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Neurosurgery:
doi: 10.1227/NEU.0000000000000018
Research-Human-Clinical Studies: Editor's Choice

Cancer After Spinal Fusion: The Role of Bone Morphogenetic Protein

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

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Author Information

Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina

§Department of Bioinformatics and Biostatistics and

Department of Neurosurgery, University of Louisville, Louisville, Kentucky

Center for Neurosurgical Outcomes Research, Maxine Dunitz Neurosurgical Institute, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California

Correspondence: Shivanand P. Lad, Division of Neurosurgery, Department of Surgery, Duke University Medical Center 3807, 200 Trent Dr, Blue Zone–Room 4529, Durham, NC 27710. E-mail: Nandan.Lad@duke.edu

* These authors have contributed equally to this article.

Received October 24, 2012

Accepted May 31, 2013

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Abstract

BACKGROUND: Bone morphogenetic protein (BMP) is used in tens of thousands of spinal fusions each year. A trial evaluating a high-dose BMP formulation demonstrated that its use may be associated with an increased risk of cancer.

OBJECTIVE: To evaluate whether BMP, as commonly used today, is associated with an increased risk of cancer or benign tumors.

METHODS: We performed a retrospective study using the Thomson Reuter MarketScan database. We retained all patients who had no previous diagnosis of cancer or benign tumor and had at least 2 years of uninterrupted enrollment in the database before and after their operations. A propensity score--matched cohort was created to ensure greater covariate balance between treatment groups.

RESULTS: Within the propensity score--matched cohort (n = 4698), BMP-exposed patients had a nonsignificant increase in the rate of cancer diagnosis (9.37% vs 7.92%; P = .08). After adjustment for covariates, BMP exposure was associated with a 31% increased risk of benign tumor diagnosis (odds ratio, 1.31; 95% confidence interval, 1.02-1.68; P < .05). When the benign tumor diagnoses were stratified by organ type, BMP patients had significantly more diagnoses of benign nervous system tumors (0.81% vs 0.34%; P = .03), and within this group, benign tumors of the spinal meninges were much more common in the BMP-treated group (0.13% vs 0.02%; P = .002).

CONCLUSION: The results of this large, independent, propensity-matched study suggest that the use of BMP in lumbar fusions is associated with a significantly higher rate of benign neoplasms but not malignancies.

ABBREVIATIONS: aOR, adjusted odds ratio

BMP, bone morphogenetic protein

CI, confidence interval

CPT-4, Current Procedural Terminology, Fourth Edition

ICD-9-CM, International Classification of Disease, Ninth Revision, Clinical Modification

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.

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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.

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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.

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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.

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Variables

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.

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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.

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RESULTS

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.

Figure 1
Figure 1
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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%).

Table 1
Table 1
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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).

Figure 2
Figure 2
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Outcome Data

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).

Table 2
Table 2
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Table 3
Table 3
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Main Results

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).

Table 4
Table 4
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Table 5
Table 5
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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).

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DISCUSSION

Key Results

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).

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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.

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CONCLUSION

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.

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Disclosures

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.

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COMMENTS

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.

Paul Park

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

Miami, Florida

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

Stanford, California

Keywords:

Bone morphogenetic protein; BMP; Cancer; Complication; Fusion; Pseudarthrosis; Spine

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