Lad, Shivanand P. MD, PhD*,‡; Bagley, Jacob H. BS*,‡; Karikari, Isaac O. MD‡; Babu, Ranjith MS‡; Ugiliweneza, Beatrice PhD, MSPH§; Kong, Maiying PhD§; Isaacs, Robert E. MD‡; Bagley, Carlos A. MD‡; Gottfried, Oren N. MD‡; Patil, Chirag G. MD¶; Boakye, Maxwell MD‖
Lumbar decompression with fusion is one of the most commonly performed spine surgeries in the United States.1 Although fusions may be performed through a variety of surgical approaches, optimal clinical results depend on the formation of a bridge of bone between adjacent vertebrae. Pseudarthrosis is the failure of bone formation and solid union between vertebrae after fusion. The reported incidence of pseudarthrosis varies widely and generally ranges from 0% to 40%.2-5 Pseudarthrosis is a major source of recurrent pain after fusion, and the treatment of pseudarthrosis often necessitates revision surgery, which adds considerably to the economic burden of lower back pain.5-9
A number of factors increase the risk of pseudarthrosis. These include patient factors like smoking, spinal deformity, osteoporosis, and malignancy, as well as a number of factors related to surgical planning such as approach and graft choice.2,10-14 To increase the rates of fusion, a number of osteoinductive substances have been developed. One of these adjuvants, recombinant human bone morphogenetic protein 2 (BMP; Medtronic, Memphis, Tennessee) has been shown to improve fusion rates, to decrease pain, to accelerate the patient’s return to work, and to decrease the need for revision surgeries.15-20
Despite its positive effects, there have been increasing concerns about the safety and use of BMP in spinal fusions.21 Recent research has suggested that BMP may cause a number of harmful effects, including ectopic bone formation, soft-tissue swelling, osteolysis, and radiculitis.22-36 The safety concerns surrounding BMP are compounded by evidence that BMP is widely overused in an off-label fashion. Although BMP was approved by the Food and Drug Administration only for a single anterior approach to the lumbar spine, recent studies have found that one-third of all spinal fusions use BMP.37 Approximately 85% of BMP use is in nonapproved surgeries, including cervical fusions, posterior lumbar fusions, minimally invasive approaches, and pediatric spine fusions.38-44
As a growth factor, BMP has the potential to affect processes regulating cell division. Consequently, there has been concern that BMP may contribute to tumorigenesis and metastasis. During the preapproval testing for a higher-dose BMP formulation, the Food and Drug Administration found that there were “notably increased cancer rates” in the BMP group and consequently denied approval.45 To date, no published study has rigorously evaluated the association between BMP, as commonly used today, and cancer risk. To evaluate the association between BMP use and cancer, we performed a retrospective study of national claims data. We examined the association between BMP and general risk of cancer and the risk of developing cancer in different tissues. In a secondary analysis, the BMP-treated patients were compared with a propensity score--matched cohort to reduce the effects of any biases that affect the choice of BMP use in lumbar fusions. We hypothesized that BMP would increase the general risk of cancer, with a specific increase in bone and connective tissue tumors based on its proximity to adjacent bone and soft tissues.
PATIENTS AND METHODS
Study Design, Setting, and Data Source
To evaluate the association between BMP exposure and cancer risk at the national level, we performed a retrospective, cross-sectional study using the commercial, Medicaid, and Medicare supplemental data sets of the Thomson Reuter MarketScan database. Using data from approximately 45 health plans, large employers, and government organizations in the United States, MarketScan databases include individual-level healthcare claims data that provide a comprehensive record of clinical resource use across inpatient and outpatient services for > 100 million individuals.46-49 For each individual, the database includes demographic information, medical claims data, and payment data. We examined a data set that included all years between 2000 and 2009.
Participants and Study Size
We queried the inpatient admission tables of the MarketScan data sets for all hospitalizations in which a primary procedure of spinal fusion was performed for a primary diagnosis of spinal stenosis for the years 2003, the first year after BMP was approved, to 2009. We limited our study to those with spinal stenosis to increase the degree of homogeneity in our sample. We used International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes 81.06, 81.07, and 81.08 and Current Procedural Terminology, Fourth Edition (CPT-4) codes 22558, 22630, and 22612 in our search for patients who underwent lumbar fusion; ICD-9-CM codes 81.01, 81.02, and 81.03 and CPT-4 codes 22600, 22590, and 22595 for cervical fusion; and ICD-9-CM codes 81.04 and 81.05 and CPT-4 codes 22610, 22554, and 22556 for thoracic fusion. If an admission lacked a primary procedure code, the secondary procedure was considered the primary procedure. We excluded patients < 18 years of age, those who had a diagnosis of cancer or benign tumors before their fusion (ICD-9-CM codes 140-239.9), and those with < 2 years of preoperative enrollment or postoperative follow-up. If the end enrollment date for a patient was available, we used that to calculate follow-up time. If no end enrollment date was available, we used December 31, 2009, as the last date to calculate follow-up time. Use of BMP was determined by the presence of the procedure code for insertion of recombinant BMP (ICD-9-CM code 84.52). The study size was determined to be the maximum number of patients who met all the inclusion criteria and none of the exclusion criteria listed above.
Addressing Bias With Propensity Score Matching
As with all observational studies, systematic differences between the BMP-treated and nontreated groups may confound the effects of treatment on the outcome of interest, cancer risk. To reduce the effects of these confounding variables, propensity score matching was used to create a nontreated cohort that closely resembled the BMP-exposed cohort. Many have used this technique to draw more meaningful causal inferences about treatment effects.20,50-54 For each patient, the propensity score can be defined as the conditional probability of use of BMP given the observed covariates. For a patient in the BMP group, the propensity score matching technique finds a match with similar propensity score. The propensity score was determined by a logistic regression using the variables insurance type, procedure type (anterior, posterior, circumferential), sex, comorbidities (as quantified by the Charlson index),55-57 year of operation, use of instrumentation, use of autograft, use of allograft, and the presence of degenerative spine disease (eg, spondylosis, spondylolisthesis) as predictor variables and the use of BMP as a dependent variable. We used the Greedy matching technique. For matching, we used a caliper of width of 0.2 of the standard deviations of the logit of the propensity scores.
Our primary outcome of interest was a diagnosis of any cancer after the index operation. The presence of any diagnosis code related to cancer (ICD-9-CM codes 140-239.9) was used to determine which patients developed cancer after their lumbar fusion. To understand how BMP might affect tumorigenesis in different tissues, the cancer diagnoses were also stratified by organ: lip, oral cavity, and pharynx; digestive organs and peritoneum; respiratory and intrathoracic organs; bone, connective tissue, skin, and genitourinary organs; other and unspecified sites; lymphatic, hematopoietic tissue, and neuroendocrine tumors; benign neoplasms; and carcinoma in situ, neoplasms of uncertain behaviors, and neoplasms of unspecified nature.
Quantitative Variables and Statistical Methods
We summarized data using means and standard deviations for continuous variables and counts and frequencies for categorical variables. For both explanatory and outcome variables, continuous variables were compared by use of the Mann-Whitney U test, and categorical variables were contrasted with the χ2 test or the Fisher exact test. For outcomes in which BMP was statistically significantly associated to the incidence of cancer, a deeper investigation was conducted through a multivariate logistic regression that, in addition to BMP use status, included age, Charlson index, and insurance type as covariates. Within our data set, all the data fields for the variables used were populated. Although some advocate using a more liberal threshold of significance when examining adverse events, we opted to use the standard and more conservative α value of 0.05 to help ensure that the associations reported were not the result of selection bias. SAS 9.2 (SAS Institute, Inc, Cary, North Carolina) was used for all data management and analyses.
Participants and Descriptive Data
In our sample, there were 201 798 patients who underwent spinal fusion procedures. Of these, 103 969 were excluded because they had < 2 years of preoperative data, and a further 57 220 were excluded because they had preoperative diagnosis codes corresponding to cancer (Figure 1). After exclusion of the 4755 patients without 2 years of postoperative follow-up, our final cohort contained 35 854 patients. The average age in the total cohort was 56 years (SD, 12 years), and the average length of follow-up was approximately 50 months (1504 days; SD, 552 days). The cohort had a slight female preponderance (57%) and was generally healthy. Only 2.5% of the sample had a Charlson score > 1. BMP was used in the fusions of 2349 patients (6.6%) in this cohort.
In the general cohort, those whose fusions used BMP were significantly younger (54 vs 56 years; P < .001), with significantly more women undergoing fusions with BMP (62.7% vs 57.0%; P < .001; Table 1). Although patients with commercial insurance made up approximately 71% of patients in both groups, significantly fewer patients with Medicaid insurance received BMP (13.8% vs 24.4%). Patients in the BMP group had more comorbidities, with fewer patients with a Charlson score of 0 (80.1% vs 85.9%) and more with Charlson scores of 1 (15.7% vs 11.7%), 2 (3.1% vs 1.9%), and ≥ 3 (1.1% vs 0.5%).
To diminish the effects of systematic differences between the 2 groups in the general cohort, a propensity score--matched cohort was created. This matched cohort consisted of 2349 patients who had lumbar fusions with BMP and 2349 whose fusions were performed without BMP (Table 1). There was much greater covariate balance in the propensity score--matched cohort (Figure 2). In the matched cohort, there was no significant difference between groups in age, enrollment time, sex distribution, insurance type, comorbidities, and year of operation (all P = .18).
In the general cohort (n = 35 854), there was no significant difference in the overall rate of cancers between patients who received BMP and those that did not (9.4% vs 8.4%; P = .10; Table 2). Analysis of the propensity score--matched cohort also showed a lack of association between BMP and the diagnosis of any cancer (9.4% vs 7.9%; P = .08). After controlling for age, Charlson score, and insurance type with multivariate regression, all-type cancer risk after spinal fusion in patients receiving BMP in the unmatched cohort was not significantly higher (adjusted odds ratio [aOR], 1.11; 95% confidence interval [CI], 0.96-1.29; Table 3). However, increasing age (aOR, 1.02; 95% CI, 1.01-1.02) and Charlson score (aOR, 1.12; 95% CI, 1.05-1.20) and Medicaid insurance type (aOR, 1.50; 95% CI, 1.29-1.75) were significant risk factors for being diagnosed with cancer (Table 3). Stratification by cancer type revealed those in the BMP group to have significantly higher rates of lip, oral cavity, and pharynx cancers (0.26% vs 0.07%; P = .007) and benign neoplasms (6.3% vs 4.8%; P = .001). After propensity score matching, the only diagnostic group that was associated with BMP was benign tumors (6.3% vs 4.9%; P = .04). In the matched cohort, multivariate regression controlling for age, Charlson score, and insurance type revealed those receiving BMP to be 31% more likely to be diagnosed with benign tumors (aOR, 1.31; 95% CI, 1.02-1.66; P = .04).
The association between BMP and the risk of developing benign tumors was probed by stratifying the benign tumor diagnoses into subgroups by organ (Table 4). The BMP-exposed group in the general cohort had a significantly higher incidence of benign tumors of the uterus (2.6% vs 1.7%; P = .002), nervous system (0.81% vs 0.31%; P < .001), and unspecified sites (0.38% vs 0.14%; P = .009). Patients receiving BMP also had higher rates of hemangiomas and lymphangiomas compared with those who did not receive BMP (0.30% vs 0.09%; P = .008). After controlling for potentially confounding covariates in the propensity score--matched cohort, the BMP-treated group had significantly more benign tumors of the nervous system (0.81% vs 0.34%; P = .03) and unspecified sites (0.38 vs 0.09; P = .03). To fully explore the association between BMP use and benign tumors of the nervous system, we stratified this diagnostic group into the individual diagnoses: benign tumors of the brain, cranial nerves, spinal cord, meninges, and spinal meninges (Table 5). Using the unmatched cohort so that we would have sufficient numbers of diagnoses to power these comparisons, we found that BMP use was associated only with an increase in the rates of benign tumors of the meninges (0.26% vs 0.11%; P = .05) and spinal meninges (0.13% vs 0.02%; P = .003).
Because previous studies have suggested that BMP use may be associated with increased risk of developing multiple tumors, we examined the rates with which patients were diagnosed with multiple tumors in our patient population (Table 2). In the propensity score--matched cohort, BMP was associated with a strong trend toward increased risk of multiple malignancies, especially those having ≥ 3 histopathologically distinct cancer diagnoses (2.98% vs 2.09%; P = .05). There was a statistically significant association between BMP use and the risk of ≥ 2 histopathologically distinct benign tumors (1.15% vs 0.47%; P = .009).
Although BMP is used as an osteoinductive adjuvant in thousands of fusions each year, our study is the first in the literature to specifically investigate the association between the use of BMP and cancer risk. Our findings suggest that the use of BMP in spinal fusions does not contribute to an overall increased cancer risk but does carry a significant increase in benign tumors. In the overall cohort, 9.4% of patients receiving BMP developed cancer compared with 8.4% of patients not receiving BMP (P = .10; Table 2). This contrasts a recent review of the records of the patients in a trial of higher-dose BMP (AMPLIFY, Medtronic, Memphis, Tennessee) in posterior lumbar fusions, which had a follow-up time of 2 years.22 The higher-dose BMP product being tested used a different delivery formulation and included 40 mg BMP, which is almost 3 times as much BMP as used in the currently marketed BMP product. In the analysis of that preapproval trial, cancer was more common in the 239 patients who received BMP during posterior lumbar fusions than in the 224 patients whose fusions did not include BMP (3.8% or 9 patients in BMP cohort were diagnosed with a new cancer compared with 0.89% or 2 patients who received autograft; P = .05).22 Other analysis suggests that the hazard ratio for developing new malignancies after this experimental high-dose BMP use was more than quadrupled. This high-dose formulation of BMP was not approved by the Food and Drug Administration.
Although our initial findings demonstrated that BMP use in spinal fusions may not increase the risk of cancer, the cancer diagnoses were stratified by organ type to evaluate whether the use of BMP affected tumorigenesis only in particular tissues (Table 2). Because the propensity score--matched cohort was designed to minimize potential selection bias, our conclusions focus on the results from this group. Although we had hypothesized that BMP would increase the risk of bone and connective tissue cancers because of its proximity to vertebrae and spinal ligaments during fusion, there was not a greater diagnosis of bone or connective tissue cancers in the BMP-treated group (P = .63). Before propensity score matching, patients receiving BMP had a higher risk of oropharyngeal cancers (0.26% vs 0.07%; P = .007), but this association became nonsignificant after matching (0.26% vs 0.09%; P = .16). This initial association between BMP and malignancies in the oropharynx might suggest that tobacco use, a risk factor for such tumors, might be confounding the results of this study. However, the fact that the BMP group was not observed to have an increase in respiratory malignancies in either the unmatched or matched group suggests that tobacco use was not a confounding variable.
There was a significant increase in the rate of benign tumor diagnoses in the propensity score--matched BMP group, with these patients being 31% more likely to receive this diagnosis (aOR, 1.25; 95% CI, 1.02-1.69; P = .04). Stratification of benign tumors in the unmatched cohort revealed that BMP was associated with significant increases in diagnoses of uterine leiomyomas, hemangiomas, and lymphangiomas; brain and nervous system benign tumors; and unspecified benign tumors (Table 4). However, after propensity score matching, only the diagnoses benign tumors of the brain and nervous system and benign tumors of other and unspecified sites had a significant relationship with BMP use. We believe that the increase in the rates of uterine leiomyomas and hemangiomas observed in the BMP-treated patients in the unmatched cohort may be due to the fact that women were overrepresented in the BMP-treated group in the unmatched cohort (62.7% vs 56.9%; P < .001; Table 1). The finding that the benign tumors of the nervous system are particularly associated with BMP use suggests a spatially limited effect of BMP on tumorigenesis, in contrast to the results of the high-dose BMP trial, which found increased tumor diagnoses in a variety of different organ systems.45
There is no clear mechanism through which exogenous BMP might affect cancer risk. In vivo and in vitro studies have provided evidence that BMP can promote tumorigenesis, neoangiogenesis, and metastasis in a variety of tumors.58,59 BMP-2, the same molecule used as an adjuvant in spinal fusions, is frequently overexpressed in gliomas and pancreatic, ovarian, and bladder cancers.60-63 Angiogenesis, which is necessary for the growth of solid tumors, is stimulated by BMPs in lung tumors and melanomas.64-66 However, it is impossible to claim that the BMP used in spinal fusions is definitively protumorigenic or antitumorigenic; as with many growth factors, the action of BMP is dependent on dose, tissue type, and hormonal milieu.67-71 In agreement with the findings in the basic science literature, our finding that BMP is associated with a greater risk of multiple histopathologically distinct benign tumors suggests that BMP may have a protumorigenic effect on multiple tissues. The BMP delivered in spinal fusions is given at a markedly supraphysiological dose to counteract the osteogenic inhibition produced by molecules naturally found in healing spinal fusions, and a significant amount of BMP diffuses away from the fusion site over time.72-74 This large, local dose may explain why benign tumors of the spinal meninges were particularly affected by BMP exposure (Table 5).
Limitations and Generalizability
There are several other reasons why these data require cautious interpretation. First, retrospective studies cannot definitively determine causality. Although our use of propensity score matching allows us to make better causal inferences from our results, a randomized controlled trial is needed to conclusively determine whether BMP use in spinal fusions results in an increased cancer risk. Because of the large sample size needed to properly power such a clinical study and the low likelihood of such a study being done, the statistical design of propensity score--matched cohorts is the closest estimation of such a randomized population in a large, retrospective analysis. Second, our study uses the diagnosis of cancers and tumors as a proxy for their incidence in the population. Thus, we rely on physicians’ ability to accurately diagnose cancers and benign tumors. Because benign tumors are often asymptomatic, it is likely that the diagnosis rate actually underestimates the true incidence of tumors in our cohort. Third, studies that use billing code data must rely on the accuracy of the coding systems that health providers and hospitals use. It is known that some diseases in national databases are coded with less frequency than they are diagnosed, although cancer codes have been found to be reasonably accurate measures of cancer diagnoses.75-77 Fourth, our inclusion criteria required patients to be enrolled for a minimum of 2 years after their index procedures, which may be too short a time frame to accurately estimate differences in cancer frequency between groups because the effects of BMP on tumorigenesis may take much longer to become apparent. However, our mean length of postoperative follow-up was > 4 years, which may be sufficient to detect a large number of cancer diagnoses. Fifth, our study was not able to control for several covariates such as tobacco exposure that are known determinants of cancer risk. Sixth, using the MarketScan database, we are unable to determine the amount of BMP to which each patient was exposed. Despite these limitations, the methodological and statistical methods used in the present study provide firm basis for conclusions about the association between BMP use during spinal fusions and subsequent cancer risk. Because our sample is drawn from a national database and the persistence of the BMP-benign tumor association in the propensity score--matched cohort, we believe that our findings apply to the general population of patients undergoing spinal fusion in the United States.
The results of this large, independent, cross-sectional, propensity score--matched study of > 4600 patients suggest that the use of BMP in lumbar fusions is associated with a significantly higher rate of benign neoplasms.
Dr Isaacs has been a consultant and research support to Nuvasive; has ownership interests in SafeRay Spine LLC, Safewire Solutions, and VillaSpine; and has received a research grant from OREF. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
1. Weinstein JN, Lurie JD, Olson PR, Bronner KK, Fisher ES. United States’ trends and regional variations in lumbar spine surgery: 1992-2003. Spine (Phila Pa 1976). 2006;31(23):2707–2714.
2. Fischgrund JS, Mackay M, Herkowitz HN, Brower R, Montgomery DM, Kurz LT. 1997 Volvo Award winner in clinical studies: degenerative lumbar spondylolisthesis with spinal stenosis: a prospective, randomized study comparing decompressive laminectomy and arthrodesis with and without spinal instrumentation. Spine (Phila Pa 1976). 1997;22(24):2807–2812.
3. Fritzell P, Hägg O, Wessberg P, Nordwall A; Swedish Lumbar Spine Study Group. Chronic low back pain and fusion: a comparison of three surgical techniques: a prospective multicenter randomized study from the Swedish lumbar spine study group. Spine (Phila Pa 1976). 2002;27(11):1131–1141.
4. Zhou ZJ, Zhao FD, Fang XQ, Zhao X, Fan SW. Meta-analysis of instrumented posterior interbody fusion versus instrumented posterolateral fusion in the lumbar spine. J Neurosurg Spine. 2011;15(3):295–310.
5. Raizman NM, O'Brien JR, Poehling-Monaghan KL, Yu WD. Pseudarthrosis of the spine. J Am Acad Orthop Surg. 2009;17(8):494–503.
6. Kornblum MB, Fischgrund JS, Herkowitz HN, Abraham DA, Berkower DL, Ditkoff JS. Degenerative lumbar spondylolisthesis with spinal stenosis: a prospective long-term study comparing fusion and pseudarthrosis. Spine (Phila Pa 1976). 2004;29(7):726–733; discussion 733-734.
7. Martin BI, Mirza SK, Comstock BA, Gray DT, Kreuter W, Deyo RA. Reoperation rates following lumbar spine surgery and the influence of spinal fusion procedures. Spine (Phila Pa 1976). 2007;32(3):382–387.
8. Adogwa O, Parker SL, Shau D, et al.. Long-term outcomes of revision fusion for lumbar pseudarthrosis: clinical article. J Neurosurg Spine. 2011;15(4):393–398.
9. Parker SL, Shau DN, Mendenhall SK, McGirt MJ. Factors influencing 2-year health care costs in patients undergoing revision lumbar fusion procedures. J Neurosurg Spine. 2012;16(4):323–328.
10. Brown CW, Orme TJ, Richardson HD. The rate of pseudarthrosis (surgical nonunion) in patients who are smokers and patients who are nonsmokers: a comparison study. Spine (Phila Pa 1976). 1986;11(9):942–943.
11. Hilibrand AS, Fye MA, Emery SE, Palumbo MA, Bohlman HH. Impact of smoking on the outcome of anterior cervical arthrodesis with interbody or strut-grafting. J Bone Joint Surg Am. 2001;83-A(5):668–673.
12. Bono CM, Lee CK. Critical analysis of trends in fusion for degenerative disc disease over the past 20 years: influence of technique on fusion rate and clinical outcome. Spine (Phila Pa 1976). 2004;29(4):455–463; discussion Z5.
13. Christensen FB, Hansen ES, Eiskjaer SP, et al.. Circumferential lumbar spinal fusion with Brantigan cage versus posterolateral fusion with titanium Cotrel-Dubousset instrumentation: a prospective, randomized clinical study of 146 patients. Spine (Phila Pa 1976). 2002;27(23):2674–2683.
14. Jorgenson SS, Lowe TG, France J, Sabin J. A prospective analysis of autograft versus allograft in posterolateral lumbar fusion in the same patient: a minimum of 1-year follow-up in 144 patients. Spine (Phila Pa 1976). 1994;19(18):2048–2053.
15. Burkus JK, Dorchak JD, Sanders DL. Radiographic assessment of interbody fusion using recombinant human bone morphogenetic protein type 2. Spine (Phila Pa 1976). 2003;28(4):372–377.
16. Burkus JK, Gornet MF, Schuler TC, Kleeman TJ, Zdeblick TA. Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2. J Bone Joint Surg Am. 2009;91(5):1181–1189.
17. Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002;27(21):2396–2408.
18. Glassman SD, Dimar JR 3rd, Burkus K, et al.. The efficacy of rhBMP-2 for posterolateral lumbar fusion in smokers. Spine (Phila Pa 1976). 2007;32(15):1693–1698.
19. Smoljanovic T, Siric F, Bojanic I. Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2. J Bone Joint Surg Am. 2010;92(15):2614–2615; author reply 2615-2616.
20. Cahill KS, Chi JH, Groff MW, McGuire K, Afendulis CC, Claus EB. Outcomes for single-level lumbar fusion: the role of bone morphogenetic protein. Spine (Phila Pa 1976). 2011;36(26):2354–2362.
21. Mitka M. Questions about spine fusion product prompt a new process for reviewing data. JAMA. 2011;306(12):1311–1312.
22. Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011;11(6):471–491.
23. Carragee EJ, Mitsunaga KA, Hurwitz EL, Scuderi GJ. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. Spine J. 2011;11(6):511–516.
24. Choudhry OJ, Christiano LD, Singh R, Golden BM, Liu JK. Bone morphogenetic protein-induced inflammatory cyst formation after lumbar fusion causing nerve root compression. J Neurosurg Spine. 2012;16(3):296–301.
25. Benglis D, Wang MY, Levi AD. A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery. 2008;62(5 suppl 2):ONS423–ONS431; discussion ONS431.
26. Wang H, Liu D, Yang Z, et al.. Association of bone morphogenetic protein-2 gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity in Chinese patients. Eur J Spine. 2008;17(7):956–964.
27. Chen NF, Smith ZA, Stiner E, Armin S, Sheikh H, Khoo LT. Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion. J Neurosurg Spine. 2010;12(1):40–46.
28. Joseph V, Rampersaud YR. Heterotopic bone formation with the use of rhBMP2 in posterior minimal access interbody fusion: a CT analysis. Spine (Phila Pa 1976). 2007;32(25):2885–2890.
29. Poynton AR, Lane JM. Safety profile for the clinical use of bone morphogenetic proteins in the spine. Spine (Phila Pa 1976). 2002;27(16 suppl 1):S40–S48.
30. Owens K, Glassman SD, Howard JM, Djurasovic M, Witten JL, Carreon LY. Perioperative complications with rhBMP-2 in transforaminal lumbar interbody fusion. Eur J Spine. 2011;20(4):612–617.
31. McClellan JW, Mulconrey DS, Forbes RJ, Fullmer N. Vertebral bone resorption after transforaminal lumbar interbody fusion with bone morphogenetic protein (rhBMP-2). J Spinal Disord Tech. 2006;19(7):483–486.
32. Mroz TE, Wang JC, Hashimoto R, Norvell DC. Complications related to osteobiologics use in spine surgery: a systematic review. Spine (Phila Pa 1976). 2010;35(9 suppl):S86–S104.
33. Smucker JD, Rhee JM, Singh K, Yoon ST, Heller JG. Increased swelling complications associated with off-label usage of rhBMP-2 in the anterior cervical spine. Spine (Phila Pa 1976). 2006;31(24):2813–2819.
34. Mindea SA, Shih P, Song JK. Recombinant human bone morphogenetic protein-2-induced radiculitis in elective minimally invasive transforaminal lumbar interbody fusions: a series review. Spine (Phila Pa 1976). 2009;34(14):1480–1484; discussion 1485.
35. Lewandrowski KU, Nanson C, Calderon R. Vertebral osteolysis after posterior interbody lumbar fusion with recombinant human bone morphogenetic protein 2: a report of five cases. Spine J. 2007;7(5):609–614.
36. Williams BJ, Smith JS, Fu KM, et al.. Does bone morphogenetic protein increase the incidence of perioperative complications in spinal fusion? A comparison of 55,862 cases of spinal fusion with and without bone morphogenetic protein. Spine (Phila Pa 1976). 2011;36(20):1685–1691.
37. Lad SP, Nathan JK, Boakye M. Trends in the use of bone morphogenetic protein as a substitute to autologous iliac crest bone grafting for spinal fusion procedures in the United States. Spine (Phila Pa 1976). 2011;36(4):E274–E281.
38. Ong KL, Villarraga ML, Lau E, Carreon LY, Kurtz SM, Glassman SD. Off-label use of bone morphogenetic proteins in the United States using administrative data. Spine (Phila Pa 1976). 2010;35(19):1794–1800.
39. Abd-El-Barr MM, Cox JB, Antonucci MU, Bennett J, Murad GJ, Pincus DW. Recombinant human bone morphogenetic protein-2 as an adjunct for spine fusion in a pediatric population. Pediatr Neurosurg. 2011;47(4):266–271.
40. Hamilton DK, Smith JS, Reames DL, Williams BJ, Chernavvsky DR, Shaffrey CI. Safety, efficacy, and dosing of recombinant human bone morphogenetic protein-2 for posterior cervical and cervicothoracic instrumented fusion with a minimum 2-year follow-up. Neurosurgery. 2011;69(1):103–111; discussion 111.
41. Hamilton DK, Smith JS, Reames DL, Williams BJ, Shaffrey CI. Use of recombinant human bone morphogenetic protein-2 as an adjunct for instrumented posterior arthrodesis in the occipital cervical region: an analysis of safety, efficacy, and dosing. J Craniovertebr Junction Spine. 2010;1(2):107–112.
42. Boden SD. Overview of the biology of lumbar spine fusion and principles for selecting a bone graft substitute. Spine (Phila Pa 1976). 2002;27(16suppl 1):S26–S31.
43. Mannion RJ, Nowitzke AM, Wood MJ. Promoting fusion in minimally invasive lumbar interbody stabilization with low-dose bone morphogenic protein-2: but what is the cost? Spine J. 2011;11(6):527–533.
44. Lindley TE, Dahdaleh NS, Menezes AH, Abode-Iyamah KO. Complications associated with recombinant human bone morphogenetic protein use in pediatric craniocervical arthrodesis. J Neurosurg Pediatr. 2011;7(5):468–474.
46. Hansen LG, Chang S. Health Research Data for the Real World: The Marketscan Databases: Thomson Reuters; 2012.
47. Zhou F, Harpaz R, Jumaan AO, Winston CA, Shefer A. Impact of varicella vaccination on health care utilization. JAMA. 2005;294(7):797–802.
48. Zhang Z, Fang J, Gillespie C, Wang G, Hong Y, Yoon PW. Age-specific gender differences in in-hospital mortality by type of acute myocardial infarction. Am J Cardiol. 2012;109(8):1097–1103.
49. Cortes JE, Curns AT, Tate JE, et al.. Rotavirus vaccine and health care utilization for diarrhea in U.S. children. N Engl J Med. 2011;365(12):1108–1117.
50. Rosenbaum PR, Rubin DB. The central role of propensity scores in observational studies for causal effects. Biometrika. 1983;70(1):41–55.
51. Aronow HD, Novaro GM, Lauer MS, et al.. In-hospital initiation of lipid-lowering therapy after coronary intervention as a predictor of long-term utilization: a propensity analysis. Arch Intern Med. 2003;163(21):2576–2582.
52. Frolkis JP, Pothier CE, Blackstone EH, Lauer MS. Frequent ventricular ectopy after exercise as a predictor of death. N Engl J Med. 2003;348(9):781–790.
53. Zhang Y, Fonarow GC, Sanders PW, et al.. A propensity-matched study of the comparative effectiveness of angiotensin receptor blockers versus angiotensin-converting enzyme inhibitors in heart failure patients age ≥65 years. Am J Cardiol. 2011;108(10):1443–1448.
54. Kendel F, Dunkel A, Müller-Tasch T, et al.. Gender differences in health-related quality of life after coronary bypass surgery: results from a 1-year follow-up in propensity-matched men and women. Psychosom Med. 2011;73(3):280–285.
55. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–383.
56. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45(6):613–619.
57. Quan H, Sundararajan V, Halfon P, et al.. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43(11):1130–1139.
58. Kim M, Choe S. BMPs and their clinical potentials. BMB Rep. 2011;44(10):619–634.
59. Singh A, Morris RJ. The Yin and Yang of bone morphogenetic proteins in cancer. Cytokine Growth Factor Rev. 2010;21(4):299–313.
60. Liu C, Tian G, Tu Y, Fu J, Lan C, Wu N. Expression pattern and clinical prognostic relevance of bone morphogenetic protein-2 in human gliomas. Jpn J Clin Oncol. 2009;39(10):625–631.
61. Kleeff J, Maruyama H, Ishiwata T, et al.. Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo. Gastroenterology. 1999;116(5):1202–1216.
62. Hung TT, Wang H, Kingsley EA, Risbridger GP, Russell PJ. Molecular profiling of bladder cancer: involvement of the TGF-beta pathway in bladder cancer progression. Cancer Lett. 2008;265(1):27–38.
63. Le Page C, Ouellet V, Madore J, et al.. Gene expression profiling of primary cultures of ovarian epithelial cells identifies novel molecular classifiers of ovarian cancer. Br J Cancer. 2006;94(3):436–445.
64. Langenfeld EM, Langenfeld J. Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res. 2004;2(3):141–149.
65. Bieniasz M, Oszajca K, Eusebio M, Kordiak J, Bartkowiak J, Szemraj J. The positive correlation between gene expression of the two angiogenic factors: VEGF and BMP-2 in lung cancer patients. Lung Cancer. 2009;66(3):319–326.
66. Rothhammer T, Bataille F, Spruss T, Eissner G, Bosserhoff AK. Functional implication of BMP4 expression on angiogenesis in malignant melanoma. Oncogene. 2007;26(28):4158–4170.
67. Brubaker KD, Corey E, Brown LG, Vessella RL. Bone morphogenetic protein signaling in prostate cancer cell lines. J Cell Biochem. 2004;91(1):151–160.
68. Ide H, Yoshida T, Matsumoto N, et al.. Growth regulation of human prostate cancer cells by bone morphogenetic protein-2. Cancer Res. 1997;57(22):5022–5027.
69. Soda H, Raymond E, Sharma S, et al.. Antiproliferative effects of recombinant human bone morphogenetic protein-2 on human tumor colony-forming units. Anticancer Drugs. 1998;9(4):327–331.
70. Wen XZ, Akiyama Y, Baylin SB, Yuasa Y. Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas. Oncogene. 2006;25(18):2666–2673.
71. Kang HW, Walvick R, Bogdanov A Jr. In vitro and in vivo imaging of antivasculogenesis induced by Noggin protein expression in human venous endothelial cells. FASEB J. 2009;23(12):4126–4134.
72. Tang Y, Ye X, Klineberg EO, Curtiss S, Maitra S, Gupta MC. Temporal and spatial expression of BMPs and BMP antagonists during posterolateral lumbar fusion. Spine (Phila Pa 1976). 2011;36(4):E237–E244.
73. Abe E, Yamamoto M, Taguchi Y, et al.. Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice: antagonism by noggin. J Bone Miner Res. 2000;15(4):663–673.
74. Barnes GL, Kostenuik PJ, Gerstenfeld LC, Einhorn TA. Growth factor regulation of fracture repair. J Bone Miner Res. 1999;14(11):1805–1815.
75. Whittle J, Steinberg EP, Anderson GF, Herbert R. Accuracy of Medicare claims data for estimation of cancer incidence and resection rates among elderly Americans. Med Care. 1991;29(12):1226–1236.
76. Kahn LH, Blustein J, Arons RR, Yee R, Shea S. The validity of hospital administrative data in monitoring variations in breast cancer surgery. Am J Public Health. 1996;86(2):243–245.
77. Cooper GS, Yuan Z, Stange KC, Dennis LK, Amini SB, Rimm AA. The sensitivity of Medicare claims data for case ascertainment of six common cancers. Med Care. 1999;37(5):436–444.
The risk of carcinogenicity with recombinant human bone morphogenetic protein-2 (rhBMP-2) is unclear. Numerous animal studies assessing the role of BMP on carcinogenicity have been performed, but the results have been contradictory.1 Given the recent concern for increased carcinogenicity2 with the use of rhBMP-2, this article is a particularly pertinent addition to the literature. This study analyzes a large number of patients exposed to rhBMP-2 and compares these patients with a matched cohort of unexposed patients. It is notable that no statistically increased risk of cancer was found between groups, although an increased risk for benign neoplasms was observed. The results of this study should be interpreted cautiously, however, given that it is retrospective and involves the use of existing databases not originally designed to assess the impact of rhBMP-2. Clearly, further investigations are needed to confirm these findings, but the authors should be congratulated for providing further insight into an area where there is a relative paucity of clinical evidence.
Ann Arbor, Michigan
1. Thawani JP, Wang AC, Than KD, et al.. Bone morphogenetic proteins and cancer: review of the literature. Neurosurgery. 2010;66(2):233–246. View Full Text | PubMed | CrossRef Cited Here... |
2. Carragee EJ, Hurvitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011;11(6):471–491. PubMed | CrossRef Cited Here... |
This article examines the incidence of systemic tumors, both benign and malignant, after the use of bone morphogenetic protein (BMP) after spinal surgery. This article adds to the literature, which is currently much debated and controversial, on the association between BMP use in spinal surgery and tumor formation.
The importance of this work lies in that the authors have analyzed the most commonly used BMP formulations as opposed to the higher-dose AMPLIFY recombinant human BMP doses previously published.1
The authors have used the Thomas Reuters MarketScan database, which contains data of a retrospective and cross-sectional nature on commercial, Medicaid, and Medicare supplemental data sets. The strengths include the following: It is the largest study in the literature (> 35 000 patients) to evaluate the link between a new diagnosis of cancer and BMP using the propensity score matching technique to reduce group-level differences and potential selection biases, and there is a relatively long follow-up that included a minimum of at least 2 years of uninterrupted preoperative and postoperative follow-up with the average length being 4 years.
Although this degree of follow-up is commendable, in terms of cancer studies, this still represents a relatively short follow-up, particularly when looking at the incidence of benign tumors. The limitations of this study, outlined in the Discussion, include the retrospective nature of the study; the accuracy of the diagnosis, particularly for benign tumors; the accuracy of coding; the length of follow-up; and the inability to control for several covariates, particularly smoking.
Smoking status was not coded in this data set. Smoking is a known risk factor for failed fusion and pseudarthrosis and would certainly be a motivational factor for surgeons to add BMP to their fusion construct. Smokers get more cancer, and findings of an increase incidence of lip, oral cavity, and pharyngeal cancers may be a reflection of this. Inclusion of more smokers in the BMP group may independently increase the risk of the cancer in the BMP group. The absence of an increased risk of intrathoracic and respiratory malignancies in the BMP group is duly noted.
Although not proven in this article, one of the most interesting findings is the absence of an increased incidence of malignant tumors after the use of a BMP for spine surgery. Specifically, there was no increased risk of malignant local boney spine tumors. I have always found it difficult conceptually to understand how a 1-time use of or exposure to BMP in the spine could produce a malignancy remote from the site of application and years from time of exposure.
The authors conclude, however, that application of BMP during spine surgery was associated with a 31% increased risk of benign tumor formation during their relatively short follow up period. The benign tumors were located in the brain, nervous system, and other unspecified sites (P < .001). In particular, benign tumors of spinal meninges appear to be increased; however, this represents a total of 3 cases of the 2349 BMP cases analyzed (Table 5). The finding of this particular cancer relies heavily on the accuracy coding. A more direct measurement of cancer would be a demonstration that the patient underwent operative treatment, radiation, chemotherapy, biopsy, or pathology confirming a diagnosis of de novo cancer formation. The results of this article are interesting and serve as an additional piece of information in the controversial field of BMP and spine surgery. One must interpret the findings of an increased risk of “benign tumors after BMP use in the spine” cautiously and practically because they rely so heavily on diagnostic coding as opposed to pathology results or tumor treatment.
Allan D. Levi
1. Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011;11(6):471–491. PubMed | CrossRef Cited Here... |
Using a retrospective, comparative-cohort design, the authors examined the incidence of new benign and malignant tumors after spinal fusion with and without bone morphogenetic protein-2 (BMP-2) exposure. Their findings reinforce concerns that ectopic bone formation and inflammatory reactions may not be the only complications of supraphysiological BMP-2, a pluripotent growth factor.
Endogenous BMP-2 normally exists at extremely small concentrations (0.1 ng/mL). The concentration of recombinant human BMP-2 delivered in spinal fusions is 1 to 10 million times ambient levels. Spikes in BMP-2 exposure, even in remote tissues, may be expected, potentially stimulating quiescent malignant cells. These exposures may alter immune or genetic controls of in situ disease. Supraphysiological BMP-2 may also have immune or neurologically mediated effects through second messengers or neurosignaling pathways. The findings reported by the authors are timely, important, and perhaps not unanticipated.
Before any human application of BMP-2, tumor promotion was considered a serious potential adverse effect. Clinical trials were often limited to patients with low malignancy risk, and in some trials, even remote malignancy history was an absolute exclusion from enrollment. Despite these precautions, a randomized controlled trial testing 40 mg BMP-2 for posterolateral lumbar fusion was highly concerning: By 30 months after exposure, 15 new malignancies were reported in the BMP-2 group compared with 2 in the control group. An additional remarkable observation was the rapid development of multiple distinct malignancies in individual patients after exposure. The Food and Drug Administration analyst of this investigational drug exemption trial reported: “The primary statistical concern is the apparent association with malignancy. In this regard, there were higher rates of cancer events with the use of the [BMP-2] product in the pivotal study, which were not contradicted by all of the pooled Medtronic trials using BMP-2.”
The present study corroborates these apprehensions. The rate of both benign and malignant tumors appeared higher in the matched BMP-2 cohort. These findings were observed despite the likely systematic bias by many surgeons to avoid BMP-2 use in subjects with higher malignancy risks, as required in the investigational drug exemption studies. The present study design could not measure or control for this selection bias. Furthermore, the dose of BMP-2 used in this dichotomous analysis was unknown, potentially diluting the observed tumor-promoting effect that would have been observed with standard or higher doses. Nonetheless, despite these inadvertent biases against finding any tumor-promoting effect, the authors report a 90% to 95% statistical confidence of increased malignancy and again observed a clearly higher risk of multiple benign and malignant tumors after BMP-2 exposure.
The authors applied a standard of 95% confidence (P = .05) to determine statistical significance. The reality, however, is that the finding of a 92% to 95% (P = .08 to .05) confidence of an association of BMP-2 with ≥ 1 malignancy events is a much greater clinical significance than the estimated 97% confidence of an association with benign tumors.
In either case, this study confirms that the confidence of tumor promotion by BMP-2, both benign and malignant, is high. Conversely, the confidence of safety for routine use is very low.
Eugene J. Carragee