Heterotopic ossification and lessons learned from fifteen years at war: A review of therapy, novel research, and future directions for military and civilian orthopaedic trauma

Kaplan, 2004, Heterotopic ossification, J. Am. Acad. Orthop. Surg., 12, 116, 10.5435/00124635-200403000-00007 Tintle, 2014, Reoperation after combat-related major lower extremity amputations, J. Orthop. Trauma, 28, 232, 10.1097/BOT.0b013e3182a53130 Lewis, 1973, Albucasis on surgery and instruments Freke, 1739, A letter from Mr. John Freke, F. R. S. Surgeon to St. Bartholomew's Hospital to the Royal Society, relating a case of extraordinary exostoses on the back of a boy, Philos. Trans. R. Soc. Lond., 41, 369, 10.1098/rstl.1739.0066 Dejerne, 1918, Para- osteo-arthropathies des paraplégiques par lesion de da moelle epinière et de la queue de cheval, Ann. Med., 5, 497 Brackett, 1927, vol. 11, 713 Belmont Jr, 2012, Combat wounds in Iraq and Afghanistan from 2005 to 2009, J. Trauma Acute Care Surg., 73, 3, 10.1097/TA.0b013e318250bfb4 Nessen, 2008 Schoenfeld, 2013, The nature and extent of war injuries sustained by combat specialty personnel killed and wounded in Afghanistan and Iraq, 2003–2011, J. Trauma Acute Care Surg., 75, 287, 10.1097/TA.0b013e31829a0970 Forsberg, 2009, Heterotopic ossification in high-energy wartime extremity injuries: prevalence and risk factors, J. Bone Joint Surg. Am., 91, 1084, 10.2106/JBJS.H.00792 Fox, 2008, Damage control resuscitation for vascular surgery in a combat support hospital, J. Trauma Acute Care Surg., 65, 1, 10.1097/TA.0b013e318176c533 Forsberg, 2010, Heterotopic ossification in wartime wounds, J. Surg. Orthop. Adv., 19, 54 Potter, 2010, Heterotopic ossification following combat-related trauma, J. Bone Joint Surg. Am., 92, 74, 10.2106/JBJS.J.00776 Mazurek, 2006, The scope of wounds encountered in casualties from the global war on terrorism: from the battlefield to the tertiary treatment facility, J. Am. Acad. Orthop. Surg., 14, S18, 10.5435/00124635-200600001-00005 Matsumoto, 2014, Heterotopic ossification in civilians with lower limb amputations, Arch. Phys. Med. Rehabil., 95, 1710, 10.1016/j.apmr.2014.03.010 Potter, 2007, Heterotopic ossification following traumatic and combat-related amputations, J. Bone Joint Surg. Am., 89, 476, 10.2106/JBJS.F.00412 Forsberg, 2014, Do inflammatory markers portend heterotopic ossification and wound failure in combat wounds?, Clin. Orthop. Relat. Res., 472, 2845, 10.1007/s11999-014-3694-7 Hawksworth, 2009, Inflammatory biomarkers in combat wound healing, Ann. Surg., 250, 1002, 10.1097/SLA.0b013e3181b248d9 Edwards, 2016, Heterotopic ossification, J. Orthop. Trauma, 30, S27, 10.1097/BOT.0000000000000666 Evans, 2012, Inflammatory cytokine and chemokine expression is associated with heterotopic ossification in high-energy penetrating war injuries, J. Orthop. Trauma, 26, e204, 10.1097/BOT.0b013e31825d60a5 Kraft, 2016, Trauma-induced heterotopic bone formation and the role of the immune system, J. Trauma Acute Care Surg., 80, 156, 10.1097/TA.0000000000000883 McCarthy, 2005, Heterotopic ossification: a review, Skelet. Radiol., 34, 609, 10.1007/s00256-005-0958-z Urist, 1978, Experimental myositis ossificans: cartilage and bone formation in muscle in response to a diffusible bone matrix-derived morphogen, Arch. Pathol. Lab. Med., 102, 312 Buck, 1953, Regeneration of tendon, J. Pathol. Bacteriol., 66, 1, 10.1002/path.1700660103 Schneider, 1998, Inhibition of heterotopic ossification with radiation therapy in an animal model, Clin. Orthop. Relat. Res., 355, 35, 10.1097/00003086-199810000-00005 Michelsson, 1980, Myositis ossificans following forcible manipulation of the leg. A rabbit model for the study of heterotopic bone formation, J. Bone Joint Surg. Am., 62, 811, 10.2106/00004623-198062050-00017 Garland, 1988, Clinical observations on fractures and heterotopic ossification in the spinal cord and traumatic brain injured populations, Clin. Orthop. Relat. Res., 86 Garland, 1982, Fractures and dislocations about the elbow in the head-injured adult, Clin. Orthop. Relat. Res., 38 Tannous, 2011, Heterotopic ossification after extremity blast amputation in a Sprague-Dawley rat animal model, J. Orthop. Trauma, 25, 506, 10.1097/BOT.0b013e31821f6265 Genêt, 2011, Troublesome heterotopic ossification after central nervous system damage: a survey of 570 surgeries, PLoS One, 6, 10.1371/journal.pone.0016632 Polfer, 2015, The development of a rat model to investigate the formation of blast-related post-traumatic heterotopic ossification, Bone Joint J., 97-B, 572, 10.1302/0301-620X.97B4.34866 Salisbury, 2011, Sensory nerve induced inflammation contributes to heterotopic ossification, J. Cell. Biochem., 112, 2748, 10.1002/jcb.23225 Lazard, 2015, Osteoblasts have a neural origin in heterotopic ossification, Clin. Orthop. Relat. Res., 473, 2790, 10.1007/s11999-015-4323-9 Pape, 2004 Olmsted-Davis, 2007, Hypoxic adipocytes pattern early heterotopic bone formation, Am. J. Pathol., 170, 620, 10.2353/ajpath.2007.060692 Nelson, 2012, Heterotopic ossification following burn injury: the role of stem cells, J. Burn Care Res., 33, 463, 10.1097/BCR.0b013e31825af547 Riddle, 2009, Role of hypoxia-inducible factor-1alpha in angiogenic-osteogenic coupling, J. Mol. Med., 87, 583, 10.1007/s00109-009-0477-9 Carlevaro, 2000, Vascular endothelial growth factor (VEGF) in cartilage neovascularization and chondrocyte differentiation: auto-paracrine role during endochondral bone formation, J. Cell Sci., 113, 59, 10.1242/jcs.113.1.59 Murray, 2009, Infections in combat casualties during operations Iraqi and enduring freedom, J. Trauma Acute Care Surg., 66, S138, 10.1097/TA.0b013e31819d894c Calhoun, 2008, Multidrug-resistant organisms in military wounds from Iraq and Afghanistan, Clin. Orthop. Relat. Res., 466, 1356, 10.1007/s11999-008-0212-9 Be, 2014, Microbial profiling of combat wound infection through detection microarray and next-generation sequencing, J. Clin. Microbiol., 52, 2583, 10.1128/JCM.00556-14 Pavey, 2015, Bioburden increases heterotopic ossification formation in an established rat model, Clin. Orthop. Relat. Res., 1 Seavey, 2017, Early local delivery of vancomycin suppresses ectopic bone formation in a rat model of trauma-induced heterotopic ossification, J. Orthop. Res., 97 Evans, 2013, Osteogenic gene expression correlates with development of heterotopic ossification in war wounds, Clin. Orthop. Relat. Res., 472, 396, 10.1007/s11999-013-3325-8 Canalis, 1981, Effect of platelet-derived growth factor on DNA and protein synthesis in cultured rat calvaria, Metabolism, 30, 970, 10.1016/0026-0495(81)90094-9 Rodan, 1987, Growth stimulation of rat calvaria osteoblastic cells by acidic fibroblast growth factor, Endocrinology, 121, 1917, 10.1210/endo-121-6-1917 Centrella, 1987, Transforming growth factor beta is a bifunctional regulator of replication and collagen synthesis in osteoblast-enriched cell cultures from fetal rat bone, J. Biol. Chem., 262, 2869, 10.1016/S0021-9258(18)61587-X Olmsted-Davis, 2003, Primitive adult hematopoietic stem cells can function as osteoblast precursors, Proc. Natl. Acad. Sci. U. S. A., 100, 15877, 10.1073/pnas.2632959100 Nesti, 2008, Differentiation potential of multipotent progenitor cells derived from war-traumatized muscle tissue, J. Bone Joint Surg., 90, 2390, 10.2106/JBJS.H.00049 Davis, 2016, Location-dependent heterotopic ossification in the rat model: the role of activated matrix metalloproteinase 9, J. Orthop. Res., 34, 1894, 10.1002/jor.23216 Jackson, 2009, Putative heterotopic ossification progenitor cells derived from traumatized muscle, J. Orthop. Res., 27, 1645, 10.1002/jor.20924 Davis, 2011, Heterotopic ossification in complex orthopaedic combat wounds, J. Bone Joint Surg. Am., 93, 1122, 10.2106/JBJS.J.01417 Ranganathan, 2015, Role of gender in burn-induced heterotopic ossification and mesenchymal cell osteogenic differentiation, Plast. Reconstr. Surg., 135, 1631, 10.1097/PRS.0000000000001266 Pakos, 2004, Radiotherapy vs. nonsteroidal anti-inflammatory drugs for the prevention of heterotopic ossification after major hip procedures: a meta-analysis of randomized trials, Int. J. Radiat. Oncol. Biol. Phys., 60, 888, 10.1016/j.ijrobp.2003.11.015 Moed, 1994, Low-dose irradiation and indomethacin prevent heterotopic ossification after acetabular fracture surgery, J. Bone Joint Surg. (Br.), 76, 895, 10.1302/0301-620X.76B6.7983114 Blokhuis, 2009, Is radiation superior to indomethacin to prevent heterotopic ossification in acetabular fractures?: a systematic review, Clin. Orthop. Relat. Res., 467, 526, 10.1007/s11999-008-0532-9 2004 Teasell, 2010, A systematic review of the therapeutic interventions for heterotopic ossification after spinal cord injury, Spinal Cord, 48, 512, 10.1038/sc.2009.175 Goodman, 2005, Temporal effects of a COX-2-selective NSAID on bone ingrowth, J. Biomed. Mater. Res. A, 72A, 279, 10.1002/jbm.a.30231 Gerstenfeld, 2003, Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs, J. Orthop. Res., 21, 670, 10.1016/S0736-0266(03)00003-2 Brown, 2004, Effect of COX-2-specific inhibition on fracture-healing in the rat femur, J. Bone Joint Surg., 86-A, 116, 10.2106/00004623-200401000-00017 Celecoxib for primary prophylaxis of combat-related heterotopic ossification, (n.d.). ClinicalTrials.gov. Rivera, 2015, Locally delivered nonsteroidal anti-inflammatory drug: a potential option for heterotopic ossification prevention, Clin. Transl. Sci., 8, 591, 10.1111/cts.12300 Tintle, 2012, Reoperations following combat-related upper-extremity amputations, J. Bone Joint Surg., 94, e1191, 10.2106/JBJS.K.00197 Pavey, 2015, What risk factors predict recurrence of heterotopic ossification after excision in combat-related amputations?, Clin. Orthop. Relat. Res., 1 Isaacson, 2016, Link between clinical predictors of heterotopic ossification and histological analysis in combat-injured service members, J. Bone Joint Surg. Am., 98, 647, 10.2106/JBJS.15.00895 Cipriano, 2009, Radiation therapy for preventing recurrence of neurogenic heterotopic ossification, Orthopedics, 32, 685, 10.3928/01477447-20090728-33 Garland, 1991, A clinical perspective on common forms of acquired heterotopic ossification, Clin. Orthop. Relat. Res., 13 Schurch, 1997, Prostaglandin E2 measurements: their value in the early diagnosis of heterotopic ossification in spinal cord injury patients, Arch. Phys. Med. Rehabil., 78, 687, 10.1016/S0003-9993(97)90074-5 Forsberg, 2015, Lessons of war: turning data into decisions, EBioMedicine, 1 Polfer, 2014, Fluid collections in amputations are not indicative or predictive of infection, Clin. Orthop. Relat. Res., 472, 2978, 10.1007/s11999-014-3586-x Alfieri, 2015, Preventing heterotopic ossification in combat casualties— which models are best suited for clinical use?, Clin. Orthop. Relat. Res., 1 Stone, 2002, Near-infrared Raman spectroscopy for the classification of epithelial pre-cancers and cancers, J. Raman Spectrosc., 33, 564, 10.1002/jrs.882 Schulmerich, 2009, Transcutaneous Raman spectroscopy of murine bone in vivo, Appl. Spectrosc., 63, 286, 10.1366/000370209787599013 Crane, 2013, Raman spectroscopic analysis of combat-related heterotopic ossification development, Bone, 57, 335, 10.1016/j.bone.2013.08.026 Kaplan, 1994 Sauer, 1994, Fourier transform Raman spectroscopy of synthetic and biological calcium phosphates, Calcif. Tissue Int., 54, 414, 10.1007/BF00305529 Crane, 2006, Raman spectroscopic evidence for octacalcium phosphate and other transient mineral species deposited during intramembranous mineralization, Bone, 39, 434, 10.1016/j.bone.2006.02.059 Freudiger, 2008, Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy, Science, 322, 1857, 10.1126/science.1165758 Zhao, 2008, Integrated real-time Raman system for clinical in vivo skin analysis, Skin Res. Technol., 14, 484, 10.1111/j.1600-0846.2008.00321.x Papour, 2015, Wide-field Raman imaging for bone detection in tissue, Biomed. Opt. Express, 6, 3892, 10.1364/BOE.6.003892 Williams, 2009, Retinoic acid receptors are required for skeletal growth, matrix homeostasis and growth plate function in postnatal mouse, Dev. Biol., 328, 315, 10.1016/j.ydbio.2009.01.031 Weston, 2002, Requirement for RAR-mediated gene repression in skeletal progenitor differentiation, J. Cell Biol., 158, 39, 10.1083/jcb.200112029 Shimono, 2010, Inhibition of ectopic bone formation by a selective retinoic acid receptor α-agonist: a new therapy for heterotopic ossification?, J. Orthop. Res., 28, 271, 10.1002/jor.20985 Shimono, 2011, Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-[gamma] agonists, Nat. Med., 17, 454, 10.1038/nm.2334 Pavey, 2016, Targeted stimulation of retinoic acid receptor-γ mitigates the formation of heterotopic ossification in an established blast-related traumatic injury model, Bone, 90, 159, 10.1016/j.bone.2016.06.014 Pacifici, 1980, Vitamin A inhibits chondrogenesis but not myogenesis, Exp. Cell Res., 129, 469, 10.1016/0014-4827(80)90517-0 Mohedas, 2013, Development of an ALK2-biased BMP type I receptor kinase inhibitor, ACS Chem. Biol., 8, 1291, 10.1021/cb300655w Bayliss, 2014, Adenosine triphosphate hydrolysis reduces neutrophil infiltration and necrosis in partial-thickness scald burns in mice, J. Burn Care Res., 35, 54, 10.1097/BCR.0b013e31829b36d6 Peterson, 2014, Treatment of heterotopic ossification through remote ATP hydrolysis, Sci. Transl. Med., 6, 255ra132, 10.1126/scitranslmed.3008810 Wang, 2016, Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling, J. Bone Miner. Res., 31, 1652, 10.1002/jbmr.2848 Agarwal, 2016, Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification, Proc. Natl. Acad. Sci. U. S. A., 113, E338, 10.1073/pnas.1515397113 National Consortium for the Study of Terrorism and Responses to Terrorism (START) Bhandarwar, 2012, Mortality pattern of the 26/11 Mumbai terror attacks, J. Trauma Acute Care Surg., 72, 1329, 10.1097/TA.0b013e31824da04f Tresson, 2017, Management of Vascular Trauma during the Paris Terrorist Attack of November 13, 2015, Ann. Vasc. Surg., 10.1016/j.avsg.2016.09.011 Carles, 2016, Mass casualty events and health organisation: terrorist attack in Nice, Lancet, 388, 2349, 10.1016/S0140-6736(16)32128-6 Edwards, 2015, Heterotopic ossification in victims of the London 7/7 bombings, J. R. Army Med. Corps, 161, 345, 10.1136/jramc-2014-000370