The traumatic bone: trauma-induced heterotopic ossification

Abstract

Heterotopic ossification (HO) is a common occurrence after multiple forms of extensive trauma. These include arthroplasties, traumatic brain and spinal cord injuries, extensive burns in the civilian setting, and combat-related extremity injuries in the battlefield. Irrespective of the form of trauma, heterotopic bone is typically endochondral in structure and is laid down via a cartilaginous matrix. Once formed, the heterotopic bone typically needs to be excised surgically, which may result in wound healing complications, in addition to a risk of recurrence. Refinements of existing diagnostic modalities, like micro- and nano-CT are being adapted toward early intervention. Trauma-induced HO is a consequence of aberrant wound healing, systemic and local immune system activation, infections, extensive vascularization, and innervation. This intricate molecular crosstalk culminates in activation of stem cells that initiate heterotopic endochondral ossification. Development of animal models recapitulating the unique traumatic injuries has greatly facilitated the mechanistic understanding of trauma-induced HO. These same models also serve as powerful tools to test the efficacy of small molecules which specifically target the molecular pathways underlying ectopic ossification. This review summarizes the recent advances in the molecular understanding, diagnostic and treatment modalities in the field of trauma-induced HO.

Mkx-Deficient Mice Exhibit Hedgehog Signaling–Dependent Ectopic Ossification in the Achilles Tendons

“…Heterotopic ossification (HO) is the pathological formation of bone in soft tissues such as muscle, tendon, and ligaments . Clinically, the most common form of HO occurs following traumatic injuries or orthopedic surgeries, for which ossification is often not detected clinically until months after the traumatic events although the pathogenic processes likely started soon after injury and the underlying pathogenic mechanisms are not understood . Patients with HO experience a wide range of problems, including chronic pain, limitation in range of motion, joint ankyloses, and skin ulceration .…”

“…Currently, the primary treatment modality for HO, besides conservative management approaches including physical therapy and use of systematic nonsteroidal anti‐inflammatory drugs, is surgical excision of the ectopic bone. However, the efficacy of surgical excision is controversial because recurrences have been reported in many patients . In addition to trauma‐induced HO, two rare genetic disorders, fibrodysplasia ossificans progressive (FOP) (OMIM 135100) and progressive osseous heteroplasia (POH) (OMIM 166350), are clinically characterized by extensive and progressive HO .…”

“…(1) Clinically, the most common form of HO occurs following traumatic injuries or orthopedic surgeries, for which ossification is often not detected clinically until months after the traumatic events although the pathogenic processes likely started soon after injury and the underlying pathogenic mechanisms are not understood. (2)(3)(4) Patients with HO experience a wide range of problems, including chronic pain, limitation in range of motion, joint ankyloses, and skin ulceration. (4) Currently, the primary treatment modality for HO, besides conservative management approaches including physical therapy and use of systematic nonsteroidal antiinflammatory drugs, is surgical excision of the ectopic bone.…”

“…However, the efficacy of surgical excision is controversial because recurrences have been reported in many patients. (3) In addition to trauma-induced HO, two rare genetic disorders, fibrodysplasia ossificans progressive (FOP) (OMIM 135100) and progressive osseous heteroplasia (POH) (OMIM 166350), are clinically characterized by extensive and progressive HO. (5)(6)(7) FOP is caused by gain-of-function mutations in the ACVR1 gene, which encodes a type-I receptor for both Activin and BMP family proteins, (6) whereas POH is caused by loss-of-function mutations in GNAS, encoding the Gas subunit involved in G-proteincoupled receptor signaling.…”

Treatments and Preventative Measures for Trauma‐Induced Heterotopic Ossification: A Review

“…Although small animal models cannot directly mimic the formation of clinically relevant HO, each type of animal study provides the opportunity to better understand the pathophysiology and pathogenesis under unique circumstances. A comprehensive evaluation of the mechanistic pathways of bone growth, healing, and complications that may contribute to HO is beyond the scope of this review but some of the discussions are provided for further investigation 28, 29, 30, 31, 32, 33, 34, 35, 36, 37. With improved understanding, better physical and pharmacological therapeutic protocols can be developed for use in human patients.…”