Korobushkin G.V., Egiazaryan K.A., Sirotin I.V., Abilemets A. S., Yuusibov R.R., Subbotin N.A.

Pirogov City Clinical Hospital No.1,
Pirogov Russian National Research Medical University, Moscow, Russia

Heterotopic ossification (HO) is the process of formation of mature lamellar bone tissue in regions, which are atypical, structurally unusual for formation of bone tissue, and have no progenitor-cells of osteoformation in the main pool of the cells. 

Classification of HO [1, 2]

HO is conventionally divided into two main types:
1. The acquired form, which is mainly presented by traumatic origin.

2. The genetic form.
I. The acquired form is classified according to the morphology of the injured system:

1. The main focus of an injury as a trigger of HO development is located in the parts of the locomotor system.

2. The main focus of an injury is located at one of the CNS levels:

1.1 Spinal cord injuries.
1.2 Brain injuries.
1.3 Brain lining injury.
II. The genetic form of HO is divided into the substrate of formation of bone tissue and different mutations in various genes:

1. Formation of bone mass through the endotracheal way (progressing ossifying fibroplasia).

2. Formation of bone mass through the intramembranous way and the way of muscular heteroplasia (progressing bone heteroplasia, Albright syndrome).

Separation of conditions of HO development

The process of bone mass formation in HO reminds the process of normal bone reparation and has the similar conditions for development, but it is characterized by higher intensity and localization. The similarity in the processes osteoregeneration and HO and presence of homotypic stages causes some difficulties in case of attempts of pharmacological treatment, since the points of administration of pharmaceuticals are the links responsible for normal growth of bone tissue, fracture union and development of heterotopic ossificates. However in case of multiple and associated injury, the priority is given to fracture union, but not to arresting the progression of growth of ossificates.
The main conditions for initiation of development of HO are [3]:

1. Osteoinduction – the process of stimulation of osteoformation by means of transmission of the key signals by protein fractions (bone morphogenetic protein (BMP)) and inflammatory mediators in patients with severe associated injury.

2. Presence of osteogenic progenitor-cells – pluripotent mesenchymal stem cells (MSC), which migrate, differentiate and multiply in response to BMP stimulation.

3. The environment for osteogenesis (“mother bed”, in case of HO, it is mostly presented by the injured muscle tissue or well perfused regions of the capsular tendinous apparatus).

4. The decrease in partial pressure (pO2), which is more common for enchondral way of development of the ossificates [3].

5. The infectious agent is another factor, which differentiates the formation of heterotopic ossificate from the normal process of osteoregeneration. The international literature reviews it as the generalized type of infection and also as the local infectious focus.

Brief description of mechanisms of HO development

The precise mechanism of HO development has not been studied thoroughly. In some degree, it is associated with polymorphous pattern of possible triggers of development high amount of complex cascades of the biochemical reactions.
However there are some parts of the hardest mechanism of HO formation.

The international literature describes the absence of inhibiting (regulating) influence of CNS on metabolism of the progenitor cells of MSC. Leptin, glutamate, calcitonin, P substance, vasoactive intestinal peptide and catecholamines are the main regulating molecules of cellular function of MSC. When CNS is damaged, the disbalance in concentration of these regulatory substances and hyperstimulation of progenitor cells of MSC on the way of osteogenesis appear [5].

Also the systemic factors in combination with local stimulating factors such as SIRS interleukins (hyperproduction of IL-6, IL-10 [6], MCp-1, MIP1f, Hifl Hif1α [7]) are reviewed.
With consideration of such morphological and biochemical features of the process of development of HO, the approximate model of the patient with predisposition to formation of the acquired form of HO is formed. A patient with associated or multiple injury answers to the description best of all.

The ways of prevention of HO development

Currently, the international literature describes the pharmaceutical variant of prevention of HO by means of administration of non-steroidal anti-inflammatory drugs (NSAIDs) (the main representative in this group – indomethacin) [8]. Also the variants of the targeted radial therapy are reviewed [9].
Therefore, the following clinical factors of HO risk are separated [10]:

1. Presence of traumatic brain injury or spinal cord injury.

2. Age < 30.

3. Amputations, multiple injuries to extremities.
4. Severity of associated injury with ISS ≥ 16.

5. Long term coma and ALV.

6. CNS injury with predominance of muscular spasticity.

7. Male gender.

8. High level of inflammatory interleukins (their disbalance) – IL-6, IL-10, MCP-1, MIP1a, MCp-1, MIP1f, Hif1α – is the sign of SIRS [11].
9. Local or generalized infection.

Each clinical risk factor has a specific morphological basis, which influences on the above-mentioned mechanisms of HO development.

Currently, the surgical treatment of HO is the most efficient. The indications for surgical treatment are the increasing amplitude of motion in the joints of the extremity, normal positioning of the extremity (correction of abnormal position). The release of vascular and nervous structures in case of their mechanic compression or folding.

Complications and hazards in surgical treatment   

Potential unboundedness of growth of the ossificates causes the high risk of significant intrasurgical blood loss because of high volume of removed tissue, the losses of the main stabilizers of the joint in case of paraarticular location of pathologic focus and damages of vascular and nervous structures. There is a high risk of infection overlay in the postsurgical period which is associated with formation of cavity (minus tissue), and higher risk of thromboembolic complications (significant soft tissue injury, appearance of the tissue factor in the in bloodstream. There is a high risk of recurrent HO.

Examination of the issue of the most appropriate choice of time of surgical treatment of HO for minimizing the risks of development of the above mentioned complications

The international literature describes two main opinions concerning the time of surgical treatment:
1. The recurrence of HO is less possible when the surgery is delayed until HO decreases its metabolic activity which is confirmed by scintigraphy [12].

2. The recent scientific articles show that the ossificates are to be removed before critical decrease in metabolic activity that minimizes the intrasurgical injury and arrests the process before involvement of important structures [12].

Surgical dissection of HO before scintigraphy confirmed appearance of metabolic activity of the ossificate. It presents the higher clinical interest since such approach decreases the intrasurgical injury, preserves the formations which are not influenced by the process, and decreases the risk of complications relating to tissue injury. Lower surgical injury decreases the local activity of the inflammatory mediators and decreases the risk of recurrent activation of MSC through the way of development of osteogeneration and recurrence of HO. It allows faster activation of the patient in the postsurgical period.


Objective – to review the clinical case of treatment of the patient with severe associated injury and subsequent development of heterotopic ossification in the region of the hip joint.
The study was conducted in compliance with
World Medical Association Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects, 201­3, and the Rules for clinical practice in the Russian Federation (the Order by Russian Health Ministry, June 19, 2003, No.266), with the written consent for participation in the study and the approval from the local ethical committee (the protocol No. 64179375THR2001, May 28, 2018).

The patient B., age of 29, was admitted to the intensive care unit of City Clinical Hospital No.1 on October 4, 2011 (the pedestrian in a road traffic accident). The clinical death was recorded at the prehospital stage. The condition was severe at the moment of admission. GCS was 8 (moderate coma). The breathing was independent. AP was 100/70 mm Hg. HR was 21.
The patient was examined by the radiologist, the neurosurgeon and the traumatologist. The tracheal intubation and ALV were conducted. The examination was conducted. The CT of the pelvis did not identify any traumatic changes in the pelvic bones and the hip joints. The X-ray examination of the injured segments was carried out.

The clinical diagnosis was made: “Severe associated injury, opened traumatic brain injury, brain contusion, traumatic subarachnoidal bleeding, a fracture of squamosal of the right temporal bone with transition to the pyramid. An opened comminuted fracture of the right leg in the middle one-third with displacement of fragments (Gustilo 3a). A fracture of nasal bones. A fracture of the rib head to the left. Lung contusion. Blood aspiration. Multiple contused wounds of soft tissues of the head and the right leg. Clinical death at the prehospital stage”. ISS = 34”.
The risk stratification of heterotopic ossification in this patient:

1. Age < 30.

2. Injury type – high energy (road traffic accident).

3. Presence of TBI – yes.

4. Multiple injuries – yes.
5. Long term coma, ALV –yes, 14 days.

6. CNS injury with predominance of spasticity – yes.

7. SIRS – yes.

8. ISS > 16.

9. Infection – yes (multiple wounds, an opened fracture of the leg bones).

The staged treatment was conducted in compliance with Damage control orthopedics (DC).

Primary surgical management of the opened fracture of the leg, and fixation of fragments with the rod device were conducted. Intensive care was conducted (infusion, vasotropic and antibacterial therapy, hemotransfusion, prevention of venous thromboembolic complications).

The patient was transferred to the neurosurgery unit on the day 22 after the injury. The treatment was continued for other 13 days. After appearance of the positive trends, the patient was transferred to the traumatology and orthopedics unit.

The rod device was dismounted on the day 35 after the injury, and the plaster bar was applied.

On the day 35, the patient had some complaints of discomfort during movement in the hip joint. The X-ray examination of the hip joint was conducted. The hip X-ray images showed some signs of HO in the left hip joint (Fig. 1). The conservative therapy was initiated (indomethacin 25 mg per day during 8 weeks).

Figure 1. The X-ray image of the left hip joint in the axial view. It was made on the 35th day after the injury. There are some initial radiologic signs of developing heterotopic ossification of the lesser and greater trochanters


Intramedullary fixation of the leg bones was conducted on the day 37 after the injury.

The patient was active at the moment of discharge, and she could walk without support for the right lower extremity. The movements in the left hip joint were within the full range and without pain. There was a discomfort in the left hip joint during movement, but it did not limit the amplitude of movements and did not hinder the activation.

One and a half year after the injury, the patient had some complaints of absence of movements in the left hip joint. The X-ray image of the left hip joint showed heterotopic ossification in theleft hip joint (Brooker, type 4) [13] (Fig. 2).

Figure 2. The X-ray image of the pelvis one and half year after the injury. There is heterotopic ossification of capsular and ligamentous apparatus of the left hip joint and the left iliac muscle

The X-ray images showed alesion of the capsular-ligamentous apparatus and the iliac muscle to the left.  Scintigraphy showed the high metabolic activity of the heterotopic focus of calcification (184 % of accumulation of the pharmaceutical from the normal value). The surgical intervention was cancelled. 
In 2015 (4 years after the injury), scintigraphy identified the minimal metabolic activity of the ossification focus (76 % of accumulation of the pharmaceutical from the normal value).

In 2016, the X-ray image (5 years after the injury) showed the absence of changes in the ossificate.

The patient had some complaints of the absence of movement in the left hip joint, claudication and decreased life quality. Computer tomography of the pelvis was conducted for estimation of precise location of the mass and assessment of lesion of the surrounding structures (Fig. 3).

Figure 3. Computer tomography of the pelvis 5 years after the injury. There is heterotopic ossification of the left hip joint. A mass lesion is located in the region of the capsule and the iliac muscle of the left hip joint

A decision on the surgical treatment was made for restoration of movement in the left hip joint. The volume of the intervention was determined during surgery: only removal of the ossificates or hip replacement after removal of the ossificates.
The risks of a surgical intervention:
blood loss was expected. The arteries rounding the femoral neck were located in the region of heterotopic ossification. The arteries were in the bone tissue that impeded hemostasis. There was a high risk of complete devitalization of the femoral head with subsequent intrasurgical estimation of a possibility of aseptic necrosis.
During surgery:
the ossificates were the completely calcified capsule of the left hip joint and the left iliac muscle (Fig. 4). The dissection of the heterotopic ossificates showed that all main sources of perfusion of the femoral head were involved into the pathological process. The head was devitalized after their complete dissection for restoration of movements in the joint. It was decided to perform total hip replacement (Fig. 5). The histological examination of the removed ossificates was conducted (Fig. 6). It showed that the removed bone tissue corresponded to compact bone substance.

Figure 4. A picture of the intrasurgical wound. The arrow indicates the region of heterotopic ossification along the iliac muscle. The tissue density corresponded to the density of the cortical bone. Ossification corresponded to the joint capsule and the left iliac bone

Figure 5. The control X-ray image of the pelvic bones after dissection of ossificates and realization of total left hip joint replacement

Figure 6.
The microsample of the removed tissue. The substance corresponds to compact bone tissue

Functional result: Harris score was 86 points of 100, i.e. the good result (Fig. 7-10).

Figure 7. The control X-ray image of the pelvic bones 2 years after surgical management

Figure 8. Demonstration of function of the left hip joint 2 years after surgical treatment (abduction)


Figure 9. Demonstration of function of the left hip joint 2 years after surgical treatment (flexion)

Figure 10. Demonstration of function of the left hip joint 2 years after surgical treatment (flexion)


1. Primary manifestations of heterotopic ossification in the hip joint were identified on the day 35 after the injury.
2. Administration of NSAIDs for prevention of HO was not sufficiently successful.

3. The surgical management after complete formation of the ossificate reduces the risks of recurrent HO, but causes the necessity for higher volume of surgery and determines more radical types of surgery without adherence to organ-saving techniques.

4. The problem of HO in patients with severe associated injury is actual and requires for further researching.

Information on financing and conflict of interests

The study was conducted without sponsorship.
The authors declare the absence of clear and potential conflicts of interests relating to publication of this article.


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