Abstract
Study Design
Retrospective observational cohort.
Objective
Although recombinant human bone morphogenetic protein-2 (rhBMP-2) has been shown to enhance fusion rates in spinal fusion surgery, its use in patients with spondylodiscitis remains controversial. This study evaluated the surgical outcomes and complication rates associated with rhBMP-2 use in the treatment of spondylodiscitis.
Methods
We retrospectively reviewed a consecutive series of patients who underwent surgical treatment for spondylodiscitis, including anterior column debridement and reconstruction with cage placement, with at least 12-month follow-up. Outcomes and complications were compared between patients who received rhBMP-2 and those who did not.
Results
A total of 133 patients (mean follow-up, 32.4 ± 27.4 months) were included; 114 (86%) received rhBMP-2 (mean dose, 14.4 ± 6.4 mg), anteriorly in 97 (73%), posteriorly in 92 (69%), and in both locations in 75 patients (56%). . The fusion rate was significantly higher in BMP_Posterior vs non-BMP_Posterior (95% vs 80%, P = 0.023, but not significantly different in other subgroup comparisons. There were no significant differences in implant-related complications, revision surgery, recurrence, or major medical complications between patients who received rhBMP-2 and those who did not. The multivariable analysis demonstrated that rhBMP-2 use in both the anterior and posterior columns (OR = 9.93, 95% CI: 1.90 - 77.7, P = 0.012) and age (OR = 0.93, 95% CI: 0.85-0.99, P = 0.042) were independently associated with fusion at the infected level.
Conclusion
The use of rhBMP-2 was not associated with increased complications and may support fusion, even in the setting of active spondylodiscitis.
Keywords
Introduction
Spondylodiscitis is a serious clinical condition associated with significant morbidity and mortality.1,2 Although antibiotic therapy is the primary treatment for spondylodiscitis, surgical intervention is indicated for patients with failure of antibiotic treatment, sepsis, neurological deficits, progressive deformity and mechanical instability.3,4 Surgical management typically involves extensive debridement and resection of infected tissues, followed by reconstruction with interbody devices and posterior segmental spinal instrumentation.5,6 Although achieving solid bony fusion and bridging the bone defect is essential for restoring spinal stability, the infected environment can compromise the fusion process due to an exaggerated inflammatory response, which leads to dysregulation of osteoblast and osteoclast activity.7,8
Bone graft selection is an important consideration for successful fusion in spinal surgery. While autologous iliac crest bone graft (ICBG) was historically the standard, its use has declined due to drawbacks such as increased operative time, related complications, and morbidity. 9 Currently, recombinant human bone morphogenetic protein-2 (rhBMP-2) is considered a viable bone graft alternative. 10 Bone morphogenetic proteins (BMPs) are bioactive molecules belonging to the transforming growth factor-beta (TGF-β) family and exhibit osteoinductive properties. 11 Although rhBMP-2 has demonstrated comparable fusion rates to ICBG, literature has reported associated complications including radiculitis, increased postoperative pain and wound dehiscence.12-15
Patients with spondylodiscitis frequently present with comorbidities that are unfavorable to bone healing, such as diabetes mellitus, smoking, chronic kidney disease, and malnutrition.16,17 In such cases, the use of rhBMP-2 may be clinically considered as an adjunct to promote fusion. However, there is limited evidence on the safety of rhBMP-2 use in the setting of active infection.18-22 Therefore, this study aimed to evaluate the fusion successes, surgical outcomes, and complications associated with rhBMP-2 use in the surgical treatment for spondylodiscitis.
Material and Methods
We retrospectively reviewed the clinical records of a consecutive series of patients who underwent surgical intervention for spondylodiscitis at a single institution between 2012 and April 2024. All patients were evaluated by an infectious disease specialist to identify the primary source and/or other sites of infection and to determine appropriate antibiotic therapy. Surgical intervention was performed for patients with failure of antibiotic therapy, uncontrolled infection, neurological impairment, or structural instability. As spondylodiscitis primarily affects the anterior spinal column, only patients who underwent anterior column debridement and reconstruction with cage placement were included in this study. Patients who did not undergo anterior debridement and reconstruction—such as those who received only posterior instrumentation or decompression—were excluded. In addition, patients with prior spine surgery within 90 days or those who received other bioactive molecules, such as anorganic bone matrix combined with a P-15 osteogenic cell-binding peptide (ABM/P-15), were also excluded.
Patient demographics and surgical data were recorded. The rhBMP-2 kits used ranged from extra-small to large, with corresponding doses as follows: extra-small, 2.1 mg; small, 4.2 mg; medium, 8.4 mg; and large, 12 mg. The rhBMP-2 collagen sponges were prepared according to the manufacturer instructions. The sponges were mixed with morselized autograft or allograft and packed inside the interbody device in the anterior column and/or placed over the decorticated posterolateral bony surfaces. In addition to rhBMP-2, DBM, allograft, and ICBG were used as bone graft materials.
Radiographic outcomes and revision surgery were assessed. Radiographic outcomes included fusion at infected levels, nonunion, cage subsidence, and screw or rod failure. Fusion was evaluated using X-ray or computed tomography (CT) and was defined as the presence of bridging bone or the formation of a substantial fusion mass surrounding the interbody device, assessed at least 12 months postoperatively. Revision surgery was defined as reoperation for mechanical failure, nonunion, or adjacent segment disease. Recurrence, medical complications, and readmissions within one year were also assessed. Surgical complications included surgical site infection, wound dehiscence, epidural hematoma, uncontrolled back pain, and radiculitis. Uncontrolled back pain and radiculitis were defined as symptoms requiring medical intervention without any identifiable cause on imaging. Major medical complications included cardiovascular events, respiratory failure, pneumonia, deep vein thrombosis or pulmonary embolism (DVT/PE), acute kidney injury, gastrointestinal events, urinary tract infections, Clostridium difficile infection, and postoperative cognitive dysfunction.
Statistical Analysis
Continuous variables were summarized as the mean ± standard deviation (SD), and categorical variables as frequencies with percentages. The Shapiro-Wilk test was used to assess the normality of continuous variables. Student’s t-test was used to compare normally distributed continuous variables between the two groups, while the Mann–Whitney U test was applied for non-normally distributed continuous variables. Categorical variables were compared using Fisher’s exact test. As a subgroup analysis, factors associated with successful fusion were analyzed by multiple logistic regression. In addition to age and sex, variables with a P-value <0.1 in the univariable analysis were included in the multivariable model. Statistical significance was defined as P < 0.05. All analyses were performed using R software (version 4.4.2).
This study was approved by the University of Louisville Institutional Review Board and was deemed exempt from review (HSPPO#23.0721) with a waiver of Informed Consent.
Results
Of the 270 patients screened, 133 met the inclusion criteria (Figure 1). A sensitivity analysis was conducted for 90 patients who were excluded due to incomplete follow-up or use of ABM/P-15. There were no significant differences in demographic or surgical characteristics between included and excluded patients. Patient Flow
Comparison of Patient Demographics and Surgical Data in Total Cohort
CKD, chronic kidney disease; HIV, human immunodeficiency virus; VBR, vertebral body replacement; rhBMP-2, recombinant human bone morphogenetic protein-2; DBM, demineralized bone matrices; EBL, estimated blood loss; LOS, hospital length of stay.
Comparison of Outcomes and Complications Between Patients Who Received BMP in the Anterior Column (BMP_Anterior) and Those Who did HOt (Non- BMP_Anterior)
ASD, Adjacent Segment Disease.
Comparison of Outcomes and Complications Between Patients Who Received BMP in the Posterior Column (BMP_Posterior) and Those Who did Not (Non-BMP_Posterior)
ASD, adjacent segment disease.
Comparison of Outcomes and Complications Between Patients Who Received rhBMP-2 in Both the Anterior and Posterior Columns (BMP_Anterior/Posterior) and Those Who did not (Non-BMP)
ASD, Adjacent Segment Disease.
Univariate and Multivariate Analyses of Factors Associated With Fusion
CKD, chronic kidney disease; HIV, human immunodeficiency virus; VBR, vertebral body replacement; rhBMP-2, recombinant human bone morphogenetic protein-2; DBM, demineralized bone matrices; EBL, estimated blood loss; LOS, hospital length of stay.
Discussion
This is the largest study to evaluate surgical outcome and complications in patients who underwent surgical intervention for spondylodiscitis with the use of rhBMP-2. Our findings suggest that the use of rhBMP-2 does not increase the risk of implant-related or medical complications and may be associated with successful fusion even in a challenging infected environment.
The rhBMP-2 plays an important role in bone remodeling and homeostasis. Its primary osteoinductive mechanism involves promoting the differentiation of mesenchymal stem cells into osteoblasts.23-25 In addition, rhBMP-2 can stimulate other molecular pathways, including the production of inflammatory cytokines—such as interleukins and tumor necrosis factor—and the activation of osteoclasts via the receptor activator of nuclear factor kappa-B.26,27 These pathways may contribute to unwanted effects related to rhBMP-2 use in spine surgery.12-15
There are five institution-based studies, evaluating the impact of rhBMP-2 use in the surgical treatment of spondylodiscitis; however, these studies are limited by small sample sizes, ranging from 14 to 57.18-22 Similar to the previous reports, our results showed that rhBMP-2 use in patients with spondylodiscitis was not associated with an increased risk of recurrence or postoperative complications. Although Sharma et al 28 reported lower complication rates and shorter hospital stays associated with rhBMP-2 use in a national database study of 2760 patients, our results did not demonstrate these benefits.
This study demonstrated a favorable fusion rate of 90% in patients who received rhBMP-2 and successful fusion was associated with the use of rhBMP-2 in both the anterior and posterior columns (OR = 9.93, 95% CI: 1.90 - 77.7, P = 0.012). Evidence suggests that rhBMP-2 may be beneficial even in the presence of infection or a contaminated environment. Southwood et al 29 demonstrated that BMP-2 gene transfer enhanced more rapid and robust bone healing in a rabbit model of infected femoral defect. Govender et al 30 conducted a prospective randomized study demonstrating that rhBMP-2 promoted both bone fusion and wound healing in patients with open tibial fractures. In the field of spine surgery, Miller et al 31 reported a trend toward increased fusion rates with rhBMP-2 use in a rabbit model of infected posterolateral lumbar fusion in their prospective randomized controlled animal study. Although the mechanism remains unclear, explanations for the potential benefits of rhBMP-2 in an infective environment include not only osteoinduction but also angiogenesis through the activation of vascular endothelial cells. 32 Increased blood supply enhances oxygen supply as well as the delivery of nutrients, immune cells, and local antibiotic concentrations, creating an environment favorable for infection eradication and bone fusion.33,34
This study has several limitations. First, it was a retrospective analysis conducted at a single institution. Second, the sample size was relatively small, resulting in limited statistical power to detect differences. Lastly, the type and dose of graft materials were not standardized, and the potential for selection bias or synergistic effects with other bone graft materials cannot be excluded. 35 Despite these limitations, our study provides meaningful insight into the surgical outcomes and complications associated with rhBMP-2 use, helping to address a gap in the current literature. Further large-scale and prospective randomized controlled studies are required to evaluate the efficacy and safety of rhBMP-2 in the treatment of spondylodiscitis.
Conclusion
The use of rhBMP-2 use was not associated with increased complications and may support fusion, even in the setting of active spondylodiscitis.
Footnotes
Author Note
The manuscript submitted contains information on off-label use of recombinant human bone morphogenetic protein-2.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
IRB Protocol
This study was reviewed by the University of Louisville Institutional Review Board.