Orthopedics

Feature Article 

Heterotopic Ossification Revisited

Andreas F. Mavrogenis, MD; Panayotis N. Soucacos, MD, FACS; Panayiotis J. Papagelopoulos, MD, DSc

Abstract

Heterotopic ossification is the abnormal formation of mature lamellar bone within extraskeletal soft tissues where bone does not exist. Heterotopic ossification has been classified into posttraumatic, nontraumatic or neurogenic, and myositis ossificans progressiva or fibrodysplasia ossificans progressive. The pathophysiology is unknown. Anatomically, heterotopic ossification occurs outside the joint capsule without disrupting it. The new bone can be contiguous with the skeleton but generally does not involve the periosteum. Three-phase technetium-99m (99mTc) methylene diphosphonate bone scan is the most sensitive imaging modality for early detection and assessing the maturity of heterotopic ossification. Nonsurgical treatment with indomethacin and radiation therapy is appropriate for prophylaxis or early treatment of heterotopic ossification. Although bisphosphonates are effective prophylaxis if initiated shortly after the trauma, mineralization of the bone matrix resumes after drug discontinuation. During the acute inflammatory stage, the patient should rest the involved joint in a functional position; once acute inflammatory signs subside, passive range of motion exercises and continued mobilization are indicated.

Surgical indications for excision of heterotopic ossification include improvement of function, standing posture, sitting or ambulation, independent dressing, feeding and hygiene, and repeated pressure sores from underlying bone mass. The optimal timing of surgery has been suggested to be a delay of 12 to 18 months until radiographic evidence of heterotopic ossification maturation and maximal recovery after neurological injury. The ideal candidate for surgical treatment before 18 months should have no joint pain or swelling, a normal alkaline phosphatase level, and 3-phase bone scan indicating mature heterotopic ossification.

Heterotopic ossification is the abnormal formation of mature lamellar bone within extraskeletal soft tissues where bone normally does not exist; it involves true osteoblastic activity and bone formation. Since the initial description in 1883 by Reidel and in 1918 by Dejerne and Ceillier,1 various forms of heterotopic ossification have been described according to the clinical setting and location of the lesions, and progressive or isolated occurrence; these include traumatic and nontraumatic heterotopic ossification, panniculitis ossificans (heterotopic ossification confined to subcutaneous fat), rider’s bones (heterotopic ossification located in the adductor muscles), shooter’s bones (heterotopic ossification located in the deltoid muscle), and heterotopic ossification following spinal cord injury, traumatic brain injury, stroke, encephalitis, poliomyelitis, tetanus, tabes dorsalis, syringomyelia, anoxic encephalopathy, Guillain-Barré syndrome, and prolonged pharmacologic paralysis during mechanical ventilation. Albright hereditary osteodystrophy, progressive osseous heteroplasia, and primary osteoma cutis have also been associated with heterotopic ossification formation.1-10

Heterotopic ossification has been classified into posttraumatic, nontraumatic or neurogenic, and myositis ossificans progressiva or fibrodysplasia ossificans progressive.2-18

Posttraumatic heterotopic ossification may occur after any type of bone or soft tissue trauma such as fractures and joint dislocations, muscle tear, or repeated minor trauma, and orthopedic procedures such as hip, knee, shoulder, or elbow arthroplasty.2-9 The incidence of posttraumatic heterotopic ossification is similar in the upper and lower extremities; it is higher in patients who undergo open reduction and internal fixation of a fracture. Fifty-five percent of patients with hip fractures develop heterotopic ossification; the incidence increases to 83% if open reduction and internal fixation is performed. The incidence of posttraumatic heterotopic ossification at the elbow approaches 90% after an elbow fracture and/or dislocation. Traumatic heterotopic ossification of the elbow occurs in 20% of forearm fractures. The incidence of heterotopic ossification after total hip arthroplasty (THA) ranges from 0.6% to 90%, with a mean incidence of 53%; the risk approaches 100% if the patient has had heterotopic ossification in a previous total joint arthroplasty site.5,10

Nontraumatic or neurogenic heterotopic ossification or myositis ossificans circumscripta without trauma occurs after neurogenic injury such as spinal cord and central nervous system injury, burns, head injuries, strokes, and brain tumors (Figures 1,…

Abstract

Heterotopic ossification is the abnormal formation of mature lamellar bone within extraskeletal soft tissues where bone does not exist. Heterotopic ossification has been classified into posttraumatic, nontraumatic or neurogenic, and myositis ossificans progressiva or fibrodysplasia ossificans progressive. The pathophysiology is unknown. Anatomically, heterotopic ossification occurs outside the joint capsule without disrupting it. The new bone can be contiguous with the skeleton but generally does not involve the periosteum. Three-phase technetium-99m (99mTc) methylene diphosphonate bone scan is the most sensitive imaging modality for early detection and assessing the maturity of heterotopic ossification. Nonsurgical treatment with indomethacin and radiation therapy is appropriate for prophylaxis or early treatment of heterotopic ossification. Although bisphosphonates are effective prophylaxis if initiated shortly after the trauma, mineralization of the bone matrix resumes after drug discontinuation. During the acute inflammatory stage, the patient should rest the involved joint in a functional position; once acute inflammatory signs subside, passive range of motion exercises and continued mobilization are indicated.

Surgical indications for excision of heterotopic ossification include improvement of function, standing posture, sitting or ambulation, independent dressing, feeding and hygiene, and repeated pressure sores from underlying bone mass. The optimal timing of surgery has been suggested to be a delay of 12 to 18 months until radiographic evidence of heterotopic ossification maturation and maximal recovery after neurological injury. The ideal candidate for surgical treatment before 18 months should have no joint pain or swelling, a normal alkaline phosphatase level, and 3-phase bone scan indicating mature heterotopic ossification.

Heterotopic ossification is the abnormal formation of mature lamellar bone within extraskeletal soft tissues where bone normally does not exist; it involves true osteoblastic activity and bone formation. Since the initial description in 1883 by Reidel and in 1918 by Dejerne and Ceillier,1 various forms of heterotopic ossification have been described according to the clinical setting and location of the lesions, and progressive or isolated occurrence; these include traumatic and nontraumatic heterotopic ossification, panniculitis ossificans (heterotopic ossification confined to subcutaneous fat), rider’s bones (heterotopic ossification located in the adductor muscles), shooter’s bones (heterotopic ossification located in the deltoid muscle), and heterotopic ossification following spinal cord injury, traumatic brain injury, stroke, encephalitis, poliomyelitis, tetanus, tabes dorsalis, syringomyelia, anoxic encephalopathy, Guillain-Barré syndrome, and prolonged pharmacologic paralysis during mechanical ventilation. Albright hereditary osteodystrophy, progressive osseous heteroplasia, and primary osteoma cutis have also been associated with heterotopic ossification formation.1-10

Classification and Incidence

Heterotopic ossification has been classified into posttraumatic, nontraumatic or neurogenic, and myositis ossificans progressiva or fibrodysplasia ossificans progressive.2-18

Posttraumatic heterotopic ossification may occur after any type of bone or soft tissue trauma such as fractures and joint dislocations, muscle tear, or repeated minor trauma, and orthopedic procedures such as hip, knee, shoulder, or elbow arthroplasty.2-9 The incidence of posttraumatic heterotopic ossification is similar in the upper and lower extremities; it is higher in patients who undergo open reduction and internal fixation of a fracture. Fifty-five percent of patients with hip fractures develop heterotopic ossification; the incidence increases to 83% if open reduction and internal fixation is performed. The incidence of posttraumatic heterotopic ossification at the elbow approaches 90% after an elbow fracture and/or dislocation. Traumatic heterotopic ossification of the elbow occurs in 20% of forearm fractures. The incidence of heterotopic ossification after total hip arthroplasty (THA) ranges from 0.6% to 90%, with a mean incidence of 53%; the risk approaches 100% if the patient has had heterotopic ossification in a previous total joint arthroplasty site.5,10

Nontraumatic or neurogenic heterotopic ossification or myositis ossificans circumscripta without trauma occurs after neurogenic injury such as spinal cord and central nervous system injury, burns, head injuries, strokes, and brain tumors (Figures 1, 2).3,12,13 Less often, neurogenic heterotopic ossification occurs after sickle cell anemia, hemophilia, tetanus, poliomyelitis, multiple sclerosis, and toxic epidermal necrolysis.14 Neurogenic heterotopic ossification develops only in sites distal to the level of the spinal cord injury, and almost always on the affected side of brain injury or stroke. Heterotopic ossification develops in 3.4% to 47% of patients with spinal cord injury and 10% to 20% of patients with closed head injury (Figure 3). The incidence is higher in a spastic extremity and complete spinal cord injuries.15 Heterotopic ossification occurs in 16% of spastic cerebral palsy children having hip osteotomies.16 In the elbow, heterotopic ossification is seen in 4% of these patients; however, if fracture or dislocation is associated with brain injury, the incidence of heterotopic ossification at the elbow rises to 89%.3

Figure 1: Neurogenic heterotopic ossification Figure 2A: Neurogenic heterotopic ossification of the right hip joint
Figure 2B: Neurogenic heterotopic ossification of the left hip joint Figure 3: Neurogenic heterotopic ossification of the left hip joint
Figure 1: AP radiograph of the pelvis of a 30-year-old man with neurogenic heterotopic ossification of the left hip joint (Brooker stage IV) after a motor vehicle accident. The patient had closed brain injury and remained in the intensive care unit for 2 months. Figure 2: AP radiograph of the pelvis of a 21-year-old man with neurogenic heterotopic ossification of the right hip joint (Brooker stage IV) after a motor vehicle accident (A). The patient had closed brain injury and a closed fracture of the right femoral diaphysis that was treated by locked intramedullary nailing. He remained in the intensive care unit for 1.5 months. Lateral (left) and AP (right) radiographs show heterotopic ossification at the quadriceps muscles bilaterally (B). Figure 3: AP radiograph of the pelvis of a 25-year-old man with neurogenic heterotopic ossification of the left hip joint (Brooker stage IV) and the right hip joint (Brooker stage III) after a motor vehicle accident. The patient had closed brain injury and remained in the intensive care unit for 3 months.

Myositis ossificans progressiva or fibrodysplasia ossificans progressiva or Münchmeyer disease is a rare hereditary metabolic bone disease associated with progressive ossification of fascial planes, muscles, tendons, and ligaments (Figure 4).17,18 The incidence is 1 case per 2 million live births. Genetic transmission is autosomal dominant with variable expression. Potentially causative mutations for fibrodysplasia ossificans progressive have been mapped to 2 sites, adding to the evidence of the bone morphogenic proteins’ role in heterotopic ossification formation. The first site lies on the long arm of chromosome 17, in the region of the noggin gene. The noggin protein inhibits bone morphogenic proteins. The second genetic location is on the long arm of chromosome 4, in the region of a known bone morphogenic protein-signaling pathway gene. Bone morphogenetic protein 4 is overproduced in patients with fibrodysplasia ossificans progressive. The condition is characterized by: (1) recurrent, painful soft tissue swelling that leads to heterotopic ossification, and (2) congenital malformation of the great toe. There is no treatment for this form of heterotopic ossification. The number and extent of lesions progress inevitably. Limited benefits have been reported using corticosteroids and etidronate. Most patients die early from restricted lung disease and pneumonia from chest wall restriction; some patients live productive lives.17,18

Figure 4A: Congenital malformation of the great toes Figure 4B: Extensive heterotopic ossification
Figure 4C: Heterotopic ossification of the sternum Figure 4D: Extensive heterotopic ossification of both knees
Figure 4: Congenital malformation of the great toes including monophalangic great toes with valgus deviation in a 21-year-old man with fibrodysplasia ossificans progressiva (A). Three-dimensional CT scan of the pelvis shows extensive heterotopic ossification (B). Radiograph of the chest showing heterotopic ossification of the sternum, the ribs, and both shoulder girdles (C). Extensive heterotopic ossification of both knees (D).

Pathophysiology

The pathophysiology of heterotopic ossification is unknown. It appears to involve the inappropriate differentiation of mesenchymal cells into osteoblastic stem cells in response to unidentified inducing factors such as the pool of available calcium in adjacent skeleton, soft tissue edema, and vascular stasis, tissue hypoxia, and mesenchymal cells with osteoblastic activity.12,13 The basic defect in heterotopic ossification is the inappropriate differentiation of fibroblasts into bone-forming cells. Heterotopic ossification originates from osteoprogenitor stem cells lying dormant within the affected soft tissues. With the proper stimulus, the stem cells differentiate into osteoblasts and begin osteoid formation, eventually leading to mature heterotopic bone showing cancellous bone and mature lamellar bone, vessels, and bone marrow with a minor amount of hematopoiesis.19

Unconscious polytrauma patients produce more abundant bony callus than conscious patients with similar fractures and union occurs more rapidly. These patients may develop heterotopic ossification. In these patients, changes in the levels of circulating catecholamines and sympathetic activity,20,21 and the high levels of calcitonin may well be related to the more rapid healing of fractures seen in this group and heterotopic ossification formation.22

The typical histologic evolution of heterotopic ossification following trauma begins with spindle cell proliferation within the first week of the traumatic event. Primitive osteoid develops within 7 to 14 days. In the second week, primitive cartilage and woven bone can be seen, and trabecular bone forms at 2 to 5 weeks after the inciting trauma. New bone formation may start in multiple foci within osteoid. At approximately 6 weeks, a zonal phenomenon characterized by immature, undifferentiated, central tissues and mature, peripherally located lamellar bone can be observed. As mineralization progresses, amorphous calcium phosphate is gradually replaced by hydroxyapatite crystals. Commonly, after approximately 6 months, the appearance of true bone in the connective tissue between the muscle planes and not within the muscle itself is noted. At approximately 30 months, the pattern of heterotopic ossification approaches that of normal young adult bone.12

Anatomically, the development of heterotopic ossification is extra-articular and occurs outside the joint capsule without disrupting it.23 The new bone can be contiguous with the skeleton but generally does not involve the periosteum. Occasionally, heterotopic ossification may attach to the cortex of adjacent bone, with or without cortical disruption.23,24

Risk Factors

Muscle inflammation and trauma are the most important initiating factors inducing ischemic degeneration of involved muscle and tissue expression of bone morphogenic proteins. The target cells in the muscle for bone morphogenic proteins are mesenchymal stem cells. These cells are precursors capable of differentiating into many cell types, including osteoblasts. Thus, bone morphogenic proteins may play a role as a paracrine factor in the differentiation of satellite cells into bone-forming cells.25

Alkaline phosphatase and bone-forming disorders, such as diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, and Paget disease, are also involved in heterotopic ossification. The major role of alkaline phosphatase in soft tissue is to remove inhibitors of mineralization.26,27 A history of previous heterotopic ossification increases the risk of future occurrences. Mechanical stress by intensive rehabilitation, transfer activities, and repeated minor trauma during activities of daily living can initiate heterotopic ossification. Race does not appear to be a strong predisposing factor for heterotopic ossification in the setting of spinal cord injury. Men with spinal cord injury are twice as likely to develop heterotopic ossification as are women.28 Age has not been related to heterotopic ossification. Isolated heterotopic ossification can occur at any age but is rare in young children. Posttraumatic heterotopic ossification is most common in young, athletic persons.

Clinical Diagnosis

Clinical diagnosis of heterotopic ossification in its initial stages is difficult. The clinical signs and symptoms of heterotopic ossification may appear as early as 3 weeks or as late as 12 weeks after the musculoskeletal trauma, spinal cord injury, or other precipitating event such as fracture, surgery, or severe systemic illness.29,30 The earliest sign of heterotopic ossification is often loss of joint mobility and resulting loss of function. Other findings include swelling, erythema, heat, local pain, a palpable mass, and contracture formation. Fever may also be present.29,30

Heterotopic ossification can be found at any site, usually around major joints such as elbows, shoulders, hips, and knees following brain injury, as well as over long-bone fractures. Common sites of posttraumatic heterotopic ossification include the pectoralis major, the biceps, the brachialis, the thigh muscles, and, rarely, the feet. Less common sites are abdominal incisions, wounds, the kidneys, the uterus, the corpora cavernosa, and the gastrointestinal tract.4,6-9 The most common postsurgical site is the hip, following THA. The hip is also the most common site of heterotopic ossification occurrence in patients with spinal cord or traumatic brain injury. At the hip, the flexors and abductors tend to be involved more frequently than the extensors or adductors. 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 are frequently involved in patients with spinal cord injury. The proximal interphalangeal joints of the hand, wrist, and spine also may be affected.29-31

Nonarticular manifestations of heterotopic ossification are rare. These include ulnar nerve compression with heterotopic ossification at the elbow, vascular (predominantly venous) compression with or without associated deep venous thrombosis (DVT), increased spasticity, and lymphatic obstruction leading to lymphedema. Large foci of heterotopic ossification can lead to pressure ulcers, skin breakdown, and inability to sit upright.32,33 Some fibrodysplasia ossificans progressive lesions follow a specific traumatic event, 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, pain and swelling improve and may resolve completely. Alternatively, a hard, nontender, ossified lesion may arise approximately 6 to 12 weeks after the onset of symptoms at the site.17,18

Clinical differential diagnosis of heterotopic ossification includes DVT, osteomyelitis, tumor, cellulites, septic arthritis, hematoma, fracture, or local trauma.34-37 Differentiating early heterotopic ossification from lower extremity DVT presents a diagnostic dilemma. The 2 conditions can present with the same symptoms of lower extremity pain, swelling, and erythema. Both occur more frequently in patients with spinal cord and traumatic brain injuries. In addition, heterotopic ossification and DVT have been positively associated, perhaps because the mass effect and local inflammation of heterotopic ossification encourage adjacent thrombus formation by causing venous compression and phlebitis.

Natural History

Eighty percent or more of heterotopic ossification cases run a relatively benign course with no complications. In the remaining 10% to 20%, significant loss of motion develops, with ankylosis in up to 10%.3 A single posttraumatic heterotopic ossification lesion usually stabilizes and may regress. Heterotopic ossification related to spinal cord injury or traumatic brain injury tends not to regress and may cause pain and decreased range of motion (ROM) in affected joints, or complete ankylosis and severe disability.35 Malignant degeneration to osteosarcoma is extremely rare.36

Laboratory

Alkaline phosphatase levels have been reported to parallel the activity of ossification. Typically, alkaline phosphatase levels become abnormal approximately 2 weeks after injury, and reach approximately 3.5 times the normal value 10 weeks after the inciting trauma before returning to normal at approximately 18 weeks.38 However, alkaline phosphatase levels cannot be used to draw clinical conclusions about maturity or recurrence of heterotopic ossification; in many patients, values may be normal in the presence of active heterotopic ossification or may remain elevated for years.38-40 In addition, the elevation can be nonspecific because of associated skeletal injuries, the surgical treatment of fractures, or hepatotoxicity.

Elevated creatine kinase levels correlate with histologic involvement of muscle and severity of disease. Although not specific for heterotopic ossification, creatine kinase may predict a higher risk for heterotopic ossification development and severity, and may be helpful in treatment planning and evaluation of response to treatment.12,41,42

The initial stage of heterotopic ossification is manifested by a prominent inflammatory response that is accompanied by changes in levels of cytokines that stimulate the production of acute-phase proteins, such as C-reactive protein. In 1 study, the normalization of C-reactive protein in serum was accompanied by a resolution of the inflammation of soft tissue heterotopic ossification after spinal cord injury.43 It seems that administering nonsteroidal anti-inflammatory drugs (NSAIDs) in the early phase of heterotopic ossification, as well as monitoring the serum C-reactive protein level, may provide added benefit in reducing the inflammatory reaction in heterotopic ossification.43

Increased urinary excretion of the 24-h PGE2 has been recommended as a valuable indicator of early heterotopic ossification. A sudden increase in PGE2 excretion points to the need for bone scans to qualify the process. Indomethacin is a PGE2-blocking agent, and thus may be useful in treating heterotopic ossification.44

Imaging

A soft tissue mass is the earliest radiographic finding of heterotopic ossification. The typical radiographic appearance of heterotopic ossification is circumferential ossification with a lucent center. However, radiographs cannot detect the mineralization of heterotopic ossification during the first weeks after the inciting trauma or the onset of symptoms. A detectable calcific density appears on standard radiographs only 4 to 6 weeks after the 3-phase bone scan becomes positive.38,45 A peripheral zone of early mineralization is the most common pattern, although many lesions have a less organized appearance. Radiographic differential diagnosis should include avulsion fracture fragments, osteochondral bodies within a distended joint capsule, nonosseous soft tissue calcification, and osteosarcoma.32,33,36 Radiography has been used to classify heterotopic ossification that develops after THA (Tables 1, 2).46,47

Table 1: Brooker Classification of Heterotopic Ossification Around the Hip Joint

Table 2: Schmidt and Hackenbroch Classification of Heterotopic Ossification

Ultrasonography has been used in the early diagnosis of heterotopic ossification about the hip joints, and as a simultaneous screening tool for heterotopic ossification and DVT in patients with spinal cord injury. Early in the preradiographic phase, ultrasonograms demonstrate a chaotic disruption of the normal lamellar structure of skeletal muscle. Later, still in the preradiographic phase, a zonal, mass-like, peripherally echogenic and centrally hypoechoic pattern develops. 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.26 However, ultrasonography is an operated-dependent examination, and no data are available on the value of ultrasonography in the diagnosis of heterotopic ossification in other joints.

Computed tomography (CT) may detect soft tissue ossification at a relatively earlier stage than by standard radiography. Typical CT findings include a low-attenuation soft tissue mass or an enlarged muscle belly, occasionally with indistinct, adjacent soft tissue planes.48,49 Magnetic resonance imaging (MRI) is not routinely used for the evaluation of heterotopic ossification. Typical MRIs of heterotopic ossification show a low-signal-intensity rim and a heterogeneous, high-signal-intensity and tumor-like enlargement of affected tissues.50,51 Intravenous gadolinium administration results in early, intense, heterogeneous enhancement of the lesions.52

Three-phase technetium-99m (99mTc) methylene diphosphonate bone scanning is the most sensitive imaging modality for early detection and assessing the maturity of heterotopic ossification.53-55 Serial bone scans have been used successfully to monitor the metabolic activity of heterotopic ossification and determine the appropriate time for surgical resection, if needed, and to predict postoperative recurrence.12,54,56,57 Bone scans are typically positive >2 weeks before radiographic evidence of heterotopic ossification. In early lesions, only the flow studies or blood pool images may be positive, reflecting the hypervascularity of early heterotopic ossification. Soft tissue uptake in the delayed phase subsequently develops within 1 week of the appearance of flow or blood pool abnormalities. Activity on the delayed bone scans usually peaks a few months after injury, after which the intensity of activity on these scans progressively lessens. Most bone scan findings return to baseline within 12 months. However, during the course of heterotopic ossification, the delayed phase may show increased activity even after the flow study and blood-pool images have returned to normal and the underlying heterotopic ossification has become mature. Early angiography in heterotopic ossification lesions shows hypervascularity, with numerous fine vessels that lack the disordered characteristics of tumor neovascularity. Mature heterotopic ossification is usually avascular but may cause the extrinsic compression of adjacent vessels.12,53-57

Management

Once heterotopic ossification begins to develop, there are no treatment options to prevent or revert this process. Management is aimed at limiting its progression and maximizing function of the affected joint. Nonsurgical treatment is appropriate for early heterotopic ossification.30,58-61 Indomethacin and other NSAIDs, including naproxen and diclofenac, and selective cyclooxygenase-2 inhibitors such as celecoxib have been proven to be effective against heterotopic ossification following hip surgery. Radiation therapy has also been used to prevent heterotopic ossification; current evidence supports radiation therapy as the preferred method for preventing heterotopic ossification after operative treatment of acetabular fractures.59 However, postoperative single-fraction radiation therapy, when used acutely after elbow trauma for prophylaxis against heterotopic ossification, may increase the rate of nonunion at the site of the fracture or an olecranon osteotomy.60 Surgical excision of heterotopic ossification should be considered in cases of joint ankylosis or significantly decreased ROM before complications arise. Patient selection, timing of excision, and postoperative prophylaxis are important components of proper surgical management.58

Prophylactic Management

Prophylaxis or early treatment of heterotopic ossification should be delivered within 3 days of THA. However, no consensus exists on which drug should be used and when treatment should begin.30,38,39,62-65 Nonsteroidal anti-inflammatory drugs such as indomethacin and selective COX-2 inhibitors have successfully been used as prophylaxis for heterotopic ossification. Direct effect of NSAIDs on the formation of heterotopic ossification refers to the inhibition of the differentiation of mesenchymal cells into osteogenic cells; indirect effect refers to the inhibition of posttraumatic bone remodeling by suppression of the prostaglandin-mediated inflammatory response.66-69 Indomethacin remains the gold standard for heterotopic ossification prophylaxis following THA. Following THA, other NSAIDs, including naproxen and diclofenac, are equally as effective as indomethacin and can be considered as alternative first-line treatments. Indomethacin prescribed for 3 weeks in a dose of 75 mg/d after spinal cord injury reduced the incidence of heterotopic ossification by 2 to 3 times. For most patients undergoing THA, a 7-day course of indomethacin has been recommended as a prophylaxis against heterotopic ossification.67,68 However, a statistically significant reduction in the incidence of severe heterotopic ossification with the use of indomethacin when compared with a placebo in patients with isolated fractures of the acetabulum has not been documented.70 Celecoxib is also of equal efficacy to indomethacin and is associated with significantly fewer gastrointestinal side effects. However, serious concerns were raised over the safety of selective cyclooxygenase-2 inhibitors for the cardiovascular system and these should be used cautiously.30

Bisphosphonates have properties similar to naturally occurring pyrophosphate, which may be a regulator of calcification. It has been recommended starting bisphosphonates as soon as elevated alkaline phosphatase is noted or imaging studies establish the presence of heterotopic ossification.38,39,71 Although bisphosphonates are effective prophylaxis if initiated shortly after the trauma, mineralization of the bone matrix resumes after drug discontinuation, making this traditional practice also controversial.15,16 In addition, bisphosphonates do not affect heterotopic ossification that has already formed. Etidronate disodium is the most extensively studied bisphosphonate for the treatment of heterotopic ossification. Long-term oral therapy using etidronate (typically for several months) has been effective treatment for early heterotopic ossification that has been detected by bone scan or ultrasonography. Etidronate acts by inhibiting precipitation of calcium phosphate from unsaturated solutions, delaying aggregation of apatite crystals into layers, and blocking conversion of calcium phosphate into hydroxyapatite. The inflammatory process and mineralization decreases with time, and no massive rebound bone formation is observed after cessation of etidronate.30,62,63

Radiation therapy has been studied mostly for the prevention of heterotopic ossification in high-risk patients for heterotopic ossification recurrence following THA. Little is known of radiation therapy’s effect on heterotopic ossification after spinal cord injury.13,72 Mesenchymal stem cells that may be in muscle and that transform into bone-forming cells are highly radiosensitive.73 However, the optimal dosage, frequency, and timing of radiation therapy have not been established.74 A single irradiation of 7 Gy may be administered in those patients in whom heterotopic ossification has developed after a previous operation or who have contraindications to receiving indomethacin.67 Fractioned radiation therapy schemes have also been suggested.75

Physical therapy in heterotopic ossification has long been controversial. There is debate between resting the joint and aggressive passive ROM. During the acute inflammatory stage, the patient should rest the involved joint in a functional position; once acute inflammatory signs have subsided, passive ROM exercises and continued mobilization are indicated.12 More aggressive joint manipulation has been suggested, although the trauma resulting from this approach carries the risk of new hematoma formation and inciting further heterotopic ossification.

Surgical Considerations

Surgery is the only treatment option once heterotopic ossification has developed to the point that it interferes significantly with the functional capacity of the patient. However, given the severe complications frequently accompanying surgery and possible recurrence of heterotopic ossification postoperatively, surgical resection should be undertaken only after patient selection, identification of functional goals, and careful preoperative planning.13 Surgical indications for removal of heterotopic ossification include improvement of function, standing posture, sitting or ambulation, and independent dressing, feeding, and hygiene. Excision should also be considered for patients in whom an underlying bone mass contributes to repeated pressure sores.13

Various recommendations have been made for the timing of surgery. Excision should be considered for patients with clinical, laboratory, or radiographic evidence of heterotopic ossification maturation since resection of immature heterotopic ossification leads to increased complications rate and recurrence rates of nearly 100%.76-78 However, waiting for the maturation of heterotopic bone before operating may take 1 to 2 years. Accurate indicators of maturity have remained difficult to obtain. Maturation of heterotopic ossification is determined by the radiographic appearance of a defined cortex and by a normal level of serum alkaline phosphatase.76,77 Reliable and practical information about the maturation of heterotopic ossification has been reported the appearance of cortical boundaries that can be seen on serial direct radiographs.76 Attempts have been made to stage the maturity of heterotopic ossification based on imaging studies.12,13,15,16,30,62,63 Serial preoperative bone scans that quantify the ratio of heterotopic to normal bone activity have successfully predicted both intraoperative complications and postoperative nonrecurrence; a decreasing or stable scintigraphic activity ratio is considered the hallmark of mature heterotopic ossification. As heterotopic ossification becomes mature, there also is a significant decrease, often reaching a normal level, in both flow study and blood-pool activity. Computed tomography may also become part of the preoperative evaluation of heterotopic ossification patients, indicating areas that should be avoided or carefully removed at surgery. Computed tomography may identify a low-density material in the soft tissue adjacent to areas of ectopic ossification postulated to be immature unossified connective tissue, the violation of which may be responsible for the serious intraoperative bleeding frequently experienced during resection of heterotopic ossification.

The timing of surgery for heterotopic ossification is controversial. The optimal timing has been suggested to be a delay of 12 to 18 months until radiographic evidence of maturation of heterotopic ossification and maximal recovery after neurological injury.3,79,80 Additional prognostic indicators for successful heterotopic ossification excision are good cognitive recovery and selective motor control in the extremity of patients with spinal cord or brain injury.76,77 Shehab et al78 have recommended 4 surgical criteria for heterotopic ossification resection, including significantly limited ROM of the involved joint; absence of local fever; swelling, erythema, or other clinical findings of acute heterotopic ossification; normal serum alkaline phosphatase; and return of bone scan findings to normal or near normal. Garland3 has recommended different schedules for surgical intervention, depending on the etiology of the condition underlying the heterotopic ossification: 6 months after direct traumatic musculoskeletal injury, 1 year after spinal cord injury, and 1.5 years after traumatic brain injury. The ideal candidate for surgical resection of heterotopic ossification before 18 months will have no joint pain or swelling, a normal alkaline phosphatase level, and a 3-phase bone scan indicating mature heterotopic ossification. In more severely compromised patients, if motor control is still improving and laboratory test values still indicate abnormalities, surgery should be delayed >18 months. With such patients, the major indication for surgery is limb positioning.12,13,62,63 However, prolonged delay usually contributes to aggravation of pain, stiffness or muscular atrophy, secondary contractures or joint ankylosis, and impaired function.81-83 In this setting, improved function without significant risk of recurrence have been reported with early surgical intervention for posttraumatic heterotopic ossification, at 4 to 8 months after injury.3,76,84

Once heterotopic ossification has matured, it can be removed surgically or partially resected if clinically indicated (Figure 5). The usual surgical technique used on heterotopic ossification occurring anteriorly at the hip is anterior wedge resection. Postoperatively, the joint should be positioned with foam wedges so that the surgical correction can be maintained and any strain on the incision or pressure sores can be prevented. Surgical removal should be followed by adjuvant treatments including passive ROM exercises, low-dose radiation, or etidronate disodium; these should be administered within 3 days postoperatively for prophylaxis against heterotopic ossification recurrence.* Complications of surgical removal of heterotopic ossification include hemorrhage, wound-healing problems, cellulitis, infection or osteomyelitis, and possible recurrence of heterotopic ossification.

*References 12, 13, 15, 16, 30, 62, 63, 67, 72-75, 85-89.

Figure 5A: Extensive neurogenic heterotopic ossification after a motor vehicle accident Figure 5B: Surgical removal of the upper and posterior heterotopic ossification Figure 5C: After partial removal of heterotopic ossification
Figure 5: AP radiograph of the left hip of a 36-year-old man with extensive neurogenic heterotopic ossification after a motor vehicle accident (A). The patient had an open abdominal wound that was treated by surgical debridement and closure, and was complicated by sepsis. He remained in the intensive care unit for 3 months. Staged heterotopic ossification removal was done; through a posterolateral approach to the upper femur, surgical removal of the upper and posterior heterotopic ossification was done at 18 months after the injury (B). Postoperative AP radiograph of the left hip after partial removal of heterotopic ossification (C).

Treatment options of fibrodysplasia ossificans progressive are limited. In these patients, recurrence is a virtual certainty. The trauma of surgery may aggravate the condition, and medical treatment with bisphosphonates to inhibit the crystallization of hydroxyapatite in the bone has been found ineffective. Combined treatment using surgical excision of heterotopic ossification, indomethacin, and single-fraction irradiation may be beneficial.17,18

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Authors

Dr Mavrogenis is from the Department of Orthopedics, Istituto Ortopedico Rizzoli, Bologna, Italy; and Drs Soucacos and Papagelopoulos are from the First Department of Orthopedics, ATTIKON University Hospital, Athens University Medical School, Athens, Greece.

Drs Mavrogenis, Soucacos, and Papagelopoulos have no relevant financial relationships to disclose.

Correspondence should be addressed to: Panayiotis J. Papagelopoulos, MD, DSc, First Department of Orthopedics, ATTIKON University Hospital, Athens University Medical School, 4 Christovassili St, 15451, Neo Psychikon, Athens, Greece (pjp@hol.gr; pjportho@otenet.gr).

doi: 10.3928/01477447-20110124-08

10.3928/01477447-20110124-08

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