Background
Heterotopic ossification (HO) is the abnormal formation of true bone within extraskeletal soft tissues. Classically, many diseases sharing this common feature were lumped into the category myositis ossificans; however, the term has fallen into disfavor because primary muscle inflammation is not a necessary precursor for such ossification and the ossification does not always occur in muscle tissue (frequently showing a predilection instead for fascia, tendons, and other mesenchymal soft tissues). The term heterotopic ossification has largely replaced myositis ossificans in the literature.

Traditionally, various forms of HO have been classified according to the clinical setting and location of the lesions, as well as according to whether the lesions are progressive or isolated in occurrence. The varieties of HO are as follows:

• Myositis ossificans traumatica - HO occurring after recalled trauma, such as blunt injury, surgery, or burns
• Nontraumatic myositis ossificans - HO that occurs when no inciting trauma can be identified
• Panniculitis ossificans - HO confined to subcutaneous fat
• Rider's bones - HO found in the adductor muscles
• Shooter's bones - HO located in the deltoid muscle

A strong association exists between HO and spinal cord injury, with lesions occurring at multiple sites and showing a strong propensity to recur. Similarly, periarticular HO is seen in patients with traumatic brain injury, with the extent and functional severity of the HO directly related to the severity of the intracranial injury. (See also the eMedicine articles Heterotopic Ossification [in the Physical Medicine and Rehabilitation section], Traumatic Heterotopic Ossification, Posttraumatic Heterotopic Ossification, and Heterotopic Ossification in Spinal Cord Injury.)

Many other causes of neurologic compromise, including tetanus, poliomyelitis, Guillain-Barré syndrome, and prolonged pharmacologic paralysis during mechanical ventilation, also have been associated with HO formation.

Fibrodysplasia ossificans progressiva (FOP), or Münchmeyer disease, is an autosomal dominant, severely disabling condition that results in progressive ossification of fascial planes, muscles, tendons, and ligaments. (See also the eMedicine article Myositis Ossificans.) Congenital malformation of the great toes also is associated with FOP. HO is a feature of several other diseases as well, including Albright hereditary osteodystrophy, progressive osseous heteroplasia, and primary osteoma cutis, but these are beyond the scope of this article.

Pathophysiology
HO originates from osteoprogenitor stem cells lying dormant within the affected soft tissues.1 With the proper stimulus, the stem cells differentiate into osteoblasts and begin the process of osteoid formation, eventually leading to mature heterotopic bone. A variety of bone morphogenetic proteins (BMPs) can stimulate HO when experimentally deposited into soft tissues, suggesting that BMPs play a role in the initiation of HO.2 A degree of neurologic control is implied but is not well understood.

Potentially causative mutations for FOP have been mapped to 2 sites, adding to the evidence of the BMPs' role in HO formation. The first site lies on the long arm of chromosome 17, in the region of the noggin gene (NOG). The noggin protein inhibits BMPs. The second genetic location is on the long arm of chromosome 4, in the region of a known BMP-signaling pathway gene. Bone morphogenetic protein 4 is overproduced in patients with FOP.

The typical histologic evolution of HO following trauma begins with spindle cell proliferation within the first week of the traumatic event. Primitive osteoid develops at the periphery of the lesion within 7-10 days. Primitive cartilage and woven bone can be seen in the second week, with trabecular bone forming at 2-5 weeks after the inciting trauma. After approximately 6 weeks, a zonal phenomenon characterized by immature, undifferentiated, central tissues and mature, peripherally located lamellar bone can be observed.

Frequency

International
Risk factors for HO include the presence of other bone-forming disorders, such as diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, and Paget disease. A personal history of previous HO also increases the risk of future occurrences. HO complicates 8-71% of total hip arthroplasty procedures, with the risk approaching 100% if the patient has had HO in a previous total arthroplasty site. Of patients with neurologic deficits, 20-30% develop HO, with as many as 50% of patients with spinal cord injury affected in some studies.

Mortality/Morbidity
The clinical impact of HO depends on the clinical setting and extent of the disease. A single lesion caused by trauma usually stabilizes and may regress; resulting symptoms depend on the location and size of the lesion. HO related to spinal cord injury or traumatic brain injury tends not to regress and may cause pain and decreased range of motion in affected joints; in such cases, the condition occasionally results in complete ankylosis and severe disability.3 Among patients with neurologic deficits, 8-10% have severe functional limitations resulting directly from HO. The extent of involvement is correlated positively with poorer outcome in rehabilitation patients recovering from traumatic brain injury. In patients with spinal cord injuries, large foci of HO can lead to skin breakdown and the inability to sit upright. Malignant degeneration to osteosarcoma has been reported but is extremely rare.

In FOP, the number and extent of lesions progress inexorably, with a consequent loss of normal limb and spinal function. Death may occur from recurrent respiratory infections resulting from chest wall restriction.

Race
Race does not appear to be a strong predisposing factor for HO in the setting of injury of the spinal cord, a site for which data are available. FOP might be expected to have racial or ethnic predilections because of its heritable nature; however, most cases are sporadic in nature because frequently patients who are affected do not have children.

Sex
Male patients with spinal cord injury are twice as likely to develop HO as are female patients.4 No strong sex predilection exists in FOP.

Age
Isolated HO can occur at any age but is rare in very young children. Posttraumatic HO is, not surprisingly, most common in young, athletic persons. In some studies, HO has been found to more frequently affect young patients (20-30 y) with spinal cord injury. Other studies have found no correlation between age and HO formation. In contrast, FOP tends to manifest in patients by age 5 years, causing severe restriction of upper extremity movement in most patients by age 15 years.

Anatomy
Posttraumatic HO can be found at any site. The most common postsurgical site is the hip, following total hip arthroplasty. The hip is also the most common site of HO occurrence in patients with traumatic brain injury or spinal cord injury. The next most common sites of involvement in patients with traumatic brain injury are the shoulders and elbows, with the knees rarely being affected. In contrast, knees frequently are involved in patients with spinal cord injury.

In FOP, involvement typically progresses from the axial to the appendicular skeleton, from cranial to caudal, and from proximal to distal. The disease typically spares the tongue, extraocular muscles, and diaphragm, as well as the cardiac and smooth muscles.

Clinical Details
Following trauma, HO often begins as a painful, palpable mass that gradually becomes nontender and smaller, as well as firmer to palpation. In spinal cord injury, patients frequently complain of lower extremity pain and swelling without antecedent trauma.

Some FOP lesions follow a specific traumatic event that the patient clearly remembers, but more often they are spontaneous, with the patient being unable to recall the occurrence of any recent trauma. Swelling, warmth, erythema, and pain are initially present. Over a period of weeks, the pain and swelling improve and may resolve completely. Alternatively, a hard, nontender, ossified lesion may arise approximately 6-12 weeks after the onset of symptoms at the site.

Differentiating early HO from lower extremity deep venous thrombosis (DVT) presents a particularly difficult diagnostic dilemma. The 2 conditions can present with the same symptoms of lower extremity pain, swelling, and erythema. Both occur more frequently in similar patient populations, namely, patients with spinal cord and traumatic brain injuries. In addition, HO and DVT have been positively associated, perhaps because the mass effect and local inflammation of HO encourage adjacent thrombus formation by causing venous compression and phlebitis.

Preferred Examination
Radiography is the preferred method of initial assessment for virtually all musculoskeletal conditions, including HO. Given their relatively low expense, radiographs should be obtained first (even if other imaging modalities are planned) in order to assess the extent of known HO.

Bone scanning is the method of choice for earliest detection and, once the diagnosis is established, for assessing the maturity of a known lesion.

Ultrasonography may have a role as a screening tool in the hip region after spinal cord injury; ultrasonograms may be obtained during a DVT screening examination.

Limitations of Techniques
Radiographs cannot detect the mineralization of HO during the first 1-2 weeks after the inciting trauma or the onset of symptoms. However, radiographs are recommended in all patients with suggested HO to assess underlying bone pathology and exclude other pathology.

Neither radiography nor computed tomography (CT) scanning should be performed in the pelvic region during pregnancy because of radiation exposure to the fetus, unless the risks of radiation exposure are outweighed by the need for a timely diagnosis. Nuclear medicine bone scanning also involves exposure of the fetus to radiation, regardless of the anatomic site being imaged, and should, if possible, be postponed until after delivery.

Ultrasonography is an operator-dependent modality. Proper evaluation of soft-tissue masses, including HO, requires considerable training and experience, available at some centers in the United States and, more commonly, in Europe. Radiologists who are less familiar with musculoskeletal ultrasonographic images may be more comfortable using CT scanning or nuclear medicine modalities to make the diagnosis of early HO.

Radiography Findings
A soft-tissue mass is the earliest radiographic finding of HO, although a mass is often overlooked at sites such as the hip and thigh. Mineralization of the osteoid lesional content can be seen as early as 10-14 days after the inciting trauma. A peripheral zone of early mineralization is the most common pattern, although many lesions have a less organized appearance. Typically, HO associated with FOP first mineralizes centrally. If untreated, mature cortical bone ultimately results.

Degree of Confidence
Peripheral ossification of a soft-tissue mass at the site of recent trauma is consistent with HO. Performing a biopsy to exclude a neoplasm should be avoided. Instead, delayed radiographs should be performed in 4 weeks to confirm maturation of the lesion into typical HO.

False Positives/Negatives
False positives can be caused by avulsion fracture fragments, osteochondral bodies within a distended joint capsule, nonosseous soft-tissue calcification (which can resemble amorphous, early mineralization of woven bone), and osteosarcoma.

False negatives are common, most often occurring in lesions in which it is too early for mineralization to be seen radiographically or at sites that have been obscured by generous, overlying soft tissues or by normal bone. Sensitivity and specificity increase with time as lesions display more mature, dense ossification.

CT Scans Findings
The earliest CT scan findings include a low-attenuation soft-tissue mass or an enlarged muscle belly, occasionally with indistinct, adjacent soft-tissue planes.5 Faint, immature bone mineralization becomes evident earlier than on radiographs, as lesions mature. With further maturation, lesions often demonstrate zonal mineralization with a mature peripheral cortex and may have central, fat-containing marrow elements. Abnormal, low-attenuation findings may persist in the soft tissues surrounding the mature cortex for months to years after the disease's onset.

Degree of Confidence
CT scans demonstrate high specificity for HO when the typical zonal pattern of peripheral mineralization is present.6 Earlier in the course of HO evolution, when the lesion appears as an enhancing mass with disorganized or absent mineralization, findings are nonspecific. A repeat CT scan after several weeks of further maturation may help resolve the diagnostic dilemma.

False Positives/Negatives
Many masslike conditions, including the presence of an inflammatory mass or a soft-tissue neoplasm, can mimic the early appearance of HO.

MRI Findings
Magnetic resonance imaging (MRI) is not routinely employed for the evaluation of HO once the diagnosis is established. Cases are most often encountered when MRI is required to assess a mass that has been detected clinically. HO may be seen incidentally in patients at risk, such as paraplegics, in whom it may be found while they are undergoing assessment for pelvic osteomyelitis.

Early HO lesions demonstrate a heterogeneous, high T2 signal and a masslike enlargement of affected tissues.7 A low–signal-intensity rim may be seen. Frequently, an extensive, ill-defined, surrounding, high T2 signal is noted. Intravenous gadolinium administration results in early, intense, heterogeneous enhancement of lesions.

Delayed imaging that takes place weeks to months after onset demonstrates a low-signal rim corresponding to maturing cortical bone on radiographs, with persistence of the heterogeneous, high T2 signal lesional content and extensive surrounding edema.

Several months after HO's onset, imaging characteristics reveal decreasing edema within and surrounding the lesion. High T1 and T2 signals that are isointense to fat develop centrally, probably representing marrow fat. Late lesions typically do not enhance.

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or magnetic resonance angiography (MRA) scans.

As of late December 2006, the Food and Drug Administration (FDA) had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.

Degree of Confidence
As on CT scans, early lesions have a very nonspecific appearance on magnetic resonance images.8 With time, the development of a zonal pattern of maturation may suggest HO, although the appearance is often misleading. Correlation with conventional radiographs is strongly recommended to confirm the diagnosis.

False Positives/Negatives
On magnetic resonance images, as on CT scans, many masslike conditions, including infectious, inflammatory, and neoplastic disorders, can have an appearance similar to that of HO.

Ultrasonography Findings
Ultrasonography is not generally used to assess HO once the diagnosis is established. However, because of the overlap of clinical presentation with deep venous thrombosis, combined with the widespread use of ultrasonography to screen for DVT, ultrasonographers can expect to encounter HO in the lower extremities of patients at risk.9 Some authors have proposed the use of ultrasonography as a simultaneous screening tool for HO and DVT in patients with spinal cord injury.

Within a few hours of the onset of clinical symptoms, ultrasonograms demonstrate a chaotic disruption of the normal lamellar structure of skeletal muscle, which can be seen up to 10-14 days before radiographic evidence of HO appears. Later, still in the preradiographic phase, a zonal, masslike pattern develops that is peripherally echogenic and centrally hypoechoic. Once early mineralization becomes radiographically visible, ultrasonograms demonstrate sheets or irregular clumps of echogenic material with acoustic shadowing. Mature lesions have the echogenicity and dense shadowing of cortical bone.

Degree of Confidence
As with HO findings on magnetic resonance images, those on ultrasonograms should be confirmed with radiographs and followed for the typical maturation pattern of HO.

False Positives/Negatives
Early in the disorganized, preradiographic phase, HO can have an appearance similar to that of a variety of posttraumatic, inflammatory, and neoplastic conditions.

Updated December 2008