A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned

This review analyzes the literature of bone grafts and introduces tissue engineering as a strategy in this field of orthopedic surgery. We evaluated articles concerning bone grafts; analyzed characteristics, advantages, and limitations of the grafts; and provided explanations about bone-tissue engineering technologies. Many bone grafting materials are available to enhance bone healing and regeneration, from bone autografts to graft substitutes; they can be used alone or in combination. Autografts are the gold standard for this purpose, since they provide osteogenic cells, osteoinductive growth factors, and an osteoconductive scaffold, all essential for new bone growth. Autografts carry the limitations of morbidity at the harvesting site and limited availability. Allografts and xenografts carry the risk of disease transmission and rejection. Tissue engineering is a new and developing option that had been introduced to reduce limitations of bone grafts and improve the healing processes of the bone fractures and defects. The combined use of scaffolds, healing promoting factors, together with gene therapy, and, more recently, three-dimensional printing of tissue-engineered constructs may open new insights in the near future.

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Bone regenerative medicine: classic options, novel strategies, and future directions

Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

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.

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

Results of the prospective, randomized, controlled multicenter Food and Drug Administration investigational device exemption study of the ProDisc-C total disc replacement versus anterior discectomy and fusion for the treatment of 1-level symptomatic cervical disc disease

Study Design/Setting. Independent, retrospective clinical record review with a concurrent control. Objective. To identify whether rhBMP-2 is associated with an increased incidence of clinically relevant postoperative prevertebral swelling problems in patients undergoing anterior cervical fusions. of Background Data. Bone Morphogenetic Protein-2 (rhBMP-2) is FDA approved as a bone graft substitute in anterior lumbar interbody fusions. rhBMP-2 has also been used "off-label" in anterior cervical fusions. We suspected that rhBMP-2 might increase the incidence of adverse swelling events. Methods. A total of 234 consecutive patients (ages 12-82 years) undergoing anterior cervical fusion with and without rhBMP-2 over a 2-year period at one institution comprised the study population. The incidence of clinically relevant prevertebral swelling was calculated. The populations were compared and statistical significance was determined. Results. A total of 234 patients met the study criteria, 69 of whom underwent anterior cervical spine fusions using rhBMP-2; 27.5% of those patients in the rhBMP-2 group had a clinically significant swelling event versus only 3.6% of patients in the non-rhBMP-2 group. This difference was statistically significant (P < 0.0001) and remained so after controlling for other significant predictors of swelling. Conclusions. Off-label use of rhBMP-2 in the anterior cervical spine is associated with an increased rate of clinically relevant swelling events.

Increased swelling complications associated with off-label usage of rhBMP-2 in the anterior cervical spine.

STUDY DESIGN A total of 115 patients were randomized in a 1:1 ratio to a Bryan artificial disc replacement (56) or an anterior cervical fusion with allograft and a plate (59). OBJECTIVE The purpose of this study is to examine the functional outcome and radiographic results of this prospective, randomized trial to determine the role of the Bryan artificial cervical disc replacement for patients with 1-level cervical disc disease. SUMMARY OF BACKGROUND DATA Artificial cervical disc replacement has become an option for cervical radiculopathy. Previous studies have evaluated the efficacy of this alternative without the scientific rigor of a concurrent control population. This study is a pooled data set from 3 centers involved in the U.S. FDA Investigational Device Exemption trial evaluating the Bryan artificial cervical disc. METHODS The purpose of this study is to examine the functional outcome and radiographic results of this prospective, randomized trial to determine the role of the Bryan artificial cervical disc replacement for patients with 1-level cervical disc disease; 12-month follow-up is available for 110 patients and 24 month follow-up complete for 99 patients. There are 30 males and 26 females in the Bryan group and 32 males and 27 females in the fusion group. The average age was 43 years (Bryan) and 46 years (fusion). Disability and pain were assessed using the Neck Disability Index (NDI) and the Visual Analog Scale (VAS) of the neck and of the arm pain. SF-36 outcome measures were obtained including the physical component as well as the mental component scores. Range of motion was determined by independent radiologic assessment of flexion-extension radiographs. We report a prospective, randomized study comparing the functional outcome of cervical disc replacement to an anterior cervical fusion with results of 99 patients at 2 years. Prospective data were collected before surgery and at 6 weeks, 3, 6, 12, and 24 months after surgery. RESULTS The average operative time for the control group was 1.1 hours and the Bryan Group 1.7 hours. Average blood loss was 49 mL (control) and 64 mL (Bryan). Average hospital stay was 0.6 days (control) and 0.9 days (Bryan). The mean NDI before surgery was not statistically different between groups: 47 (Bryan) and 49 (control). Twelve-month follow-up NDI is 10 (Bryan) and 18 (control) (P = 0.013). At 2-year follow-up, NDI for the Bryan group is 11 and the control group is 20 (P = 0.005). The mean arm pain VAS before surgery was 70 (Bryan) and 71 (control). At 1-year follow-up, Bryan arm pain VAS was 12 and control 23 (P = 0.031). At 2-year follow-up, the average arm pain VAS for the Bryan group was 14 and control 28 (P = 0.014). The mean neck pain VAS before surgery was 72 (Bryan) and 73 (control). One-year follow-up scores were 17 (Bryan) and 28 (control) (P = 0.05). At 2 years: 16 (Bryan) and 32 (control) (P = 0.005). SF-36 scores: Physical component--Before surgery Bryan 34 and control 32. At 24 months: Bryan 51 and control 46 (P = 0.009). More motion was retained after surgery in the disc replacement group than the plated group at the index level (P < 0.006 at 3, 6, 12, and 24 months). The disc replacement group retained an average of 7.9 degrees of flexion-extension at 24 months. In contrast, the average range of motion in the fusion group was 0.6 degrees at 24 months. There were 6 additional operations in this series: 4 in the control group and 2 in the investigational group. There were no intraoperative complications, no vascular or neurologic complications, no spontaneous fusions, and no device failures or explantations in the Bryan cohort. CONCLUSION The Bryan artificial disc replacement compares favorably to anterior cervical discectomy and fusion for the treatment of patients with 1-level cervical disc disease. At the 2-year follow-up, there are statistically significant differences between the groups with improvements in the NDI, the neck pain and arm pain VAS scores, and the SF-36 physical component score in the Bryan disc population.

Artificial disc versus fusion: a prospective, randomized study with 2-year follow-up on 99 patients.

IntroductionThis 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 a

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.

Validation of a C2-C7 cervical spine finite element model using specimen-specific flexibility data

Study design Prospective, randomized, single-center, clinical trial. Objective To prospectively examine the 7- and 10-year outcomes of cervical arthroplasty to anterior cervical discectomy and fusion (ACDF). Summary of background data Degeneration of the cervical discs causing radiculopathy is a frequent source of surgical intervention, commonly treated with ACDF. Positive clinical outcomes are associated with arthrodesis techniques, yet there remains a long-term concern for adjacent segment change. Cervical disc arthroplasty has been designed to mitigate some of the challenges associated with arthrodesis whereas providing for a similar positive neurological outcome. As data has been collected from numerous prospective US FDA IDE trials, longer term outcomes regarding adjacent segment change may be examined. Methods As part of an FDA IDE trial, a single center collected prospective outcomes data on 47 patients randomized in a 1:1 ratio to ACDF or arthroplasty. Results Success of both surgical interventions remained high at the 10-year interval. Both arthrodesis and arthroplasty demonstrated statistically significant improvements in neck disability index, visual analog scale neck and arm pain scores at all intervals including 7- and 10-year periods. Arthroplasty demonstrated an advantage in comparison to arthrodesis as measured by final 10-year NDI score (8 vs. 16, P = 0.0485). Patients requiring reoperation were higher in number in the arthrodesis cohort (32%) in comparison with arthroplasty (9%) (P = 0.055). Conclusion At 7 and 10 years, cervical arthroplasty compares favorably with ACDF as defined by standard outcomes scores in a highly selected population with radiculopathy. Level of evidence 1.

Joseph D. Smucker

Papers

Increased swelling complications associated with off-label usage of rhBMP-2 in the anterior cervical spine.

Artificial disc versus fusion: a prospective, randomized study with 2-year follow-up on 99 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.

Validation of a C2-C7 cervical spine finite element model using specimen-specific flexibility data

Long-term Clinical Outcomes of Cervical Disc Arthroplasty: A Prospective, Randomized, Controlled Trial.