19-1-10.dvi

Heterotopic Ossification in Wartime
Wounds
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.
After appropriate patient selection and preoperative coun- Incidence and a method of classification. J. Bone Joint Surg.
seling, we advocate surgical excision as soon as symp- toms warrant following appropriate efforts at conserva- 10. Riegler, H. F., Harris, C. M. Heterotopic bone formation after total hip arthroplasty. Clin. Orthop. Relat. Res. 117:209 - 216, 1976.
tive management. Regarding the amputee with variable 11. Triantaphillopoulos, P. G., et al. Long-term results in surgically cognitive and minimal other physical disability, excel- treated acetabular fractures through the posterior approaches.
lent results of excision can be achieved. In one series of 25 combat-related amputations, an 8% recurrence rate of 12. Sanchez-Sotelo, J., Torchia, M. E., O'Driscoll, S. W. Complex mild, asymptomatic ectopic bone has been reported with distal humeral fractures: internal fixation with a principle-basedparallel-plate technique. J. Bone Joint Surg. 89-A, 961 - 969, 2007.
secondary prophylaxis treatment in 84% of cases (26).
13. Mikic, Z. D., Vukadinovic, S. M. Late results in fractures of the radial head treated by excision. Clin. Orthop. Relat. Res.
Conclusion
14. Kamineni, S., Morrey, B. F. Distal humeral fractures treated with noncustom total elbow replacement. J. Bone Joint Surg.
Heterotopic ossification is a complex disorder with numerous proven and putative risk factors and varied 15. Giannoudis, P. V., Grotz, M. R., Papakostidis, C., et al. Operative initiating external stimuli, ultimately resulting from both treatment of displaced fractures of the acetabulum. A meta- local and systemic internal biologic factors. Lesions are analysis. J. Bone Joint Surg. 87-B:2 - 9, 2005.
often asymptomatic but can result in profound patient 16. Garland, D. E., Dowling, V. Forearm fractures in the head-injured adult. Clin. Orthop. Relat. Res. 176:190 - 196, 1983.
disability due to pain and joint stiffness. Primary prophy- 17. Garland, D. E., O'Hollaren, R. M. Fractures and dislocations about laxis via radiation therapy is neither practical nor recom- the elbow in the head-injured adult. Clin. Orthop. Relat. Res.
mended in patients with high-energy penetrating extremity wounds, though nonsteroidal anti-inflammatory drugs may 18. Dias, D. A. Heterotopic para-articular ossification of the elbow be effective in carefully selected patients. After an appro- with soft tissue contracture in burns. Burns Incl. Therm. Inj.
priate trial of conservative measures, operative exci- 19. Ahrengart, L. Periarticular heterotopic ossification after total hip sion of symptomatic heterotopic bone provides gener- arthroplasty. Risk factors and consequences. Clin. Orthop. Relat.
ally good results with low recurrence rates in appropri- ately selected patients treated with secondary prophylaxis.
20. Morrey, B. F., Adams, R. A., Cabanela, M. E. Comparison of Future research regarding biomarker-based prognostica- heterotopic bone after anterolateral, transtrochanteric, and posterior tion and identification of initiating chemokines, genes, and approaches for total hip arthroplasty. Clin. Orthop. Relat. Res.
cellular origin of ectopic bone may permit individualized 21. Kaplan, F. S., Hahn, G. V., Zasloff, M. A. Heterotopic ossification: prophylaxis and development of novel targeted therapies.
two rare forms and what they can teach us. J. Am. Acad. Orthop.
Surg. 2:288 - 296, 1994.
References
22. Kaplan, F. S., et al. Genetic transmission of fibrodysplasia ossificans progressiva. Report of a family. J. Bone Joint Surg.
75-A:1214 - 1220, 1993.
1. Kypson, A. P., Morphew, E., J.ones, R., et al. Heterotopic 23. Kaplan, F. S., Shore, E. M. Progressive osseous heteroplasia. J.
ossification in rectal cancer: rare finding with a novel proposed Bone Miner. Res. 15:2084 - 2094, 2000.
mechanism. J. Surg. Oncol. 82:132 - 136; discussion 137, 2003.
24. Forsberg, J. A., et al. Heterotopic ossification in high-energy 2. Kaplan, F. S., Glaser, D. L., Hebela, N., et al. Heterotopic wartime extremity injuries: prevalence and risk factors. J. Bone ossification. J. Am. Acad. Orthop. Surg. 12:116 - 125, 2004.
Joint Surg. 91-A:1084 - 1091, 2009.
3. Hoffer, M. M., et al. The orthopaedic management of brain-injured 25. Potter, B. K., Burns, T. C., Lacap, A. P., et al. Heterotopic children. J. Bone Joint Surg. 53-A:567 - 577, 1971.
4. Garland, D. E., Razza, B. E., Waters, R. L. Forceful joint ossification in the residual limbs of traumatic and combat-related manipulation in head-injured adults with heterotopic ossification.
amputees. J. Am. Acad. Orthop. Surg. 14:S191 - 197, 2006.
Clin. Orthop. Relat. Res. 169:133 - 138, 1982.
26. Potter, B. K., Burns, T. C., Lacap, A. P., et al. Heterotopic 5. Garland, D. E., Hanscom, D. A., Keenan, M. A., et al. Resection ossification following traumatic and combat-related amputations.
of heterotopic ossification in the adult with head trauma. J. Bone Prevalence, risk factors, and preliminary results of excision. J.
Joint Surg. 67-A:1261 - 1269, 1985.
Bone Joint Surg. 89-A:476 - 486, 2007.
6. Garland, D. E., Keenan, M. A. Orthopedic strategies in the 27. London, P. S. Medical lessons from the Falkland Islands' management of the adult head-injured patient. Phys. Ther.
Campaign. Report of a meeting of the United Services Section of the Royal Society of Medicine held at the Royal College of 7. Garland, D. E. A clinical perspective on common forms Surgeons on February 17 and 18, 1983. J. Bone Joint Surg. 65- of acquired heterotopic ossification. Clin. Orthop. Relat. Res.
28. Gofrit, O. N., et al. The trimodal death distribution of trauma 8. Como, J. J., Yowler, C. J., Malangoni, M. A. Extensive victims: military experience from the Lebanon War. Mil. Med.
heterotopic mesenteric ossification after penetrating abdominal 29. Mabry, R. L., et al. United States Army Rangers in Somalia: an analysis of combat casualties on an urban battlefield. J. Trauma et al. Ectopic ossification following total hip replacement.
49:515 - 528; discussion 528 - 529, 2000.
30. Islinger, R. B., Kuklo, T. R., McHale, K. A. A review of 55. J.ackson, W. M., Aragon, A. B., Bulken - Hoover, J. D., et al.
orthopedic injuries in three recent U.S. military conflicts. Mil.
Putative heterotopic ossification progenitor cells derived from traumatized muscle. J. Orthop. Res. 27:1645 - 1651, 2009.
31. Covey, D. C. Blast and fragment injuries of the musculoskeletal 56. Lounev, V. Y., et al. Identification of progenitor cells that system. J. Bone Joint Surg. 84-A:1221 - 1234, 2002.
contribute to heterotopic skeletogenesis. J. Bone Joint Surg. 91- 32. Champion, H. R., Bellamy, R. F., Roberts, C. P., et al. A profile of combat injury. J. Trauma 54:S13 - 19, 2003.
57. Brumback, R. J., et al. Heterotopic ossification about the hip after 33. Lin, D. L., Kirk, K. L., Murphy, K. P., et al. Evaluation of intramedullary nailing for fractures of the femur. J. Bone Joint orthopaedic injuries in Operation Enduring Freedom. J. Orthop.
58. Griffin, D. B., Beaule, P. E.,, Matta, J. M. Safety and efficacy 34. Patel, T. H., et al. A U.S. Army Forward Surgical Team's experi- of the extended iliofemoral approach in the treatment of ence in Operation Iraqi Freedom. J. Trauma 57:201 - 207, 2004.
complex fractures of the acetabulum. J. Bone Joint Surg. 87- 35. Covey, D. C. Combat orthopaedics: a view from the trenches. J.
Am. Acad. Orthop. Surg. 14:S10 - 17, 2006.
59. Oh, C. W., et al. Results after operative treatment of transverse 36. Hofmeister, E. P., Mazurek, M., Ingari, J. Injuries sustained to the acetabular fractures. J. Orthop. Sci. 11:478 - 484, 2006.
upper extremity due to modern warfare and the evolution of care.
60. Petsatodis, G., et al. Surgically treated acetabular fractures via a J. Hand Surg. 32A:1141 - 1147, 2007.
single posterior approach with a follow-up of 2 - 10 years. Injury 37. Fox, C. J., et al. Damage control resuscitation for vascular surgery in a combat support hospital. J. Trauma 65:1 - 9, 2008.
61. Rath, E. M., Russell, G. V. J., Washington, W. J., et al.
38. Hayda, R. A., et al. From Iraq back to Iraq: modern combat orthopaedic care. Instr. Course Lect. 57:87 - 99, 2008.
heterotopic ossification after acetabular fracture fixation. Injury 39. Kragh, J. F. J., et al. Survival with emergency tourniquet use to stop bleeding in major limb trauma. Ann. Surg. 249:1 - 7, 2009.
62. Schara, K., Herman, S. Heterotopic bone formation in total 40. Garland, D. E. Clinical observations on fractures and heterotopic hip arthroplasty: predisposing factors, classification and thesignificance for clinical outcome. Acta Chir. Orthop. Traumatol.
ossification in the spinal cord and traumatic brain injured populations. Clin. Orthop. Relat. Res. 233:86 - 101, 1988.
63. Burd, T. A., Lowry, K. J., Anglen, J. O. Indomethacin compared 41. Garland, D. E., Rothi, B., Waters, R. L. Femoral fractures in head- with localized irradiation for the prevention of heterotopic injured adults. Clin. Orthop. Relat. Res. 166:219 - 225, 1982.
ossification following surgical treatment of acetabular fractures.
42. Garland, D. E., Toder, L. Fractures of the tibial diaphysis in adults J. Bone Joint Surg. 83-A:1783 - 1788, 2001.
with head injuries. Clin. Orthop. Relat. Res. 150:198 - 202, 1980.
64. Fransen, M., Neal, B. Non-steroidal anti-inflammatory drugs 43. Steinberg, G. G., Hubbard, C. Heterotopic ossification after for preventing heterotopic bone formation after hip arthroplasty.
femoral intramedullary rodding. J. Orthop. Trauma 7:536 - 542, Cochrane Database Syst. Rev. CD001160, 2004.
65. Gregoritch, S. J., Chadha, M., Pelligrini, V. D., et al. Randomized 44. Spencer, R. F. The effect of head injury on fracture healing. A trial comparing preoperative versus postoperative irradiation for quantitative assessment. J. Bone Joint Surg. 69-B:525 - 528, 1987.
prevention of heterotopic ossification following prosthetic total hip 45. Giannoudis, P. V., et al. Accelerated bone healing and excessive replacement: preliminary results. Int. J. Radiat. Oncol. Biol. Phys.
callus formation in patients with femoral fracture and head injury.
Injury 37 (suppl 3):S18 - 24, 2006.
66. Knelles, D., et al. Prevention of heterotopic ossification after 46. Lazansky, M. G. Complications revisited. The debit side of total total hip replacement. A prospective, randomised study using hip replacement. Clin. Orthop. Relat. Res. 95:96 - 103, 1973.
acetylsalicylic acid, indomethacin and fractional or single-dose 47. Ritter, M. A., Vaughan, R. B. Ectopic ossification after total hip irradiation. J. Bone Joint Surg. 79-B:596 - 602, 1997.
arthroplasty. Predisposing factors, frequency, and effect on results.
67. Kolbl, O., et al. Randomized trial comparing early postoperative J. Bone Joint Surg. 59-A:345 - 351, 1977.
irradiation vs. the use of nonsteroidal antiinflammatory drugs for 48. Dalury, D. F., Jiranek, W. A. The incidence of heterotopic prevention of heterotopic ossification following prosthetic total hip replacement. Int. J. Radiat. Oncol. Biol. Phys. 39:961 - 966, 1997.
49. Shafritz, A. B., et al. Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N. Engl. J. Med.
heterotopic ossification following total hip replacement: the results of a randomized trial. Int. J. Radiat. Oncol. Biol. Phys.
50. de la Pena, L. S., et al. Fibrodysplasia ossificans progressiva (FOP), a disorder of ectopic osteogenesis, misregulates cell surface 69. Moore, K. D., Goss, K., Anglen, J. O. Indomethacin versus expression and trafficking of BMPRIA. J. Bone Miner. Res.
radiation therapy for prophylaxis against heterotopic ossification in acetabular fractures: a randomised, prospective study. J. Bone 51. Roush, W. Protein builds second skeleton. Science 273:1170, 70. Pakos, E. E., et al. Prevention of heterotopic ossification in high- 52. Feldman, G., et al. Fibrodysplasia ossificans progressiva, a risk patients with total hip arthroplasty: the experience of a heritable disorder of severe heterotopic ossification, maps combined therapeutic protocol. Int. Orthop. 30:79 - 83, 2006.
71. Pellegrini, V. D. J., Konski, A. A., Gastel, J. A., et al.
Prevention of heterotopic ossification with irradiation after total 53. Olmsted-Davis, E., et al. Hypoxic adipocytes pattern early hip arthroplasty. Radiation therapy with a single dose of eight heterotopic bone formation. Am J. Pathol. 170:620 - 632, 2007.
hundred centigray administered to a limited field. J. Bone Joint 54. Nesti, L. J., et al. Differentiation potential of multipotent progenitor cells derived from war-traumatized muscle tissue. J.
Bone Joint Surg. 90-A:2390 - 2398, 2008.
ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation 93. Haran, M., Bhuta, T., Lee, B. Pharmacological interventions for therapy. Int. J. Radiat. Oncol. Biol. Phys. 39:161 - 171, 1997.
treating acute heterotopic ossification. Cochrane Database Syst.
73. Sell, S., et al. The suppression of heterotopic ossifications: radia- tion versus NSAID therapy - a prospective study. J. Arthroplasty 94. Back, D. L., Smith, J. D., Dalziel, R. E., et al. Incidence of heterotopic ossification after hip resurfacing. ANZ. J. Surg.
74. Matta, J. M., Siebenrock, K. A. Does indomethacin reduce heterotopic bone formation after operations for acetabular 95. Ebraheim, N. A., Patil, V., Liu, J., et al. Sliding trochanteric fractures? A prospective randomised study. J. Bone Joint Surg.
osteotomy in acetabular fractures: a review of 30 cases. Injury 75. Blokhuis, T. J., Frolke, J. P. Is radiation superior to indomethacin 96. Garland, D. E., Blum, C. E., Waters, R. L. Periarticular heterotopic to prevent heterotopic ossification in acetabular fractures?: a ossification in head-injured adults. Incidence and location. J. Bone systematic review. Clin. Orthop. Relat. Res. 467:526 - 530, 2009.
Joint Surg. 62-A:1143 - 1146, 1980.
76. Pakos, E. E., Ioannidis, J. P. Radiotherapy vs. nonsteroidal anti- 97. Grohs, J. G., Schmidt, M., Wanivenhaus, A. Selective COX - 2 inflammatory drugs for the prevention of heterotopic ossification inhibitor versus indomethacin for the prevention of heterotopic after major hip procedures: a meta-analysis of randomized trials.
ossification after hip replacement: a double-blind randomized Int. J. Radiat. Oncol. Biol. Phys. 60:888 - 895, 2004.
trial of 100 patients with 1-year follow-up. Acta Orthop.
77. Bergenstock, M., Min, W., Simon, A. M., et al. A comparison between the effects of acetaminophen and celecoxib on bone 98. Higo, T., Mawatari, M., Shigematsu, M., et al. The incidence of fracture healing in rats. J. Orthop. Trauma 19:717 - 723, 2005.
heterotopic ossification after cementless total hip arthroplasty. J.
78. Herbenick, M. A., Sprott, D., Stills, H., et al. Effects of a cyclooxygenase 2 inhibitor on fracture healing in a rat model.
99. Kasetti, R. J., Shetty, A. A., Rand, C. Heterotopic ossification after Am. J. Orthop. 37:E133 - 137, 2008.
uncemented hydroxyapatite-coated primary total hip arthroplasty.
79. Mullis, B. H., et al. Effect of COX - 2 inhibitors and non- J. Arthroplasty 16:1038 - 1042, 2001.
steroidal anti-inflammatory drugs on a mouse fracture model.
100. Kreder, H. J., et al. Determinants of functional outcome after simple and complex acetabular fractures involving the posterior 80. Simon, A. M., Manigrasso, M. B., O'Connor, J. P. Cyclo - oxy- wall. J. Bone Joint Surg. 88-B:776 - 782, 2006.
genase 2 function is essential for bone fracture healing. J. Bone 101. Saudan, M., et al. Celecoxib versus ibuprofen in the prevention of heterotopic ossification following total hip replacement: 81. Simon, A. M., O'Connor, J. P. Dose and time-dependent effects a prospective randomised trial. J. Bone Joint Surg. 89- of cyclooxygenase-2 inhibition on fracture healing. J. Bone Joint 102. van der Heide, H. J., Rijnberg, W. J., Van Sorge, A., et al.
82. Macfarlane, R. J., et al. Pharmacological treatment of heterotopic Similar effects of rofecoxib and indomethacin on the incidence ossification following hip and acetabular surgery. Exp. Opin.
of heterotopic ossification after hip arthroplasty. Acta Orthop.
83. O'Connor, J. P., Lysz, T. Celecoxib, NSAIDs and the skeleton.
103. Hendricks, H. T., Geurts, A. C., van Ginneken, B. C., et al. Brain Drugs Today (Barc) 44:693 - 709, 2008.
injury severity and autonomic dysregulation accurately predict 84. Banovac, K. The effect of etidronate on late development of heterotopic ossification in patients with traumatic brain injury.
heterotopic ossification after spinal cord injury. J. Spinal Cord Clin. Rehabil. 21:545 - 553, 2007.
104. Potter, B. K., et al. In Rehabilitation of Combat Casualties 85. Banovac, K., Gonzalez, F., Renfree, K. J. Treatment of heterotopic With Limb Loss, edited by P. C. R. Pasquina, Borden Institute, ossification after spinal cord injury. J. Spinal Cord Med.
105. Ehde, D. M., Smith, D. G. Chronic pain management. In Atlas 86. Banovac, K., Gonzalez, F., Wade, N., et al. Intravenous disodium of Amputations and Limb Deficiencies: Surgical, Prosthetic, and etidronate therapy in spinal cord injury patients with heterotopic Rehabilitation Principles, 3rd ed., edited by D. G. Smith, J. W.
ossification. Paraplegia 31:660 - 666, 1993.
Michael, J. H. Bowker, pp. 711 - 726, American Academy of 87. Spielman, G., Gennarelli, T. A., Rogers, C. R. Disodium etidronate: its role in preventing heterotopic ossification in severe 106. Furman, R., Nicholas, J. J., J.ivoff, L. Elevation of the serum head injury. Arch. Phys. Med. Rehabil. 64:539 - 542, 1983.
alkaline phosphatase coincident with ectopic-bone formation in 88. Finerman, G. A., Stover, S. L. Heterotopic ossification following paraplegic patients. J. Bone Joint Surg. 52-A:1131 - 1137, 1970.
hip replacement or spinal cord injury. Two clinical studies with 107. Hsu, J. D., Sakimura, I., Stauffer, E. S. Heterotopic ossification EHDP. Metab. Bone Dis. Relat. Res. 3:337 - 342, 1981.
around the hip joint in spinal cord injured patients. Clin. Orthop.
89. Stover, S. L., Niemann, K. M., Miller, J. M. Disodium etidronate in the prevention of postoperative recurrence of heterotopic 108. Pittenger, D. E. Heterotopic ossification. Orthop. Rev. 20:33 - 39, ossification in spinal cord injury patients. J. Bone Joint Surg.
109. Beingessner, D. M., Patterson, S. D., King, G. J. Early 90. Garland, D. E., Alday, B., Venos, K. G., et al. Diphosphonate excision of heterotopic bone in the forearm. J. Hand Surg.
treatment for heterotopic ossification in spinal cord injury patients.
Clin. Orthop. Relat. Res. 176:197 - 200, 1983.
110. Chalidis, B., Stengel, D., Giannoudis, P. V. Early excision and late 91. Hu, H. P., Kuijpers, W., Slooff, T. J., et al. The effect of excision of heterotopic ossification after traumatic brain injury are biphosphonate on induced heterotopic bone. Clin. Orthop. Relat.
equivalent: a systematic review of the literature. J. Neurotrauma 92. Thomas, B. J., Amstutz, H. C. Results of the administration of 111. Ellerin, B. E., et al. Current therapy in the management of diphosphonate for the prevention of heterotopic ossification after heterotopic ossification of the elbow: a review with case studies.
total hip arthroplasty. J. Bone Joint Surg. 67-A:400 - 403, 1985.
Am. J. Phys. Med. Rehabil. 78:259 - 271, 1999.
112. Freebourn, T. M., Barber, D. B., Able, A. C. The treatment 116. Moritomo, H., Tada, K., Yoshida, T. Early, wide excision of of immature heterotopic ossification in spinal cord injury with heterotopic ossification in the medial elbow. J. Shoulder Elbow combination surgery, radiation therapy and NSAID. Spinal Cord 117. Tsionos, I., Leclercq, C., Rochet, J. M. Heterotopic ossification of 113. Garland, D. E., Orwin, J. F. Resection of heterotopic ossification the elbow in patients with burns. Results after early excision. J.
in patients with spinal cord injuries. Clin. Orthop. Relat. Res.
Bone Joint Surg. 86-B:396 - 403, 2004.
118. Viola, R. W., Hanel, D. P. Early "simple" release of posttraumatic 114. McAuliffe, J. A., Wolfson, A. H. Early excision of heterotopic elbow contracture associated with heterotopic ossification. J. Hand ossification about the elbow followed by radiation therapy. J. Bone 119. Wysocki, R. W., Cohen, M. S. Radioulnar heterotopic ossification 115. Mitsionis, G. I., et al. Functional outcome after excision of after distal biceps tendon repair: results following surgical heterotopic ossification about the knee in ICU patients. Int. Orthop.
resection. J. Hand Surg. 32A:1230 - 1236, 2007.

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