Acute epidural lipedema: a novel entity and potential complication of bone morphogenetic protein use in lumbar spine fusion

Background context

Bone morphogenetic proteins (BMPs) induce osteogenesis, making them useful for decreasing time to union and increasing union rates. Although the advantages of BMP-2 as a substitute for iliac crest graft have been elucidated, less is known about the safety profile and adverse events linked to their use in spinal fusion. An accumulation of reactive edema in the epidural fat may lead to neural compression and significant morbidity after lumbar spinal fusion. Bone morphogenetic protein has never been implicated as a cause of spinal epidural lipedema.

Purpose

We report on a case of rapid accumulation of edematous adipose tissue in the epidural space after lumbar spine decompression and fusion with bone morphogenic protein.

Study design

Case report.

Methods

The patient was a 45-year-old woman with chronic back pain, worsening bilateral L5 radiculopathy, and degenerative disc disease. Surgery consisting of a one-level transpedicular decompression, transforaminal lumbar interbody fusion, and posterolateral fusion was performed using BMP-2 as an adjunct for arthrodesis.

Results

Two days postoperatively, the patient developed progressive cauda equina syndrome. Lumbar magnetic resonance imaging revealed edematous epidural fat extending above the initial laminectomy, compromising the spinal canal, and compressing the thecal sac. Emergent laminectomies at L3, L4, and L5 were performed, and intraoperative pathology revealed edematous epidural adipose tissue. The patient's cauda equina syndrome resolved after spinal decompression and the removal of epidural fat. Final cultures were negative for infection, and histology report yielded an accumulation of edematous fibroadipose tissue.

Conclusions

We present a case of rapid accumulation of edematous adipose tissue causing cauda equina syndrome after a lumbar decompression and fusion surgery. The acute nature and extensive development of the lipedema presented in this case indicate an intense inflammatory reaction. We hypothesize that there may be a link between the use of BMP-2 and the accumulation of this edematous tissue. A thorough understanding of the mechanisms of BMP-2 and specific guidelines for their role in spinal surgery may improve functional outcomes and reduce the number of preventable complications. To the best of our knowledge and after a thorough literature search, this is the only reported case of epidural lipedema causing cauda equina syndrome.     

Experimental anterior spine fusion using bovine bone morphogenetic protein: a study in rabbits

We developed an experimental model to study the merit of bovine bone morphogenic protein (bBMP) injection into the intervertebral disc to induce anterior interbody fusion. A total of 24 rabbits, divided into three groups of 8 animals each, were used. One hundred and fifty μg of partially purified bBMP was employed in the first group and 10 μg bBMP in the second group. In the control group, a sham operation was performed. The animals were followed radiographically at weekly intervals and animals were killed 3, 6, and 12 weeks postoperatively. After sacrifice, a mechanical and histologic evaluation of fusion was performed. Results of radiographic and histologic evaluation showed bone formation, which had resulted in the bridging of adjacent endplates, in the 150-μg group. In the 10-μg group, new bone formation was less extensive. In the control group, intradiscal bone formation was seen in only 1 animal. Range of motion measurements on flexion/extension films showed significantly decreased motion in segments that were fused with 150-μg of BMP. This study demonstrated the utility of an experimental model which allowed investigation of how anterior spine fusion may be further studied. Intradiscal injection of BMP could ultimately play a role in the development of minimally invasive techniques for anterior spinal fusion. Received for publication on Jan. 6, 1999; accepted on Aug. 18, 1999     

脊柱融合中应用BMP的并发症综述

骨形态发生蛋白(BMP)目前广泛使用于脊柱融合手术中以提高融合率。BMP只被批准用于腰椎前路手术,而实际临床中超范围使用。BMP的使用带来很多并发症,因此需要审视BMP在脊柱融合手术的价值以及安全性。认清BMP在脊柱融合手术中的并发症。同时展望未来,新的载体或者材料技术可能促进BMP在脊柱融合手术发挥优势,减少不良并发症。     

The use of bone morphogenetic protein in thoracolumbar spine procedures: analysis of the MarketScan longitudinal database

Background contextThe use of recombinant human bone morphogenetic protein (BMP) in the thoracolumbar spine remains controversial, with many questioning the risks and benefits of this new biologic.PurposeTo describe national trends, incidence of complications, and revision rates associated with BMP use in thoracolumbar spine procedures.Study design/settingAdministrative database study.Patient sampleA matched cohort of 52,259 patients undergoing thoracolumbar fusion surgery from 2006 to 2010 were identified in the MarketScan database. Patients without BMP treatment were matched 2:1 to patients receiving intraoperative BMP.Outcome measuresRevision rates and postoperative complications.MethodsThe MarketScan database was used to select patients undergoing thoracolumbar fusion procedures, with and without intraoperative BMP. We ascertained outcome measures using either International Classification of Disease, ninth revision, or Current Procedural Terminology coding, and matched groups were evaluated using a bivariate and multivariate analyses. Kaplan-Meier estimates of fusions failure rates were also calculated.ResultsPatients receiving intraoperative BMP underwent fewer refusions, decompressions, posterior and anterior revisions, or any revision procedure (single level 4.53% vs. 5.85%, p<.0001; multilevel 5.02% vs. 6.83%, p<.0001; overall cohort 4.73% vs. 6.09%, p<.0001). After adjusting for comorbidities, demographics, and levels of procedure, BMP was not associated with the postoperative development of cancer (odds ratio 0.92). Bone morphogenetic protein use was associated with an increase in any complication at 30 days (15.8% vs. 14.9%, p=.0065), which is only statistically significant among multilevel procedures (19.74% vs. 18.02%, p=.0013). Thirty-day complications in multilevel procedures associated with BMP use included new dysrhythmia (4.68% vs. 4.01%, p=.0161) and delirium (1.08% vs. 0.69%, p=.0024). A new diagnosis of chronic pain was associated with BMP use in both single-level (2.74% vs. 2.15%, p=.0019) and multilevel (3.7% vs. 2.52%, p<.0001) procedures. Bone morphogenetic protein was negatively associated with infection in single-level procedures (2.12% vs. 2.64%, p=.0067) and wound dehiscence in multilevel procedures (0.84% vs. 1.18%, p=.0167).ConclusionsIn national data analysis of thoracolumbar procedures, we found that BMP was associated with decreased incidence of revision spinal surgery and with a slight increased risk of overall complications at 30 days. Although no BMP-associated increased risk of malignancy was found, lack of long-term follow-up precludes detection of between-group differences in malignancies and other rare events that may not appear until later.     

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.     

Longer follow-up continues to reveal no increased risk of cancer with the use of recombinant human bone morphogenetic protein in spine fusion

BACKGROUND CONTEXTLarge observational studies on potential oncogenic effects of recombinant human bone morphogenetic protein (rhBMP) in spine fusion surgery are limited by relatively short follow-up times.PURPOSETo study the possible association between rhBMP and cancer risk in a long-term follow-up study.STUDY DESIGNA retrospective cohort study using a combination of the Washington State Comprehensive Hospital Abstract Reporting System, the Washington State Cancer Registry, State of Washington death certificates, and the Washington State Department of Licensing.PATIENT SAMPLEParticipants were adults age ≥21 years who underwent spine fusion surgery enhanced by rhBMP for degenerative spine disease between January 1, 2002 and December 31, 2010. A comparison group matching each patient receiving rhBMP with three patients not receiving rhBMP was created using the indicators of age, sex, and year of treatment. We excluded patients receiving spine fusion for vertebral fractures or infection, and those with a diagnosis of cancer before or at the index procedure.OUTCOME MEASURESThe primary outcome was the first diagnosis of any cancer as identified in the records of the state cancer registry or death certificate through the end of 2015.METHODSWe compared cancer risk between those receiving spine fusion with and without rhBMP using survival analysis. We calculated incidence rates (hazards) by computing the ratio of the number of events and total time at risk. Unadjusted hazard ratios (HR) and adjusted HR (aHR) and their respective 95% confidence intervals (CI) were calculated assuming a Cox proportional hazard regression model. We adjusted the model to include the site of surgery (lumbar vs. cervical) as a covariate as this differed in frequency between the two treatment groups. To assess whether rhBMP adversely affects the progression of cancer, we compared mortality between rhBMP users and nonusers in those who developed cancer. Research support toward this study was received from Medtronic Sofamor Danek USA. The investigators alone, and not Medtronic, were solely responsible for the design, conduct, analysis, and reporting of this study.RESULTSWe included 16,914 patients who had spine fusion, of whom 4,246 received rhBMP. During the study period, 1,342 patients were diagnosed with some form of cancer. The incidence rate was similar between the two groups: 11.2 per 1,000 person years in the rhBMP group and 10.4 per 1,000 person years in the non-rhBMP group, with an aHR of 0.96; 95% CI, 0.85 to 1.10. Similarly, rhBMP use was not associated with an increased risk of commonly occurring individual cancer types, nor with cancer specific mortality after a cancer diagnosis, aHR, 0.92; 95% CI, 0.69 to 1.22.CONCLUSIONSLong-term follow-up confirms previous findings that rhBMP application treated with elective spinal fusion did not result in an increased cancer risk in a large population of US adults.     

Complications with the use of bone morphogenetic protein 2 (BMP-2) in spine surgery

Background contextRecombinant human bone morphogenetic protein 2 (rhBMP-2) is a very potent osteogenic growth factor that has been used successfully in various spine fusions, obviating the need for autologous iliac crest bone graft harvest and therefore avoiding the associated morbidities.PurposeIn the past few years, a tremendous increase in rhBMP-2 usage was noted, and concerns regarding costs, benefits, and safety issues were raised by many. The goal of this work was to provide a comprehensive review of the adverse events and complications associated with use of rhBMP-2.Study designLiterature review.MethodsThis is a review of the current literature on the reported adverse events, complications, and concerns associated with rhBMP-2 use.ResultsThis article discusses the wide spectrum of adverse outcomes related to rhBMP-2 use in the lumbar and the cervical spine; retrograde ejaculation, antibodies formation, postoperative radiculitis, postoperative nerve root injury, ectopic bone formation, vertebral osteolysis/edema, dysphagia and neck swelling, hematoma formation, interbody graft lucency, and wound healing complications are reviewed. Cost-related concerns, dosage considerations, carrier types, and theoretical carcinogenesis concerns were also presented.ConclusionsDespite the excellent spinal fusion rates promoted by this powerful molecule, the increasingly reported adverse outcomes associated with bone morphogenetic protein usage have created real concerns. This article will provide the reader with a good understanding of the reported complications associated with rhBMP-2 use and ultimately help recognize its safety spectrum and limits for better clinical application.     

Augmentation of spinal fusion with bone morphogenetic protein in dogs

Bone morphogenetic protein (BMP) induces mesenchymal cells to differentiate into cartilage and bone. To investigate the action of BMP on the growth of host bed-derived bone in experimental spinal fusions, posterior intervertebral spinal fusions of the lower thoracic spine were performed in 13 mature mongrel dogs. Four different fusion methods were used at single intervertebral levels within each dog. Three levels in each dog were used as controls for the BMP level. The spinal columns were examined by radiohistomorphometric methods at three weeks, six weeks, and 12 weeks and showed the BMP level to have two to three times more new bone than control levels. At the BMP level, an increase in the amount of new bone was observed in the interval from three to 12 weeks, in contrast to a decrease seen at the control levels. Fusion was present in five of seven of the BMP levels compared with zero of seven, one of seven, and two of seven in the control levels. The BMP level exhibited an increased number and volume of areas of de novo cartilage and woven bone formation at all time intervals compared to all control levels. The polylactic acid polymer carrier was not resorbed and partially retained in the fusion site. The preliminary observations suggest that BMP may serve as a useful adjunct in spinal fusions, but research is required to find a rapidly degradable delivery system. The objective of BMP research is to augment the host bed capacity for bone generation and regeneration and to spare children and adults the pain and complications involved in removing excessive volumes of iliac crest bone grafts.     

Evaluation of carriers of bone morphogenetic protein for spinal fusion

STUDY DESIGN: Posterolateral lumbar transverse process fusion in a rabbit model was performed using two different carriers for recombinant human morphogenetic protein-2, one having a porous structure and the other being a Type I collagen sheet. OBJECTIVES: To compare the effectiveness of two different carriers for recombinant human morphogenetic protein-2 in achieving lumbar intertransverse process arthrodesis. SUMMARY OF BACKGROUND DATA: The application of osteoinductive growth factors at various anatomic sites, such as in long bones and spinal segments, has been performed experimentally by many researchers. Although many carriers of osteoinductive factors have been reported, the most effective carrier has not been established. We have reported the efficacy of sintered bovine bone, True Bone Ceramics, which is coated with Type I collagen as a carrier of recombinant human bone morphogenetic protein-2 in achieving lumbar intertransverse process arthrodesis. True Bone Ceramics is a crystallized form of bone minerals made from sintering bovine bone at high temperatures and possesses natural trabecular structure. The crystalline character of True Bone Ceramics is similar to that of artificial hydroxyapatite. In this study we focused on the structure of two different carriers to facilitate osteosynthesis in lumbar arthrodesis. METHODS: Fifty-four adult rabbits underwent bilateral lumbar intertransverse process arthrodesis at L4-L5. The animals were divided into five groups and had implants placed as follows: Group 1, autograft group, harvested autologous corticocancellous bone from the posterior iliac crest; Group 2, TBC group, True Bone Ceramics alone; Group 3, TBC-TBMP group, True Bone Ceramics coated with Type I collagen infiltrated with 100 microg of recombinant human bone morphogenetic protein-2; Group 4, collagen group, Type I collagen sheet; and Group 5, collagen-BMP group, implanted collagen sheet containing 100 microg of recombinant human bone morphogenetic protein-2. Spinal fusion was evaluated by radiographic analysis, manual palpation, biomechanical testing, and histologic examination at both 3 and 6 weeks after surgery. RESULTS: Radiographs in the TBC-TBMP group showed a continuous trabecular pattern within the intertransverse area at 3 weeks after surgery. The fusion mass in the intertransverse area was more prominent than in the other groups. At 3 weeks after surgery the TBC-TBMP group had higher fusion rates based on manual palpation, and the fusions showed significantly higher tensile strength and stiffness. The histologic findings in the TBC-TBMP group at 3 weeks after surgery showed a cortical bone rim around the edge of the fusion mass, and contiguous new bone appearing between the recipient bone and the matrix of TBC without evidence of foreign body formation. In the collagen-BMP group, less mature bone formation was present within the grafted area and the new bone was not contiguous, even at 6 weeks after surgery. CONCLUSIONS: As a carrier for recombinant human bone morphogenetic protein-2, True Bone Ceramics, possessing a bony or porous structure, was more effective than a Type I collagen sheet in achieving a faster and stronger lumbar spinal fusion in a rabbit model.     

The use of osteo-conductive stem-cells allograft in lumbar interbody fusion procedures: an alternative to recombinant human bone morphogenetic protein

The use of autogenous bone graft in spinal fusion is progressively declining. Different allografts including the human bone morphogenetic protein have been proposed to facilitate fusion rates but are associated with various adverse effects. Osteocel belongs to a new class of allograft tissue material that is a re-absorbable biomaterial with allogenic mesenchymal stem cells. The purpose of the present retrospective study was to analyze the clinical effectiveness of mesenchymal stem cells allograft (Osteocel") to achieve radiological arthrodesis in adult patients undergoing lumbar interbody fusion surgery for different indications. Fifty-two consecutive patients received lumbar interbody fusion at one (69%) or two contiguous (31%) levels of lumbar spine for various indications. The mean age was 50 (range, 27 to 77) years; 60% were females; 43% were habitual smokers and 21% had previously failed surgery at the index level(s). Outcome measures: Radiographic analyses of fusion by plain films and CT scans. Procedures performed were circumferential fusion (67%), ALIF (17%) and TLIF (16%). Followup radiographic data was analyzed to establish arthrodesis versus failure (pseudarthrosis), number of months until achievement of fusion, and possible factors affecting the fusion rate. Followup ranged from 8 to 27 (median, 14) months. Solid arthrodesis was achieved in 92.3% of patients at median followup time of 5 months (95% Cl; range, 3 to 11 months). Kaplan-Meier survival curves and Mantle-Cox test were conducted to assess the effect of various factors on the rate of fusion. Statistics showed that increasing age (older than 50 years) (p = 0.017) and habitual smoking (p = 0.015) delayed the fusion time and increased the risk of pseudarthrosis. The use of Osteocel allograft is safe and effective in adult patients undergoing lumbar interbody spinal fusion procedure. Increased age and habitual smoking delays fusion but gender, previous surgery at the index level, type of procedure and number of levels do not affect the fusion rates.     

The use of bone morphogenetic protein 7 in fracture non‐unions

Objective: To assess the rate of clinical and radiological union with the use of bone morphogenetic protein 7 (BMP‐7) in a range of fractures. Methods: This case series retrospectively reviews a series of 16 fracture non‐unions in 13 patients. These patients were treated with the commercially available BMP‐7. Time to radiological and clinical union was assessed by serial out‐patient follow‐up. Results: At nine months post‐surgery in which BMP‐7 was added, 12 of 16 non‐unions had achieved clinical and radiographic union. Three patients required repeat grafting. The mean time to union was 5.1 ± 1.6 months after the application of BMP‐7. Conclusion: The use of the osteo‐inductive agent, BMP‐7 results in good clinical and radiological outcomes which are not restricted to tibial non‐unions.