Heterotopic Ossification

Updated: Aug 18, 2023
  • Author: John Speed, MBBS; Chief Editor: Elizabeth A Moberg-Wolff, MD  more...
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Overview

Practice Essentials

The term heterotopic ossification (HO) describes bone formation at an abnormal anatomical site, usually in soft tissue. [1] HO can be classified into the following 3 types:

  • Myositis ossificans progressiva (fibrodysplasia ossificans progressiva) - This disorder is among the rarest genetic conditions, with an incidence of 1 case per 2 million persons. Transmission is autosomal dominant with variable expression. The condition is characterized by (a) recurrent, painful soft-tissue swelling that leads to HO and (b) congenital malformation of the great toe. There is no treatment for this form of HO. Limited benefits have been reported using corticosteroids and etidronate. Most patients die early from restricted lung disease and pneumonia; however, some patients live productive lives. [2]
  • Traumatic myositis ossificans - In this condition, a painful area develops in muscle or soft tissue following a single blow to the area, a muscle tear, or repeated minor trauma. The painful area gradually develops masses with a cartilaginous consistency; within 4-7 weeks, a solid mass of bone can be felt. Common sites include the pectoralis major, the biceps, and the thigh muscles. A nontraumatic type of myositis ossificans also may exist.
  • Neurogenic heterotopic ossification - This condition is the one that comes to mind when the generic phrase heterotopic ossification is used. This type of HO is the subject of this article.

In 1918, Dejerine and Ceilier first described HO in patients with spinal cord injury (SCI) from the First World War. Now HO is recognized as a fairly common sequela of SCI, especially after traumatic cord injury. The condition has also been described with lesser frequency in other severe neurologic disorders (eg, traumatic brain injury, stroke, encephalitis, polio, tetanus, tabes dorsalis, syringomyelia, anoxic encephalopathy), as well as following severe burns. [3, 4, 5]

Signs and symptoms of heterotopic ossification

A diagnosis of HO can be made clinically if localized inflammatory reaction, palpable mass, or limited range of motion (ROM) is observed.

Clinically, the onset of larger masses of HO is often characteristic of any inflammatory reaction.

Fairly suddenly, a warm and swollen extremity becomes obvious, and fever is present. If sensation is intact, the area of swelling is painful.

With the development of early HO at the hip or knee, effusion may be noted at the knee.

Workup in heterotopic ossification

Laboratory studies include the following:

  • Creatine kinase - This test is not specific for HO but is of value in determining the severity of muscle involvement and may be helpful in planning treatment of HO
  • C-reactive protein
  • Alkaline phosphatase (AlkP) - The AlkP level, once a commonly used test, is not often employed today

Imaging studies include the following:

  • Bone scintigraphy - Highly sensitive in the early diagnosis of HO
  • Ultrasonography - This is also used in the early diagnosis of HO about the hips
  • Radiography - While plain radiography is highly specific in the diagnosis of HO, this method lacks sensitivity in early diagnosis
  • Computed tomography (CT) scanning and magnetic resonance imaging (MRI) - CT scanning and MRI may be useful in delineating local anatomy prior to resection; the role of CT scanning and MRI in the evaluation of other aspects of HO has not been well established
  • Three-dimensional (3D) stereolithography - This can be beneficial in the perioperative management of symptomatic HO

Management of heterotopic ossification

Palovarotene, the first drug approved for fibrodysplasia ossificans progressiva (FOP), reduces HO volume. [6, 7]

The developing consensus in the literature appears to be that aggressive passive range of motion (PROM) and continued mobilization, once acute inflammatory signs have subsided, are indicated, because they help to maintain ROM; in more extensive HO, though, they may lead to the formation of a pseudarthrosis.

Although no effective protocol had previously been developed for preventing HO after SCI, the authors' studies, based on the well-documented beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of HO after total hip arthroplasty, showed that the following drugs can also be helpful in reducing the incidence and severity of HO after SCI [8, 9, 10, 11, 12] :

  • The nonselective NSAID indomethacin SR prescribed for 3 weeks in a dose of 75 mg/d, after SCI, reduced the incidence of HO by 2-3 times
  • A 25 mg/d prescription of the selective cyclo-oxygenase-2 (COX-2) inhibitor rofecoxib decreased the risk of HO formation by 2.5 times
  • Once HO has developed to the point that it interferes significantly with the functional capacity of the patient, the only treatment option remaining is surgery, which most commonly is required at the hip. [13] The usual surgical technique used on HO occurring anteriorly at the hip is anterior wedge resection.

Related Medscape Drugs & Diseases topics:

Fibrodysplasia Ossificans

Heterotopic Ossification Imaging

Heterotopic Ossification in Spinal Cord Injury

Pediatric Fibrodysplasia Ossificans Progressiva (Myositis Ossificans)

Posttraumatic Heterotopic Ossification

Traumatic Heterotopic Ossification

Related Medscape resource:

Resource Center Joint Disorders

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Pathophysiology

Despite many investigations, the etiology and pathogenesis of neurogenic heterotopic ossification remain unknown. [13, 14, 15] An extensive review of the problem in 1973 by Rossier and colleagues attempted to address the question of pathogenesis by investigating the following parameters [16] :

  • Radiographs
  • Lower limb angiography
  • Venous and arterial blood gas analyses
  • Serial serum calcium
  • Phosphorus
  • Creatine kinase (CK) and alkaline phosphatase (AlkP)
  • Urine calcium and hydroxyproline
  • Skin temperature
  • Bone scans
  • Biopsy

None of these observations explain the factors responsible for the development of HO. Although the etiology of HO remains unknown, clinical and experimental evidence supports the hypothesis that trauma is one of the most important initiating factors. [17, 18] In the studies in which HO was induced experimentally, 2 factors were found to be prerequisites for ectopic ossification: (1) traumatic ischemic degeneration of involved muscle and (2) tissue expression of bone morphogenic proteins (BMPs).

It also has been shown that expression of many genes, including BMP, is regulated by mechanical stress. The target cells in the muscle for BMP are mesenchymal stem cells, also called satellite cells. These cells are precursors capable of differentiating into many cell types, including osteoblasts. Thus, BMP may play a role as a paracrine factor in the differentiation of satellite cells into bone-forming cells. [19]

Most likely, other factors also are involved in the etiology of HO. Studies have shown that AlkP may have an important role in ectopic calcification and ossification of soft tissues. The major role of AlkP in soft tissue is to remove inhibitors of mineralization. An increased expression of AlkP was found in vascular smooth muscle cells in the presence of macrophages and inflammatory cytokines. These observations may have clinical importance, because inflammation and trauma have long been suggested by many investigators as possible etiologic factors.

Clinically, muscle trauma has been reported as a cause of HO after SCI by numerous investigators, including Bodley and colleagues, [20] as well as Snoecx and co-investigators. [21] The types of muscle trauma proposed as initiating HO are muscle tears, ruptures, edema, and bleeding.

It has also been suggested that factors such as intensive rehabilitation, transfer activities, and repeated minor trauma during activities of daily living can cause superimposed mechanical stress and initiate HO. The hypothesis that trauma is an important factor in HO formation after SCI also has been documented by ultrasonographic and histologic studies. Various degrees of muscular damage with evidence of tissue bleeding have been found in the early stage of HO.

A literature review by Yeung et al indicated that the likelihood of HO developing after surgical fixation of an acetabular fracture is affected by various patient-, injury-, and care-related risk factors. Patient-related risk factors include the following [22] :

  • Greater body mass index (BMI)
  • Male sex
  • Increased age

Injury-related risk factors include the following [22] :

  • Intensive care unit (ICU) admission and length of stay
  • More than 10 days of non-ICU hospitalization
  • Requirement for 2 or more days of mechanical ventilation
  • Abdominal and/or chest injuries
  • The number and type of associated fractures
  • Traumatic brain injuries (TBIs)
  • T-type acetabular fractures
  • Injury to the pelvic ring
  • Hip dislocation

Care-related risk factors include the following [22] :

  • Delayed surgery
  • Extensile and posterior surgical approaches to the hip
  • Trochanteric osteotomy
  • Postoperative step-off of more than 3 mm
  • Delayed post-injury or postoperative prophylaxis

During the formation of HO, initially immature connective tissue, fibroblasts, ground substance, and collagen fibers are seen. Eventually, usually within 7-14 days, osteoblasts are noted, located irregularly in osteoid. New bone formation may start in multiple foci within osteoid. As mineralization progresses, amorphous calcium phosphate is gradually replaced by hydroxyapatite crystals. Commonly, after approximately 6 months, the appearance of true bone is noted. Rossier noted that after approximately 30 months, the pattern in HO approached that of normal young adult bone. [16]  Anatomically, HO is always extra-articular, but it may attach to the joint capsule without disrupting it. Occasionally, HO may attach to the cortex of adjacent bone, with or without cortical disruption. 

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Epidemiology

Frequency

United States

The reported incidence of HO following SCI varies greatly from study to study. Incidence varies from a low of 3.4% to a high of 47% reported by Hassard, who found HO around the hips of 62 of 131 patients with SCI who were admitted to the Hot Springs Rehabilitation Center over a 2-year period. [23] Most studies cite a range between these 2 extremes. Peak incidence is noted from 4-12 weeks postinjury and can occur up to 5 months following trauma. Later onset has been reported but is very rare.

In 1954, Irving and LeBrun first documented HO in patients with hemiplegia. Roberts reported 6 cases of HO following intracranial lesions (3 traumatic, 2 vascular, and 1 neoplastic) in 1968, and subsequent studies cited the incidence of clinically significant HO following severe closed head injury (CHI) as being 11-76%. Incidence of HO following other neurologic disorders has not been delineated yet, but it appears to be lower than the incidence following SCI or head injury.

The following reasons may be postulated for the large variability in incidence seen in different studies:

  • Different authors use different criteria to define HO. For example, using a radiologic screening survey yields higher incidence figures than does reporting only clinically significant HO detected on physical examination.

  • Although neurogenic heterotopic ossification (NHO) generally occurs periarticularly (as noted in the European term paraosteoarthropathy), some authors include patients with calcification or bone formation, possibly secondary to other causes (eg, decubitus ulcers, septic arthritis, trauma, surgery), in their studies.

  • Various authors study different populations (eg, early vs late cord injured patients).

Mortality/Morbidity

Approximately 10-35% of all patients with HO secondary to SCI have significant reduction of range of motion (ROM) at the affected joint or joints. [13] Wharton and Morgan found that 3% of patients with SCI have an ankylosed joint caused by HO. Effects on activities of daily living (ADL) and functional mobility (eg, transfers) are not difficult to imagine. In addition, abnormal weight distribution may lead to increased frequency of decubitus ulceration, as Hassard noted in 1975. [23]

Race

No known correlation exists between race and incidence of HO.

Sex

No known correlation exists between sex and incidence of HO.

Age

Age has no significant correlation with HO formation, although the condition is somewhat less frequent in pediatric and geriatric patients with SCI.

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