Correlation Analysis between Residual Pain after Vertebral Augmentation and the Diffusion Distribution of Bone Cement: A Retrospective Cohort Study

Objective To explore the influence and potential factors of the bone cement dispersion state on residual pain after vertebral augmentation. Methods The cases included in this retrospective cohort study were patients treated with vertebral augmentation (VA) for osteoporotic vertebral compression fractures (OVCFs) between July 2018 and June 2021. According to the type of cement diffusion distribution, the patients were divided into a sufficient diffusion group (Group A) and an insufficient diffusion group (Group B). The differences in the baseline data, visual analog scale (VAS), Oswestry disability index score (ODI), injured vertebral height (IVH), and local kyphosis angle (LKA) between the two groups were analyzed. Assessments were performed preoperatively on the 2nd day postoperation and at the last follow-up. The imaging data of injured vertebrae were accurately reconstructed by a GE AW4.7 workstation, and the differences in the vertebral body volume, bone cement volume, and bone cement volume ratio were compared between the groups. Result After screening, 36 patients were included. (1) The postoperative VAS and ODI scores of the two groups were significantly improved compared with the preoperative scores. (2) On the 2nd day postoperation and the last follow-up, the VAS and ODI scores of Group A were significantly different from those of Group B, and Group A outperformed Group B. (3) The IVH and LKA of the two groups were improved after the operation, and no significant difference was found between the groups. (4) Significant differences were found in the bone cement volume and bone cement volume ratio between the groups, and Group A was larger than Group B. Conclusions Sufficient bone cement diffusion can reduce residual pain after vertebral augmentation.


Introduction
Osteoporotic vertebral compression fractures (OVCFs) occur secondary to osteoporosis [1]. Osteoporosis is characterized by decreased bone mass and bone microstructure destruction, increasing the risk of fragility fractures. OVCFs are one of the most severe fracture types, accounting for approximately 50% of osteoporotic fractures, and have become the third most common fragility fracture worldwide [2,3]. OVCFs are commonly found in the elderly and can lead to chronic pain, motor disorders, spinal deformity, decreased quality of life and increased mortality, seriously afect human physical health and quality of life, and place a heavy burden on families and society [4][5][6]. Currently, conservative treatment usually adopts bed rest, nonsteroidal anti-infammatory drugs, antiresorptive medications, external fxed braces, traditional Chinese medicine functional reduction, and other methods [7]. However, conservative treatment increases the risk of bone nonunion, bedsores, venous thromboembolism, persistent pain, and spinal deformity [8,9]. Terefore, vertebral augmentation (VA) has become a widely accepted, safe, and efective treatment method because of its minimal trauma, short operation time, rapid pain relief, partial restoration of vertebral height, and efective increase in vertebral stability [10,11].
Although VA is the main surgical method for treating OVCFs and has many advantages, residual pain after surgery has always been a challenge for doctors and patients [12,13]. Many reasons can account for postoperative residual pain, such as osteoporosis, vertebral degeneration, vertebral instability, vertical spinal muscle spasm, thoracolumbar fascia injury, intraoperative injury, vertebral infection, and mental factors [14][15][16][17]. Recently, the difusion distribution of cement in the injured vertebra was found to afect treatment [18,19]. However, the correlation between intraoperative cement dispersion and postoperative residual pain has not been clarifed, and no literature clearly indicates the relationship between the degree of cement dispersion and residual pain. We hypothesize that when the difusion distribution of the cement in the vertebral body is insufcient, the characteristics of the cement itself cannot be fully developed, and it cannot provide efective biological stability for the vertebral body and ultimately cannot achieve analgesia, resulting in postoperative residual pain.
Terefore, we retrospectively analyzed the case data of OVCFs treated with VA, set the difusion distribution status of bone cement within the fracture line as an independent variable, and evaluated the variability in the visual analog scale (VAS), Oswestry disability index score (ODI), injured vertebral height (IVH), and local kyphosis angle (LKA) at diferent times after surgery. In addition, to analyze the potential infuencing factors of residual pain, we used the GE AW4.7 workstation to model the patient imaging data accurately and measure the volume of injured vertebra, cement volume, and cement volume ratio (the ratio of cement volume to vertebral volume). Furthermore, we comprehensively analyzed the efect of the bone cement difusion distribution status on postoperative residual pain.

Methods
Tis retrospective cohort study comprised patients with OVCFs treated at the Afliated Hospital of Shandong University of Traditional Chinese Medicine from July 2018 to June 2021. Te study was approved by the Ethics Committee of the Afliated Hospital of Shandong University of Traditional Chinese Medicine (2022-104-KY).

Inclusion Criteria.
Te inclusion criteria include the following: ① patients with a clear medical history, clinically diagnosed with OVCFs, and with a single vertebral fracture of the thoracic or lumbar spine subjected to conservative treatment for 2-6 weeks that was inefective; ② patients with X-ray flms showing wedge-shaped and fat vertebral changes of the thoracic or lumbar vertebral bodies; ③ patients with radiologically confrmed fresh compression fracture, magnetic resonance imaging (MRI) showing edema, or an X-ray/computed tomography (CT) scan proven fracture not older than 3 months, without neurospinal compression symptoms; ④ patients treated with unilateral puncture balloon kyphoplasty (BKP); ⑤ patients with no diseases afecting bone metabolism such as abnormal parathyroid function.

Exclusion Criteria.
Te exclusion criteria include the following: ① patients with incomplete imaging and medical records and a follow-up time of less than 12 months; ② patients with other neurovascular injuries or serious cardiovascular diseases; ③ patients with pathological fractures caused by the long-term use of hormones or tumors; ④ patients with spinal metastases; ⑤ patients with postoperative complications such as bone cement leakage, nerve compression, vascular embolism, infection, and pulmonary embolism.

Surgical Criteria.
Surgical method: percutaneous kyphoplasty. Te surgery was performed by the same trained team of physicians in strict compliance with the procedures. Te details are as follows: the patient is in the prone position, C-arm fuoroscopy is used to determine and mark the needle entry point of the injured vertebra (right side of injured vertebra, outside of pedicle), the operation area is routinely disinfected, and 1% lidocaine is used for local anesthesia. Under fuoroscopy, a puncture needle was used to puncture the middle and posterior 1/3 of the injured vertebral body, the needle core was withdrawn, and the guide drill was rotated into the anterior and middle 1/3 of the vertebral body through the puncture channel, anteroposterior to the spinous process. Te pilot drill was withdrawn, the balloon was inserted, and the balloon was gradually pressurized and maintained at 10 atm. After observing the recovery of the height of the injured vertebra, the balloon was removed. Te bone cement (Spine PMMA; OSTEOPAL ® V; Heraeus Medical GmbH, Germany) was adjusted to the toothpaste stage and slowly injected into the vertebral body through the puncture channel under fuoroscopy. Te flling degree of the bone cement and presence or absence of leakage were observed by fuoroscopy. After the bone cement hardened, the puncture needle was slowly removed, and the needle hole was covered with a sterile dressing.

Group Formation.
Based on the inclusion and exclusion criteria, we screened cases meeting the criteria from the hospital electronic medical record system for a total of 36 cases. Te time span was three years. Tis study comprised two groups, Group A with sufcient difusion ( Figure 1) and Group B with insufcient difusion (Figure 2). Referring to the evaluation method of the difusion status of bone cement within the fracture line, cases were assigned to the corresponding group after reaching a consensus by three experienced physicians based on the imaging data. Finally, Group A included 23 cases, and Group B included 13 cases.
Te evaluation method for the degree of difusion within the bone cement fracture line are as follows: frst, the fracture line location was determined preoperatively. Te CT sagittal view showed that the fracture line was band-like, with compressed dense shadows or vacuum fssures. Te position of the cortical fssure around the vertebral body was observed to determine the specifc direction of the fracture line (Figures 1(a)-1(d) and 2(a)-2(d)). Ten, the degree of bone cement dispersion was observed postoperatively. Referring to the specifc location of the fracture line determined before the operation, the X-ray flms were observed in the frontal, lateral or coronal, and sagittal views of CT after the operation. If the bone cement fully covered the fracture line, it was considered to have good difusion, and if it did not  fully cover the fracture line, it was considered to have poor difusion (Figures 1(e)-1(g) and 2(e)-2(g)).

Primary Outcomes.
Te primary outcomes included the VAS scores and ODI scores in the patients at preoperation, 2nd day postoperation, and last follow-up. Both scores were extracted from the medical record system. Te VAS score ranges from 0 to 10; the higher is the score, the more severe is the pain. Te ODI score ranges from 0 to 100; the higher is the score, the more severe is the dysfunction. Tose scores are recorded by the patient according to their own conditions.
2.6. Secondary Outcomes. Secondary outcomes included the following indicators: ① baseline patient data, including age (years), sex, bone mineral density (BMD, g/cm³), imaging data (X-ray, MRI, CT), surgery time (min), and bone cement injection volume (ml); ② IVH (mm, lateral X-ray, the distance between the upper terminal lamina and the lower terminal lamina) and LKA (degrees, angle between the superior endplate from the vertebral body one level above the injured vertebral body and the inferior endplate of the vertebral body one level below); ③ postoperative vertebral body volume (cm³), bone cement volume (cm³), and bone cement volume ratio (%) calculated by the GE AW4.7 workstation.
Te GE AW4.7 workstation processed the Digital Imaging and Communications in Medicine (DICOM) images of thin-slice CT scans using 3D functions to calculate the bone cement and vertebral volumes. Tin-layer CT images of the patient 2 d after surgery were extracted using the following scanning parameters: voltage, 120 kV; current smart mA, 200-500 mA; matrix, 512 × 512 pixels; scanning slice thickness, 0.625 mm. Te imaging data were stored in the DICOM format. Te images were transferred to the GE AW4.7 workstation, and the soft tissue thin-layer sequence was selected in the software and entered into the VR mode for volume reconstruction. Te soft tissue thin-layer sequence was selected in the software, the VR mode was entered, and volume reconstruction was performed. scalpel, add, remove, and pick from VR and other functions were used to fnely adjust the vertebral body, bounded by the upper and lower cuts of the pedicle, to retain the diseased vertebra, form a separate fracture vertebral model and measure the vertebral volume. Ten, the bone cement was separated from the diseased vertebra in the software, and a high-qualitythree-dimensional model of the bone cement was obtained using the three-dimensional reconstruction function. Te volume of the bone cement was measured, and the volume ratio of the bone cement was calculated (Figures 1(h) and 2(h)).

Pain Research and Management
Te VAS and ODI changes in the overall sample (n � 36) were observed using paired sample t-test, both showing P < 0.001, with a statistically signifcant diference (Table 3).

Secondary Outcomes.
Te secondary outcomes are presented in Table 1. On the 2nd day postoperation, the IVH was increased in both groups compared with that preoperatively ( Figure 5), and no signifcant diference was found in the comparison between Group A and Group B (18.74 ± 4.56 mm vs. 18.83 ± 3.75 mm; 95% CI: −3.121 to 2.933; P � 0.950). Regarding the LKA (Figure 6), both groups were reduced compared with before surgery, and no signifcant diference was found between Group A and Group B (14.89°± 8.76°vs. 13 Concerning the vertebral body volume, no signifcant diference was found between Group A and Group B (29.86 ± 7.99 cm³ vs. 33.81 ± 9.27 cm³; 95% CI: −9.921 to 2.016; P � 0.187). Regarding the bone cement volume, Group A was larger than Group B (7.08 ± 2.25 cm³ vs. 5.14 ± 1.60 cm³; 95% CI: 0.501 to 3.381; P � 0.010), and the diference was statistically signifcant. Te volume ratio of Group A (23.70%) was greater than that of Group B (15.11%), with P < 0.001, and the diference was statistically signifcant.

Vertebral Augmentation Can Reduce Pain in Patients with
OVCFs. Te study fndings showed that the postoperative VAS and ODI scores of OVCF patients treated by vertebral body augmentation were signifcantly improved (  [20] fndings showed that vertebral augmentation provides greater pain relief than conservative treatment for acute OVCFs. Klazen et al.'s [21] study also showed that vertebral reinforcement is superior to conservative treatment in pain relief. However, Firanescu et al.'s [22] randomized shamcontrolled clinical trial reported that vertebral reinforcement did not show a statistically signifcant improvement in pain reduction over sham surgery for OVCFs in the acute phase. However, vertebral augmentation has the advantages of a rapid efect, easy operation, little damage, and a short operation time and wide use in clinical practice [23]. Te mechanism of vertebral augmentation for pain relief remains controversial, and current research suggests that it may be related to the following factors [24]: (1) the operation provides corresponding mechanical strength and stability for the injured vertebra and relieves pain caused by the abnormal activity of the vertebral body; (2) the polymerization of bone cement produces a thermal efect, which burns the nerve tissue at the fractured end; (3) the chemical toxicity of bone cement itself causes nerve ending necrosis. In general, vertebral augmentation can rapidly relieve pain and restore functional activity by injecting bone cement to improve vertebral stability and reduce nerve ending stimulation, which is also the primary goal of OVCF treatment [25,26].

Sufcient Dispersion of Bone Cement Is More Conducive to
Reducing Postoperative Residual Pain. No signifcant difference was found in the preoperative scores between the groups through intergroup comparison analysis of the VAS  (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Note: paired sample t-test. Paired 1, preoperation was paired with the 2nd day postoperation. Paired 2 and 2nd day postoperation were paired with the last follow-up. 6 Pain Research and Management and ODI scores (Table 1). However, the VAS and ODI scores of Group A were signifcantly better than those of Group B on the 2nd day postoperation and at the last follow-up. Te present study showed that sufcient difusion of bone cement within the fracture line is more conducive to reducing postoperative residual pain and improving patients' quality of life. Mo et al.'s [27] study found that an insufcient distribution of bone cement can lead to inadequate shortand medium-term postoperative pain relief, which may be related to the uneven distribution of bone cement leading to displacement of the fractured vertebral body and micromotion around the fracture [28]. Tan et al. [29] found that bone cement is evenly distributed and in close contact with the upper and lower endplates, leading to better maintenance of the strength and height of the vertebral body, a reduced risk of refracture, and improved chronic back pain in the patient.
In addition, other studies have found that residual pain after vertebral augmentation is associated with thoracolumbar fascia injury, erector spinae muscle spasm, intraoperative puncture injury, the bone cement injection volume, bone mineral density, vertebral body infection, adverse psychological and mental factors, and the bone cement volume ratio [30]. Terefore, in the present study, we analyzed the factors that might afect the efcacy of surgery, such as recovery of the injured vertebral height, the local kyphosis angle, bone mineral density, the vertebral body volume, the bone cement volume, and the bone cement volume ratio.

VA Can
Raise the IVH and Reduce the LKA. After VA, IVH was higher than before; correspondingly, LKA was lower than before. Te present study further confrmed the role of VA in restoring the height of the injured vertebra, reducing the LKA, and thereby improving the stability of the vertebra. However, we compared IVH and LKA between the two groups; no signifcant diference was found. Tis fnding indicates that, in the present study, diferent distribution states of bone cement did not afect IVH and LKA. At the same time, diferent difusion states of bone cement did not afect the relationship between IVH, LKA and postoperative   Pain Research and Management residual pain. Vertebral augmentation can promote the height recovery of the injured vertebra and reduce the LKA in the short-term, which is conducive to reducing the pain of joints, muscles, and ligaments caused by spinal deformations [31,32].

Sufcient Dispersion of Bone Cement Is Benefcial to
Improve the Volume Ratio and Reduce Pain. In this study, no signifcant diference was found in the injection volume between the groups (P � 0.122), among which Group A was 6.11 ± 1.65 ml and Group B was 5.15 ± 1.88 ml. Te bone cement injection volume is an important factor afecting residual pain after vertebral augmentation. Some studies have found that an injection volume of bone cement >4.5 ml can achieve pain relief [33]. When the injection volume of bone cement is 5 ml to 6 ml, the overall treatment efect is more ideal [34]. Te vertebral body volume was 29.86 ± 7.99 cm³ in Group A and 33.81 ± 9.27 cm³ in Group B, and the statistical analysis was P � 0.187. No signifcant diference was found between the groups. However, the bone cement volume in Group A was higher than that in Group B, which was 7.08 ± 2.25 cm³ in Group A and 5.14 ± 1.60 cm³ in Group B (P � 0.010). After calculation, the volume ratio of bone cement was 23.70% in Group A and 15.11% in Group B (P < 0.001). Studies have shown that the volume ratio of bone cement is positively correlated with pain relief. When the volume ratio of bone cement is greater than 27.8%, the analgesic efect is better [35]. In addition, a cement volume ratio of more than 40.5% increases the risk of adjacent vertebral fractures [36]. Tus, injecting a sufcient amount of bone cement and maintaining a sufcient dispersion state can increase the volume and volume ratio of bone cement and is more conducive to reducing postoperative residual pain.

Surgical Options.
Regarding the surgical methods, vertebral augmentation mainly includes percutaneous vertebroplasty and kyphoplasty. We chose percutaneous unilateral extrapedicular balloon kyphoplasty, whose advantages are as follows [37][38][39][40]: frst, kyphoplasty has more advantages in restoring the height of the injured vertebra and promoting the difusion and distribution of bone cement in the fracture line. Second, unilateral puncture can shorten the operation time, and the external pedicle approach can also ensure better dispersion of bone cement. Tird, kyphoplasty reduces the damage to important organs, spinal cord, nerves, vertebral body attachments, the dural sac, and the soft tissue caused by bilateral puncture.
In the present study, the difusion of bone cement in the vertebral body was visually displayed. By establishing a threedimensional model, the shape of bone cement in the diseased vertebra can be more intuitively analyzed, and the difusion volume and volume ratio of bone cement can be accurately calculated. Te present study demonstrated that the better is the dispersion of bone cement in the fracture line area, the better is the surgical efect. In summary, after determining the surgical plan, controlling the period of the operation, choosing the acute phase for the operation, controlling the amount of bone cement injected, injecting it in the bone cement toothpaste period, and ensuring the proportion of the bone cement volume in the vertebral body are all necessary to ensure the efect of the operation and improve clinical efcacy. At the same time, clarifying the mechanism of bone cement analgesia and fnding more potential factors afecting residual pain are future research directions.

Limitations
Our study has limitations. Tis study was a single-center retrospective analysis with a time span of three years and a relatively small number of cases, and the data were easily available through the electronic medical record system. Terefore, we did not perform routine power or sample size calculations. Further large-scale, multifactor, and prospective studies must be performed.

Conclusions
Our study showed that bone cement has sufcient difusion in the fracture line area, which is benefcial for relieving postoperative pain and improving quality of life.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.