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

Abstract

Background context

Recombinant 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.

Purpose

In 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 design

Literature review.

Methods

This is a review of the current literature on the reported adverse events, complications, and concerns associated with rhBMP-2 use.

Results

This 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.

Conclusions

Despite 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.

Introduction

In 1965, Marshall Urist discovered the bone morphogenetic protein (BMP) [1], a class of growth factors belonging to the transforming growth factor-β family [2]. Numerous types of BMP molecules have been discovered; however, few have been involved in osteoblast differentiation and bone development [3].

Recombinant human bone morphogenetic protein 2 (rhBMP-2) (InFUSE; Medtronic Sofamor Danek, Memphis, TN, USA) is a commercially available form and currently approved by the U.S. Food and Drug Administration (FDA) for use in the anterior lumbar interbody fusion (ALIF) within a titanium tapered cage [4], [5].

Multiple studies on ALIFs by Burkus et al. reported excellent fusion rates, decreased operative time, lower blood loss, and shorter hospital stay with the use of rhBMP-2 compared with autologous iliac crest bone graft (ICBG) [4], [5], [6].

Besides its application in ALIF, all other uses of rhBMP-2 are considered off label [4], [6], [7], [8], [9], [10].

A meta-analysis looked at the benefits of rhBMP-2 in promoting posterolateral fusion. The authors reported significantly lower rates of fusion failures, shorter hospitalization, and less blood loss with the use of BMP-2 compared with autologous ICBG [11].

Even in smokers, Glassman reported the superiority of BMP-2 (95%) over autologous ICBG (76%) in promoting solid posterolateral lumbar fusion at a single level, after 2 years follow-up [12].

Similarly, other investigators reported 95% to 100% successful arthrodesis with the use of BMP-2 in posterior lumbar interbody fusion (PLIF) [7], [8], [13].

Additionally, the role of BMP-2 in promoting arthrodesis, as a substitute for ICBG in patients with multilevel spinal deformity, was investigated by Mulconrey et al. At 2-year follow-up, the investigators concluded that the use of rhBMP-2 eliminated the necessity for ICBG and yielded an excellent fusion rate [14].

Recent systematic reviews questioned the effectiveness and advantages of BMP-2 over ICBG as previously reported by the industry-sponsored trials. Reviews and investigations from the Yale University Open Data base Project, the Medtronic internal reports, the FDA reports, and a thorough literature search concluded that there are no clear advantages of BMP-2 use in spine fusion over bone graft, and even more serious adverse events were found to be associated with BMP-2 use; therefore, clear indications for BMP-2 use and its safety were precluded [15], [16].