Heterotopic ossification (HO) refers to ectopic bone formation, typically in residual limbs and/or periarticular regions, after trauma and injury.1 This pathological process manifests outside the skeleton2 and is composed of a hybrid of cortical and cancellous bone.3 Heterotopic ossification was first reported by El Zahrawi (Albucasis) in 1000 CE, in which he noted that stony hard prominences occasionally developed during fracture healing and demanded urgent removal.4 Although the etiology of HO has not been elucidated in the 1000 years since its initial observance,5,6 there has been a general agreement in the orthopedic literature that HO is induced from damage to soft tissue and inflammation,5,7; and ectopic bone growth has been most frequently observed after combat-related trauma to service members with blast injuries.8
Reviews of orthopedic injuries from Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) have reported that approximately 70% of war wounds have involved the musculoskeletal system,9 largely in part from the use of improvised explosive devices (IEDs) and rocket-propelled grenades (RPGs). Given the intense nature of blast injuries, which require rapid tourniquet use, debridement, and surgical intervention, HO has been reported to occur in approximately 63% to 65% of wounded service members.10–12 Reports of recent OIF and OEF combat-related amputees with known HO have indicated that approximately 7% required surgery to excise their bony masses.13 Symptomatic HO may delay rehabilitation regimens, as ectopic bone resection often requires modifications to prosthetic limb componentry and socket size.13,14
Current methods for assessing HO growth in periarticular regions have involved the collection of serum alkaline phosphatase (AP) during inpatient care, nuclear scintigraphic (i.e., “bone scan”) activity, patient pain scores, observation of redness to the affected region, and radiographic/radiologic evidence of HO maturity based on the appearance of a clearly defined cortical rind. Most physicians note that the osseous overgrowth should not be removed until HO has fully matured7,15–17 and/or until patients have demonstrated normalized AP levels.11 However, other surgeons have cautioned against using this approach, as AP levels may not correlate with the severity of HO,18 and in some instances, HO may manifest within normal AP levels.19 To date, no clear experimental findings have indicated a mechanism for quelling or preventing metabolically active HO.1 Correlative factors such as sex,1,20 genetics,7,19,21,22 bioelectric signals,7 infection,23 and age20 have been associated with ectopic bone growth, but HO studies have often lacked histologic corroboration or advanced radiologic quantification.24
The gold standard for assessing periarticular HO severity after total hip arthroplasty (THA) was developed by Brooker et al.,25 in which supine anteroposterior radiographs were used to classify ectopic bone on a I–IV grading scale. Although the criteria of Brooker et al.25 are acceptable for ranking periartcular HO after total joint replacement, this method lacks reliable objectivity and is an insufficient tool for assessing HO in the residual limb. To offset this limitation, Potter et al.12 developed a scale for assessing the magnitude of HO within the residual limb of injured service members using anteroposterior and lateral radiographs and by grouping individuals based on the cross-sectional area of ectopic bone within their residual limb (<25%, mild; 25% to 50%, moderate; >50%, severe). However, a more thorough method for calculating HO volumes has since been developed by Isaacson et al.1 for quantifying the volume of ectopic bone formation within the residual limb or at other anatomic locations. We hypothesized that by using the method developed by Isaacson et al.,1 there would be a direct correlation between volumetric HO calculations and clinical factors including serum AP levels, subjective pain scores, and white blood cell (WBC) counts.
MATERIALS AND METHODS
To determine if a relationship existed between the volume of HO in the residual limb of service members and currently used clinical assessment tools, previous computed tomography (CT) scans were collected in accordance with Walter Reed National Military Medical Center (WRNMMC) and University of Utah Institutional Review Board approvals.1 Ten servicemen with prior CT scans of their transfemoral amputations were included in this study. Computed tomography was selected as the preferred imaging modality because this diagnostic tool provided clear distinction between tissue types and was necessary for determining the volume of HO. The small study population was necessitated by the frequent presence of metal fragments or fixation devices within the residual limbs of many amputees in the WRNMMC database at the time of radiologic review. Metal debris has been well known for generating image artifacts during three-dimensional reconstructions and thus would have created errors during volume calculations.26 Subjects were on average 22.0 ± 5.2 years old at the time of injury and sustained limb loss because of combat-related injuries. In this study, IEDs accounted for the highest frequency of traumatic amputations, occurring in 9 of 10 subjects, whereas an RPG served as the other mechanism for limb loss (Table 1). Of the 10 patients included in this study, 3 did not have radiologic signs of HO and were included to establish baseline AP levels, WBC counts, and subject pain scores.
The 10 servicemen included in this retrospective study were monitored as inpatients for up to 3 months to access fluctuations in AP levels, pain score ratings, and WBC counts starting at the date of their arrival at WRNMMC. Because HO has been noted to occur within several weeks after combat-related trauma, a 3-month assessment period ensured that ectopic bone formation had adequate time to manifest within the residual limb. Heterotopic ossification formations were confirmed to be mature at the time of radiologic review, and CT scans were performed an average of 12.6 ± 6.2 months (range, 6–22 months) after injury.
Subject chart reviews were used for reporting localized and systemic infections, and bacterial colonization was determined by using wound cultures, blood cultures, and in specific cases, peritoneal fluid (Table 2). Pain score ratings were documented twice daily using a Likert scale, and subjects were asked to rate their pain on a measure of 0 to 10, with 0 being absolutely no pain and 10 representing excruciating pain (Table 1). Alkaline phosphatase levels and WBC counts were recorded daily.
Ectopic bone volume was computed using a model developed previously by Isaacson et al.1 In short, software that multiplied voxel height and width by CT slice thickness was used to determine the volume of HO (Analyze 9.0, Mayo Clinic, OH, USA). Axial CT slices were manually inspected to determine HO connected to the periosteum and bony islands, which manifested within the soft tissue (Fig.1). All HO sections were identified, thresholded, and computed separately to determine ectopic bone volumes.
Serum AP levels, WBC counts, and subject pain scores were independently assessed to determine if these factors were significant predictors of HO volume. To accurately associate the predictor and outcome measures, without introducing over fitting or having confounding variables, each factor was correlated independently. All statistical evaluations were performed using a linear regression and were conducted with commercially available software at α ≤ 0.05 (SPSS, Inc, Chicago, IL, USA).
Ten service members were included in this retrospective study to assess the relationship between HO volumes, AP levels, WBC counts, and patient pain scores. However, one subject (serviceman 4) did not have AP laboratory documentation and was omitted from the HO volume and AP level assessment. Data from 9 of the 10 servicemen indicated that the volume of HO (44.73 ± 39.35 cm3) and average serum AP levels (177.40 ± 122.39 U/L) were significantly correlated (p = 0.002). An R2 value of 0.782 indicated that a positive linear relationship existed, in which higher volumes of HO were associated with elevated AP levels. When average pain scores (3.5 ± 1.3) were compared with HO volumes to assess if ectopic bone formation increased subject pain, this association was not significantly correlated (p = 0.212). An R2 value of 0.187 demonstrated no relationship between these two variables. However, there is reason to believe that disassociation between pain and HO volumes may have been influenced by subject comorbidities or neurological complications such as a traumatic brain injury (TBI). Traumatic brain injuries occurred in 3 of the 10 servicemen. In almost all cases, the service members in this patient series experienced concurrent bone fractures and soft tissue injuries aside from HO formation. This likely skewed patient pain scores as values were not solely dependent on just ectopic bone formation.
Infection and tissue culture data were reported for 9 of 10 servicemen. For the one subject without documented infection data (serviceman 10), medical records did not indicate positive or negative cultures, and therefore, this person was not included in this phase of analysis. Review of the subjects’ medical records indicated that bacterial colonization consisted of Acinetobacter baumannii, Pseudomonas aeruginosa, Aspergillosis, Staphylococcus, Klebsiella pneumoniae, and Enterococcus (Table 2). In fact, four of the nine of the subjects with positive infection signs also had multiple strains of cultured bacteria. When WBC count was compared with the volume of HO to determine if this was a predictor for ectopic bone growth, there was a significant correlation (p = 0.028). An R2 value of 0.474 indicated a low to moderate association.
The prevalence of HO in combat-wounded servicemen and women has been reported to be approximately 63% to 65% for those returning from theater,10–12 a significantly higher proportion than the documented HO rate within civilian trauma facilities. Because blast injuries sustained in OIF and OEF induce orthopedic trauma, neurovascular damage, and soft tissue injuries (key contributors to HO induction1), ectopic bone formation has and will remain a challenging orthopedic and rehabilitation issue. Therefore, the objective of this study was to use a novel HO volume measurement method to determine if a relationship existed between ectopic bone formation and serum AP levels, WBC counts, and patient pain scores. To the authors’ knowledge, directly computing HO volume has not been evaluated by any other team to date.27 Conventional methods for assessing ectopic bone development have included measuring the length of HO using anteroposterior or lateral radiographs28 and by developing grading scales to group HO severity based on a percentage of occupied space around the affected region.5 However, direct HO volumetric measurements serve as a more accurate mechanism for assessing ossification severity, preventing observer bias, and, of course, providing quantitative data of ectopic bone volume.
It is worth noting that ectopic bone formation is not unique to combat-related blast injuries, as HO has been reported after burns,29 TBIs,30 spinal cord injuries (SCIs),16,20 rotator cuff surgery,31 and THA.5,32 However, the severity/magnitude of HO has been most pronounced in the residual limbs of individuals with combat wounds, potentially because of the greater volume of space for ectopic bone to manifest as well as the massive zones of polysystemic injury and associated inflammation. Ectopic bone percentages have been known to drastically differ based on the injury mechanism. In the case of THA, HO has been most noted to occur in approximately 10% to 30% of patients,33 in 3.1% of burn victims,15 and in 63% to 65% of the military population injured in theater.10–12 Ectopic bone formation continues to be a problem for wounded service members with limb loss who wish to return to active duty or an energetic lifestyle,34 as an improper interface between the residual limb and prosthetic socket may lead to skin breakdown35 and significantly limit their mobility.8,36
Although an association between serum AP levels and HO formation seems conceptually clear (given that AP is an enzyme secreted by osteoblast and has long been associated with calcification),37 the relationship between AP and HO development has been subject to frequent debate in the literature. Mollan37 previously reported in his study of 131 THA patients that elevated serum AP levels resulted in an almost threefold increase in postoperative HO. Data from the present study agreed with the reported relationship between HO and elevated AP levels, as a direct positive correlation existed between AP and the volume of HO within the residual limb of injured service members.
The data from our study are also supported by Kjaersgaard-Andersen et al.,38 who noted that an increase in AP levels of greater than 250 IU/L 12 weeks after surgery was associated with the development of severe heterotopic bone in 13 of 17 patients. In this study, the highest serum AP level occurred in subject 3 (461.22 ± 380.94 U/L), who also had the largest volume of ectopic bone formation within their residual limb (115.96 cm3). Therefore, it may be postulated that AP levels monitored within 3 months of combat-injured service members may be an accurate predictor for developing HO and may directly correlate with ectopic bone volume.
Increased ectopic bone volume because of neurological impairment remains highly likely, as Forsberg et al.10 noted that the presence and severity of a TBI were significantly associated with HO. Studies conducted on neurological-based HO by Furman et al.16 noted that ectopic bone formation occurred in 47% (7/15) of his patient population with SCIs and that HO development was accompanied by elevations in serum AP. Hsu et al.18 also reported that 100% (20/20) of their SCI subjects had periarticular HO around the hip and experienced increased AP levels as well. Data from this patient series demonstrated that TBIs occurred in 30% of the patient population, a higher rate than that reported in the literature and was likely attributed to the subject sample size. Symptomatic HO requiring surgical intervention has been noted to occur in approximately 11% of patients with a TBI and 20% of SCI patients.39,40 Although a correlation between HO volumes and neurological-based HO was not possible in this study, it is worth noting that two of the three subjects with TBIs had the third and fourth highest volumes of HO present within their residual limb. Future studies assessing if a relationship exists between HO volumes and TBI and SCI subjects would provide valuable data as to the impact of nervous system damage and ectopic bone volume.
One prospective HO induction factor underreported in the orthopedic literature has been the potential of elevated WBC counts or infection for increasing the likelihood of HO development. Potter et al.23 noted that although it has been well regarded that infections inhibit bone formation and fracture healing, six of six service members who had intraoperative cultures during surgical resection of HO all tested positive for bacterial contamination. Data from our study confirms the ability for HO to manifest concurrently with positive infection signals; however, it is important to note that the only 6 of the 10 servicemen in our study had a documented infection on their residual limb, whereas the remaining positive cultures were determined using tracheal aspirate, blood, and peritoneal fluid. Therefore, before conclusions can be made on the association between combat-injured service members with infections and HO induction, a large retrospective study must be performed within the military healthcare facilities to ensure adequate statistical power.
Lastly, subjective patient pain scores demonstrated to not be an effective tool for assessing HO development, as this quantitative data did not correlate with HO volumes. Although HO development is often observed using the four cardinal signs of inflammation (redness, swelling, heat, and pain), the sole factor of pain alone was not a predictor for the servicemen included in this study. One explanation for this disassociation may have been the individualized pharmacologic regimens, extensive comorbidities and concurrent injuries, and variable personal pain tolerances. When subjects reported their pain scores, the Likert-based scale used in this study did not distinguish between overall pain and pain related to HO, and therefore, pain was grouped based as a personal whole.
Although ectopic bone formation has been previously categorized using bone scans and serum AP levels, no quantitative measurement method has existed for assessing HO volume. In a previous study by Isaacson et al.,1 the coauthors used a thresholding tool to determine the volume of HO within the residual limb of service members but did not corroborate this model with clinical predictors of HO presence, maturation, or severity. Data from this study indicated that serum AP levels and WBC counts were significant predictors of HO volumes. However, patient pain scores were not a valid predictor. In the future, the magnitude of serum AP levels and WBC counts may better predict the expected volume of trauma-related HO, but requires large-scale studies with adequate power to confirm the findings of this small patient series. Improved ectopic bone diagnostic tools in both the military and general populations have high clinical relevance, as these may influence HO prognostication, operative resection timing, and treatment strategies and subsequently reduce recurrence rates.
Gratitude is expressed to Gwenevere Shaw for support with manuscript preparation and to Rob MacLeod and Jeroen Stinstra for providing technical support.
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