Evaluations of minimally invasive transforaminal lumbar interbody fusion performed with rhBMP-2

morphogenetic protein, rhBMP-2, Degenerative lumbar disease, Radiographic outcome. Abstract Background: The of and recombinant human bone morphogenetic protein 2 (rhBMP-2) is widely used for its advantage of rapid recovery and improved bone fusion. However, no previous study has reported the synergistic effect of MIS-TLIF with rhBMP-2 in patients with degenerative lumbar disease (DLD). Objective: To investigate the radiographic and patient-reported outcomes (PROs) in patients with DLD who underwent MIS-TLIF with and without a low dose of rhBMP-2. Methods: We retrospectively reviewed 48 patients treated with MIS-TLIF from 2013 to 2016. The patients were classified into the rhBMP-2 group (n = 25) and non-rhBMP-2 group (n = 23). Fusion-related parameters were measured before and after the operation. Clinical data included the numeric rating scale (NRS) score, Japanese Orthopedic Association (JOA) scores, and the MOS 36-item short form health survey (SF-36) score, which were documented to evaluate the effect of surgery. Results: In the 48 patients who underwent MIS-TLIF, the operated disc was predominantly at the L4/5 and L5/S1 levels. ADH, MDH, and PDH increased significantly in both groups after surgery (P < 0.05). FH improved in the rhBMP-2 group, but not in the non-rhBMP-2 group. There was no obvious improvement in SA in both groups. Furthermore, the SL showed a significant difference in both groups and a significant improvement over the baseline. The LL showed significant improvement in the two groups at the early follow-up (P < 0.05), but the improvement did not persist. Cage subsidence had no significant effect on different subsidence grades. In addition, no differences in cage subsidence were observed in different types of modic change (MC), except for MC 0 in both groups. There was no difference in PROs even though all clinical outcomes improved significantly during the postoperative follow-up period in both groups. Conclusion: MIS-TLIF radiologic possible these parameters

Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF), Bone morphogenetic protein, rhBMP-2, Degenerative lumbar disease, Radiographic outcome. possibility of surgical site infection, and alleviation of adjacent segment degeneration. [1] Additionally, the TLIF procedure shows advantages in the treatment of degenerative diseases because of its ability to preserve the bony structure and pars interarticularis and restore the intervertebral height, foraminal height (FH), and segmental lordosis. [2] However, cage migration within the disc space may cause progressive spinal deformity and narrowing disc space or even intraoperative injuries. [3] BMP is a member of the TGF β superfamily and promotes bone formation by regulating cell differentiation and matrix synthesis. [4] Administration of rhBMP-2, a subtype of BMP, has been combined with the MIS-TLIF procedure due to higher integration rates. [5] However, no previous studies have investigated the radiologic parameters and clinical outcomes of rhBMP-2 administration in the MIS-TLIF procedure. Prior literature demonstrated the presence of adverse effects, such as pseudarthrosis and ectopic bone formation, in many patients. [6] Other studies have further stratified the relationship between clinical outcomes and rhBMP-2 dosage.
[7] Although promising results were obtained in rhBMP-2-assisted spinal fusion, the effect was poor since researchers failed to control the confounding variables because of the lack of a specific protocol to evaluate the outcome of surgery.
[8] However, recent literature has documented that distinct radiographic changes can be assessed to evaluate the effect of rhBMP-2-assisted spinal fusion. Fusion-related sagittal parameters, cage subsidence, and MC can be well detected on CT or MRI. Jang et al. suggested that there is a relationship between sagittal parameters, cage subsidence, and clinical outcomes in degenerative cervical disease.
[9] However, the radiographic sagittal parameters of MIS-TLIF performed with and without rhBMP-2 in the disk space have not been fully evaluated.
In the current study, we reviewed our experience with MIS-TLIF to elucidate the effect of rhBMP on the sagittal parameters, cage subsidence, and MC of the operated segment. We aim to explore potential relationships between use of rhBMP-2 and improvement in radiologic parameters and clinical outcomes. Further, possible correlations of these parameters were investigated.

Methods
This study identified 48 patients who had complaints of low back pain or neurologic symptoms. Data for age, gender, and operated level were collected from inpatient medical records. Single or two-level MIS-TLIF procedures were performed on all patients from March 2013 to February 2016. This protocol was approved by the ethics committee of the Affiliated People's Hospital with Jiangsu University. All patients gave written informed consent for their information to be stored in the hospital database and used for research. This study was conducted according to the principles expressed in the Declaration ofHelsinki. Our exclusion criteria were as follows: spinal fracture, lumbar infection and tumor, prior history of lumbar surgery, and MIS-TLIF operated on levels above the lumbar spine. A total of 25 patients received additional rhBMP-2 treatment (rhBMP-2 group), while 27 patients did not receive rhBMP-2 treatment (non-rhBMP-2 group). We collected clinical data from inpatient medical records, pre-and postoperative plain radiographs, and postoperative CT or MR images. All patients were contacted by cellphone to collect missing information. Demographics and procedure data listed in Table 1 were recorded prospectively for both groups.

Radiologic outcome evaluation
We measured anterior disc height (ADH), middle disc height (MDH), posterior disc height (PDH), segmental angle (SA), segmental lordosis (SL), and foraminal height (FH) of the operated levels and lumbar lordosis (LL) on pre-and postoperative radiographs to quantify the postoperative distraction of disc height and indirect decompression. We evaluated disk height by measuring the ADH, MDH, and PDH. The ADH was defined as the distance between the anterosuperior edge and the anteroinferior edge, PDH was defined as the distance between the posterior inferior edge and the posterosuperior edge, whereas the MDH was defined as the distance from the inferior endplate to the superior endplate at the midpoints of the vertebral body. The SA was defined as the angle between the superior endplate and the inferior endplate of the operated level. The SL was the angle between the superior endplate and the inferior endplate of the segment. The LL was defined as the angle between the superior endplate of L1 and the superior endplate of S1. (Figure 1) Cage subsidence was evaluated by measuring migration of the cage into the endplate. Cage subsidence was defined as a mean of the sum of the left and right cage subsidence on CT ( Figure 2).

Clinical outcome evaluation
Pain and functional results were documented during the preoperative period and 1, 3, 6, and 12 months postoperatively to evaluate the clinical outcomes. The clinical results included numeric rating scale (NRS) scores, Japanese Orthopedic Association (JOA) scores, and the MOS 36-item short form health survey (SF-36) scores. The NRS scores were adopted to evaluate the intensity of low back pain as well as leg pain. The JOA and SF-36 scores were used to evaluate the daily functionality of patients.

Statistical analyses
We performed data analysis with SPSS (version 21.0, SPSS Inc, Chicago, IL). We compared the preand postoperative radiologic and clinical outcomes with independent and paired Student t-tests. The mean values of the two groups were compared by one-way ANOVA. We calculated the correlation between the variables using Pearson correlation coefficients and Spearman correlation coefficients.
values less than 0.05 were considered statistically significant.

Results
The patients presented with spondylolisthesis, spinal stenosis, and recurrent disc herniation. Both groups showed no significant difference with respect to mean age and gender distribution. (Table 1)

Radiologic evaluation
The postoperative ADH, MDH, and PDH at early follow-up differed significantly from the preoperative Our results revealed a stronger correlation between ADH and MDH (r = 0.660; P = 0.001). The MDH was correlated with the PDH (r = 0.656; P = 0.001). The PDH was correlated with the FH (r = 0.449; P = 0.024). The FH was correlated with the NRS leg (r = 0.476; P = 0.016). The SA was correlated with the SL (r = 0.427; P = 0.033). The SL was also correlated with the LL (r = 0.478; P = 0.016), NRS back (r = 0.427; P = 0.033), and NRS leg (r = 0.409; P = 0.043). The LL was correlated with the NRS back (r = 0.400; P = 0.048). Cage subsidence or MC were not related to postoperative sagittal parameters (Data not shown). (Table 3)

Fusion rate
Many studies assessing long-term follow-up data have shown that poor bone fusion results in degeneration of the vertebral body, functional disability, lumbar spine instability, and pain. [16,17] We observed a higher fusion rate in the rhBMP-2 group than in the non-rhBMP-2 group, which was consistent with prior studies reporting a higher fusion rate compared with autologous bone grafts. [18] Vaidya et al. demonstrated that radiologic signs of fusion in patients receiving allografts and rhBMP-2 appeared earlier than those in patients not receiving rhBMP-2, with the signs appearing at 6 and 19 months, respectively. However, the exact time of fusion is difficult to determine because it is unrealistic for return visit patients to undergo surgical reexploration in the short time interval after surgery. We confirmed that application of low doses of rhBMP-2 leads to a significantly different fusion rate between both groups at 3 months postoperatively. Radiographic evidence of reexploration for recurrence of pain suggests that the cage was securely fused by 8-12 weeks, which indicates that the actual process began sooner than that detected on radiography. [19]

Sagittal parameters
Previous studies demonstrated that disc degeneration causes an increase in ADH and PDH. [20,21] Hsieh et al. found that SL decreased at the operated segment. [22] The compensatory increase in PDH relative to the increase in ADH led to the maintenance of the SL. Biomechanical research has suggested that procedures improve the disc height and FH deficits caused by disc degeneration. [23] We found a significant increase in ADH, MDH, and PDH at the operated level in both groups. The disc height and FH in the rhBMP-2 group decreased more significantly than that in the non-rhBMP-2 group.
Further, recent studies involving MIS-TLIF evaluated SL and presented variable results. Some reported an insufficient ability of MIS-TLIF to restore SL at the surgical level, whereas others showed substantial increases in SL. We found a significant increase in LL in patients with DLD, which was consistent with a previous study that confirmed that the interbody fusion is highly effective in improving LL. [24] Some investigators demonstrated an association between postoperative LL and better clinical outcomes.
Previous studies evaluated short-and long-term complications associated with off-label rhBMP-2 use with TLIF. Some studies suggest that these complications may be dose-positive, and the higher the dose, the greater the probability of complications. [25] Complications and results were analyzed by BMP dose and primary versus revision surgery. Based on these results, surgical technique and rhBMP-2 dose recommendations were proposed.

Disc height restoration
No consensus regarding the results of the restoration of disc height was reached. Liu et al. suggested that the improvement in disc space height plays a vital role in facet joint subluxation. [26] Kaito et al.
proposed that the distraction of disc space was a potent risk factor for the progression of adjacent segment disease (ASD), which may affect clinical outcomes of patients. [27] Michael C et al. found that disc height restoration was positively associated with segmental lordosis. [28] Our results are the first to investigate the effect of rhBMP-2 in the restoration of disc height. However, even though rhBMP-2 slightly slowed down restoration of disc height and FH to some extent, we did not find any significant differences in the two groups.
Biomechanical studies have proven that diminished LL may increase the risk of ASD. [29] Kepler et al.
reported that the decrease in LL was related to worse clinical outcomes, which was consistent with our results. [30] Hence, our results showed that rhBMP-2 increased postoperative SL and LL by 0.9°a nd 3.1°, thus improving clinical outcomes by restoring sagittal alignment. Some researchers found a relationship between restoration of LL and improvement in clinical outcomes.
[31] However, the relationship between radiographic improvement and clinical outcomes was not found in the current study. Postoperative maintenance of the SL may lead to a compensatory gain of adjacent segment lordosis, which is confirmed by the correlation between the postoperative LL and the SL of the adjacent levels.

Clinical outcome
Even though all clinical outcomes improved significantly in the two groups, we found no significant difference between the groups. We demonstrated that the degrees of sagittal correction, fusion rates, and incidence of cage migration were not related with clinical outcomes in the first 12 months postoperatively. Compared with prior studies, our procedure integrated the advantages of MIS-TLIF and rhBMP-2 and confirmed that MIS-TLIF combined with rhBMP-2 is a better choice for lumbar degenerative disease.

Limitations
Some limitations could not be avoided in this retrospective study. First, as the properties of L4-5 and L5-S1 are different in terms of their contribution to disc height, FH, SA, and the dimensions of the disc space, the bias resulting from the different numbers of operated levels could not be avoided. Second, our sample size was too small to obtain an accurate evaluation of the results. Third, long-term postoperative clinical assessment data were unavailable because some patients were lost to followup, making it impossible to reliably assess the clinical outcome of surgery. Fourth, our results did not identify the optimal rhBMP-2 dose in DLD surgeries. Prospective, randomized clinical trials are needed to determine the optimal rhBMP-2 dosage and complications.

Conclusions
We conclude from this research that single-level MIS-TLIF combined with or without rhBMP-2 significantly increased the ADH, MDH, and PDH but not the SL. However, LL shows a slight but significant improvement resulting from an increase in the cranial SL. A higher fusion rate was observed in the rhBMP-2 group. However, intraoperative use of rhBMP-2 in the MIS-TLIF procedure has no effect on postoperative clinical outcomes since the NRS scores, JOA scores, and SF-36 scores in both groups were not statistically different. The study was approved by the Ethics Committee of the Affiliated People's Hospital of Jiangsu University; due to the retrospective nature of the study, the need for informed consent was waived.

Consent for Publication
Not applicable.

Availability of data and material
All data has been showed in tables and picutres.

Competing interests:
The authors declare that they have no conflict of interest.        Differences are statistically significant if P < 0.05.