The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study

Abstract

Background context

Although autogenous bone is still considered to be the gold standard graft material for promoting spinal fusion, other bone graft substitutes have been developed in an attempt to improve arthrodesis rates and avoid the complications associated with the procurement of autograft. The bone morphogenetic proteins (BMPs) represent a family of osteoinductive growth factors that are known to stimulate the osteoblastic differentiation of stem cells. Osteogenic protein-1 (OP-1) Putty is a commercially available BMP preparation that is already approved for use in humans. Previous clinical studies involving patients with degenerative spondylolisthesis have reported that the efficacy and safety of OP-1 Putty is comparable to that of autograft at both 1- and 2-year follow-up.

Purpose

The purpose of this study was to evaluate the intermediate-term efficacy and safety of OP-1 Putty as an alternative to autogenous bone by comparing the 4-year radiographic, clinical, and safety data of these same patients who underwent decompression and uninstrumented fusion with either OP-1 Putty or iliac crest autograft.

Study design/setting

A prospective, randomized, controlled, multicenter clinical pilot study.

Patient sample

Thirty-six patients undergoing decompressive laminectomy and single-level uninstrumented fusion for degenerative spondylolisthesis and symptomatic spinal stenosis were randomized in a 2:1 fashion to receive either OP-1 Putty (24 patients) or autogenous iliac crest bone graft (12 patients).

Outcome measures

Patient-reported outcome measures consisting of Oswestry Disability Index and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) scores were used to evaluate clinical efficacy. Perioperative data including operative time, estimated blood loss, and duration of hospital stay were also recorded for each surgery. Postoperatively, a neurological examination and an assessment of donor-site pain (if applicable) were performed at every follow-up visit. Radiographic fusion success was defined as the presence of continuous bridging bone formation between the transverse processes at the level of the spondylolisthesis with minimal motion evident on dynamic lateral x-ray films. The primary efficacy endpoint was the overall success rate, a composite measure derived from both radiographic and clinical parameters. The safety of OP-1 Putty was confirmed by comparing the nature and frequency of all adverse events and complications that were prospectively observed in either of the groups.

Methods

Thirty-six patients with degenerative spondylolisthesis and symptoms of neurogenic claudication underwent decompressive laminectomy and single-level uninstrumented fusion with either OP-1 Putty or autograft. All patients were evaluated at 6 weeks and 3, 6, 9, 12, and 24 months, after which time they were instructed to return on a yearly basis. Multiple neuroradiologists blinded to the assigned treatment reviewed static and dynamic X-ray films with digital calipers to assess fusion status according to the presence of continuous bridging bone across the transverse processes as well as the amount of residual motion evident at the level of interest. Oswestry Disability Index surveys and SF-36 questionnaires were used to assess clinical outcomes.

Results

At the 48-month time point, complete radiographic and clinical data were available for 22 of 36 patients (16 OP-1 Putty and 6 autograft) and 25 of 36 patients (18 OP-1 Putty and 7 autograft), respectively. Radiographic evidence of a solid arthrodesis was present in 11 of 16 OP-1 Putty patients (68.8%) and 3 of 6 autograft patients (50%). Clinically successful outcomes defined as at least a 20% improvement in preoperative Oswestry scores were experienced by 14 of 19 OP-1 Putty patients (73.7%) and 4 of 7 autograft patients (57.1%); these clinical findings were corroborated by similar increases in SF-36 scores. The respective overall success rates of the OP-1 Putty and autograft group were 62.5% and 33.3%. In this study, there were no incidents of local or systemic toxicity, ectopic bone production, or other adverse events directly related to the use of OP-1 Putty.

Conclusion

Despite the challenges associated with obtaining a solid uninstrumented fusion in patients with degenerative spondylolisthesis, the rates of radiographic fusion, clinical improvement, and overall success associated with the use of OP-1 Putty were at least comparable to that of the autograft controls for at least 48 months after surgery. These results appear to validate the short-term results previously reported for OP-1 Putty and suggest that this material may potentially represent a viable bone graft substitute for certain fusion applications.

Introduction

The most common surgical procedure for symptomatic spinal stenosis secondary to degenerative spondylolisthesis is lumbar decompression and posterolateral arthrodesis. Even with the use of autogenous bone graft, pseudarthrosis has been reported to be a common complication after this type of surgical treatment [1], [2], [3]. In addition, the procurement of iliac crest autograft for spinal fusions may also result in significant donor-site morbidity in as many as 25% of these cases [4], [5], [6], [7]. Supplemental instrumentation may increase the rate of radiographic healing relative to that of uninstrumented fusions by minimizing the motion between adjacent vertebrae [2], [3], [8], [9]; however, the implantation of adjunctive internal fixation has not eliminated the risk of pseudarthrosis and its effects on clinical outcomes remain controversial [10], [11], [12], [13].

Although autogenous bone is still considered to be the gold standard graft material for promoting successful arthrodesis of the spine, a number of bone graft extenders and substitutes have been developed in an attempt to improve fusion rates and avoid the complications associated with the harvesting of autograft. Since their discovery by Marshall Urist in 1965, the bone morphogenetic proteins (BMPs) have been distinguished by their ability to induce ectopic bone formation when implanted in extraosseous tissues [14], [15]. The BMPs are members of the transforming growth factor-β superfamily of cytokines that have been shown to stimulate the osteoblastic differentiation of pluripotential mesenchymal stem cells by binding to cell-surface receptors and activating intracellular signal transduction cascades [16]. The potent osteoinductive properties of the BMPs have generated significant interest in their use as an alternative to autogenous bone for a variety of orthopedic applications, including fracture healing and spinal fusion [17].

Osteogenic protein-1 (OP-1), also known as BMP-7, represents one of the two commercially available preparations currently approved for clinical practice. The osteoinductive potential and safety profile of recombinant human OP-1 (rhOP-1) have been validated by a number of different animal models, and collectively the results of these preclinical studies have established rhOP-1 as a viable replacement for autograft [17], [18], [19], [20], [21], [22], [23], [24]. In 2001, a rhOP-1 product received a Humanitarian Device Exemption from the United States Food and Drug Administration (FDA) for use as a substitute for autogenous bone in patients with recalcitrant long bone fracture nonunions.

The effects of rhOP-1 in the posterolateral spine have also been assessed by multiple human clinical trials [25], [26], [27], [28], [29]. In one prospective, randomized, controlled, multicenter pilot study conducted under an Investigational Device Exemption granted by the FDA, patients with degenerative spondylolisthesis and neurogenic claudication undergoing laminectomy and single-level uninstrumented posterolateral arthrodesis were treated either with iliac crest autograft or OP-1 Putty (Stryker Biotech, Hopkinton, MA) [25], [26]. At a minimum 2-year follow-up, the subjects receiving OP-1 Putty showed radiographic and clinical outcomes at least equivalent to those in the autograft cohort, and no specific OP-1 implant-related adverse events were reported. However, because the success of fusions may progressively deteriorate over time, these individuals were followed for several years after their surgical procedures to determine whether the initially favorable results were ultimately maintained. The purpose of this study was to evaluate the long-term safety and efficacy of OP-1 Putty as an alternative to autogenous bone for uninstrumented posterolateral fusion in this same patient population; these objectives were accomplished by comparing the radiographic and clinical outcomes as well as the respective complication rates of the OP-1 Putty and control groups.