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CLINICAL RESEARCH

Heterotopic Ossification After an Achilles Tendon Rupture Cannot Be Prevented by Early Functional Rehabilitation: A Cohort Study

Magnusson, S. Peter DMSc; Agergaard, Anne-Sofie MSc; Couppé, Christian PhD; Svensson, René B. PhD; Warming, Susan PhD; Krogsgaard, Michael R. PhD; Kjaer, Michael DMSc; Eliasson, Pernilla DMSc

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Clinical Orthopaedics and Related Research: May 2020 - Volume 478 - Issue 5 - p 1101-1108
doi: 10.1097/CORR.0000000000001085

Abstract

Introduction

Heterotopic ossification is the formation of pathologic bone in soft tissue and is often connected to an inflammatory event [11]. It is a rare condition in intact Achilles tendons, but the incidence increases after tendon injuries [1-3, 9, 10, 16]. Heterotopic ossification has been linked to pain or tendon weakness, but clinical studies have so far not shown any effect on clinical outcomes [1, 2, 13]. However, previous human studies have been mainly case reports or long-term follow-up reports several years after tendon rupture [1-3, 9, 10].

The cause for heterotopic ossification after an Achilles tendon injury, in some patients, is unclear. Tendon loading, and especially the magnitude of loading, might play a role in the development of heterotopic ossification [1, 2, 13]. Animal studies have shown that too much loading and unloading increase the incidence of heterotopic ossification [4, 13, 15]. Heavy loading during early tendon healing has also been shown to induce microinjuries in the tissue and prolong the proinflammatory response [6, 7], which could explain a higher risk of heterotopic ossification. At the same time, early functional rehabilitation after an Achilles tendon rupture (with early weightbearing and mobilization) has been suggested to reduce the risk of heterotopic ossification compared with immobilization [2], although this has not been investigated clinically.

The purposes of this study were to investigate (1) whether the presence of heterotopic ossification after Achilles tendon ruptures influences clinical outcome and (2) whether early mobilization or weightbearing prevents the development of heterotopic ossification.

Patients and Methods

This is a retrospective study based on a cohort of 75 patients from a randomized controlled trial. During this trial, we observed that some patients had major ossification in the tendon, and decided to explore this in a systematic way using radiographs taken during the trial. Six patients in the original study dropped out (two because of re-rupture, one because of adhesions, two did not attend follow-up visits, and one lacked radiographs), leaving 69 patients available for this study (Fig. 1). All patients were given oral and written information and provided written informed consent to participate. Ethical approval was obtained from the regional ethics committee (number H-3-2012-060). The study was performed in accordance with the principles of the Declaration of Helsinki. The original randomized trial is registered under the reference number (www.clinicaltrials.gov; trial number NTC02422004).

F1
Fig. 1:
This flowchart shows the patients included in the study.

All patients underwent open suture repair using the Kessler technique, followed by 6 weeks in an orthosis (Nextep Contour II Walker; DJO Nordic AB Sverige, Malmo, Sweden) that inhibited ankle movement. To keep the foot in plantarflexion, three 2-cm heel wedges were worn for the first 4 weeks, and patients were instructed to remove one heel wedge every week thereafter. Tantalum beads (1.0 mm) were inserted during surgery to mark the proximal and distal stump of the ruptured tendon.

Postoperatively, the patients were randomized to three different rehabilitation protocols with various degrees of loading during the initial 8 weeks after surgery: (1) Group 1: late weightbearing and ankle immobilization; patients were completely restricted from weightbearing and joint mobilization until week 7. (2) Group 2: late weightbearing and ankle mobilization; patients were restricted from weightbearing until week 7 but performed active ankle mobilization exercises. The exercise (dorsiflexion and plantarflexion) was performed without load (25 repetitions, five times per day) beginning in week 3. Patients in group 1 and 2 were allowed partial weightbearing (with crutches) at weeks 7 to 8 and full weightbearing as tolerated after week 8. (3) Group 3: early weightbearing and ankle mobilization; patients were allowed partial weightbearing from day 1 (with crutches) and full weightbearing as tolerated from week 5. They were also allowed to perform the ankle mobilization exercise as in Group 2. All groups received the same instructions in home exercise starting from week 9. A heel-raise exercise was allowed after 16 weeks, jogging was allowed after 24 weeks, and return to sports was permitted after 34 weeks. The results of this randomized controlled trial have been published previously [5].

Assessment of Heterotopic Ossification with Plain Radiographs

Two-dimensional radiographs were used to detect heterotopic ossification, tendon elongation, and tendon strain. To measure elongation and heterotopic ossification, we used lateral radiographs. Patients were positioned prone with their feet in a relaxed position away from the table during radiography. The distance between the radiographic source and the film plate was fixed at 120 cm with a perpendicular focus on the midpoint of the Achilles tendon. Radiographs were obtained at weeks 2, 6, 12, 26, and 52 postoperatively and ImageJ 1.47 software (National Institutes of Health, Bethesda, MD, USA) was used to analyze the radiographs.

A blinded investigator (PE) reviewed all radiographs to determine whether or not heterotopic ossification was present. The proximal-distal length of each ossification was measured twice by the same examiner, and the mean was calculated (Fig. 2). Each radiograph was graded from 0 to 4, and this is referred to as the ossification score. A score of 0 means no heterotopic ossification, 1 means weak but not measurable heterotopic ossification, 2 means small heterotopic ossification (< 10 mm in proximal-distal length), 3 means medium heterotopic ossification (> 10 and < 20 mm), and 4 means large heterotopic ossification (> 20 mm). The grading was performed at each time point. If a patient had multiple heterotopic ossification areas, we measured each area separately, and we used the sum of the length for grading. A radiography calibration sphere with a known diameter was used to calibrate the measurement in each image. We detected heterotopic ossification in 13 patients (19%, Table 1): 12 men and one woman. Overall, the initial sign of heterotopic ossification was seen at 6 weeks postoperatively in 12 of 13 patients; one patient had signs of heterotopic ossification as early as 2 weeks postoperatively (Table 2). Ossifications tended to increase in size and radiopacity with time as indicated by an increased ossification score, and no ossification disappeared during the first year after rupture. Six patients presented with heterotopic ossification longer than 10 mm, and three patients had multiple areas of heterotopic ossification. The position of ossification relative to the rupture (distal, proximal, or within the rupture) and the AP location was assessed by using beads inserted at each side of the rupture. Generally, the ossifications tended to be located in the anterior part of the tendon. Furthermore, eight patients had ossifications proximal to the rupture area, four patients had ossifications distal to the rupture area, and four patients had ossifications close to the rupture (between the beads).

F2
Fig. 2:
Radiographs showing heterotopic ossification in two patients. Patient H had multiple large ossifications and patient K had a single small ossification. The radiographs were taken at 2, 6, 12, 26, and 52 weeks after tendon repair, and the first sign of ossification was seen at 6 weeks in one patient. A blinded investigator reviewed all radiographs to determine whether or not heterotopic ossification was present. The proximal-distal length of each ossification was measured and graded from 0 to 4, and this is referred to as the ossification score. (0) means no heterotopic ossification, 1 means weak but not measurable heterotopic ossification, 2 means small heterotopic ossification (< 10 mm in proximal-distal length), 3 means medium heterotopic ossification (> 10 and < 20 mm), and 4 means large heterotopic ossification (> 20 mm). The grading was performed at each timepoint. If a patient had multiple heterotopic ossification areas, each area was measured separately, and the sum of the length was used for grading. A radiography calibration sphere with a known diameter was used to calibrate the measurement in each image. During surgery, four or five tantalum beads with a diameter of 1.0 mm were implanted in the tendon on either side of the rupture (two beads in each end) which are indicated by a red asterisk.
T1
Table 1.:
ATRS, VISA-A, heel-raise index, maximum ankle ROM, tendon strain, and tendon elongation in patients with and without heterotopic ossification
T2
Table 2.:
Location of the ossification area and ossification score in each patient

Measuring Tendon Elongation, and Tendon Strain

Tendon elongation was calculated at week 52 by measuring the distance between one proximal and one distal tantalum bead in the tendon using Image J and the lateral radiograph at week 52 and related this to the distance at week 2.

We measured tendon strain at weeks 26 and 52. During the test, the patient was seated in a rigid frame with the knee flexed to 90° and the ankle at 0°. The foot was fixed on a footplate and a strain gauge was attached to the footplate to register plantar flexion force (in Newtons). A wireless transmitter was used for force recording (8-channel, TeleMyo 2400T G2, Telemetry System, Noraxon Inc, Cologne, Germany). The position of the film plate was fixed relative to the foot and radiographs were recorded in the same manner as described for tendon elongation. We obtained oblique radiographs, and we used ImageJ 1.47 software (National Institutes of Health) to analyze each radiograph. We estimated strain by calculating the change in distance between one proximal and one distal tantalum bead under a predefined load (1200 N) and related this to the neutral position with 0 N force on the tendon. The detailed methods by which tendon elongation and strain were assessed are described elsewhere [5].

Patient-reported Outcome and Functional Measurements

We evaluated self-reported perception of disability at 26 and 52 weeks postoperatively with the Achilles tendon total rupture score (ATRS) and the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire to assess symptoms, function, and pain during sports activities [12, 14]. The ATRS questionnaire contains 10 items; patients grade their limitations/symptoms on a scale from 0-10 (0 = major limitations and 10 = no limitation). The VISA-A questionnaire consists of eight questions that measure the domains of pain, function in daily living, and sporting activity. Results range from 0 to 100, where 100 represents the perfect score. We evaluated muscle endurance with a single-leg standing heel-raise test [18]. MuscleLab (Ergotest Technology, Porsgrunn, Norway) computer software and a linear encode sensor attached to the heel were used for the evaluation. Total work (body weight x total distance) was calculated as a percentage of the non-injured side and used for data analysis. The maximum ROM in dorsiflexion was assessed with a weightbearing lunge test. In this test, we measured the maximum distance between the wall and each foot while the patient could still touch the wall with their knee [8]. A percentage of the non-injured side was calculated.

Statistics

We analyzed differences between patients with heterotopic ossification and no heterotopic ossification (irrespective of their rehabilitation group) with unpaired t-tests. Pearson’s correlation analysis was used to analyze correlations between the ossification score and functional or patient-reported outcomes. Differences in heterotopic ossification occurrence (yes or no) or ossification score between the three rehabilitation groups was analyzed by chi-square test. The analysis was performed using SPSS software (IBM Svenska AB, Stockholm, Sweden), and a p value ≤ 0.05 was considered significant.

Results

The presence of heterotopic ossification had no adverse effect on patient-reported outcomes; VISA-A and ATRS (Fig. 3); or other measurable outcomes, such as tendon strain, tendon elongation, and ROM when comparing patients with and without ossification (Table 1) at 26 weeks and 52 weeks after injury. In fact, patients with heterotopic ossification had a better HRI at 52 weeks compared with patients without (mean difference 14% [95% CI -0.2 to 27]; p = 0.053). There was no difference in the mean age (37 ± 9 years versus 38 ± 10 years) or BMI (25 ± 3 kg/m2 versus 24 ± 4 kg/m2) between patients with ossification and patients without (p = 0.698 and p = 0.647, respectively).

F3
Fig. 3:
These graphs show the VISA-A and ATRS questionnaire scores in patients with and without heterotopic ossification. The mean ± standard error at 26 and 52 weeks after rupture (VISA-A and ATRS) is shown in patients with heterotopic ossification and those without. The white bars indicate patients with no ossification and the gray bars indicate patients with ossification. There was no difference between patients with ossification (n = 56) and those without (n = 13) when analyzed with a t-test; VISA-A = Victorian Institute of Sport Assessment-Achilles questionnaire; ATRS = Achilles tendon total rupture score.

Neither the occurrence of heterotopic ossification (yes/no) nor the severity of heterotopic ossification (as measured by the ossification score) differed between the three rehabilitation groups (p = 0.367 for occurrence and p = 0.390 for the ossification score). Seventeen percent of patients with early functional rehabilitation (early weightbearing and ankle mobilization exercise) had heterotopic ossification (with a score ranging between 2-3), and 13% of patients with late weightbearing and immobilization had heterotopic ossification. These patients scored between 3-4 (Table 3).

T3
Table 3.:
Characteristics of the rehabilitation groups

Discussion

The cause for heterotopic ossification after an Achilles tendon rupture is unclear, but tendon loading and especially the degree of loading, might play a role in its development [1, 2, 4, 13, 15]. Early functional rehabilitation (early weightbearing and mobilization) has been suggested to reduce the risk of heterotopic ossification compared with immobilization, although this has not been investigated clinically [2]. We found heterotopic ossification in 19% of patients in this study, but the occurrence of heterotopic ossification was not linked to any adverse healing outcomes for the patients (for example, tendon strain and joint ROM). In fact, patients with ossification tended to have a better heel-raise index at 1 year compared with patients without ossification. The ossification occurred during the first 6 weeks after rupture while patients were using an orthosis to reduce load on the tendon; early weightbearing and ankle mobilization could not prevent this from occurring.

This study has several limitations. It is a retrospective analysis of a cohort of patients from a randomized trial. We detected heterotopic ossification in 19% of patients, but this analysis might be underpowered to detect differences between the groups. However, we found heterotopic ossification in all groups and can therefore conclude that early functional rehabilitation is not enough to prevent this from occurring as previously suggested. In the present study, we used 2-D radiography to detect heterotopic ossification, which has inherent limitations; ultrasound may be more sensitive method [9]. Furthermore, this radiographic approach precludes us from distinguishing whether all ossifications are located in the tendon or whether some of them are anterior to the tendon. Moreover, it is not possible to measure the volume of the heterotopic ossification. We inserted tantalum beads in the tendons, but this did not appear to contribute to the process. The incidence of heterotopic ossification is similar to that reported in previous studies [1, 3, 9, 13], and the ossifications did not appear to be associated directly with the beads. There are other factors that could influence the development of heterotopic ossification such as the use of NSAIDs during the initial 6 weeks after surgery, but unfortunately this was not registered. Finally, this was a 1-year follow-up, and we cannot rule out whether these ossifications might have a long-term negative effect.

There was no difference in any functional outcomes or reported pain between patients with ossification and those without, similar to the results of earlier long-term follow-up studies [1, 2]. In contrast, one study showed that areas larger than 10 mm appeared to induce poorer functional outcomes [9]. Therefore, we tested whether the outcome in our patients with more extensive ossification differed from the outcome of the other patients, but we did not detect any difference.

The magnitude of loading has been suggested to play a role in the development of this condition [4, 13, 15] since both unloading and overloading have been shown to increase ossification in animal studies [4, 15]. All 13 patients with heterotopic ossification had a visually detectable heterotopic ossification at week 6, which indicates that ossification develops early while patients are wearing an orthosis. Early functional rehabilitation with early weightbearing (comparable to Group 3) has been suggested to reduce the risk of postoperative calcification compared with immobilization (similar to our Group 1) [1]. However, we were not able to confirm this in our study. We evaluated three different groups of patients who underwent various forms of rehabilitation with varying levels of weightbearing on the orthosis or ankle mobilization and found no difference in the occurrence or severity of ossification. Early weightbearing on the orthosis does not necessary mean tensile loading [17], and the ankle mobilization exercises were active but unloaded foot movements. We therefore cannot rule out whether specific tensile loading would have an influence on heterotopic ossification.

In conclusion, heterotopic ossification after an Achilles tendon rupture is initiated during the first 6 weeks after rupture, while the patients wear an orthosis. Early functional rehabilitation with weightbearing or motion exercises during this time does not prevent heterotopic ossification, but heterotopic ossification does not necessarily influence the clinical outcome.

Acknowledgments

We thank all employees who helped us acquire the radiographs.

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