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19-1-10.dviHeterotopic Ossification in Wartime
LCDR Jonathan Agner Forsberg, MD,1,2 and MAJ Benjamin Kyle Potter, MD1–3
Heterotopic ossification (HO) refers to the formation of mature lamellar bone in nonosseous tissue. In thesetting of high-energy wartime extremity wounds, HO is expected to complicate up to 64% of patients,has a predilection for the residual limbs of amputees, and remains a significant source of disability.
Although the inciting events and the definitive cell(s) of origin continue to remain elusive, animal modelsand human histology samples suggest that HO formation follows a predictable sequence of eventsculminating in endochondral ossification. Primary prophylaxis is not medically or logistically practicalin most cases because patients have generally sustained massive wounds and are undergoing serialdebridements during an intercontinental aeromedical evacuation. Surgical excision of symptomaticlesions is warranted only after an appropriate trial of conservative measures and is associated withlow recurrence rates in appropriately selected patients. Future research regarding prognosticationand defining the early molecular biology of ectopic bone may permit individualized prophylaxis anddevelopment of novel targeted therapies. ( Journal of Surgical Orthopaedic Advances 19(1):54 – 61,2010) Key words: heterotopic ossification, trauma, war wounds surgical dissection (9, 12 – 20). Less common causes of heterotopic ossification (HO) refers to the heterotopic bone formation include the genetic disor- formation of mature lamellar bone in nonosseous tissue.
ders fibrodysplasia ossificans progressiva and progressive In moderate and severe cases, this disorder can lead to osseous heteroplasia (21 – 23). Although both proven risk significant disability, though most cases are mild and factors and genetic predispositions exist, the underlying asymptomatic. Classically, HO is associated with severe cause(s) of HO, the initiating molecular biology, and the systemic insults including spinal cord injury, traumatic cellular origin remain largely unknown.
brain injury, and neoplasm (1 – 8). Also, HO forms assequelae to hip arthroplasty and fractures of the acetab-ulum or elbow, particularly those requiring operative The Combat Wounded Population
fixation (9 – 12). These associations imply a relationshipbetween HO and muscle traumatized due to injury and/or Recently, HO has been observed to be more common than previously reported in patients sustaining high-energywartime extremity wounds (24 – 26). Blasts and high- From 1Regenerative Medicine Department, Combat Casualty Care, Naval Medical Research Center, Silver Spring, MD; 2Department of velocity projectiles inflict a high percentage of modern Surgery, Uniformed Services University of Health Sciences, Bethesda, war wounds and predominately affect the extremities MD; 3Integrated Department of Orthopaedics and Rehabilitation, Walter (27 – 38). This injury mechanism results in a unique injury Reed National Military Medical Center, Bethesda, MD. Address corre-spondence to: LCDR Jonathan Agner Forsberg, MD, Regenerative pattern — one comprised of severely traumatized limbs, Medicine Department, Combat Casualty Care, Naval Medical Research open fractures, and extensive zones of injury with frequent Center, 503 Robert Grant Avenue, Silver Spring, MD 20910; e-mail: bone and soft tissue loss, often in association with both Each author certifies that his institution has approved the human gross foreign body and bacterial contamination. Serial protocol for this investigation and that all investigations were conducted debridement procedures are performed every 24 – 72 hours in conformity with ethical principles of research. The views expressed prior to definitive wound closure or coverage in an effort in this article are those of the authors and do not necessarily reflect theofficial policy or position of the Department of the Army, Department to remove devitalized tissue and gross contamination.
of the Navy, Department of Defense, or the United States Government.
Antibiotic-impregnated polymethylmethacrylate beads are This work was supported by the US Navy Bureau of Medicine and routinely used to reduce the bacterial bioburden, as are Surgery under the Medical Development Program (PE 0604771N).
negative pressure wound dressings. Despite the severity Received for publication September 8, 2009; accepted for publication of these injury patterns, patient survival approaches 90%, For information on prices and availability of reprints call 410-494- due in part to improved body armor, the judicious use of 4994 X226.
1548-825X/10/1901-0054$22.00/0 tourniquets, and a robust casualty treatment and evacua- Copyright 2010 by the Southern Orthopaedic Association The incidence of HO in combat-wounded service originally described by one of the authors (BKP) has members has consistently been reported as 63% – 64.6%, been adopted. The severity of HO is graded using the far greater than that described in civilian trauma centers.
single radiographic projection (anteroposterior, lateral, or Formation of HO in this patient population is associated oblique) that maximizes the extent of the ectopic bone with blast injuries, a combat-related amputation within the within the soft tissues of the residual limb. For example, zone of injury, and injury severity scores greater than 16 ectopic bone formation is considered to be mild if it occu- (24, 26). In contrast, the largest civilian series examining pies less than 25%, moderate if it occupies 25% – 50%, and fracture care and HO found that ectopic bone complicated severe if it occupies >50% of the soft tissues on a single the extremities in 11% of severe traumatic brain-injured patients and 20% of spinal cord injuries (40). Earlier workin civilian patients reported baseline rates of ectopic bone Basic Science Efforts
growth in various long-bone fractures, including forearmfractures (20%) (16), femoral shaft fractures (52%) (41), Recent HO research by Gannon and others (49) has and tibial shaft fractures (0%) (42), all in the setting successfully identified genetic mutations that localize to of significant head injury. The authors are aware of no chromosome 4q (27 – 31). Although the BMP4 gene itself consensus regarding the rate of heterotopic ossification does not harbor a genetic mutation, overexpression of in civilian long-bone extremity trauma without concomi- BMP4 and its receptor BMPRIA coupled with underex- tant head injury. Nevertheless, the incidence of clinically pression of its antagonists is thought to be required for HO relevant or symptomatic HO in this setting is generally formation (49 – 52). This phenomenon, first identified in considered to be low (7, 43 – 45).
patients with fibrodysplasia ossificans progressiva, firmlyestablishes a link between some forms of HO and tradi- Amputees
tional osteoblastic signaling. Davis, in association withGannon (53), further defined the microenvironment by The predilection of heterotopic bone for growth within identifying the presence of brown (hypoxic) adipocytes in the residual limbs of amputees is an important recent the early stages of HO development. The hypoxic environ- observation (24, 26). Definitive amputations are often ment induces both chondrogenesis and neovascularization.
performed within or near the zone of injury (which is The result is an increase in oxygen tension enabling endo- extensive in blast injuries) in an effort to preserve residual chondral ossification to occur. Nesti and coauthors (54) limb length, joint levels, and subsequent function. As isolated a population of mesenchymal progenitor cells a result, there exists a strong association between these present in traumatized muscle. The authors concluded, injuries and the subsequent development of both radio- based on their ability to demonstrate pluripotency, that these cells may play a central role in the pathologic Several grading classification systems exist to classify osteogenic response. The team also noted that the progen- its formation about the hip, knee, and elbow (5, 9, 10, itor cells derived from traumatized muscle had a certain 20, 46 – 48). These were later extrapolated to other joints, propensity to become osteoprogenitor cells, more so than but none apply or adapt directly to the residual limbs those derived from non-age- or sex-matched geriatric of amputees. For these patients, a classification system, bone marrow donors (55). They further concluded that Walter Reed classification of heterotopic ossification in residual limbs of amputees.
muscle-derived progenitor cells are the “putative osteo- of debridement procedures and the duration of nega- progenitor cells that initiate ectopic bone formation in tive pressure dressing therapy are ostensibly also indica- HO,” but provided no suitable justification for this conclu- tors of greater local injury severity; therefore, establish- sion and thus the matter requires further study. In another ment of a causal linkage between local ectopic bone and study, Lounev and others (56) implicate progenitor cells these wound care modalities is difficult and fraught with of a vascular lineage. It is therefore plausible that more than one source of progenitor cells plays a role in the The type of definitive fracture treatment (internal fixa- initiation of ectopic bone formation, either as the cells of tion, external fixation, or amputation) appears unrelated origin or the source of the sentinel cellular signals, but to the formation of HO in extremity trauma, despite an the precise inciting event(s) and cellular origin(s) remain historic association with certain surgical approaches to the hip and acetabulum (9, 11, 15, 20, 58 – 62). This theoret- Ongoing studies from our own institutions examine ical concern has not been borne out in clinical studies of sera, tissue, and wound effluent from high-energy wartime extremity wounds. We are developing predictive bio-marker and gene-based profiles for HO formation in these Prophylaxis
patients. These profiles will permit the early identificationof patients most at risk for HO via computer-based algo-rithms, potentially allowing aggressive primary prophy- Several randomized studies have documented the effi- laxis. We are characterizing the differentiation propen- cacy of primary prophylaxis for the prevention of HO.
sity and genetic expression of muscle-derived progen- This type of prophylaxis is given following high-risk itor cells isolated from high-energy wounds, compared index procedures, such as revision total hip arthroplasty to age- and sex-matched healthy controls. Finally, we or operative fixation of acetabular fractures (63 – 73).
have successfully induced stem-cell production of bone Typically, 5 – 10 Gy of local radiation therapy is dosed in vitro utilizing patient sera and wound effluent, with the in a single fraction, with or without nonsteroidal anti- composite goal of identifying molecular triggers of HO inflammatory medication. Nonsteroidal anti-inflammatory production, evaluating therapeutic targets, and developing medications alone can be expected to provide a cost- and testing novel preventative treatments.
effective, dose-related decrease in heterotopic bone forma-tion, though the risk of treatment-related complications(i.e., gastrointestinal, renal, or hemorrhagic), as well as Factors Associated With HO Formation
patient noncompliance, appears higher (64, 74). Althoughsome randomized series have demonstrated no difference The Injury Severity Score (ISS) is associated with in ectopic bone formation between nonsteroidal treatment the development of HO (24, 57). Critics of ISS utility and radiation therapy (63, 69, 72), the bulk of the litera- as a prognostic factor for HO growth argue that head- ture, including two meta-analyses, modestly favors radi- injured patients score higher and therefore are inherently ation therapy, arguably related to compliance issues with more likely to develop heterotopic bone. However, Stein- medical treatment (67, 73, 75, 76). Two randomized series berg and coauthors (43) reported that the ISS, indepen- found no difference between preoperative and postoper- dent of a head injury, remained an important predictor ative radiation when dosing single fraction of 7 – 10 Gy, of the development of HO in a civilian trauma popu- provided it is given less than 4 hours prior or 48 hours lation after intramedullary nailing of femoral fractures.
These findings add to the growing body of evidence Evidence supporting secondary prophylaxis following suggesting that systemic factors, arguably related to the excision of symptomatic HO is lacking. The authors are degree of systemic inflammation, initiate or contribute to aware of no randomized trials of any secondary preven- an exaggerated osteogenic response that may ultimately tion modality. Nevertheless, the rate of recurrence in the be responsible for the development of heterotopic bone.
appropriate surgical candidate is generally accepted to be The association between heterotopic bone growth and low, and the theoretical benefit of secondary prophylaxis the number and method of surgical debridement proce- outweighs the risks of symptomatic recurrence for most dures, including the use of intermediate-pressure pulsatile lavage irrigation devices and negative pressure woundtherapy, is not well understood. Two recent studiesreported trends toward an association between HO forma- Pitfalls of Prophylaxis
tion and the number of debridement procedures as wellas the duration of negative pressure dressing therapy The use of the aforementioned methods of primary and (24, 26). However, these results should be interpreted secondary HO prophylaxis is not without consequence.
with caution because the increases in both the number Following radiation therapy, wound- and implant-related complications have been reported (60, 73). Considering Treatment
the relatively high prevalence of wound and fracture-related complications in patients with high-energy pene- The treatment of heterotopic ossification is individual- trating extremity wounds, external beam radiation is theo- ized. Numerous series in many different patient popula- rized to result in an unacceptably high wound complica- tions report that most cases are mild and result in little or tion rate as well as potential untoward effects on fracture no functional impairment (10, 11, 14, 15, 17, 46 – 48, 57,58, 62, 66 – 68, 70, 71, 74, 94 – 102). Moderate to severe healing. As such, radiation as primary prophylaxis for HO cases can be highly debilitating, particularly in periartic- remains highly controversial and is not currently recom- ular locations or in the residual limbs of amputees (26, mended by the authors for use in this patient population.
96, 103). Once heterotopic ossification has been identified Nonsteroidal anti-inflammatory drugs (NSAIDs) may by plain radiographs, one must assess the impact on the also be problematic in certain patient populations. Cyclo- patient’s level of function and activities of daily living.
oxygenase-2 is required for endochondral bone forma- In amputees, it is imperative that other likely sources tion, a mechanism critical to the development of hetero- of residual limb pain, such as painful bursae, myodesis topic ossification, as well as early fracture healing (53).
failure, and neuromata, are identified and treated, prior to Concerns about NSAIDs in an orthopaedic population considering surgical management (104, 105).
stem from this blunting of “helpful” inflammation neces- Conservative management including rest, local and sary for endochondral ossification (77 – 81), leading to systemic medications, activity modification, and pros- increased time to union and increase in the number thetic socket/suspension modifications requires a multi- of delayed unions in several studies (77, 78, 80 – 83).
disciplinary approach. Close consultation with skilled NSAIDs are also contraindicated in patients with intracra- prosthetists, physical therapists, and physiatrists is crit-ical. Likewise, in nonamputees, alternative causes of nial vascular trauma that is common in severe trau- pain and functional limitations, including infection, frac- matic brain and penetrating head injuries. The potential ture nonunion, and neuropathic pain syndromes, must be benefit of NSAIDs for HO prophylaxis must be weighed evaluated and treated. Surgical excision is reserved for heavily against potential fracture-related complications.
pain, ulceration, or joint stiffness attributable to HO that The authors, nevertheless, emphasize the importance of remains refractory to exhaustive conservative measures.
individualizing primary prophylaxis and that the concernsregarding fracture healing are somewhat moot in patients Timing and Results of Excision
without long-bone fractures, including many amputees.
Etidronate is the only drug FDA approved for the The timing of excision for symptomatic lesions remains primary prophylaxis of HO and thus warrants discussion.
controversial. Historically, excision was advocated only The FDA label states that etidronate is indicated following after prolonged observation ensuring that the ectopic bone total hip replacement or spinal cord injury, though the was “mature,” as evidenced by quiescent three-phase bone drug has been evaluated off-label in other settings such scans and the relative normalization of the serum alkaline as civilian orthopaedic extremity trauma and in burns.
phosphatase (106 – 108). This practice has long been ques- Etidronate blocks the aggregation, growth, and mineraliza- tioned because these measures do not accurately predict tion of hydroxyapatite crystals, necessary for the forma- recurrence (5). Numerous other studies support earlier tion of heterotopic bone. Early randomized and pseudo- excision based on the roentgenographic appearance of the randomized trials demonstrated efficacy (84 – 89), but only lesion(s) (26, 109 – 119). This approach has been shown as long as the drug was administered. “Rebound” forma- to allow earlier range of motion and return of functional tion of HO following cessation of therapy was common mobility, with recurrence rates similar to that of late exci- (84 – 87, 89), and follow-on studies failed to corroborate sion (110). Garland (5) identified other prognostic factorsfor HO excision in patients with head injuries, using a earlier results (90 – 92). In fact, a recent Cochrane database classification system based on the patient’s cognitive and review did not demonstrate pharmacologic efficacy and physical disability. In his series, motion-related outcomes could not recommend etidronate treatment for the primary and recurrence rates were excellent in classes I and II prophylaxis of HO (93). Additionally, etidronate is rela- and uniformly poor, with a 100% recurrence rate, in tively nonselective and inhibits osteoblasts as well as class V. He theorized that the latter group of patients osteoclasts, prompting concerns similar to those applicable possessed a systemic osteogenic stimulus, possibly the to NSAIDs, which are known to delay fracture healing in result of a prolonged systemic inflammation, which may orthopaedic trauma patients. For these reasons, etidronate persist for years after the initial injury. Knowledge of is infrequently utilized for primary HO prophylaxis in our this can help set patient and family expectations, partic- ularly in cases involving severe traumatic brain injury.
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Mount Auburn Hospital Formulary Updated 10/8/03 Generic Name Trade Name and Form Formulary Notes ALEMTUZUMAB CAMPATH 30 MG/3 ML INJ Oncologist ONLY ALTEPLASE TPA 50 MG INJ Restricted ALTEPLASE TPA 100 MG INJ Restricted AMIFOSTINE ETHYOL 500 MG INJ Oncologist ONLY Mount Auburn Hospital Formulary Updated 10/8/03 AMIKACIN AMIKIN 500 MG INJ ID