Radiological Analysis of Bone Regeneration in Different Tibial Distraction Osteogenesis Zones and Parts

Abstract

Background

This study aimed to explore whether asymmetrical bone regeneration is present in tibial distraction osteogenesis (DO) and analyze its etiologies.

Methods

In total, 56 patients with tibial bone defects treated with DO were retrospectively analyzed (38 men and 18 women; average age, 47.3 years). Single proximal DO was conducted for 30 patients, single distal DO was conducted for 16 patients, and both proximal and distal DO were conducted for 10 patients. Bone regeneration, notably the healing time of the proximal and distal zones and different DO parts, was analyzed via radiological examination, and the possible etiologies were investigated.

Results

There were 5 patients with poor regenerate formation (4 in the distal and 1 in the proximal), 3 patients with premature mineralization in the proximal, and 3 patients with DO zone fracture (1 in the proximal and 2 in the distal). The proximal healing time (11.8 ± 2.3 months) was shorter than the distal healing time (13.2 ± 2.5 months) (p = 0.040). The posterior part had the shortest healing time (10.4 ± 1.8 months), followed by the lateral part (11.1 ± 2.2 months) and the medial part (11.6 ± 2.5 months). The anterior part had the longest healing time (12.5 ± 3.8 months). Furthermore, pairwise comparison showed that the posterior and the anterior parts were significantly different from the other parts (p < 0.05).

Conclusions

Bone regeneration in different tibial DO zones and parts is asymmetrical, with faster regeneration in the proximal zone and posterior part and slower in the distal zone and anterior part, which may be due to differences in the local biological and external environments. These findings suggest that different distraction rates can be applied in different tibial regions, and more attention should be paid to protecting the anterior tibia.

Distraction osteogenesis (DO), also known as the Ilizarov technique, was first described by Ilizarov in the 1950s and is a method that promotes bone regeneration. It extends peripheral nerves, blood vessels, muscles, internal or external distractors after normal bone osteotomy.¹,²,³,⁴⁾ It consists of 3 consecutive phases, including the latency, distraction, and consolidation phases. After a short latency period, bone distraction initiates at an appropriate speed/frequency to spontaneously promote bone regeneration in the distraction gap (distraction period). Next, a long period of consolidation is needed to achieve new bone mineralization and remodeling (mineralization period). Currently, DO is widely utilized to treat bone defects, limb unequal lengths, and deformities. The classic distraction speed is 1 mm per day.⁵,⁶,⁷⁾ Some scholars reported that the distraction rate may be 1–2 mm per day, but there is a lack of appropriate clinical evidence.⁸,⁹,¹⁰,¹¹⁾ Bone distraction exceeding the osteogenic ability can lead to poor regenerate formation, bone deformation, fracture, and nonunion. On the other hand, too slow bone distraction does not allow the bone to be pulled to the target position due to mineralization, known as premature mineralization.¹²,¹³⁾ In addition, at least 3 of the 4 cortices should connect the bone ends with similar bone mineral density, as the bone ends are a common radiologic criterion for removing external fixation frames after DO. Therefore, effective monitoring of DO and individualized distraction rate is crucial. Currently, the monitoring of DO relies on quantitative computed tomography (CT), dual-energy x-ray absorptiometry, x-ray, CT, ultrasound, biomechanical evaluation, and biochemical markers. Among them, radiological methods, including x-ray and CT scan, are the gold standard methods and are commonly used in clinical practice.¹⁴⁾ Pixel value ratio (PVR) can be measured by digital x-rays, which were shown to be correlated well with bone mineral density. Therefore, PVR is a quantitative indicator of mineralization in DO healing. Scholars have reported that femoral DO monitored by PVR was asymmetrical.¹⁴,¹⁵,¹⁶⁾ Although the tibia is the most widely used site of DO, due to the lack of studies, it is still unclear whether there is asymmetrical DO in the tibia. During the healing of fractures and bone defects, the bone healing speed depends on the site and surrounding soft tissue. Based on clinical experience, after osteotomy, the bone regeneration in tibial proximal DO is faster than that in the tibial distal DO. In addition, bone regeneration in the posterior part of the tibia is faster than that in the anterior part of the tibia. Therefore, we hypothesized that asymmetrical DO may exist in the tibia. Based on radiological assessment, this study aimed to explore (1) the difference between the tibial proximal and distal DO zones, (2) the difference between different parts of the tibial DO zone, and (3) the possible reasons.

METHODS

The study was approved by the Institutional Review Board of Wuxi Ninth People’s Hospital Affiliated to Soochow University (IRB No. JY-KT2023121, registration date: December 30, 2024). Written informed consent was waived for this study due to its retrospective design and the use of de-identified patient data, as approved by the Institutional Review Board. It was conducted in compliance with international guidelines for human research protection, such as the Declaration of Helsinki, the Belmont Report, and the International Conference on Harmonization in Good Clinical Practice.

Patient Selection

Patients who were treated with DO for tibial segmental bone defects in our hospital between January 2018 and December 2024 were included in this study. The exclusion criteria were as follows: (1) patients who did not complete the full course of DO; (2) follow-up time less than 12 months; (3) postoperative infection affecting bone healing; (4) patients who were receiving medications that could affect bone healing (e.g., medications for malignant tumors and autoimmune diseases); (5) incomplete radiological data; (6) age less than 15 years; and (7) poor compliance.

The sample size was calculated using PASS 15.0 software (NCSS LLC.). Considering a power of 90% and an α of 0.05, a minimum of 56 samples were needed to have adequate power to test our hypotheses and measure the effect size we hoped to detect.¹⁷,¹⁸⁾ In total, 79 patients with tibial defects who were treated with DO were screened, and 56 participants were selected (Fig. 1). The participants included 38 men and 18 women, with a mean age of 47.3 years (range, 17–79 years). Patients had traumatic bone defects (20 cases) or bone defects associated with infection (36 cases). Ring external fixation frames were used in 44 cases, and unilateral fixation frames were used in 12 cases. The tibia was divided into 3 equal segments: proximal, middle, and distal. Proximal DO refers to the DO zone located in the proximal one-third of the tibia, while distal DO refers to the DO zone located in the distal one-third of the tibia. Thirty patients underwent single proximal DO, 16 patients underwent single distal DO, and 10 patients underwent both proximal and distal DO simultaneously. There were no differences in the baseline characteristics between the proximal and distal DO groups (p > 0.05) (Table 1). In the process of DO, the patients underwent monthly x-ray examinations to assess and determine the condition of the healing. CT scans were conducted when x-ray films were unclear.

Fig. 1. Flowchart for patient inclusion.

Table 1. Comparison of Patients’ Baseline Characteristics between the Proximal and Distal DO Groups.

Baseline characteristics	Proximal DO (n = 40)	Distal DO (n = 26)	χ2/t	p-value
Sex (male : female)	28 : 12	17 : 9	0.155*	0.694
Age (yr)	47.0 ± 13.9	46.8 ± 12.8	0.245*	0.807
Defect type (traumatic : infective)	14 : 26	9 : 17	0.001*	0.974
Time from injury to surgery (wk)	8.18 ± 2.98	8.31 ± 2.26	0.194†	0.847
Defect length (cm)	7.16 ± 1.83	7.72 ± 2.16	1.139†	0.259
External fixation frame (ring : unilateral)	31 : 9	19 : 7	0.168*	0.682
Bone density	–1.31 ± 1.13	–1.25 ± 1.20	0.136†	0.891
BMI (kg/m2)	23.10 ± 2.33	22.38 ± 3.05	0.889†	0.381
Pain VAS score	4 (3–5)	4 (3–5)	0.197†	0.845

Values are presented as mean ± standard deviation or median (interquartile range).

DO: distraction osteogenesis, BMI: body mass index, VAS: visual analog scale.

^*Chi-squaure test. ^†t-test.

Surgical Methods

The surgery was conducted by senior surgeons in our hospital. Proximal and/or distal tibial osteotomy was performed through an anterior minimally invasive approach. Thereafter, a ring or unilateral external fixation frame was placed. The bone distraction was initiated 1 week after the operation (the distraction rate was 1 mm/day, and the distraction rhythm was 3 times/day) and continued until reaching the target position. The growth of the callus was monitored monthly. In case of unbearable pain and/or lower limb blood circulation disorders during distraction, distraction was paused for a few days until the symptoms disappeared and then continued with the distraction. The external fixation frame was removed when at least 3 of the 4 cortices connected the bone ends with similar bone mineral density as the bone ends and there was no abnormal feeling of complete load-bearing after loosening the nut.

Assessment

On lateral x-ray images, the tibia was divided into 2 equal parts, anterior and posterior, while on anteroposterior x-ray images, the tibia was divided into 2 equal parts, medial and lateral.¹⁴⁾ In radiological assessment, a newly formed continuous bone with at least 2 mm thickness on anteroposterior and lateral radiographs, and connecting the 2 ends of the defect on either side of the anterior, posterior, medial, or lateral parts of the DO zone, usually along with PVR ≥ 0.85, was considered bone regeneration healing on that part. Bone regeneration healing on each zone was confirmed when at least 3 of the 4 continuous cortices with at least 2 mm thickness on anteroposterior and lateral radiographs of the DO zone were developed, usually along with PVR ≥ 0.85.¹⁴,¹⁶⁾ Poor regenerate formation was defined as new bone formation less than 50% of the defect area in the first postoperative year. Nonunion was diagnosed when new bone did not form and connect the 2 ends within 18 months after surgery. Premature mineralization was diagnosed when DO mineralization occurred before the transportation section was pulled to the target location. The regenerate healing time of the anterior, posterior, medial, and lateral parts of the DO zone and the proximal and distal ends was recorded.

Statistical Analysis

Data were analyzed using SPSS 26.0 software version 26 (IBM Corp.). The Kolmogorov-Smirnov test was employed to assess the normality of quantitative variables. Normally distributed quantitative data are expressed as mean ± standard deviation, and an independent sample t-test was used to compare the 2 groups, while comparison between more than 2 groups was conducted using analysis of variance, and further pairwise comparisons were conducted using least significant difference t-test and Bonferroni correction. Quantitative data not conforming to normal distribution are presented as median (interquartile range), and Mann-Whitney U-test was used to compare the 2 groups. Count data are expressed as numbers, and the chi-square test or Fisher’s exact test was used to compare count data. All the statistical analyses were 2-tailed, with the significance level set at α = 0.05.

RESULTS

All the DO zones had new bone formation. There were 5 cases of poor regenerate formation (4 cases in the distal end and 1 case in the proximal end), 3 cases of premature mineralization at the proximal end leading to leg length discrepancy, 3 cases of DO zone fracture (1 case at the proximal end and 2 cases at the distal end), and 5 cases of nonunion of the docking site, of whom 6 cases underwent secondary surgery due to nonunion or re-fracture. The proximal regenerate healing time was 11.8 ± 2.3 months (range, 9–19 months), shorter than the distal regenerate healing time (13.2 ± 2.5 months; range, 9–22 months) with a significant difference (t = 2.097, p = 0.040; Cohen’s d = 1.117) (Fig. 2).

Fig. 2. Comparison of healing time in different tibial distraction osteogenesis zones. ^*p < 0.05.

The posterior part of the DO zone had the shortest regenerate healing time (10.4 ± 1.8 months; range, 7–16 months), followed by the lateral part (11.1 ± 2.2 months; range, 8–18 months) and the medial part (11.6 ± 2.5 months; range, 8–20 months). The anterior part had the longest healing time (12.5 ± 3.8 months; range, 8–25 months). The differences among the 4 parts were significantly different (F = 10.280, p < 0.01; η² = 0.281). Furthermore, pairwise comparison showed that the posterior side was significantly shorter than the other sides, and the anterior part was significantly longer than the other parts (p < 0.05) (Fig. 3). A typical case is shown in Fig. 4.

Fig. 3. Comparison of healing time in different tibial distraction osteogenesis sites. ^*p < 0.05.

Fig. 4. A 52-year-old male patient with a right tibial segmental defect treated using distraction osteogenesis. (A) X-rays showed that both proximal and distal osteotomy were conducted during distraction osteogenesis. (B) X-rays at 5 months postoperatively showed that the 2 bone ends were distracted and almost touched each other. (C) X-rays at 15 months postoperatively showed that the proximal end healed with poor regenerate formation of the anterior part (red arrow), whereas the distal exhibited less regeneration formation (yellow arrows). (D) X-rays at 21 months postoperatively showed healing of the proximal end, whereas the distal end did not heal (yellow arrows). (E) X-rays at 2 years postoperatively showed that both the proximal and distal ends healed.

DISCUSSION

PVR was shown to be well correlated with the bone mineral density of the regenerated bone. Therefore, PVR can be deemed a quantitative indicator of mineralization in DO healing. Vulcano et al.¹⁶⁾ reported that the 4 cortical PVRs for femoral regeneration healing were as follows: lateral 0.84, medial 0.89, anterior 0.92, and posterior 0.98 with significant differences (p < 0.05). Liu et al.¹⁴⁾ also reported that the femoral posterior PVR in the bone union group was significantly higher than that in the bone nonunion group (p = 0.039). They concluded that the early posterior cortex PVR grew faster than the medial, lateral, and anterior sides in the bone union group, which represents an asymmetrical development pattern. Bafor et al.¹⁹⁾ and Zhao et al.²⁰⁾ found that the femoral PVR of different DO parts varies in starting or full weight-bearing. They speculated that it is associated with different periosteum and soft-tissue destruction during osteotomy. Nakahara et al.²¹⁾ conducted an experiment using rat femurs with intact periosteum or rat femurs with completely excised periosteum. The study found that the new bone volume was higher in the group with intact periosteum than in the group without periosteum, suggesting that the periosteum plays an indispensable role in DO. Our study also found that the new bone grew from the cortical end. Bone regeneration in the tibial DO zone was asymmetrical with the posterior part showing the fastest growth while the anterior part showed the slowest growth, supporting the viewpoint of asymmetric bone regeneration in different DO parts. In addition, our study indicated that the distal tibia was prone to poor osteogenesis, while the proximal tibia was prone to premature mineralization, suggesting different bone regeneration rates in different DO zones.

The reasons for different bone regeneration rates in different DO zones and parts are as follows: (1) different biological environments. The posterior and lateral parts of the tibia have richer muscle coverage than the anterior and medial parts. Muscles not only provide rich nutrition through blood supply but also offer various osteogenic factors.²²⁾ Experimental studies have shown that osteogenic and angiogenic factors, such as Experimental studies have shown that osteogenic and angiogenic factors, such as bone morphogenetic protein-2, transforming growth factor-β1, and vascular endothelial growth factor, are produced in bone defects.²³,²⁴,²⁵⁾ Therefore, the biological environment of the posterior and lateral sides is superior to that of the anterior and medial sides. (2) Different external interference factors. The incision is usually located in the front, which is usually associated with more periosteal damage than the posterior side. In addition, the front of the DO zone is susceptible to external interference; thus, anterior bone regeneration is prone to fracture and bone resorption.

Studies have shown that osteotomy sites with abundant blood supply have faster regeneration and higher distraction rates compared to those with insufficient blood supply.⁶,⁸,⁹⁾ Poor regenerate formation, fracture, premature mineralization, and nonunion are the complications of DO. To avoid or reduce these complications, the distraction rate should be adjusted to different DO zones and patient conditions. This study also showed that the bone regeneration of the proximal tibial DO zone is faster than that of the distal DO zone. Moreover, we revealed that poor osteogenesis and premature mineralization are associated with the distraction rate and site; thus, the distraction rate of tibial DO can be adjusted based on DO zones. For the proximal tibia, the distraction rate of DO can be more than 1 mm/day, whereas for the distal tibia, the traction rate of DO should not be more than 1 mm/day. In addition, considering that intact periosteum and external interference play important roles in bone regeneration in DO, it is necessary to avoid stripping the periosteum in front of the tibia and protect the front of the tibia against external interference during DO. Therefore, this article explored the phenomenon of asymmetrical bone regeneration in different DO zones and parts and investigated the possible causes. These findings can help improve existing surgery techniques and reduce the complications of DO.

The Ilizarov technique is associated with a high risk of complications. Liu et al.²⁶⁾ reported that in 282 patients with large bone defects in lower limbs who underwent treatment with the Ilizarov bone transport technique, there were 406 complications (257 minor and 149 major complications) based on the Association for the Study and Application of the Method of Ilizarov criteria. The most common major complications included joint stiffness (37.58%), delayed union of the docking site (19.46%), axial deviation (18.79%), re-fracture (8.05%), and muscle contractures (6.04%). In this study, we only conducted radiological analysis. The overall incidence of complications was 19.6%, which was lower than that reported in the literature. The incidence of nonunion was 8.9%, and the incidence of re-fracture was 5.4%, similar to that reported in the literature.²⁶,²⁷,²⁸⁾

This study had some limitations as many factors can affect bone regeneration in the DO zone and there are significant individual differences, such as smoking status, diabetes, or nutritional status. It is also difficult to achieve good consistency in fixation stability and rehabilitation intensity. Therefore, there may be a substantial risk of bias that can affect the results of this study. Further multicenter, large-scale, prospective studies or animal experiments are needed to compare the differences in bone regeneration in different DO zones and parts. Furthermore, PVR ≥ 0.85 should be interpreted as a reference value, and its utility in clinical decision-making for tibial DO requires prospective validation.

In summary, bone regeneration is not the same in different tibial DO zones and parts, with faster regeneration in the proximal zone and posterior part and slower in the distal zone and anterior part. This difference may be due to different local biological and external environments. These findings suggest that different distraction rates can be applied in different tibial regions, and more attention should be paid to protecting the anterior tibia. This strategy can improve existing surgery techniques and prevent complications in the DO zone.