Study design: A review was conducted.
Objective: To determine the safety profiles of human recombinant bone morphogenetic protein-2 (rhBMP-2) and osteogenic protein-1 (OP-1) used clinically in spine applications.
Summary of background data: Safety issues associated with the use of bone morphogenetic proteins in spine applications include the possibility of bony overgrowth, interaction with exposed dura, cancer risk, systemic toxicity, reproductive toxicity, immunogenicity, local toxicity, osteoclastic activation, and effects on distal organs. These issues have been given detailed examination in both human and animal studies, and safety data are available for both rhBMP-2 and OP-1. The safety data available for OP-1 are less detailed.
Methods: The study involved reviews of published reports and the safety data submitted to the Food and Drug Administration (rhBMP-2 and OP-1) and to the European Agency for the Evaluation of Medicinal Products (OP-1), as well as personal communication with the manufacturers of rhBMP-2 (Medtronic Sofamore Danek, Memphis, TN) and OP-1 (Stryker Biotech, Hopkinton, MA).
Results: Application of either rhBMP-2 or OP-1 to raw decorticated bony surfaces leads to new bone formation, which is desirable in the intertransverse or interbody regions. However, new bone formation also may occur if rhBMP-2 or OP-1 comes in contact with laminectomy sites or decompressed neuroforamina, and may lead to restenosis. Inadvertent placement of either rhBMP-2 or OP-1 in the spinal canal leads to formation of bone. Leakage of rhBMP-2 or OP-1 outside the fusion area may lead to adjacent-level fusion. Accurate placement of these factors and adequate retention by their carrier are highly important factors in minimizing these problems. Subdural bone formation occurs if OP-1 is implanted directly beneath the dura. Osteoclastic overstimulation does not appear to be a significant problem with rhBMP-2. However, bone resorption has been associated with OP-1 used in the setting of thoracolumbar fractures. Findings show that RhBMP-2 has an antiproliferative effect on many cancer cells, and no evidence exists that it is carcinogenic. It is unlikely that OP-1 has carcinogenic potential, although fewer data are available. Systemic and local toxicity, significant adverse effects, and harmful effects on distant organs have not been observed in either human or animal studies on rhBMP-2 and OP-1. The benign safety profile of rhBMP-2 may result from its rapid systemic clearance, which results in very little systemic exposure. Systemic exposure to OP-1 also is low. No reproductive toxicity has been observed with either rhBMP-2 or OP-1. However, there is no human safety data. Subclinical immune responses in human subjects to collagen carriers have been reported. Antibody responses to rhBMP-2 have been detected in less than 1% of spine patients. Low titer immune responses have been observed in 38% of patients treated with OP-1. There were no associated clinical adverse effects.
Conclusions: Given the available data, both rhBMP-2 and OP-1 appear to be safe provided they are used appropriately, placed accurately, not allowed to come into contact with decompressed areas, and contained in the region of fusion. They must be used with caution in the presence of dural defects.