J.D. Golden, A.L. Jones, R.W. Bucholz, M.J. Bosse, T.R. Lyon, L.X. Webb, and A. Valentin-Opran reply:
Dr. Krause and colleagues are correct in the fact that the local and systemic exposure in patients treated with rhBMP-2 is very short; animal studies have shown that the systemic half-life of rhBMP-2 is between seven and sixteen minutes, and the local mean residence time of rhBMP-2 when implanted on its collagen carrier is eight days. BMP-2 and BMP-2 receptors are expressed in a variety of tissues and cell types, including both normal and malignant cells. BMPs (as well as other proteins) have been shown to be expressed in many epithelium-derived neoplasms, including those involving the prostate, pancreas, breast, etc. To our knowledge, however, there are no data demonstrating that BMPs induce malignant transformation of cells.
Data regarding the effect of exogenous BMP-2 on malignant cells are conflicting; some publications have suggested that BMP-2 may stimulate the proliferation of malignant cells1,2, while the majority of studies have shown that BMP-2 inhibits or has no effect on the proliferation of malignant cells3-8. Because of the potential risk of stimulating existing cancer growth, rhBMP-2 should not be implanted at the site of a resected tumor and patients who have an active malignancy or are undergoing treatment for a malignant lesion should not be treated with rhBMP-2.
rhBMP-2 has been the subject of three separate reviews by the Food and Drug Administration, resulting in approvals for its use in spinal fusion, tibial fracture, and oral maxillofacial augmentation in the United States (with further reviews and/or approvals still pending). In addition, rhBMP-2 has been reviewed by regulatory authorities outside the United States and has been approved for use in more than twenty other countries. It is estimated that rhBMP-2 has now been used in more than 500,000 patients. In the five years since its first approval, Wyeth and Medtronic have continued to monitor reports from health care professionals and other sources and there have been no reports of malignant bone tumors related to the commercial use of rhBMP-2.
Wyeth and its marketing partner, Medtronic, routinely monitor cancer reports in randomized clinical trials and long-term trial extensions. As of September 2007, twenty-three malignant tumors (excluding nonmelanoma skin cancers) were observed among 2043 patients treated with rhBMP-2 over 4498 patient-years of follow-up (a mean follow-up of 2.2 years posttreatment). Of note, none of those reports involved malignant bone tumors. To interpret these data, the standardized incidence ratio for malignancy was determined. The standardized incidence ratio, which is a proxy for relative risk, compares the observed and the expected number of events. The expected number was calculated with use of reference rates from the U.S. Surveillance, Epidemiology and End Results9 cancer registry applied to the exposure time from the rhBMP-2 studies, adjusting for age, gender, and race to specifically reflect the population exposed to rhBMP-2. The standardized incidence ratio was 0.9 (95% confidence interval, 0.6 to 1.3). This indicates that the frequency of malignant lesions observed in the patients treated with rhBMP-2 in clinical studies is consistent with what one would expect for the general population of similar demographic makeup.
Wyeth and Medtronic will continue with active pharmacovigilance of this important issue.
These letters originally appeared, in slightly different form, on . They are still available on the web site in conjunction with the article to which they refer.