Cancer Risk After Use of Recombinant Bone Morphogenetic Protein-2 for Spinal Arthrodesis

Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Pavilion C, 4th Floor, Redwood City, CA 94063. E-mail address for E.J. Carragee: .
The Journal of Bone and Joint Surgery (Impact Factor: 5.28). 09/2013; 95(17):1537-45. DOI: 10.2106/JBJS.L.01483
Source: PubMed

ABSTRACT Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a growth factor known to have in vitro effects on the growth and invasiveness of cancer. It has been approved by the U.S. Food and Drug Administration in limited doses for single-level anterior spinal arthrodesis, but it is commonly used off-label and at high doses. The effect of rhBMP-2 on the risk of cancer has been a concern. We sought to evaluate the risk of new cancers in patients receiving high-dose rhBMP-2.
We used publicly available data from a pivotal, multicenter, randomized controlled trial of patients with degenerative lumbar spine conditions who underwent a single-level instrumented posterolateral arthrodesis with either high-dose rhBMP-2 in a compression-resistant matrix (CRM) (rhBMP-2/CRM; n = 239) or autogenous bone graft (control group; n = 224). We compared the risks of new cancers in the rhBMP-2/CRM and control groups at two and five years after surgery.
At two years, with 86% follow-up, there were fifteen new cancer events in eleven patients in the rhBMP-2/CRM group compared with two new cancer events in two patients in the control group treated with autogenous bone graft. The incidence rate of new cancer events per 100 person-years was 3.37 (95% confidence interval [CI], 1.89 to 5.56) in the rhBMP-2/CRM group at two years compared with 0.50 (95% CI, 0.06 to 1.80) in the control group. The incidence rate ratio was 6.75 (95% CI, 1.57 to 60.83; p = 0.0026) at two years. Calculated in terms of the number of patients with one or more cancer events two years after the surgery, the incidence rate per 100 person-years was 2.54 (95% CI, 1.27 to 4.54) in the rhBMP-2/CRM group compared with 0.50 (95% CI, 0.06 to 1.82) in the control group at two years; the incidence rate ratio was 5.04 (95% CI, 1.10 to 46.82; p = 0.0194). At five years, there was a 37% loss of follow-up, but a significantly greater incidence of cancer events was still observed in the rhBMP-2/CRM group.
A high dose of 40 mg of rhBMP-2/CRM in lumbar spinal arthrodesis was associated with an increased risk of new cancer.
Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

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    • "More recently, BMP-2 has demonstrated to be effective at lower in vivo doses (verbal communication, Medtronic). The potential off-label risks of BMP-2 have been documented in the literature and include: ectopic bone formation [26], swelling/hematoma [27], neoplasia [28], and wound problems; [29] this should be taken into consideration when using these therapies off-label. As basic science researchers, translational scientists and surgeons further understand the temporospatial orchestration of growth factor/cytokines during fracture healing, more precise delivery, timing and dosing of these factors could be delivered to these defects. "
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    Patient Safety in Surgery 12/2014; 8(1):40. DOI:10.1186/s13037-014-0040-7
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    • "Recent studies showed that the off-label use of a high dose (more than 40 mg) of rhBMP-2 was associated with an increased risk of new cancer. We should therefore, further evaluate the potential risk of cancers in patients receiving high-dose rhBMP2 [31], [32]. "
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    PLoS ONE 06/2014; 9(6):e100424. DOI:10.1371/journal.pone.0100424 · 3.23 Impact Factor
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    • "After washed with PBS, the treated cells were lysed with 0.1% TritonX-100/PBS and repeatedly frozen/thawed for three times to disrupt the cell membranes. Alkaline phosphatase (ALP) activities were determined using an alkaline phosphatase reagent kit (ANASPEC, Fremont, CA, USA) and Protein concentrations was measured by the Bicinchoninic Acid (BCA) protein assay reagent (Santa Cruz Biotechnology, USA) [9], [11]. "
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    PLoS ONE 05/2014; 9(5):e98480. DOI:10.1371/journal.pone.0098480 · 3.23 Impact Factor
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