Use of Recombinant Human Bone Morphogenetic Protein-2 to Achieve Posterolateral Lumbar Spine Fusion in Humans

Scott D. Boden, MD, James Kang, MD, Harvinder Sandhu, MD, John G. Heller, MD

Disclosures

Spine. 2002;27(23) 

In This Article

Abstract and Introduction

Study Design: A prospective randomized clinical study was conducted.
Objective: To determine whether the dose and carrier that were successful in rhesus monkeys could induce consistent radiographic spine fusion in humans.
Summary of Background Data: Preclinical studies have demonstrated that recombinant human bone morphogenetic protein-2 (rhBMP-2), an osteoinductive bone morphogenetic protein, is successful at generating spine fusion in rabbits and rhesus monkeys.
Methods: For this study, 25 patients undergoing lumbar arthrodesis were randomized (1:2:2 ratio) based on the arthrodesis technique: autograft/Texas Scottish Rite Hospital (TSRH) pedicle screw instrumentation (n = 5), rhBMP-2/TSRH (n = 11), and rhBMP-2 only without internal fixation (n = 9). On each side, 20 mg of rhBMP-2 were delivered on a carrier consisting of 60% hydroxyapatite and 40% tricalcium phosphate granules (10 cm3/side). The patients had single-level disc degeneration, Grade 1 or less spondylolisthesis, mechanical low back pain with or without leg pain, and at least 6 months failure of nonoperative treatment.
Results: All 25 patients were available for follow-up evaluation (mean, 17 months; range 12-27 months). The radiographic fusion rate was 40% (2/5) in the autograft/TSRH group and 100% (20/20) with rhBMP-2 group with or without TSRH internal fixation (P = 0.004). A statistically significant improvement in Oswestry score was seen at 6 weeks in the rhBMP-2 only group (-17.6; P = 0.009), and at 3 months in the rhBMP-2/TSRH group (-17.0; P = 0.003), but not until 6 months in the autograft/TSRH group (-17.3; P = 0.041). At the final follow-up assessment, Oswestry improvement was greatest in the rhBMP-2 only group (-28.7, P > 0.001). The SF-36 Pain Index and PCS subscales showed similar changes.
Discussion: This pilot study is the first with at least 1 year of follow-up evaluation to demonstrate successful posterolateral spine fusion using a BMP-based bone graft substitute, with radiographs and CT scans as the determinant. Consistently, rhBMP-2 was able to induce bone in the posterolateral lumbar spine when delivered at a dose of 20 mg per side with or without the use of internal fixation. Patients with spondylolisthesis classified higher than Meyerding Grade 1 or with more than 5 mm of translational motion may still require internal fixation. Some patients did smoke during the postoperative period, and all in the rhBMP-2 groups still obtained solid fusions.
Conclusions: Consistently, rhBMP-2 with the biphasic calcium phosphate granules induced radiographic posterolateral lumbar spine fusion with or without internal fixation in patients whose spondylolisthesis did not exceed Grade 1. Statistically greater and quicker improvement in patient-derived clinical outcome was measured in the rhBMP-2 groups.

The two primary drawbacks in performing a spinal arthrodesis are the morbidity of harvesting autogenous iliac crest bone graft[1,2,23] and the relatively high frequency of pseudarthrosis. Although various bone graft substitutes have had limited success in the arthrodesis of adolescents with thoracic deformities, there is not yet a proven bone graft substitute for spine arthrodesis in adults with degenerative spinal conditions such as spondylolisthesis.[9] As a result, an intensive search continues for extenders, enhancers, and substitutes for autogenous bone graft suitable for spinal arthrodesis.[3]

An exciting bone graft substitute candidate includes the family of growth factors called bone morphogenetic proteins (BMPs).[52,56] It has been more than 35 years since the concept of a bone morphogenetic protein was described by Urist et al.[49,50,51,52] It has been more than 13 years since the first BMPs were isolated, cloned, and sequenced.[42,43,53,57] Despite this considerable time span, there is yet to be a commercially prepared product containing highly purified or recombinant BMP available for general clinical use. Early studies with recombinant BMPs and purified BMP extracts were successful in a variety of rodent models, yet early clinical trials, some of which were not published, resulted in disappointing outcomes.[4,28,31] Recombinant human BMP-7 has demonstrated variable success in rodents.[17,18,24,32] Ne-Osteo, a bovine-derived mixture of BMPs, has demonstrated consistent bone induction in a rodent model of spine fusion.[7,10,11,12,46] Recombinant human BMP-2 (rhBMP-2) has demonstrated consistent success in rodents and in nonhuman primates.[8,26,33,45]

In retrospect, the early clinical failures with BMPs likely resulted from suboptimal carrier matrices used to deliver the BMP and a failure to recognize the requirement for the substantially increased doses of BMP needed to induce bone formation in nonhuman primates, as compared with rodents.[11,34] To date, only one clinical pilot study using a BMP has shown its ability to induce bone consistently in the anterior lumbar spine in humans, and we know of no published study testing BMP in the posterolateral lumbar spine.[13] The purpose of this investigation was to determine whether the dose and carrier for rhBMP-2, which was successful in rhesus monkeys, can induce consistent radiographic spine fusion in humans, and to determine which patient-derived outcomes measurements were most appropriate for performing such trials.

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