JBJS -- Letters to the Editor for Jones et al., 88 (7) 1431-1441

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Letters to the Editor to:

Scientific Articles:
Alan L. Jones, Robert W. Bucholz, Michael J. Bosse, Sohail K. Mirza, Thomas R. Lyon, Lawrence X. Webb, Andrew N. Pollak, Jane Davis Golden, Alexandre Valentin-Opran the BMP-2 Evaluation in Surgery for Tibial Trauma–Allograft (BESTT-ALL) Study Group
Recombinant Human BMP-2 and Allograft Compared with Autogenous Bone Graft for Reconstruction of Diaphyseal Tibial Fractures with Cortical Defects. A Randomized, Controlled Trial
J Bone Joint Surg Am 2006; 88: 1431-1441 [Abstract] [Full text] [PDF]

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Electronic letters published:

Implication of BMPs in the development of tumors.: Fabian Krause, Alastair Younger, and Martin Weber (22 January 2008)

Ms. Davis Golden et al. respond to Dr. Krause et al.: Jane Davis Golden, PT, MHP, Alan L. Jones, MD, Robert W. Bucholz, MD, Michael J. Bosse, MD, Thomas R. Lyon, MD, Lawrence X. Webb, MD, and Alexandre Valentin-Opran, MD (22 January 2008)

Implication of BMPs in the development of tumors. 22 January 2008

Fabian Krause,
Orthopedic Surgeon
Department of Orthopedic Surgery, Inselspital Berne, Switzerland,
Alastair Younger, and Martin Weber
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Re: Implication of BMPs in the development of tumors.

dr.fkrause{at}gmx.net Fabian Krause, et al.

To The Editor:
We congratulate the authors of this excellent study demonstrating the equivalence in efficacy and safety of autograft and allograft/BMP in the reconstruction of tibial cortical defects. Although safety has been shown in the short-term and no incidents of longterm adverse effects have been reported to our knowledge, concerns still arise from reports on an association of BMP to primary and secondary bone tumors (1,2,3). Aberrations in BMPs signaling have also been identified in various neoplasms(3).
Locally applied BMPs will be biologically active over only a short period of time, and bone is a tissue with very slow turnover. The risk of locally inducing a bone tumor may seem negligibly low. Still, it is an unphysiological and aggressive stimulus the longterm implications of which remain to be seen.
Because of their experience in treating patients with BMP, we would like to pose the following questions to the authors:
- Have they seen any development of primary or secondary (bone) tumors in patients treated with BMP?
- Do they continue to follow-up patients that received BMP for tumor-onset?
- Is there a need for a comparative study regarding the prevalence of tumor-onset in patients treated with and without BMP?
The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
References:
1. Weiss KR, Cooper GM, Jadlowiec JA, McGough RL 3rd, Huard J. VEGF and BMP expression in mouse osteosarcoma cells. Clin Orthop Relat Res. 2006 Sep;450:111-7.
2. Ye L, Lewis-Russell JM, Kyanaston HG, Jiang WG. Bone morphogenetic proteins and their receptor signaling in prostate cancer. Histol Histopathol. 2007 Oct;22(10):1129-47.
3. Yoshikawa H, Nakase T, Myoui A, Ueda T. Bone morphogenetic proteins in bone tumors. J Orthop Sci. 2004;9(3):334-40.

Ms. Davis Golden et al. respond to Dr. Krause et al. 22 January 2008

Jane Davis Golden, PT, MHP,
Clinical Research Director
Wyeth Research, Cambridge, MA,
Alan L. Jones, MD, Robert W. Bucholz, MD, Michael J. Bosse, MD, Thomas R. Lyon, MD, Lawrence X. Webb, MD, and Alexandre Valentin-Opran, MD
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Re: Ms. Davis Golden et al. respond to Dr. Krause et al.

jdavis{at}wyeth.com Jane Davis Golden, PT, MHP, et al.

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 the systemic half-life of rhBMP-2 to be between 7 to 16 minutes and the local mean residence time of rhBMP-2 when implanted on its collagen carrier is 8 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 epithelial-derived neoplasms including 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 suggest that BMP-2 may stimulate the proliferation of malignant cells(1,2), while the majority of studies have shown that BMP-2 inhibits or has no effect on the proliferation of malignant cells(3-8). 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 malignancy should not be treated with rhBMP-2.
rhBMP-2 has been the subject of 3 separate reviews by the Food and Drug Administration, resulting in approvals for spinal fusion, tibial fracture, and oral/maxillofacial indications in the United States (with further reviews/approvals still pending). In addition, rhBMP-2 has been reviewed by regulatory authorities outside of the United States and is approved for use in more than 20 other countries. It is estimated that rhBMP-2 has now been used in more than 500,000 patients. In the 5 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 malignancies of bone 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, 23 malignancies (excluding non-melanoma skin cancers) were observed among 2043 patients treated with rhBMP-2 over 4498 patient- years of follow-up (mean follow-up 2.2 years post-treatment). Of note, none of these reports involved malignancies of bone. To interpret these data, the standardized incidence ratio (SIR) for malignancy was determined. The SIR, which is a proxy for relative risk, compares observed and expected number of events. The expected number was calculated using reference rates from the US Surveillance, Epidemiology and End Results (SEER)(9) 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 SIR was 0.9 (95% CI: 0.6 - 1.3). This indicates that the frequency of malignancies 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 pharmacovigilence of this important issue.
References:
1. Langenfeld EM, Calvano SE, Abou-Noukta F, Lowry S Amenta P, Langenfeld J. The mature bone morphogenetic protein-2 is aberrantly expressed in non-small lung carcinoma and stimulates tumor growth of A549 cells. Carcinogenesis. 24 (9): 1445-54, 2003 Sep.
2. Kleff J, Muruyama H, Ishiwata T, Sawhney H, Friess H, Buchler M, Kore M. Bone morphogenetic protein-2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo. Gastroenterology. 116 (5): 1202-16, 1999 May.
3. Soda H, Raymond E, Sharma S, Lawrence R, Cerna C, Gomez L, Timony GA, Von Hoff DD, Izbicka E. Antiproliferative effects of recombinant human bone morphogenetic protein-2 on human tumor colony-forming units. Anti- Cancer Drugs. 9:327-331, 1998.
4. Orui H, Imaizumi S, Ogino T, Motoyama T. Effects of bone morphogenetic protein-2 on human tumor cell growth and differentiation: a preliminary report. J Orthop Sci 5:600-4, 2000.
5. Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 444(7120):761-5, 2006.
6. Kumagai T, Shimizu T, Takeda K. Bone morphogenetic protein-2 suppresses invasiveness of TSU-Pr1 cells with the inhibition of MMP-9 secretion. Anticancer Res. 26(1A):293-8, 2006.
7. Wen XZ, Miyake S, Akiyama Y, Yuasa Y. BMP-2 modulates the proliferation and differentiation of normal and cancerous gastric cells. Biochem Biophys Res Commun. 316(1):100-6, 2004.
8. Ghosh-Choudhury N, Woodruff K, Qi W, Celeste A, Abboud SL, Ghosh Choudhury G. Bone morphogenetic protein-2 blocks MDA MB 231 human breast cancer cell proliferation by inhibiting cyclin-dependent kinase-mediated retinoblastoma protein phosphorylation. Biochem Biophys Res Commun. 272(3):705-11, 2000.
9. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 13 Regs Limited -Use, Nov 2006 Sub (1992-2004) - Linked To County Attributes - Total U.S., 1969-2004 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2007, based on the November 2006 submission.