Use of rhBMP-2 in combination with structural cortical allografts: clinical and radiographic outcomes in anterior lumbar spinal surgery

BACKGROUND: Recombinant human bone morphogenetic protein-2 soaked into an absorbable collagen sponge (rhBMP-2/ACS) has been shown in a nonhuman primate study and in a pilot study in humans to promote new bone formation and incorporation of an allograft device when implanted in patients undergoing anterior lumbar interbody arthrodesis. However, a larger series with longer follow-up is needed to demonstrate its superiority to autogenous iliac crest bone graft. METHODS: Between 1998 and 2001, a two-part, prospective, randomized, multicenter study of 131 patients was conducted to determine the safety and efficacy of the use of rhBMP-2/ACS as a replacement for autogenous iliac crest bone graft in anterior lumbar spinal arthrodesis with threaded cortical allograft dowels. Patients were randomly assigned to a study group that received rhBMP-2/ACS or to a control group that received autograft. The clinical and radiographic outcomes were determined with use of well-established instruments and radiographic assessments. RESULTS: The patients in the study group had significantly better outcomes than the control group with regard to the average length of surgery (p < 0.001), blood loss (p < 0.001), and hospital stay (p = 0.020). Fusion rates were significantly better in the study group (p < 0.001). The average Oswestry Disability Index scores, Short-Form-36 physical component summary scores, and low-back and leg-pain scores were significantly better in the study group (p < 0.05). CONCLUSIONS: In patients undergoing anterior lumbar interbody arthrodesis with threaded allograft cortical bone dowels, rhBMP-2/ACS was an effective replacement for autogenous bone graft and eliminated the morbidity associated with graft harvesting.     

A cost analysis of bone morphogenetic protein versus autogenous iliac crest bone graft in single-level anterior lumbar fusion

An economic model was developed to compare costs of stand-alone anterior lumbar interbody fusion with recombinant human bone morphogenetic protein 2 on an absorbable collagen sponge versus autogenous iliac crest bone graft in a tapered cylindrical cage or a threaded cortical bone dowel. The economic model was developed from clinical trial data, peer-reviewed literature, and clinical expert opinion. The upfront price of bone morphogenetic protein (3380 dollars) is likely to be offset to a significant extent by reductions in the use of other medical resources, particularly if costs incurred during the 2 year period following the index hospitalization are taken into account.     

Posterolateral lumbar intertransverse process spine arthrodesis with recombinant human bone morphogenetic protein 2/hydroxyapatite-tricalcium phosphate after laminectomy in the nonhuman primate.

STUDY DESIGN: A nonhuman primate lumbar intertransverse process arthrodesis model was used to evaluate recombinant human bone morphogenetic protein 2 (rhBMP-2) in a hydroxyapatite-tricalcium phosphate (HA-TCP) carrier as a complete bone graft substitute. OBJECTIVES: To assess the ability of a ceramic material to serve as a carrier for various doses of rhBMP-2 as a bone graft substitute in a primate model of posterolateral intertransverse process spinal fusion after laminectomy. SUMMARY OF BACKGROUND DATA: The reported non-union rates for posterolateral lumbar spine fusion with autogenous iliac crest bone range from 5-35%. Recombinant human bone morphogenetic protein 2 has shown potential to serve as a bone graft substitute for posterolateral intertransverse process spine fusion. Although a resorbable collagen sponge was a suitable carrier in rabbits and dogs, it was too compressible for the paraspinal muscles in rhesus monkeys. This failure of the collagen carrier has prompted evaluation of the feasibility of an alternative carrier material and the required dose of rhBMP-2. METHODS: Twenty-one adult rhesus monkeys underwent a laminectomy at L4-L5 followed by bilateral intertransverse process arthrodesis via the same midline incision (n = 16) or a minimally invasive video-assisted posterolateral approach (n = 5). Bone graft implants on each side consisted of either 5 cm3 of autogenous iliac crest bone or 60:40 HA-TCP blocks (1.2 x 0.5 x 3.7 cm) loaded with a solution containing 0, 6, 9, or 12 mg of rhBMP-2 per side. The monkeys were killed 24 weeks after surgery. Inspection, manual palpation, radiography, and histology were used to assess fusion and to detect any bony growth into the laminectomy defect. RESULTS: Fusion was not achieved in any of the monkeys treated with autogenous iliac crest bone graft. Both of the monkeys treated with the HA-TCP blocks with 0 mg rhBMP-2 achieved fusion. All 15 monkeys treated with the HA-TCP blocks and either of the three doses of rhBMP-2 achieved solid fusion. Two animals had extension of the fusion on one side because of malpositioned ceramic block. The results in animals fused via the minimally invasive video-assisted technique were the same as inthose fused with the open technique. Histologic analysis showed some ingrowth of bone into the ends but not-through the ceramic block in the absence of rhBMP-2. When the ceramic blocks were loaded with rhBMP-2 there was a dose-dependent increase in the amount and quality of bone throughout the ceramic carrier based on qualitative assessment. No significant bone encroachment on the exposed thecal sac through the laminectomy defect was observed in any of the monkeys. CONCLUSION: Hydroxyapatite-tricalcium phosphate proved to be a suitable carrier for rhBMP-2 in the posterolateral spine fusion model in rhesus monkeys. Even in the presence of a laminectomy defect, there was no evidence of bone induction outside the confines of the ceramic carrier.     

The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report

STUDY DESIGN: A prospective randomized controlled human clinical pilot trial. OBJECTIVES: To determine the feasibility of using rhBMP-2/collagen as a substitute for autogenous bone graft inside interbody fusion cages to achieve arthrodesis in humans. SUMMARY OF BACKGROUND DATA: Preclinical studies have shown rhBMP-2 to be an effective substitute for autogenous bone graft, but there are no studies to date documenting such efficacy for human spine fusion. METHODS: Fourteen patients with single-level lumbar degenerative disc disease refractory to nonoperative management were randomized to receive lumbar interbody arthrodesis with a tapered cylindrical threaded fusion cage filled with rhBMP-2/collagen sponge or autogenous iliac crest bone. Patients were evaluated with radiographs, sagittally reformatted computed tomography scans, and Short Form-36 and Oswestry outcome questionnaires. RESULTS: All 11 patients who received rhBMP-2 were judged by three independent radiologists to have solid fusions (at 6, 12, and 24 months postimplantation), whereas only 2 of the 3 control patients, who received the standard treatment of autogenous iliac crest bone, were deemed to be fused. The Oswestry Disability Questionnaire scores of the rhBMP-2 group improved sooner (after 3 months) than those of the autograft group, with both groups demonstrating similar improvement at 6 months. Short Form 36 scores continued to improve up to 24 months. CONCLUSION: The arthrodesis was found to occur more reliably in patients treated with rhBMP-2-filled fusion cages than in controls treated with autogenous bone graft, although the sample size was limited. There were no adverse events related to the rhBMP-2 treatment. This study is one of the first to show consistent and unequivocal osteoinduction by a recombinant growth factor in-humans.     

The effectiveness of rhBMP-2 in replacing autograft: an integrated analysis of three human spine studies

In anterior lumbar spinal fusion, patients treated with rhBMP-2 on a collagen sponge carrier had statistically superior outcomes compared to patients treated with autogenous bone graft. A collagen sponge carrier should replace autogenous bone graft for this patient population.     

Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence

We carried out a prospective study to determine whether the addition of a recombinant human bone morphogenetic protein (rhBMP-2) to a machined allograft spacer would improve the rate of intervertebral body fusion in the spine. We studied 77 patients who were to undergo an interbody fusion with allograft and instrumentation. The first 36 patients received allograft with adjuvant rhBMP-2 (allograft/rhBMP-2 group), and the next 41, allograft and demineralised bone matrix (allograft/demineralised bone matrix group). Each patient was assessed clinically and radiologically both pre-operatively and at each follow-up visit using standard methods. Follow-up continued for two years. Every patient in the allograft/rhBMP-2 group had fused by six months. However, early graft lucency and significant (> 10%) subsidence were seen radiologically in 27 of 55 levels in this group. The mean graft height subsidence was 27% (13% to 42%) for anterior lumbar interbody fusion, 24% (13% to 40%) for transforaminal lumbar interbody fusion, and 53% (40% to 58%) for anterior cervical discectomy and fusion. Those who had undergone fusion using allograft and demineralised bone matrix lost only a mean of 4.6% (0% to 15%) of their graft height. Although a high rate of fusion (100%) was achieved with rhBMP-2, significant subsidence occurred in more than half of the levels (23 of 37) in the lumbar spine and 33% (6 of 18) in the cervical spine. A 98% fusion rate (62 of 63 levels) was achieved without rhBMP-2 and without the associated graft subsidence. Consequently, we no longer use rhBMP-2 with allograft in our practice if the allograft has to provide significant structural support.     

Posterolateral intertransverse process spinal arthrodesis with rhBMP-2 in a nonhuman primate: important lessons learned regarding dose, carrier, and safety.

Recombinant osteoinductive proteins have been used successfully in canine and rabbit models of posterolateral intertransverse process arthrodesis, but little is known about the ability of these compounds to achieve fusion in nonhuman primates. The goals of this investigation were to compare different combinations of recombinant human bone morphogenetic protein-2 (rhBMP-2) dosages and carriers in a nonhuman primate model of posterolateral intertransverse process spinal fusion and to determine the feasibility of using rhBMP-2 in the presence of exposed dura in a laminectomy model. Posterolateral intertransverse process arthrodeses were performed at L4-5 in 29 rhesus monkeys. The most striking findings were as follows: rhBMP-2 could induce bone in a nonhuman primate spine; the presence of a laminectomy defect with exposed dura did not preclude the safe use of rhBMP-2 for posterolateral fusion; soft tissue compression of the collagen sponge carrier prevented bone induction at standard BMP doses, presumably due to squeezing of the protein out of the sponge; and longer rhBMP-2 loading time into the collagen carrier and mechanical protection from the soft tissue compression both allowed more bone induction at a lower dose of rhBMP-2.     

Accelerating lumbar fusions by combining rhBMP-2 with allograft bone: a prospective analysis of interbody fusion rates and clinical outcomes.

BACKGROUND CONTEXT: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is an osteoinductive protein approved for use in the anterior lumbar interspace. High fusion rates with rhBMP-2 have been reported with threaded interbody allograft dowels. There may be a clinical benefit for the patient by adding rhBMP-2 to the allograft. PURPOSE: To compare the fusion rates and clinical outcomes of patients treated with allograft interbody fusions with and without the addition of rhBMP-2. STUDY DESIGN: Prospective consecutive patient enrollment with minimum 24-month follow-up. PATIENT SAMPLE: Seventy-five patients with lumbar interbody fusions at 1-3 spinal segments. OUTCOMES MEASURES: Clinical: Numerical Rating Scale (NRS) and Oswestry Disability Index (ODI). Radiographic: X-ray and computed tomographic scan analysis using the Molinari-Bridwell fusion scale. METHODS: Seventy-five patients scheduled for lumbar fusion were enrolled sequentially. Group 1: 30 patients had anterior interbody allografts alone. Group 2: 45 patients had anterior interbody allograft filled with rhBMP-2. All cases had posterior pedicle screw instrumentation. A total of 165 surgical levels (62 allograft alone/103 allograft+BMP) were included. Fusion data and clinical outcomes were collected for a minimum of 2 years after surgery. RESULTS: Statistically higher fusion rates were observed in the patients with BMP at all time points compared with allograft alone. Group 2 (+ BMP) fusion rates were 94%, 100%, and 100% at 6, 12, and 24 months after surgery. Group 1 (-BMP) fusion rates were 66%, 84%, and 89% at the same time intervals. Clinical outcomes were significantly improved in Group 2 compared with Group 1 at 6 months. There were no revisions (0%) in the BMP group and 4 revision fusion surgeries (13%) in the allograft group. No untoward effects were attributable to the rhBMP-2. CONCLUSIONS: Our study confirms the efficacy of an innovative lumbar fusion technique: an interbody femoral ring allograft, combined with an osteoinductive stimulant (rhBMP-2), protected by pedicle screws. This combination of a structural interbody allograft with rhBMP-2 eliminates the insult of iliac crest harvest, allows for reliable radiographic analysis, and results in successful fusion formation in 100% of the cases in this study.     

Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages

In a multicenter, prospective, randomized, nonblinded, 2-year study, 279 patients with degenerative lumbar disc disease were randomly divided into two groups that underwent interbody fusion using two tapered threaded fusion cages. The investigational group (143 patients) received rhBMP-2 on an absorbable collagen sponge, and a control group (136 patients) received autogenous iliac crest bone graft. Plain radiographs and computed tomographic scans were used to evaluate fusion at 6, 12, and 24 months after surgery. Mean operative time (1.6 hours) and blood loss (109.8 mL) were less in the investigational rhBMP-2 group than in the autograft control group (2.0 hours and 153.1 mL). At 24 months the investigational group's fusion rate (94.5%) remained higher than that of the control group (88.7%). New bone formation occurred in all investigational patients. At all intervals, mean postoperative Oswestry, back pain, and leg pain scores and neurologic status improved in both treatment groups with similar outcomes. In the control group, eight adverse events related to the iliac crest graft harvest occurred (5.9%), and at 24 months 32% of patients reported graft site discomfort and 16% were bothered by its appearance. Lumbar fusion using rhBMP-2 and a tapered titanium fusion cage can yield a solid union and eliminate the need for harvesting iliac crest bone graft.     

Direct current stimulation of titanium interbody fusion devices in primates.

BACKGROUND CONTEXT: The fusion rate for anterior lumbar interbody fusion (ALIF) varies widely with the use of different interbody devices and bone graft options. Adjunctive techniques such as electrical stimulation may improve the rate of bony fusion. PURPOSE: To determine if direct current (DC) electrical stimulation of a metallic interbody fusion device enhanced the incidence or extent of anterior bony fusion. STUDY DESIGN/SETTING: ALIF was performed using titanium alloy interbody fusion devices with and without adjunctive DC electrical stimulation in nonhuman primates. METHODS: ALIF was performed through an anterolateral approach in 35 macaques with autogenous bone graft and either a titanium alloy (Ti-6Al-4V) fusion device or femoral allograft ring. The fusion devices of 19 animals received high (current density 19.6 microA/cm2) or low (current density 5.4 microA/cm2) DC electrical stimulation using an implanted generator for a 12- or 26-week evaluation period. Fusion sites were studied using serial radiographs, computed tomography imaging, nondestructive mechanical testing and qualitative and semiquantitative histology. RESULTS: Fusion was achieved with the titanium fusion device and autogenous bone graft. At 12 weeks, the graft was consolidating and early to moderate bridging callus was observed in and around the device. By 26 weeks, the anterior callus formation was more advanced with increased evidence of bridging trabeculations and early bone remodeling. The callus formation was not as advanced or abundant for the allograft ring group. Histology revealed the spinal fusion device had an 86% incidence of bony fusion at 26 weeks compared with a 50% fusion rate for the allograft rings. DC electrical stimulation of the fusion device had a positive effect on anterior interbody fusion by increasing both the presence and extent of bony fusion in a current density-dependent manner. CONCLUSIONS: Adjunctive DC electrical stimulation of the fusion device improved the rate and extent of bony fusion compared with a nonstimulated device. The fusion device was equivalent to or better than the femoral allograft ring in all evaluations. The use of adjunctive direct current electrical stimulation may provide a means of improving anterior interbody fusion.     

Laparoscopic anterior lumbar interbody fusion with rhBMP-2: a prospective study of clinical and radiographic outcomes

STUDY DESIGN: To prospectively evaluate the clinical and radiographic outcome of laparoscopic anterior lumbar interbody fusion with rhBMP-2. OBJECTIVES: It was hypothesized that discogenic pain could be treated successfully with an anterior lumbar interbody fusion performed laparoscopically using rhBMP-2 as a replacement for autogenous bone. SUMMARY OF BACKGROUND DATA: The traditional surgical treatment of discogenic pain involves painful incisions of muscles, with potential loss of integrity and strength. Harvesting of bone graft is associated with significant complications including persistent pain at the donor site. METHODS: Twenty-two consecutive patients were studied prospectively with the surgery performed by one surgeon. Patients were evaluated clinically and radiographically at 6 and 12 months after surgery. An unbiased radiologist read postoperative computed tomography scans for evidence of fusion. RESULTS: There were 8 male (36%) and 14 female (64%) patients. The average age was 38 years (range, 21-56 years). At 6 and 12 months after surgery 95% (21 of 22) were available for follow-up; 100% were satisfied with treatment at 12 months. Concerning their symptoms, 100% reported relief of back pain, 100% had improvement of leg pain, and 100% described significant functional improvement. Improvements were seen at 6 and 12 months on Oswestry (P < 0.001), functional testing (P < 0.001), and pain analog scale (P < 0.001). Radiographic analysis showed that all of the patients had evidence of a solid fusion at 6 months after operation. CONCLUSION: Discogenic low back pain can be effectively treated surgically with a laparoscopic anterior lumbar interbody fusion using rhBMP-2 in place of autogenous bone. The fusion occurs quickly and predictably with no adverse effects identified.     

Vertebral bone resorption after transforaminal lumbar interbody fusion with bone morphogenetic protein (rhBMP-2)

OBJECTIVE: Bone morphogenetic protein (rhBMP-2) has demonstrated an increased rate of interbody fusion when placed in the intervertebral space. Owing to this advantage, rhBMP-2 is being implanted with increasing frequency in the lumbar spine. The purpose was to quantify and describe the presence of bone resorption within the vertebral body after transforaminal lumbar interbody fusion with placement of rhBMP-2 within the disc space. METHODS: Twenty-six patients were selected from a clinical database. Patients included in the study had undergone a transforaminal lumbar interbody fusion with BMP. Interbody implants included allograft dowels or interbody cages augmented with autograft or allograft bone. A computed tomography study of the lumbar spine a minimum of 3-month postoperatively was another inclusion criterion. Osteolytic defects were grouped into 3 categories on the basis of the size and extent of involvement in the vertebral body. RESULTS: A total of 32 lumbar levels were reviewed. Fourteen males and 12 females with an average age of 46.0 years were included in the study. Bone resorption defects were noted in 22 of the 32 levels reviewed (69%). The defects were characterized as mild in 50% (11 of 22), moderate in 18% (4 of 22), and severe in 31% (7 of 22). CONCLUSIONS: The benefit of rhBMP-2 to promote interbody fusion in the lumbar spine has been well documented. BMP has demonstrated an increased fusion rate and the ability to produce a robust fusion mass. rh-BMP-2's osseous remodeling potential may lead to bone resorption within the vertebral body.     

Complications of anterior cervical discectomy and fusion using recombinant human bone morphogenetic protein-2

The use of bone morphogenetic protein-2 (rhBMP-2) in spinal fusion has increased dramatically since an FDA approval for its use in anterior lumbar fusion with the LT cage. There are several reports of its use in transforaminal lumbar interbody fusion, posterolateral fusion, and anterior cervical fusion. Reports on adverse effects of rhBMP-2 when used in spinal fusion are scarce in literature. An Institutional Review Board approved retrospective study was conducted in patients undergoing anterior spinal fusion and instrumentation following diskectomy at a single center. Forty-six consecutive patients were included. Twenty-two patients treated with rhBMP-2 and PEEK cages were compared to 24 in whom allograft spacers and demineralized bone matrix was used. Patients filled out Cervical Oswestry Scores, VAS for arm pain, neck pain, and had radiographs preoperatively as well at every follow up visit. Radiographic examination following surgery revealed end plate resorption in all patients in whom rhBMP-2 was used. This was followed by a period of new bone formation commencing at 6 weeks. In contrast, allograft patients showed a progressive blurring of end plate-allograft junction. Dysphagia was a common complication and it was significantly more frequent and more severe in patients in whom rhBMP-2 was used. Post operative swelling anterior to the vertebral body on lateral cervical spine X-ray was significantly larger in the rhBMP-2 group when measured from 1 to 6 weeks after which it was similar. These effects are possibly due to an early inflammatory response to rhBMP-2 and were observed to be dose related. With the parameters we used, there was no significant difference in the clinical outcome of patients in the two groups at 2 years. The cost of implants in patients treated with rhBMP-2 and PEEK spacers was more than three times the cost of allograft spacers and demineralized bone matrix in 1, 2, and 3-level cases. Despite providing consistently good fusion rates, we have abandoned using rhBMP-2 and PEEK cages for anterior cervical fusion, due to the side effects, high cost, and the availability of a suitable alternative.     

Experimental spinal fusion with use of recombinant human bone morphogenetic protein 2.

STUDY DESIGN: Posterolateral lumbar spinal fusion with use of recombinant human bone morphogenetic protein 2 (rhBMP-2) was tested in rabbits by implanting composites of rhBMP-2 and collagen carrier. OBJECTIVES: To examine the bone-formation-inducing activity of rhBMP-2 and find the optimal amount of rhBMP to add to a collagen carrier to constitute bone-formation-inducing implants to be substituted for bone graft in posterolateral spinal fusion in rabbits. SUMMARY OF BACKGROUND DATA: In animal models, rhBMP-2--impregnated collagen has been successfully used for posterolateral spinal fusion, indicating that it is a potential substitute for the autogenous corticocancellous bone graft currently used most routinely in posterolateral lumbar spinal fusion. METHODS: Nine rabbits were divided into three equal groups. The bilateral L4-L5 transverse processes were exposed, and collagen strips impregnated with rhBMP-2 (10, 50, or 200 micrograms) were placed on the left transverse processes, and collagen strips alone were inserted on the right. All rabbits were killed 24 weeks after surgery. The implanted sites were assessed for new bone formation and bony fusion by radiography and histologic examination. RESULTS: New bone formation was noted in intertransverse spaces on the left side of all rabbits except one (10 micrograms rhBMP-2). Twelve weeks after implantation, no new bone formation was seen on the right side of all animals. The newly formed bone masses were significantly larger in the 50-microgram and 200-microgram rhBMP-2 groups than in the 10-microgram rhBMP-2 group (P < 0.01), but there was no significant difference between bone formation in the 50-microgram and 200-microgram groups (P = 0.647). CONCLUSIONS: The rhBMP-2/collagen composite implant was an effective bone graft substitute for achieving posterolateral spinal fusion. When combined with a collagen carrier, the optimal rhBMP-2 dose for achieving posterolateral spinal fusion seemed to be approximately 50 micrograms per segment in rabbits.     

Vertebral osteolysis originating from subchondral cyst end plate defects in transforaminal lumbar interbody fusion using rhBMP-2. Report of two cases

Background ContextVertebral osteolysis has been reported as a complication of off-label recombinant human bone morphogenetic protein-2 (rhBMP-2) use in transforaminal lumbar interbody fusion (TLIF). It has been postulated that end plate violation during disc space preparation, rhBMP-2 overdosing, or a combination thereof can contribute to the development of vertebral osteolysis when rhBMP-2 is used in the lumbar interspace.PurposeTo present two cases of vertebral osteolysis that occurred after TLIF in which rhBMP-2 was used. In each case, the osteolysis originated from subchondral cysts that were present on preoperative computed tomographic (CT) scans.Study DesignCase report.MethodsTwo patients underwent instrumented TLIF using INFUSE (Medtronic, Inc., Littleton, MA, USA) on an absorbable collagen sponge carrier. In each patient, approximately 4 mg of rhBMP-2 was placed anteriorly in the disc space with 0.1 mg of rhBMP-2 being placed inside a polyetheretherketone interbody cage. Morcellized allograft bone mixed with demineralized bone matrix was also placed in the disc space and cage. The remaining rhBMP-2 was placed posterolaterally on the contralateral side. Each patient presented with worsening back pain approximately 3 to 4 months postoperatively and CT scans revealed osteolysis affecting the L4 and L5 vertebral bodies. The osteolysis appeared to originate from preoperative vertebral defects caused by subchondral cysts.ResultsOne patient underwent removal of the interbody cage at the L4–L5 level and revision of the fusion with iliac crest autograft. At 15-month follow-up, he had no complaints of back pain, and CT scanning revealed solid fusion across the L4–L5 disc space. The other patient was offered revision of his fusion but declined any further surgery. At 2-year follow-up, that patient had persistent back pain but still declined any further surgery. A CT scan revealed unchanged osteolysis at the L4 and L5 levels.ConclusionsIt has been proposed that rhBMP-2-induced vertebral osteolysis occurring in TLIF procedures may be secondary to end plate violation during disc preparation or overdosing of rhBMP-2. Although overdosing may have also contributed to vertebral osteolysis in our two cases, the end plate violation from subchondral cyst formation that was present on preoperative CT scans seemed to be the origin of the osteolysis suggesting that the presence of preoperative subchondral cysts may be an additional risk factor for development of osteolysis in these patients.     

Use of recombinant human bone morphogenetic protein-2 as an adjunct in posterolateral lumbar spine fusion: a prospective CT-scan analysis at one and two years

INTRODUCTION: This study determines whether recombinant human bone morphogenetic protein-2 (rhBMP-2) (12 mg at the rate of 1.5 mg/mL) delivered on an absorbable collagen sponge with an added bulking agent can increase posterolateral lumbar spine fusion success rates and decrease time for fusion with autogenous bone grafts. METHOD: A prospective, single institution, clinical case-matched, radiographic, cohort study was undertaken. A total of 52 patients underwent posterolateral lumbar arthrodesis with pedicle screw instrumentation. The experimental group (n=41) underwent placement of Iliac crest bone graft (ICBG) with InFUSE (12 mg/level at the rate of 1.5 mg/mL). The control group (n=11) consisted of sex-matched patients, consecutively collected over the same time period with an instrumented posterolateral arthrodesis and ICBG placed in the intertransverse space. OUTCOME MEASURES: Thin-cut (2 mm) axial, coronal, and sagittal reconstructions were blindly evaluated for evidence of bridging bone and cortication of the fusion mass by 3 separate reviewers. Fusions were graded and an overall score was given to the quality of the fusion mass. RESULTS: Fifty patients (ICBG alone n=11; ICBG/rhBMP-2 n=39) were available for CT evaluation at 2-year follow-up. An overall 97% (68/70 levels; Definite+Probably Fused) fusion rate in the rhBMP-2 group was achieved as compared to the 77% fusion rate (17/22 levels) in the ICBG alone group (P<0.05). In the rhBMP-2 group, 92% of the patients (36/39 patients) received an overall excellent subjective fusion rating as compared to 27% (3/11) in the control group (P<0.05). There was no computed tomographic evidence of soft-tissue ossification, dural ossification, or laminar bone regrowth in any patient. CONCLUSIONS: The adjunctive use of rhBMP-2 and ICBG seems to be safe and results in significantly larger and more consistent posterolateral fusion masses.     

Is INFUSE bone graft superior to autograft bone? An integrated analysis of clinical trials using the LT-CAGE lumbar tapered fusion device

Multicenter human clinical studies of patients undergoing anterior lumbar fusion have been conducted using recombinant bone morphogenetic protein or rhBMP-2 on an absorbable collagen sponge, marketed as INFUSE Bone Graft, or autograft implanted in the LT-CAGE Lumbar Tapered Fusion device. An integrated analysis of multiple clinical studies was performed using an analysis of covariance to adjust for preoperative variables in a total of 679 patients. Of these patients, 277 had their cages implanted with rhBMP-2 on an absorbable collagen sponge and 402 received autograft transferred from the iliac crest. The patients treated with rhBMP-2 had statistically superior outcomes with regard to length of surgery, blood loss, hospital stay, reoperation rate, median time to return to work, and fusion rates at 6, 12, and 24 months. Oswestry Disability Index scores and the Physical Component Scores and Pain Index of the SF-36 scale at 3, 6, 12, and 24 months showed statistically superior outcomes in the rhBMP-2 group.     

The safety and utility of recombinant human bone morphogenetic protein-2 for cranial procedures in a nonhuman primate model

OBJECT: The goal of this study was to evaluate the safety and efficacy of recombinant human bone morphogenetic protein 2 (rhBMP-2) in cranial applications. METHODS: Critical-sized calvarial defects were created bilaterally in four rhesus monkeys, and bilateral rectangular bone flaps were created in six others. Control and rhBMP-2-treated sides were randomly chosen for each animal, and an absorbable collagen sponge was used to deliver the growth factor. Over a 6-month period postoperatively, the animals were serially evaluated for bone healing and adverse BMP-related consequences by using the following methods: computerized tomography (CT) scanning, magnetic resonance (MR) imaging, electroencephalography, histological investigations, and cerebrospinal fluid (CSF) analysis. The critical-sized defects for the rhBMP-2-treated and control sides attained 71 +/- 12% and 28 +/- 11% closure, respectively (four animals; p = 0.04). The CT scans demonstrated that the bone flaps treated with rhBMP-2 had complete osteointegration in five of six animals, whereas scans of the untreated bone flaps demonstrated uniformly poor osteointegration with the intact skull. Histological analysis confirmed well-formed bridges of bone on the rhBMP-2-treated sides. No epileptogenic activity was detected in any of the animals, and MR imaging revealed no evidence of adverse effects on the brain parenchyma. Meningitic irritation was not found on postoperative CSF sample analysis. CONCLUSIONS: Treatment of bone flaps and critical-sized cranial defects with rhBMP-2 leads to improved bone formation and osteointegration in nonhuman primates. Initial evaluation of rhBMP-2 appears to indicate a good safety profile for use in cranial procedures in primates.     

A comprehensive clinical review of recombinant human bone morphogenetic protein-2 (INFUSE® Bone Graft)

The combination of recombinant human bone morphogenetic protein-2 (rhBMP-2) on an absorbable collagen sponge (ACS) carrier has been shown to induce bone formation in a number of preclinical and clinical investigations. In 2002, rhBMP-2/ACS at a 1.5-mg/cc concentration (INFUSE Bone Graft, Medtronic Spinal and Biologics, Memphis, TN) was FDA-approved as an autograft replacement for certain interbody spinal fusion procedures. In 2004, INFUSE Bone Graft was approved for open tibial fractures with an intermedullary (IM) nail fixation. Most recently, in March 2007, INFUSE Bone Graft was approved as an alternative to autogenous bone grafts for sinus augmentations, and for localised alveolar ridge augmentations for defects associated with extraction sockets. The culmination of extensive preclinical and clinical research and three FDA approvals makes rhBMP-2 one of the most studied, published and significant advances in orthopaedics. This review article summarises a number of clinical findings of rhBMP-2/ACS, including the FDA-approved investigational device exemption (IDE) studies used in gaining the aforementioned approvals.