Bone morphogenetic proteins are low molecular weight proteins which have extensive similarity in structure and function to the transforming growth factor beta factors. They bind receptors on the surface of osteoprogenitor stem cells and activate intracellular signal transduction cascades resulting in the osteoblastic differentiation of pluripotential stem cells.

Bone morphogenetic proteins (BMP) are being increasingly used in orthopaedic surgery including spinal fusion. These small molecules are capable of inducing bone formation when delivered in the appropriate concentration and on the appropriate scaffold. Recombinant BMP usually is combined with an osteoconductive carrier to form a composite graft. The osteoconductive carrier not only supports cellular adhesion but restricts the diffusion of these soluble factors away from the fusion site increasing local concentration of BMP. There is currently no consensus as to the ideal carrier but the optimal carrier may be dependent upon the specific clinical application for which it is used. In addition osteogenic cells that are able to respond to these osteoinductive signals must also be present for a successful spinal fusion to occur.

Not all BMPs are equally effective. Over 15 BMPs have been identified and there are currently only two Food and Drug Administration (FDA)-approved BMPs (BMP-2 with a full PMA approval and BMP-7 with an HDE approval).

Recombinant BMPs have been used successfully in anterior lumbar interbody fusions. Multiple animal studies have shown recombinant human BMP to be superior to autograft in the cervical, thoracic and lumbar spine, while human clinical trials have also shown recombinant human BMP-2 to be superior to autograft for anterior fusion. Similarly, multiple animal studies and clinical trials have shown that recombinant human BMPs result in equivalent or superior fusion rates for posterior spinal fusion compared to autograft. The use of BMPs may obviate the need for decortication and overcome the negative effects of nicotine and anti-inflammatories

In all studies, the concentration of BMPs necessary to produce successful spinal fusion was substantially greater than physiological levels, raising several potential safety concerns including bony overgrowth and bone formation which may lead to neural compression or unintended extension of the fusion. There are also the risks of local toxicity and a host immunologic response. These potential complications related to off-label use of BMPs need to be understood. For this reason, it is essential to determine the appropriate dose for each clinical application and develop efficient carrier systems.

There are economic concerns associated with the use of this new technology. A single treatment of recombinant human BMP is expensive but may be cost effective if clinical outcomes are improved or other costs are avoided. The increased cost of BMP may offset the complications associated with harvesting autograft bone. When used properly, these molecules have the potential to eliminate the need for iliac crest bone graft harvest and improve the speed and success of spinal fusion.

Purpose: Interbody fusion cages have met with great success as an adjunct in the treatment of painful degenerative disc disease. One of the limitations is the need for the use of autogenous cancellous bone graft. In preclinical studies recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered in a variety of carriers has been shown to be an effective substitute for autogenous bone, resulting in more rapid and reliable healing than that seen in control groups. The goal of this study was to report the early results of the first human trial attempting to use rhBMP-2 in interbody fusion cages.

Methods: This study was an FDA approved IDE multicenter pilot study. From 1/97 to 4/97, 14 patients were entered into a prospective, randomized trial. All patients had single level lumbar degenerative disc disease that was refractory to prolonged nonoperative care and were candidates for anterior interbody fusion of L4-5 or L5-S1. After consent, patients were randomized to either the control group (N-3) and received autogenous bone inside tapered titanium fusion cages (NOVUS LT, Sofamor Danek Memphis, TN) or to the investigational group (N = 11) and received rhBMP-2 (1.5 mg/ml)(Genetics Institute, Cambridge MA) delivered in a collagen sponge (Helistat, Integra Life Sciences, Plainsboro, NJ) inside the fusion cages. Depending on the size, the sponge in each cage was soaked with from 1.3 to 2.6 ml of the rhBMP2 solution. Patients were followed at regular intervals with plain x-ray, CT scan with reconstruction, and a full panel of blood tests. Radiographs were reviewed by an independent blinded radiologist with fusion defined as < 5 degrees of sagittal motion, absence of radiolucent lines, and presence of continuous bone through the cages. Clinical results were assessed using an outcomes questionnaire including the SF-36 general health status and Oswestry low back specific instruments.

Results: All 14 patients were available for 1-year follow-up. No cages displaced and no further surgeries were required. Mean hospital stay was 2.0 days for the rhBMP-2 patients compared to 3.3 days for the autograft controls. Of the 11 rhBMP2 patients, 10 of 11 were judged to be fused at 3 months. At 6 months and 1-year all 11 rhBMP-2 patients were noted to have a solid arthrodesis. Of the 3 control patients, 2 had solid arthodesis and one had an apparent nonunion at 1 year. On sagittal CT scan reconstruction new bone growth was seen throughout and anterior to the cages that were filled with rhBMP-2. No patients had bone formation outside of the desired area. The control patient with the nonunion had a halo surrounding the cage on the sagittal CT reconstruction. This patient had persistence of low back pain. Compared to preop, the Oswestry scores at 3 months were decreased in the rhBMP-2 group (39 to 30) compared to controls which were increased (35 to 43) and both mean scores were similar at 6 months (28 and 27). Conclusion: The preliminary results from this clinical trial with rhBMP-2 inside interbody fusion cages were excellent and support a larger pivotal trial. The arthrodesis was found to occur more rapidly and reliably than in the controls, although the sample size was limited. In addition to faster bone healing, a major advantage was the elimination of bone graft donor site morbidity and realization of decreased hospital stay. No evidence of excessive bone formation or systemic complications occurred. Moreover, this study provides one of the first demonstrations of consistent and unequivocal osteoinduction by a recombinant growth factor in humans.