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.
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
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.
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