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Frequency of Change in Assessment from Bony Union to Nonunion after Lumbar Interbody Fusion: A Multicenter Study

Introduction Assessments of early postoperative bony union after posterior lumbar interbody fusion via computed tomography (CT) have revealed cases in which interbody fixation by bony union resulted in nonfusion due to bone absorption. The apparent bone union state reverted to a nonunion state several months later, exhibiting a so-called “fake union” phenomenon. Additionally, few reports have evaluated the effect of teriparatide on bony union. The present study aimed to evaluate the frequency of change in assessment from fusion to nonfusion in the postoperative follow-up of lumbar interbody fusion, compare the late postoperative bony union rates in groups with or without early postoperative fusion, and examine the effect of postoperative teriparatide in those groups. Methods Sixty-nine subjects enrolled from multiple hospitals were prospectively evaluated following single-level lumbar interbody fusion. The patients were randomly allocated into treatment with or without weekly postoperative teriparatide. The subjects were then classified as having bony union or nonfusion at 2 months postoperatively, and fusion rates at 6 months were compared. For the evaluation of bony union, blinded radiological examinations were performed via CT. Additional comparisons were made according to teriparatide use. Results The rate of nonunion at 6 months postoperatively in patients with fusion at 2 months postoperatively was 27.8%. Among subjects with bony union at 2 months postoperatively, the fusion rate at 6 months in those who received teriparatide was 93.3% (p=0.027) versus 57.1% in those who did not. Conclusions The rate of nonunion at 6 months postoperatively in patients exhibiting union at 2 months after surgery was 27.8%. Postoperative weekly teriparatide treatment significantly reduced the rate of fake union.


Introduction
The rapid progression of societal aging has been accom-panied by an increase in lumbar degenerative disease 1) . Posterior (PLIF) or transforaminal lumbar interbody fusion (TLIF) is usually conducted to treat lumbar degenerative disease in the elderly [2][3][4] , although these procedures sometimes fail to achieve bony union 5) . If bone union is not attained after the initial operation, failure rates as high as 40%-70% have been reported for repeat fusion surgery because of the development of pseudarthrosis [6][7][8][9][10] .
In some cases, patients assessed as having early postoperative bony union are subsequently diagnosed as having nonfusion, or a so-called "fake union," several months later. We defined fake union as the phenomenon of bone continuity observed via computed tomography (CT) at 2 months after surgery but not at 6 months after surgery. This process is likely the result of bone absorption that is detectable on CT (Fig. 1). To the best of our knowledge, no reports have addressed the frequency or prevention of fake union.
The present study evaluated bony union at 2, 4, and 6 months after surgery in 69 subjects who underwent singlelevel interbody fusion to determine 1) the frequency of fake union; 2) the relationship between the presence/absence of bony union at 2 or 4 months postoperatively and fusion at 6 months postoperatively, as well as the effect of weekly teriparatide on the fake union in subjects assessed as having fusion at 2 or 4 months postoperatively; and 3) the factors associated with bony union at 2, 4, and 6 months after sur-gery.

Patients and study measures
This was an additional analysis using data obtained by a prior 2) multicenter, prospective, randomized trial to investigate the impact of weekly teriparatide administration on bony union enhancement after PLIF or TLIF for osteoporosis-associated lumbar degenerative disease during the early postoperative period. Patient consent for additional research was obtained in the previous study 2) . The subjects were enrolled from among three university hospitals and their affiliates. The patients were all women aged >50 years having a bone mineral density/young adult mean ratio of < 80% and/or previous spinal compression and/or hip fracture, as well as a lumbar degenerative disease. Single-level PLIF or TLIF was applied to treat lumbar spinal stenosis, degenerative spondylolisthesis, and isthmic spondylolisthesis. Multilevel decompression was performed when necessary, and these cases were included in the study. All subjects were treated using posterior instrumentation with pedicle screws. Posterolateral fusion was not conducted. Interbody spaces were filled by a box cage of polyetheretherketone filled with local bone. Residual bone was discarded. After receiving informed patient consent, we registered each case with an independent central office, which randomly assigned the subjects into treatment groups of either teriparatide once weekly administered subcutaneously starting at week 1 for 6 months postoperatively or no teriparatide treatment. Postoperatively, all patients commenced 1.2 g/day calcium l-aspartate after 1 week as a basic treatment for osteoporosis, wore a soft lumbar corset for 3 months, and performed standardized physical training that included exercises to strengthen back muscles and improve walking.

Evaluation method for bony union
Bony union was assessed by CT and dynamic X-rays at 2, 4, and 6 months postoperatively by four physicians who were blinded to the results using a fusion grading system described by Bridwell 11) . Two CT slices at the center of the cage in both the coronal and sagittal views were used to evaluate bone healing. Each evaluation was conducted by four clinicians (two clinicians each from two universities excluding the university at which the surgery was performed) using CT images. During the initial evaluation, a consensus was achieved after the agreement of " 3 evaluators. If ! 2 evaluators agreed, further evaluation was performed until a unanimous decision.

Radiological assessment
Subjects were classified into either the fusion or nonfusion groups at 2 and 4 months postoperatively, and the fusion rate in each group was determined at 6 months postop-eratively. Additional analyses were conducted according to the use/nonuse of postoperative weekly teriparatide. Baseline characteristics, surgical method and levels, and teriparatide administration after surgery were compared between the fusion and nonfusion groups at 2, 4, and 6 months postoperatively. We also examined for parameters related to bony union at those time points.

Statistical analysis
Analyses were conducted using Fisher's exact test for categorical data and Student's t-test for continuous data. Bony union scores were analyzed using analysis of covariance and adjusted for age as a covariate. For all analyses, the level of significance was set at p<0.05. Statistical testing was conducted independently by three academic medical statisticians. All analyses were performed using SPSS Statistics 24 for Windows (SPSS Inc., Chicago, Illinois, USA).

Overall data
A total of 69 subjects (all female, mean age at surgery: 71.5 years) who completed the evaluation of bony union using dynamic X-rays and three-dimensional CT at 2, 4, and 6 months postoperatively were enrolled. Surgery was performed for degenerative spondylolisthesis in 54 subjects, degenerative scoliosis in two subjects, spinal stenosis in 10 subjects, and isthmic spondylolisthesis in three subjects. Six subjects received osteoporosis treatment before surgery. Table 1 shows the baseline characteristics. PLIF was conducted in 65 patients and TLIF in four patients. No significant post-  operative complications, such as epidural hematoma or surgical site infection, were recorded. Postoperative weekly teriparatide was administered to 36 subjects. The overall bony union rates at 2, 4, and 6 months postoperatively were 51%, 50%, and 46%, respectively ( Table 2).

Rate of fake union
In patients with fusion at 2 and 4 months postoperatively, 72.2% and 73.0%, respectively, also achieved fusion at 6 months (Table 3). Accordingly, the respective rates of fake union in subjects with fusion at 2 and 4 months were 27.8% and 27.0%. Among the patients in the fusion (36 subjects) and nonfusion groups (33 subjects) at 2 months postoperatively, the fusion rates at 6 months were 72.2% and 24.2%, respectively. Therefore, subjects with fusion at 2 months postoperatively were more likely to achieve fusion at 6 months. Table 4 summarizes the additional analysis of fusion rates according to use/nonuse of postoperative weekly teriparatide. Patients receiving weekly teriparatide were more likely to maintain fusion. Of the 36 subjects who achieved fusion at 2 months after surgery, 15 subjects used teriparatide and 21 subjects did not. The numbers of patients achieving bony union with and without teriparatide at 6 months postoperatively were 14 (93.3%) and 12 (57.1%), respectively. Accordingly, the respective rates of fake union in the teriparatide use and nonuse groups were 6.7% and 42.9%. Table 5 shows the associations between predictive factors and bony union at 2, 4, and 6 months postoperatively. The procedure performed (TLIF or PLIF) was not a significant predictor of bony union. The bony union rates including and excluding L5/S were comparable at 57.1% and 48.4%, respectively. The use of weekly teriparatide was not remarkably associated with bony union at 2 or 4 months postoperatively but was significantly related to fusion at 6 months after surgery (p=0.022) (Fig. 2).

Discussion
This study made three important clinical observations regarding bony union after TLIF or PLIF. First, early (2 and 4 months) postoperative bony union was reassessed as nonfusion at 6 months, i.e., fake union, at an unexpectedly high frequency. Second, subjects judged as achieving early postoperative fusion showed higher bony union rates at the final evaluation than did those who did not attain early fusion. Third, although the use of weekly teriparatide was not notably related to bony union at 2 or 4 months postoperatively, it was significantly associated with bony union at 6 months (p=0.022).
Among the subjects assessed as having bony union at 2 months postoperatively, 27.8% were later reassessed as having nonfusion at the final evaluation. More alarmingly, 27.0% of subjects classified as having fusion at 4 months postoperatively were reclassified as having nonfusion at the final time point. We routinely perform follow-up to detect implant failure or screw back-out and determine the need for trunk orthosis until bony union. This study revealed that over a quarter of subjects with fusion at 4 months postoperatively might have had fake union. Hence, patients should be advised of a possibility of nonunion, and careful followup and lifestyle guidance should be continued.
In subjects with bony union at 2 months postoperatively, 72.2% maintained fusion at the final evaluation, whereas only 24.2% of patients with nonfusion at 2 months could achieve fusion at 6 months. Early postoperative CT can predict the likelihood of bony union at the final evaluation and provide the meaningful information needed to establish a treatment plan. However, early postoperative CT images appearing to show bony union may be misread, which instead represents curettage of endplate cartilage or dense bone grafting with the actual bony union not yet present. Fake union is presumed to be a failure of a biological bony union as a result of the reabsorption of the impacted bone graft. Cho et al. performed PLIF on 47 patients with osteoporosis  and evaluated bony union with or without weekly teriparatide use at 24 months postoperatively using Ito's classification 12) . The 6 month postoperative fusion rates with and without teriparatide were 77.8% and 53.6%, respectively. In our cohort, the fusion rates at 6 months postoperatively with and without weekly teriparatide use were lower at 58.8% and 41.2%, respectively. This finding might be attributed to a different evaluation method used in our study, with the fusion grading system by Bridwell 11) being stricter than that of Ito. The overall fusion rate in our study was also lower than that in previous studies, possibly because of the involvement of four evaluators, as described previously 13) . Moreover, the inclusion of women aged ! 50 years in our study population might have decreased the bony union rate 13) . Teriparatide use was not related to bony union at 2 or 4 months postoperatively but was significantly related to fusion at 6 months (p=0.022). Among the subjects assessed as having bony union at 2 months postoperatively, 6.7% who received weekly teriparatide in fact had fake union, whereas 42.9% of those who did not take the drug had fake union. Hence, teriparatide use was associated with a significantly lower fake union rate (p=0.024). No other factors were found to be related to bony union at 2 months postoperatively, suggesting that the occurrence of fusion at that time was related more to the quality of bone graft surgery and less to patient status. Weekly teriparatide administration may promote osteogenesis and increase fusion rates at 6 months 2) . Bone absorption leading to fake union in the early stages (approximately 2-6 months) is typically followed by bone union; teriparatide may help mitigate these initial symptoms. Accordingly, we recommend at least 6 months of continuous weekly teriparatide in women with lower bone density.
Several studies have examined pseudarthrosis and methods to reduce its incidence 12,14) , one of which is the use of teriparatide. Ohtori et al. prospectively analyzed bony union rates after posterolateral lumbar fusion with local bone grafting in patients postoperatively treated with daily subcutaneous injections of 20 μg of teriparatide and revealed a fusion rate of 82% in the teriparatide group and 68% in the oral bisphosphonate group 13) . Similarly, in 2016, our team described that combined lumbar interbody fusion and weekly teriparatide administration could be an option for the management of lumbar degenerative disease in the elderly 2) since the drug was effective in reducing pseudarthrosis. Teriparatide use was not remarkably related to fusion at 2 or 4 months but was significantly associated with fusion at 6 months (p=0.022). Abbreviation: M: months A p-value of<0.05 was defined as statistically significant. *Statistically significant.  ion rates. Lastly, the number of subjects in this study was relatively small.

Conclusion
Subjects assessed as having an early postoperative bony union at 2 months tended to achieve fusion at the final evaluation at 6 months more frequently than those without bony union at an early stage. However, 27.8% of patients with fusion at 2 months postoperatively were reassessed as having nonfusion at 6 months after surgery, a condition considered to be fake union. Hence, careful follow-up remains necessary even with apparent early postoperative bony union. Since postoperative weekly teriparatide significantly reduced the rate of fake union and was significantly associated with bony union at 6 months, the drug may be advisable for improving surgical outcomes.

Conflicts of Interest:
The authors declare that there are no relevant conflicts of interest.

Sources of Funding:
Funding was provided by the Asahi Kasei Pharma Corporation.