|Year : 2019 | Volume
| Issue : 1 | Page : 1-7
Long-term effects of inorganic osteogenesis-inducing scaffold versus autologous bone in lumbar interbody fusion: a non-randomized controlled study
Zhi-Xing Xue, Jian-Wei Zhou, Cheng Chi, Fei Wang, Yu-Quan Ma
Department of Orthopedics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
|Date of Submission||28-Dec-2018|
|Date of Acceptance||30-Jan-2019|
|Date of Web Publication||13-Mar-2019|
Department of Orthopedics, Beijing Tongren Hospital, Capital Medical University, Beijing
Source of Support: None, Conflict of Interest: None
Background and objective: Lumbar interbody fusion is the main surgical repair method for lumbar degenerative diseases. The best material for interbody fusion is autologous ilium, but its use is limited because of limited sources. Furthermore, autologous ilium implantation leads to the formation of osteophytes, which negatively affect bone healing. Inorganic osteogenesis-inducing scaffold material exhibits good biocompatibility and bone-inducing effects in posterior lumbar interbody fusion, with encouraging short-term outcomes. The present study will investigate the safety and long-term effects of inorganic osteogenesis-inducing scaffold materials versus autologous ilium in lumbar interbody fusion.
Subjects and methods: This prospective, single-center, non-randomized, controlled trial will include 120 patients who receive treatment for lumbar degenerative diseases at the Department of Orthopedics, Beijing Tongren Hospital, Capital Medical University, China. These patients will receive lumbar repair surgery with inorganic osteogenesis-inducing scaffold materials (test group, n = 60) or autologous ilium (control group, n = 60). All patients will be followed up at 1 week, and 1 and 2 years postoperatively. This study was approved by the Medical Ethics Committee, Beijing Tongren Hospital, Capital Medical University, China (approval No. TRECKY2017-158) on September 28, 2017. Study protocol version: 1.0. All participants will provide written informed consent after fully understanding the study protocol.
Results: The primary outcome measure of this study is the Oswestry Disability Index at 2 years postoperatively. The secondary outcome measures are the Oswestry Disability Index preoperatively and at 1 week and 1 year postoperatively, the Visual Analog Scale score, Japanese Orthopedic Association score, and lumbosacral angle preoperatively and at 1 week, and 1 and 2 years postoperatively, and the incidence of adverse reactions at 1 week, and 1 and 2 years postoperatively. A pilot study involving 52 patients with lumbar degenerative diseases treated during 2016–2017 revealed no significant differences between the test (n = 32, 61%) and control groups (n = 20, 39%) in the Oswestry Disability Index, Visual Analog Scale score, and Japanese Orthopedic Association score at 1 week postoperatively; at 12 months postoperatively, plain radiography revealed bony fusion in both groups.
Conclusion: This study will provide evidence to validate whether inorganic osteogenesis-inducing scaffold material results in similar long-term outcomes to autologous ilium in lumbar interbody fusion.
Trial registration: This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1900021333) on February 15, 2019.
Keywords: lumbar interbody fusion; posterior lumbar interbody fusion internal fixation; intervertebral foramen; lumbar degeneative disease; inorganic osteogenesis-inducing scaffolds; non-randomized controlled study
|How to cite this article:|
Xue ZX, Zhou JW, Chi C, Wang F, Ma YQ. Long-term effects of inorganic osteogenesis-inducing scaffold versus autologous bone in lumbar interbody fusion: a non-randomized controlled study. Clin Trials Orthop Disord 2019;4:1-7
|How to cite this URL:|
Xue ZX, Zhou JW, Chi C, Wang F, Ma YQ. Long-term effects of inorganic osteogenesis-inducing scaffold versus autologous bone in lumbar interbody fusion: a non-randomized controlled study. Clin Trials Orthop Disord [serial online] 2019 [cited 2019 Jul 23];4:1-7. Available from: http://www.clinicalto.com/text.asp?2019/4/1/1/253723
| Introduction|| |
Lumbar interbody fusion is an effective treatment for lumbar degenerative diseases.,,, The optimal implant material for interbody fusion is autologous ilium, but its use is limited in clinical application because of limited sources and excessive injury caused during harvesting.,,, Although decompressed autologous bone is widely used for interbody fusion, the small joints and laminar bones that are cut at the time of decompression from patients with lumbar degenerative diseases often have hyperplastic epiphyses, which may inhibit their osteogenic activity and bone healing potential. Allogeneic bone grafts are also not ideal, as they carry a risk of allergic reaction and disease transmission. As an alternative to bone grafts, biosynthetic materials such as inorganic osteogenesis-inducing scaffold material exhibit good biocompatibility and osteoinductive effects.,, However, little has been reported on the application of biosynthetic materials in lumbar interbody fusion.
The PubMed database was searched for relevant articles published during 2014–2018 using the search terms lumbar fusion AND implant material AND lumbar degeneration disease. The three most recent articles,, regarding lumbar interbody fusion for the treatment of lumbar degenerative diseases are summarized in [Table 1].
|Table 1: Three most representative clinical studies on lumbar interbody fusion for treatment of lumbar degenerative diseases published during 2014–2018|
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Results from a pilot study revealed that the use of inorganic osteogenesis-inducing scaffolds in posterior lumbar interbody fusion through the intervertebral foramen can achieve similar intervertebral fusion and clinical efficacy to that achieved with autologous bone. However, although the clinical efficacy of inorganic osteogenesis-inducing scaffolds for lumbar interbody fusion in lumbar degenerative diseases is satisfactory at 1 year postoperatively, the long-term efficacy has not yet been reported.
The objective of this study is to further investigate the long-term efficacy of inorganic osteogenesis-inducing scaffold material versus autologous ilium for lumbar intervertebral bone fusion.
| Participants and Methods|| |
A prospective, single-center, non-randomized, controlled, 2-year follow-up trial.
Beijing Tongren Hospital of Capital Medical University, China.
Each surgeon responsible for performing posterior lumbar interbody fusion and imaging evaluation will have received professional medical training, have a professional title of associate chief physician or higher, and have 5–10 years of clinical experience in orthopedic surgery.
Prior to recruitment, the study protocol and recruitment advertisement will be approved by the Beijing Tongren Hospital of Capital Medical University. Leaflets containing recruitment information will be handed out in Beijing Tongren Hospital of Capital Medical University. Interested patients or their family members will contact the investigators responsible for subject recruitment, and provide the patient's name and telephone number. In accordance with applicable regulations and laws, patients or their family members will be informed of the study protocol details. Trial involvement will be voluntary. Eligible patients will be included after providing written informed consent.
During the trial, patients will have access to the latest treatment information and will receive free close follow-up monitoring by the professional medical teams in Beijing Tongren Hospital. In addition, related imaging examinations and registration will be performed without charge.
- Patients with lumbar degenerative diseases confirmed on anteroposterior and lateral radiographs and MRI examination of the lumbar spine, including lumbar spinal stenosis and lumbar spondylolisthesis, and those with lumbar disc herniation undergoing decompression by fenestration
- Lower back pain and lower extremity nerve root pain at the time of treatment
- Age 40–75 years, of either sex
- Single segment fusion repair
- Provision of written informed consent
- Lumbar spine trauma
- Severe infection
- Bone tumor
- Space-occupying lesion in the pelvis
- Pathological fracture
- Severe cardiovascular disease that prohibits surgery
Compensation to patients
Patients participating in this clinical trial must have inpatient medical insurance, and most of the medical expenses during hospitalization will be paid by the insurance company in accordance with the agreed ratio. The medical expenses mainly comprise the hospitalization fees. The hospitalization insurance premium will be paid in accordance with the actual insured bed cost, and the daily payment limit and the maximum length of hospitalization will be specified. For the miscellaneous expenses and surgical expenses incurred by the insured for each hospitalization, the contract validity is terminated when the accumulated insurance premium reaches the total amount of insurance specified in the medical insurance contract, and the remaining medical expenses will be paid by the patient.
Randomized grouping will not be used in this study. Grouping will be performed according to different types of repair materials.
The investigators responsible for outcome evaluation will be blinded to the study protocol.
Implant information is shown in [Table 2].
Patients will be in prone position. After the induction of general anesthesia and routine sterilization, a posterior median incision will be made. The periosteum will be dissected downward along the bilateral spinous processes to the lateral margins of the bilateral facet joints. Pedicle screws will be implanted in the corresponding surgical segments. On the symptomatic side, interbody fusion will be performed using interbody fusion cages (Johnson & Johnson, USA). After pedicle screw implantation, a connecting rod will be used on the opposite side to the interbody fusion to appropriately expand the intervertebral space and decompress the symptomatic side. After discectomy, the upper and lower endplates will be treated. An osteotome will be used to remove the medial edge and tip of the inferior articular process of the superior vertebrae and the upper articular process of the inferior vertebrae. After cutting open the intervertebral disc, the nucleus pulposus will be removed and the upper and lower end plates will be treated with a reamer. The cartilage plate will be scraped using an annular spatula, and the endplate will be further treated to remove as much cartilage as possible.
In the test group, inorganic osteogenesis-inducing scaffold material 1 g (Osteobone™, China Jiangsu Yenssen Biotech Co., Ltd.,) will be implanted in the interbody interspace for bone fusion. In the control group, the decompressed vertebral plate and facet joints will be cut into 3 mm × 3 mm × 3 mm granules and implanted into the intervertebral space. During the resection process, osteophytes and articular surface tissue will be removed as much as possible. Cancellous bone will be implanted as much as possible. If there is insufficient cancellous bone, cortical bone will be implanted in the intervertebral space. After intervertebral fusion, the pedicle screw on the ipsilateral side will be pressurized to adequately close the intervertebral space. If necessary, contralateral spinal canal decompression will be performed. After rinsing, a wound drainage tube will be placed before closure of the incision.
After surgery, routine infection prophylaxis and hydration will be performed, followed by hormonal therapy and neuropharmacological treatment. The drainage tube will be removed 36–48 hours postoperatively. Patients will be encouraged to commence physical activities from 2–5 days postoperatively.
Patients will be followed up at 1 week, and 1 and 2 years postoperatively. Outcomes will be assessed at each follow-up examination.
Primary outcome measure
The primary outcome measure will be the Oswestry Disability Index (ODI) at 2 years postoperatively. The ODI covers 10 domains, including pain intensity, personal care, lifting, walking, sitting, standing, sleeping, sex life, social life, and traveling. Each domain is assigned a score ranging from 0 to 5. If responses are recorded for all 10 domains, the formula used will be: actual score/45 (possible highest score) × 100%. A higher score indicates more severe dysfunction.
Secondary outcome measures
- ODI scores preoperatively, and at 1 week and 1 year postoperatively; scoring criteria are the same as for the primary outcome measure.
- Visual Analog Scale scores preoperatively, and at 1 week, and 1 and 2 years postoperatively; the score ranges from 1 to 10, with higher scores indicating more severe pain.
- Japanese Orthopedic Association (JOA) scores preoperatively, and at 1 week, and 1 and 2 years postoperatively. The JOA score ranges from 0 to 29, and is used to evaluate the symptom improvement rate. A lower JOA score indicates more obvious dysfunction.
- Lumbar lordosis (L1–S1) evaluated on plain radiography preoperatively, and at 1 week, and 1 and 2 years postoperatively. Standard lateral lumbar radiographs will be used to measure Cobb's angle between the upper endplate of L1 and the upper endplate of S1. Lumbar lordosis will be recorded as positive, while lumbar kyphosis will be recorded as negative. The criteria for interbody fusion will be lumbar over-flexion and hypertension of less than 4°.
- Incidence of adverse reactions at 1 week, and 1 and 2 years postoperatively. Possible adverse reactions include dural tear, nerve root traction, interbody fusion cage collapse, interbody fusion cage displacement, and intervertebral space infection. The incidence of adverse reactions = (the number of patients with adverse reactions/total number of patients) × 100%.
Schedule for primary and secondary outcome measures is shown in [Table 3].
Data authenticity management
Patients' baseline data, outcome measures, and other trial data will be collected retrospectively, and will be recorded on the case report forms.
The data recorded on the case report forms will be inputted into the database using a double-entry strategy, and will be password-protected. With the exception of the investigators, no person has the right to access the trial data.
Data quality control
During the clinical trial, the clinical monitor must visit the trial site on a regular basis or in response to a specific situation to conduct clinical audit work.
Study protocol modification
During the trial, research personnel may not modify the content of the study protocol (such as the inclusion criteria, outcome indicators, and data analysis) without the permission of the investigators in charge.
After rechecking the data accuracy, the results of patients with lumbar degenerative disease will be audited by data managers, principle investigators, and clinical monitors.
The investigators confirm and support the principle that the patients have the right to protect their privacy from infringement. At all stages of the study, patient data will be identified only by the patient's identifier and initials, and the patient's personal information will be strictly confidential.
This study was approved by the Medical Ethics Committee, Beijing Tongren Hospital, Capital Medical University, China (approval No. TRECKY2017-158) on September 28, 2017 (Additional file 1[Additional file 1]). This study will be performed in strict accordance with the Declaration of Helsinki. Study protocol version: 1.0. This manuscript was prepared in accordance with the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) statement (Additional file 2[Additional file 2]).
All patients will provide written informed consent for study participation (Additional file 3[Additional file 3]).
Sample size calculation
Approximately 60 patients with lumbar degenerative disease undergo lumbar fusion surgery each year at Beijing Tongren Hospital of Capital Medical University, China. Recruitment is scheduled to occur from August 30, 2019 to August 30, 2021, and it is estimated that at least 100 patients will be recruited. Assuming a patient loss rate of 20%, we will require 60 patients per group.
All data will be statistically analyzed using SPSS 22.0 software (IBM, Armonk, NY, USA). Measurement data will be expressed using the mean, standard deviation, median, minimum and maximum values, and upper and lower quartiles. Count data will be statistically described using the number and percentage. The two sample t-test (for normally distributed data) or the Mann-Whitney U test (for non-normally distributed data) will be used to compare the ODI, Visual Analog Scale score, JOA score, and lumbar lordosis (Cobb's angle between L1–S1) between the test and control groups at each timepoint. Repeated measures analysis of variance and the Least Significant Difference test will be used to compare the abovementioned indices among different time points within each group. The Pearson's chi-square test will be used to compare the incidence of adverse reactions between the two groups. An inspection level of α = 0.05 (two-tailed) will be considered to indicate a significant difference.
| Results|| |
Study flow chart
Flow chart of interventions is shown in [Figure 1].
Estimated subject recruitment
According to previous subject recruitment in our hospital (approximately 60 patients per year), it is estimated that at least 100 patients will be recruited.
Before surgery, each subject's baseline information will be recorded in detail, including age, sex, type of disease, etiology, and number of injured lumbar segments.
All abovementioned scores and the incidence of adverse reactions during follow-up will be recorded.
Anticipated adverse reactions
The main adverse reactions include dural tear, nerve root traction, interbody fusion cage collapse, interbody fusion cage displacement, and intervertebral space infection.
Pilot study results
A pilot study involving 52 patients with lumbar degenerative disease was performed during 2016–2017. The test group (n = 32) received lumbar fusion with inorganic osteogenesis-inducing scaffold material, while the control group (n = 20) received lumbar fusion with vertebral plate and small joint bone tissue fragments resected during decompression. All repair operations comprised single segment fusion [Table 4].
There were no significant differences between the test and control groups in the ODI, Visual Analog Scale score, and JOA score at 1 year postoperatively (P > 0.05). Plain radiography showed that intervertebral fusion was achieved at 12 months postoperatively in both groups.
Adverse reactions occurring during follow-up will be recorded. During follow-up, we will record the onset time, type, and measures required for possible adverse reactions, including dural tear, nerve root traction, interbody fusion cage collapse, interbody fusion cage displacement, and intervertebral space infection. These findings will be reported to the principle investigator and the ethics committee within 24 hours.
| Discussion|| |
Because of the restrictions of the experimental conditions, it is impossible to perform randomization and blinded grouping, which may influence the accuracy of the results.
Little has been reported on the biocompatibility of inorganic osteogenesis-inducing scaffold materials with nerve tissue. This study aims to provide evidence to validate the hypothesis that lumbar fusion with inorganic osteogenesis-inducing scaffold materials does not lead to large-scale nerve stimulation and irreversible nerve injury. If inorganic osteogenesis-inducing scaffold material exhibits good nerve tissue biocompatibility and shows similar reparative effects to autologous ilium, its use deserves to be clinically generalized.
A good bone graft substitute requires a graft with good osteoinductive and osteogenic capabilities and a stable biological environment for osteoblast differentiation. Allogeneic bones are widely available and can promote bone healing by inducing osteogenesis and initiating the “crawling replacement” mechanism. Allogeneic bones are an ideal substitute for bone grafts,, while an exogenous graft may cause immunological rejection. Although the chances of immunological rejection have been substantially reduced by advances in cryopreserved bone and freeze-dried bone technology, they have not been completely eliminated. The nano-scale micropore morphology of the inorganic osteogenesis-inducing scaffold material increases the specific surface area, which is beneficial for osteoinduction, facilitates platelet aggregation, and promotes coagulation function; thus, inorganic osteogenesis-inducing scaffold material is suitable for surgical application. The pilot study results revealed that intervertebral fusion with inorganic osteogenesis-inducing scaffold material resulted in a significant improvement in lumbar lordosis. This suggests that the intervertebral fusion obtained by the inorganic osteogenesis-inducing scaffold material can effectively maintain the lumbar lordosis, and that the repair effect is equivalent to that of autologous bone.
Date of registration: February 15, 2019.
Recruitment: August 30, 2019 to August 30, 2021.
Study completed: September 30, 2021.
Trial status: Active, not recruiting.
Additional file 1: Hospital Ethics Approval (Chinese).
Additional file 2: TREND Checklist.
Additional file 3: Informed Consent Form (Chinese).
Study design and protocol authorization: ZXX; patient recruitment: JWZ and CC; data collection and analysis: FW and YQM. All authors approved the final version of this manuscript.
Conflicts of interest
All authors declare that they have not received relevant financial support and that there are no conflicts of interest.
Institutional review board statement
This study was approved by the Hospital Ethics Committee, Bejing Tongren Hospital, Capital Medical University, China (approval No. TRECKY2017-158) on September 28, 2017, and will be performed in strict accordance with the Declaration of Helsinki.
Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the forms, the patients will give their consent for patients' images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
This manuscript was prepared in accordance with the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) statement.
The statistical methods of this study were reviewed by the biostatistician of Beijing Tongren Hospital, Capital Medical University, China.
Copyright license agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Data will be available immediately following publication, with no end date. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
Checked twice by iThenticate.
Externally peer reviewed.
C-Editor: Zhao M; S-Editors: Wang J, Li CH; L-Editor: Song LP; T-Editor: Jia Y
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[Table 1], [Table 2], [Table 3], [Table 4]