Secondary Logo

Journal Logo

Heterotopic Ossification: A Review of Current Understanding, Treatment, and Future

Edwards, Dafydd S. FRCS(Tr&Orth); Kuhn, Kevin M. MD; Potter, Benjamin K. MD, FACS; Forsberg, Jonathan A. MD, PhD

Journal of Orthopaedic Trauma: October 2016 - Volume 30 - Issue - p S27–S30
doi: 10.1097/BOT.0000000000000666
Supplement Article
Free

Summary: Heterotopic ossification is the formation of bone at extraskeletal sites. The incidence of heterotopic ossification in military amputees from recent operations in Iraq and Afghanistan has been demonstrated to be as high as 65%. Heterotopic ossification poses problems to wound healing, rehabilitation, and prosthetic fitting. This article details the current evidence regarding its etiology, prevention, management, and research strategies.

*The Royal British Legion Centre for Blast Injury Studies, Imperial College London, London, United Kingdom;

The Royal Centre for Defence Medicine, Birmingham, United Kingdom;

Naval Medical Center, San Diego, CA;

§Orthopaedic Surgery Service, Uniformed Services University of Health Sciences—Walter Reed National Military Medical Center, Department of Surgery, Bethesda, MD; and

Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD.

Reprints: Dafydd S. Edwards, FRCS(Tr&Orth), The Royal British Legion Centre for Bast Injury Studies, Imperial College London, Exhibition Rd, London SW7 2AZ, United Kingdom (e-mail: taffedwards100@hotmail.com).

J. A. Forsberg serves as a consultant to Clement Pharmaceuticals, Inc. The remaining authors report no conflict of interest.

Accepted July 19, 2016

Back to Top | Article Outline

INTRODUCTION

Heterotopic ossification (HO) was first described in the literature nearly 1000 years ago in the healing of fractures.1 In relation to military wounds and complications of amputations, texts from the American Civil War and World War I make specific reference to HO.2 In the present day, HO continues to cause problems to service members3 with and without amputations throughout early wound and soft tissues complications, subsequent rehabilitation,4,5 and prosthesis use.

A renewed interest in HO by military academics because of veteran functional outcomes has impressed the need for further work on its etiology, structure, biology, prevention, and management. This review summarizes the current risk factors, clinical management, and future research directions regarding trauma- and combat-related HO.

Back to Top | Article Outline

SCIENTIFIC BASIS OF HO-RELATED DISEASES

HO may develop after traumatic or surgical insult or because of genetic diseases. Genetic causes provide evidence of the genetic make-up required for the formation of HO. Fibrodysplasia ossificans progressiva and progressive osseous hyperplasia are rare genetic conditions that result in severe disability secondary to extensive HO in the soft tissue.6 In fibrodysplasia ossificans progressiva, an inflammatory pathogenetic process has been identified through a lymphocyte-associated mechanism, an increased expression of bone morphogenetic protein 4 (BMP-4),7 and the downregulation of Noggin, a BMP-4 antagonist.8

More commonly, HO develops because of neurotrauma or musculoskeletal trauma or after surgery. Neurogenic HO has been demonstrated to have a genetic element, with the injury dictating the temporal relation to its formation and the presence of HLA B27 identifying the population at risk of HO. The absence of HLA B27 precludes the formation of neurogenic HO.9

HO after surgery is most associated with total hip arthroplasty with a reported incidence ranging from 8% to 90%.10

Posttraumatic HO (THO) is formed after trauma ranging from muscle sprains to open fractures of long bones.11 The mechanism of formation is characterized by inflammation, myofibroblast proliferation and differentiation into chondroblasts (cartilage seen in early histology of HO, which forms predominantly through endochondral ossification) or osteoblasts.12 Proinflammatory mediators Platelet Derived Growth Factor,13 Fibroblast Derived Growth Factor,14 Transforming growth factor beta,15 and prostaglandins have all be implicated in osteoblast DNA synthesis and are present in bone matrix.

Studies suggest that serum alkaline phosphatase levels increase during the early stages of HO formation, even before HO is clinically apparent, reaching a maximum at approximately 10 weeks.11 Prostaglandin E2, a proinflammatory mediator easily assayed in the urine, is significantly increased in patients who subsequently develop HO. Therefore, not only is its expression implicated in HO but also it is a clinically a valuable indicator in the early diagnosis of HO.16

Back to Top | Article Outline

HO IN THE MILITARY SETTING

Advances in medical evacuation capabilities, modern body armor, and use of battlefield tourniquets have resulted in increased survivability of service members with catastrophic injuries not seen in previous conflicts. The blast-related amputation has become a signature wound of the military engagements in Iraq and Afghanistan, and it is in these casualties that the incidence of HO has increased precipitously. Furthermore, terrorist bombing in the civilian environment also results in high rates of HO.17

The incidence of HO after civilian trauma ranges from 10% to 30%, particularly spinal cord, brain, elbow, and pelvic trauma,18 whereas it is 60%–64% in combat-injured patients.19 In contrast, a recent study in a civilian amputee population reported an overall incidence of 22.8%, with 94% being graded as mild and 11% of affected patients requiring excision.20

The risk factors for developing HO in combat-wounded service personnel are detailed in Table 1. These findings suggest that both systemic and local events play a critical role in creating conditions that contribute to pathologic bone formation. It is likely that local wound conditions and the systemic inflammatory response to injury together cause alterations in osteoprogenitor cell differentiation in the injured soft tissues. Systemic elevations of inflammatory cytokines, such as interleukin-6, interleukin-10, and Monocyte Chemoattractant Protein-1, have been demonstrated to be persistent in the serum of casualties with penetrating war injuries.21 Analysis of wound effluent from war wounds has also been shown to have high osteogenic potential, which accelerated the in vitro osteogenic differentiation of multipotent bone-derived mesenchymal cells.21 A 30- to 50-fold increase in colony-forming progenitor cells has been reported in the injured muscle tissue of combat-injured casualties compared with controls.22 Local tissue hypoxia and an acidic environment have been implicated in creating a cellular environment, which favors bony mineralization and is capable of causing modulation of the cellular lineage in the injured soft tissues23 (Fig. 1).

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

Back to Top | Article Outline

COMBAT-RELATED HO PREVENTION AND TREATMENT

In the civilian setting, nonsteroidal anti-inflammatory drugs and local radiotherapy are proven to prevent HO formation24; however, these modalities are generally either medically contraindicated in the complex trauma patient or logistically infeasible in a far-forward deployed environment. Early risk stratification to best identify wounds and patients at greatest risk is now possible via testing of local and systemic inflammatory biomarkers after injury,25 and predictive statistical models have been developed to aid in prognostication and allow prophylaxis of patients at greatest risk.26

Fortunately, not all combat-related HO is symptomatic. However, for symptomatic lesions, initial management consists of pain management, physical therapy, and socket modifications. Surgical excision, if required, is best delayed until local inflammation has subsided and the HO has matured via demonstration of a stable neocortex on serial radiographs. However, dogmatic waiting for quiescence of technetium-99 bone scans or normalization of serum alkaline phosphatase is not required and in fact may never occur in some patients.

It is reported that 20% of upper-extremity and 40% of lower-extremity combat-related amputations may require excision of symptomatic HO,27,28 compared with 11% in a civilian amputee cohort.20 Surgical excision should take a direct approach toward the lesions, use existing incisions, include tourniquet use and blood product support because substantial bleeding is common. Longitudinal dissection spares residual muscle and soft tissue, and careful protection of incarcerated neurovascular structures may be required. Revising an amputation proximal to the level of HO is almost never indicated as it sacrifices valuable functional residual limb length. In carefully selected patients, partial excision of only symptomatic areas may be performed. However, the best results are achieved with complete excision of lesions performed at least 6 months from injury, with low radiographic (7%) and even lower symptomatic (2%) recurrence risk.29 Although no supporting evidence exists, the authors advocate secondary recurrence prophylaxis with a nonsteroidal anti-inflammatory drug for 4 weeks. Wound complications and infections are common after excision. However, functional results, symptom relief, and patient satisfaction are typically high.

Back to Top | Article Outline

FUTURE RESEARCH DIRECTION

Surgical excision and primary prophylaxis of HO in the polytrauma victims carry inherent risk. Therefore, much related research focuses on methods of primary prevention. Animal models have been developed that recreate the physiologic response to combat-related injuries in a reproducible manner.30,31 These models allow for the evaluation of the effects of blast overpressure, bioburden,32 and the cellular response resulting in HO.31,33–37

Successful models include a tunable and scalable means to deliver a blast overpressure that acts systemically, the recreation of an open fracture with soft tissue injury, amputation through the zone of injury, the introduction of bioburden using combat casualty isolates, and a burn injury. Small animals have limitations because of their size and the degree of systemic inflammation after combat-type injuries, and rats may have limitations given their inability to activate Matrix metallopeptidase 9.34 Therefore, larger animal models may be required to test various means of primary prophylaxis currently in development.

The mechanisms behind HO development are similar to those postulated by Chalmers more than 4 decades ago.38 In particular, nonosseous progenitor cells induction down an osteoblastic lineage. In a blast wound, several sources of progenitors cells are possible, including bone marrow, injured muscle, and peripheral nerves34,36–38 participating in an “all hands on deck” healing response. The degree of injury seen after a blast has no evolutionary precedent and reveals a dysregulated local and systemic inflammation,25 and for these reasons, the increased risk of HO formation is hypothesized after blast injury.25,39

Several osteogenic and chondrogenic genes seem to be upregulated after a massive injury,33,40,41 which sets the stage for endochondral ossification, the process by which THO forms. Two pathways have emerged as targets for effecting primary prophylaxis. The first pathway is inhibiting chondrogenesis, arguably the initial step in the process of endochondral ossification. Retinoid acid receptor (RAR) agonists are known to inhibit chondrogenesis because the RAR-γ receptor expressed on chondrogenic cells represses cell transcription.42 Therefore, treatment with an RAR-γ receptor agonist could inhibit both chondrogenic differentiation and chondrocyte function.43 This is being tested on an RAR-γ receptor agonist in both BMP-2–mediated44 and blast-related HO models (unpublished data). Questions remain on the effect of RAR-γ agonists on wound healing, but altering the timing and duration of administration may mitigate these effects.

The second pathway is targeting the canonical SMAD-dependent BMP signaling, the most commonly accepted mechanism for the formation of THO. After injury, cells produce an osteogenic response through canonical BMP/SMAD signaling. Topical treatment with apyrase limits HO formation in a mouse extremity trauma and burn model by inhibiting SMAD1/5/8 phosphorylation and signaling.33 Furthermore, small-molecule BMP inhibitor LDN-193189, acting via activin receptor-like kinase-2 and activin receptor-like kinase-3, affects bone formation in the same model. The efficacy of both apyrase and LDN-193189 in blast-related models is currently underway.

Cyclooxygenase-2–specific inhibitors are very well tolerated in combat casualties and are already used as part of a comprehensive pain management regimen. Though combat operations and subsequent recruitment are thankfully on hold, a randomized trial is currently underway to elucidate its effect in preventing HO after blast injury.45

Back to Top | Article Outline

CONCLUSIONS

HO continues to be a substantial problem and frequent complication after both combat-related and civilian trauma. To date, safe and effective primary prophylaxis for most indications does not exist. However, lessons learned from recent conflicts continue to inform that the best medical and surgical strategies be used when managing a symptomatic patient. Current research direction is focused on primary prophylaxis at the cellular level.

Back to Top | Article Outline

REFERENCES

1. Khalaf ibn Abbās, Abū al-Qāsim. Albucasis on Surgery and Instruments. Vol. 12. Berkeley, CA: Univ of California Press; 1973.
2. Dejerne A, Ceillier A. Para-osteo-arthropathies des paraplegiques par lesion medullaire; etude clinique et radiographique [in French]. Ann Med. 1918;5:497.
3. Brown KV, Dharm-Datta S, Potter BK, et al. Comparison of development of heterotopic ossification in injured US and UK armed services personnel with combat-related amputations: preliminary findings and hypotheses regarding causality. J Trauma. 2010;69:S116–S122.
4. Masini BD, Waterman SM, Wenke JC, et al. Resource utilization and disability outcome assessment of combat casualties from Operation Iraqi Freedom and Operation Enduring Freedom. J Orthop Trauma. 2009;23:261–266.
5. Gajewski D, Granville R. The United States Armed Forces amputee patient care program. J Am Acad Orthop Surg. 2006;14:S183–S187.
6. Connor JM, Evans DA. Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J Bone Joint Surg Br. 1982;64:76–83.
7. Shafritz AB, Shore EM, Gannon FH, et al. Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N Engl J Med. 1996;335:555–561.
8. Ahn J, Serrano de la Pena L, Shore EM, et al. Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis. J Bone Joint Surg Am. 2003;85-A:667–674.
9. Larson JM, Michalski JP, Collacott EA, et al. Increased prevalence of HLA-B27 in patients with ectopic ossification following traumatic spinal cord injury. Rheumatol Rehabil. 1981;20:193–197.
10. Edwards DS, Barbur SA, Bull AM, et al. Posterior mini-incision total hip arthroplasty controls the extent of post-operative formation of heterotopic ossification. Eur J Orthop Surg Traumatol. 2015;25:1051–1055.
11. Garland DE. A clinical perspective on common forms of acquired heterotopic ossification. Clin Orthop Relat Res. 1991;263:13–29.
12. Urist MR, Nakagawa M, Nakata N, et al. Experimental myositis ossificans: cartilage and bone formation in muscle in response to a diffusible bone matrix-derived morphogen. Arch Pathol Lab Med. 1978;102:312–316.
13. Canalis E. Effect of platelet-derived growth factor on DNA and protein synthesis in cultured rat calvaria. Metabolism. 1981;30:970–975.
14. Rodan SB, Wesolowski G, Thomas K, et al. Growth stimulation of rat calvaria osteoblastic cells by acidic fibroblast growth factor. Endocrinology. 1987;121:1917–1923.
15. Centrella M, McCarthy TL, Canalis E. 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. 1987;262:2869–2874.
16. Schurch B, Capaul M, Vallotton MB, et al. Prostaglandin E2 measurements: their value in the early diagnosis of heterotopic ossification in spinal cord injury patients. Arch Phys Med Rehabil. 1997;78:687–691.
17. Edwards DS, Clasper JC, Patel HD. Heterotopic ossification in victims of the London 7/7 bombings. J R Army Med Corps. 2015;161:345–347.
18. Edwards DS, Clasper JC. Heterotopic ossification: a systematic review. J R Army Med Corps. 2015;161:315–321.
19. Alfieri KA, Forsberg JA, Potter BK. Blast injuries and heterotopic ossification. Bone Joint Res. 2012;1:192–197.
20. Matsumoto ME, Khan M, Jayabalan P, et al. Heterotopic ossification in civilians with lower limb amputations. Arch Phys Med Rehabil. 2014;95:1710–1713.
21. Potter BK, Forsberg JA, Davis TA, et al. Heterotopic ossification following combat-related trauma. J Bone Joint Surg Am. 2010;92(suppl 2):74–89.
22. Davis TA, O'Brien FP, Anam K, et al. Heterotopic ossification in complex orthopaedic combat wounds: quantification and characterization of osteogenic precursor cell activity in traumatized muscle. J Bone Joint Surg Am. 2011;93:1122–1131.
23. Pape HC, Marsh S, Morley JR, et al. Current concepts in the development of heterotopic ossification. J Bone Joint Surg Br. 2004;86:783–787.
24. Pakos EE, Ioannidis JP. 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. 2004;60:888–895.
25. Forsberg JA, Potter BK, Polfer EM, et al. Do inflammatory markers portend heterotopic ossification and wound failure in combat wounds? Clin Orthop Relat Res. 2014;472:2845–2854.
26. Alfieri KA, Potter BK, Davis TA, et al. Preventing heterotopic ossification in combat casualties-which models are best suited for clinical use? Clin Orthop Relat Res. 2015;473:2807–2813.
27. Tintle SM, Baechler MF, Nanos GP, et al. Reoperations following combat-related upper-extremity amputations. J Bone Joint Surg Am. 2012;94:e1191–e1196.
28. Tintle SM, Shawen SB, Forsberg JA, et al. Reoperation after combat-related major lower extremity amputations. J Orthop Trauma. 2014;28:232–237.
29. Pavey GJ, Polfer EM, Nappo KE, et al. What risk factors predict recurrence of heterotopic ossification after excision in combat-related amputations? Clin Orthop Relat Res. 2015;473:2814–2824.
30. Polfer EM, Hope DN, Elster EA, et al. The development of a rat model to investigate the formation of blast-related post-traumatic heterotopic ossification. Bone Joint J. 2015;97-B:572–576.
31. Peterson JR, De La Rosa S, Sun H, et al. Burn injury enhances bone formation in heterotopic ossification model. Ann Surg. 2014;259:993–998.
32. Pavey GJ, Qureshi AT, Hope DN, et al. Bioburden increases heterotopic ossification formation in an established rat model. Clin Orthop Relat Res. 2015;473:2840–2847.
33. Peterson JR, De La Rosa S, Eboda O, et al. Treatment of heterotopic ossification through remote ATP hydrolysis. Sci Transl Med. 2014;6:255ra132.
34. Davis EL, Sonnet C, Lazard ZW, et al. Location-dependent heterotopic ossification in the rat model: the role of activated matrix metalloproteinase 9. J Orthop Res. 2016.
35. Salisbury E, Rodenberg E, Sonnet C, et al. Sensory nerve induced inflammation contributes to heterotopic ossification. J Cell Biochem. 2011;112:2748–2758.
36. Olmsted-Davis E, Gannon FH, Ozen M, et al. Hypoxic adipocytes pattern early heterotopic bone formation. Am J Pathol. 2007;170:620–632.
37. Jackson WM, Aragon AB, Bulken-Hoover JD, et al. Putative heterotopic ossification progenitor cells derived from traumatized muscle. J Orthop Res. 2009;27:1645–1651.
38. Chalmers J, Gray DH, Rush J. Observations on the induction of bone in soft tissues. J Bone Joint Surg Br. 1975;57:36–45.
39. Gillern SM, Sheppard FR, Evans KN, et al. Incidence of pulmonary embolus in combat casualties with extremity amputations and fractures. J Trauma. 2011;71:607–612; discussion 612–613.
40. Evans KN, Potter BK, Brown TS, et al. Osteogenic gene expression correlates with development of heterotopic ossification in war wounds. Clin Orthop Relat Res. 2014;472:396–404.
41. Forsberg JA, Davis TA, Elster EA, et al. Burned to the bone. Sci Transl Med. 2014;6:255fs37.
42. Williams JA, Kondo N, Okabe T, et al. Retinoic acid receptors are required for skeletal growth, matrix homeostasis and growth plate function in postnatal mouse. Dev Biol. 2009;328:315–327.
43. Weston AD, Chandraratna RA, Torchia J, et al. Requirement for RAR-mediated gene repression in skeletal progenitor differentiation. J Cell Biol. 2002;158:39–51.
44. Shimono K, Morrison TN, Tung WE, et al. Inhibition of ectopic bone formation by a selective retinoic acid receptor alpha-agonist: a new therapy for heterotopic ossification? J Orthop Res. 2010;28:271–277.
45. Forsberg J. Prophylaxis of heterotopic ossification in wartime penetrating injuries: a randomized clinical trial. 2013. Available at: http://www.clinicaltrials.gov. Accessed May 2, 2016.
Keywords:

heterotopic ossification; amputee; military; blast injury

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.