patients who received autograft, the degree of pain at the donor
site (none, mild, moderate, or severe) was recorded.
All perioperative and postoperative complications were reported
and classified as severe (potentially life threatening and requiring
treatment), moderate (non-life threatening but requiring therapeutic intervention),
or mild (resolved without any treatment). Whether the complication
was related to the OP-1 implant or the bone autograft was determined.
Retrospectively, all adverse events were classified as serious or
non-serious according to International Conference of Harmonization
(ICH) Guidelines20.
Immunological Assessment
All of the patients were screened for antibodies to OP-1 and
type I collagen by an enzyme-linked immunoabsorbent assay (ELISA)
with sera collected at each follow-up visit. The specificity of
the response was confirmed with use of Western blot analysis for
those patients demonstrating positive anti-OP-1 or anti-collagen
activity in the screening assay.
Radiographic Assessment
Standard radiographs were obtained in the anteroposterior, lateral,
and two oblique projections. A panel of three musculoskeletal radiologists,
blinded to treatment and time following the surgical procedure,
independently assessed whether bridging by new bone existed across
the fracture site and on how many of the four views this bridging
was apparent. The final result reflected the consensus
of at least two of these three radiologists.
Statistical Analysis
Analyses of efficacy outcomes were conducted with use of a chi-square
test, and a p value of < 0.05 was considered statistically
different. Differences in the frequency of adverse events were evaluated by
a two-tailed chi-square or Fisher’s exact test, as appropriate.
Comparison of the means of operative blood loss was performed with
a Student t test. For the length of stay and operative
time, Wilcoxon rank sum tests were performed, which are appropriate
for variables that are not normally distributed. A p value of < 0.05
for analysis of safety variable was considered significant.
Demographics
The demographics of the study groups are presented in Table II. These two
randomly assigned populations were similar in most respects, including
age, sex ratio, duration of nonunion, and the number of prior surgical
interventions. There was, however, a statistically higher prevalence
of atrophic nonunions (41 compared with 25%, p = 0.048)
and a strong trend toward more smokers (74 compared with 57%,
p = 0.057) in the OP-1 group. There were also trends toward
higher percentages of comminuted fractures at injury, prior failures
of bone autografts, and prior use of intramedullary rods in the
individuals in the OP-1 treated group.
The maximum number of units of OP-1 implants used in this study
was two, and 47 of the 63 nonunion sites were treated with a single
OP-1 implant. The volume of bone autograft used for each patient was
left to the discretion of the surgeon and was not reported.
Treatment of 41% of nonunions was accompanied by a fibulectomy
(40% of the OP-1 and 43% of the autograft-treated
groups). Overall, 92% of the intramedullary rods were locked,
including 94% in the OP-1 and 92% in the autograft-treated
groups.
Clinical Outcomes
Length of stay, operative time, and operative blood loss are
recorded in Table III.
The trend toward longer operative and hospitalization times and
the statistically significant increased blood loss (p = 0.049)
in the autograft-treated group were imposed by the nature of a bone
donor recovery site. In addition, all patients in the autograft group
had pain at the donor site following the operative procedure, and
more than 80% judged their postoperative pain as moderate
or severe. Furthermore, more than 20% of patients had persistent pain,
mild or moderate in nature, at their 6-month visit, and approximately
13% had persistent pain at the donor site 12 months following
the operative procedure.
All patients in each group had at least one adverse event, usually
mild or moderate and non-serious in nature. Examples of these events
included common postoperative sequelae such as fever, nausea and vomiting,
leg edema, discomfort, and hematoma at the operative site. The incidence
of these events was similar in both groups (Table IV). Forty-four
percent of both groups had serious adverse events, none of which
were considered related to the OP-1 implant or the bone autograft. Osteomyelitis
was reported at the fracture site in 21% of patients (13
of 61, Table IV)
following treatment with bone autograft but in only 3% (2
of 61; Table IV)
of those receiving OP-1 (p = 0.002).
Clinical success in this study required a patient to be fully
weight-bearing with less than severe pain at the fracture site (Table V). By these
criteria, at 9 months following surgery, 81% (51 of 63)
of the OP-1-treated group and 85% (52 of 61) of the autograft-treated
group were considered to have successful outcomes (p = 0.524,
not statistically different). This high level of satisfactory outcome
remained present, with both groups demonstrating an 82% success
rate after 24 months of observation (37 of 45 patients treated with
OP-1 and 31 of 38 patients receiving autograft, p = 0.939).
By the 9-month follow-up visit, surgical re-treatment occurred
in 5% of the OP-1-treated patients and in 10% of
those receiving autograft. Physician satisfaction with the healing
process at 9 months following surgery was favorable for 86% of
those treated with OP-1 and 90% of the autograft-treated patients.
Radiographic Results
Seventy-five percent (47 of 63) of the nonunions in the OP-1-treated
group demonstrated radiographic evidence of bone bridging on at
least one view, compared with 84% of those treated with
autograft (p = 0.218, not statistically significant) at
9 months following surgery (Table V). The use of more rigorous criteria—bridging
in at least three of four views—resulted in lower radiographic
healing rates in both groups: specifically, 62% of the
OP-1 recipients and 74% of the autograft-treated group
(p = 0.158, not statistically significant).
Influence of a Prior Autograft
Nineteen (31%) of the 61 nonunions treated with autografts
in the present study and 27 (43%) of 63 nonunions in the
OP-1-treated group had received autograft in the course of their
previous treatment for the nonunion. Clinical success and radiographic outcomes
in these subsets were not significantly different from the nonstratified
results.
Immunological Results
Circulating antibodies against type I collagen were detected
postoperatively in the sera of 5% of those patients receiving
this matrix, and low levels of anti-OP-1 antibodies developed in
10% of those treated with OP-1. All of the anti-OP-1 antibody responses
were transient, and all titres were low. No adverse events related
to sensitization were reported. By 9 months, five of the six patients
with an anti-OP-I antibody response had unions that were healed
clinically and radiographically. The nonunion in the remaining patient
went on to heal radiographically at 24 months.
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 colleagues17recently
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,
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