AUTHOR AND EDITOR INFORMATION

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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
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Background

In 1918, Dejerine and Ceillier first described heterotopic ossification (HO) in paraplegic patients injured in World War I, referring to the process as paraosteoarthropathy. HO has been defined as the formation of mature lamellar bone in soft tissues. The process involves true osteoblastic activity and bone formation. HO has been reported in cases of brain injury, spinal cord injury, stroke, poliomyelitis, myelodysplasia, tabes dorsalis, carbon monoxide poisoning, spinal cord tumors, syringomyelia, tetanus, and multiple sclerosis. This condition also has been reported after burns and total hip replacement/joint arthroplasty.

Several terms have been used to describe the condition, including heterotopic ossification, ectopic ossification, and myositis ossificans. HO usually involves the large joints of the body (eg, hips, elbows, shoulders, knees). Excessive bone formation may result in significant disability by severely limiting the range of motion (ROM) of these joints (see Image 1).

The following 3 categories of HO have been described:

• Myositis ossificans progressiva - This is a rare metabolic bone disease in children with progressive metamorphosis of skeletal muscle to bone; it is characterized by an autosomal dominant pattern of genetic transmission.
• Myositis ossificans circumscripta without trauma - Also referred to as neurogenic HO, this is a localized soft-tissue ossification occurring after neurologic injury or burns.
• Traumatic myositis ossificans - This condition occurs from direct injury to the muscles. Fibrous, cartilaginous, and osseous tissues near bone are affected; the muscle may not be involved.

Related eMedicine topics:
Heterotopic Ossification [Physical Medicine and Rehabilitation]
Heterotopic Ossification [Radiology]
Heterotopic Ossification in Spinal Cord Injury
Myositis Ossificans
Traumatic Heterotopic Ossification

Related Medscape topic:
Resource Center Joint Disorders

Pathophysiology

The specific cause and pathophysiology of heterotopic ossification (HO) remain uncertain, but the condition appears to involve the inappropriate differentiation of mesenchymal cells into osteoblastic stem cells in response to still-unidentified inducing agents.

HO may be due to an interaction between local factors (eg, the pool of available calcium in adjacent skeleton, soft-tissue edema, vascular stasis tissue hypoxia, mesenchymal cells with osteoblastic activity) and an unknown systemic factor or factors. The basic defect in HO is the inappropriate differentiation of fibroblasts into bone-forming cells. Early edema of connective tissue proceeds to tissue with foci of calcification and then to maturation of calcification and ossification.

Frequency

United States

The reported incidence of heterotopic ossification (HO) varies. In cases of severe trauma or insult to the central nervous system (CNS), 10-20% of patients develop HO, and the condition has been observed in 20% of patients with severe brain injury. The incidence is higher in patients who undergo open reduction and internal fixation of a fracture. With an elbow fracture, dislocation, or fracture-dislocation, the incidence of traumatic HO at the elbow approaches 90%. Traumatic HO of the elbow occurs in 20% of forearm fractures. Fifty-five percent of patients with hip fractures develop HO. The incidence increases to 83% if open reduction and internal fixation are performed. The incidence is similar in the upper and lower extremities.

An association has been cited between spasticity and HO. The incidence is higher in a spastic extremity; 84% of patients with HO had spasticity, and 54% of patients with HO had no spasticity. HO is seen in the elbow in 4% of patients with traumatic brain injury (TBI); however, if fracture or dislocation is associated with brain injury, the incidence of HO rises to 89%.

Related eMedicine topics:
Classification and Complications of Traumatic Brain Injury
Neurointensive Care for Traumatic Brain Injury in Children
Traumatic Brain Injury: Definition, Epidemiology, Pathophysiology

International

Studies from Europe and Japan have shown the incidence of HO to range between 11% and 76%, depending on the population studied and on the method of detection.

Mortality/Morbidity

Only 10-20% of all heterotopic ossification (HO) patients have functionally significant deficits.

Race

No race predilection exists for heterotopic ossification.

Sex

The development of heterotopic ossification is independent of the patient's sex.

Age

An increased incidence of heterotopic ossification (HO) has been found in persons over age 30 years. The incidence of HO in children appears to be lower than that in adults (8-22.5%).

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
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History

The earliest sign of heterotopic ossification (HO) often is decreased joint ROM. Other findings include swelling, erythema, heat, pain with ROM testing, and contracture formation, but the condition may be occult. Fever also may be present. Patients with HO can experience pain, increased spasticity, vascular and nerve compression, and lymphedema.

Physical

In heterotopic ossification (HO), ectopic bone usually forms around major joints (eg, elbows, shoulders, hips, knees) following brain injury, as well as over long-bone fractures. The proximal interphalangeal joints of the hand, wrist, and spine also may be affected. Local pain and a palpable mass may be noted in the periarticular region, usually presenting 1-3 months after the injury, but the onset of HO also has been reported at 1-7 months following severe brain injury.

HO can mimic thrombophlebitis, with pain, swelling, erythema, and induration of the affected area. If HO affects a joint, a decrease in ROM often is observed. Major, long-term disability from untreated HO can include limited ROM or even joint ankylosis.

In patients with a history of fractures, spasticity, and low-level responsiveness, the detection of restricted motion should suggest HO. Excessive bone formation may result in significant disability by severely limiting the ROM of a joint.

Complete elbow ankylosis without severe injury of the CNS has been described.

Causes

Patients with brain injuries are at greater risk for developing heterotopic ossification (HO) if they have significant spasticity or increased muscle tone in the involved extremity, unconsciousness lasting longer than 2 weeks, long-bone or associated fractures, and decreased ROM. Therefore, the risk of development of HO in a patient with brain injury increases as the severity of injury, length of immobilization, and duration of coma increase.

In patients with fibrodysplasia ossificans progressiva (FOP) (often misdiagnosed as cancer), any soft-tissue trauma (eg, biopsies, surgical procedures, intramuscular injections, mandibular blocks for dental procedures) and viral illnesses are likely to induce episodes of rapidly progressive HO, with a resultant permanent loss of motion in the affected area.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to Be Considered

The differential diagnosis for heterotopic ossification (HO) in patients with soft-tissue swelling or loss of ROM includes thrombophlebitis, cellulites, septic arthritis, hematoma, fracture, or local trauma. The presence of fever due to HO may mimic deep venous thrombosis in presentation or osteomyelitis from hematogenous or contiguous spread.

FOP, a rare, genetic, autosomal dominant disease characterized by episodes of permanent HO of soft tissues, occurs worldwide without race, ethnic, or geographic predilection. No effective treatment is available, and soft-tissue trauma (eg, biopsies, surgical procedures, intramuscular injections, mandibular blocks for dental procedures), as well as viral illnesses, are likely to induce episodes of rapidly progressive HO, with a resultant permanent loss of motion in the affected area. Accurate diagnoses can be made based on the clinical findings of tumorlike swellings on the head, neck, back, or shoulders and characteristic short great toes with hallux valguslike malformations and missing interphalangeal joints.

For the nonfunctional shoulder, 70º of abduction and 45º of external rotation are usually sufficient to allow access to the axilla for washing and sufficient ROM for dressing. HO, typically inferomedial, does not interfere with ROM; restriction of shoulder motion is more likely attributable to other soft-tissue tightness. If present at the shoulder, HO is likely to be present at other joints, such as the elbow, hips, or knees; in these locations, HO usually causes a considerable number of clinical problems.

WORKUP

Section 5 of 11  

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Lab Studies

• Progressive loss of joint mobility and markers of increased osteoblastic activity, such as an elevated fractionated alkaline phosphatase level, warrant a comprehensive musculoskeletal examination with a 3-phase bone scan and radiographs to confirm the presence, distribution, and extent of heterotopic ossification (HO).^{1, 2, 3}
• The diagnosis of HO following brain injury typically is made by the clinical examination and by assessing for elevations in alkaline phosphatase. Early increases in alkaline phosphatase may be difficult to interpret, because the level rises with other causes, such as fractures or hepatotoxicity. The level of alkaline phosphatase has been reported to parallel the activity of ossification. It was found that when ossification stopped, the level returned to normal. Alkaline phosphatase fractionation studies reportedly can distinguish among different reasons for electrical levels.
• Osteocalcin, another marker of osteoblastic activity, does not appear to be useful in the early detection of HO or in the assessment of its maturity. The erythrocyte sedimentation rate is too nonspecific to be of much help in the diagnosis of HO, but an elevated level associated with other clinical features suggests the need for further evaluation.

Imaging Studies

• Heterotopic ossification (HO) typically cannot be seen on plain radiographs until several weeks after clinical manifestations (including pain, swelling, erythema, restricted ROM) become evident.
• Radiographs may not show abnormalities during the acute phase of erythema and swelling. Later radiographs (1-2 weeks after onset) often show only soft-tissue swelling. Radiographs show immature ossification and then the appearance of mature bone. HO may take 8-14 months to reach maturity. Plain radiographs may not show evidence of HO until 4-5 weeks after injury.
• Because of the limitations of plain radiography, radionuclide bone scanning is the preferred diagnostic test for earlier detection.⁴
• On anteroposterior radiography, HO is usually located inferior and medial to the humeral head.
• Excision may be undertaken to improve passive shoulder functions. Computed tomography (CT) scans of the shoulder (cross sections) and 3-dimensional reconstruction assist with preoperative planning. Radiographic assessment of joints with HO may be severely limited by difficulties in positioning the patient for the necessary view.

Other Tests

• Many clinicians rely on triple-phase bone scanning technology for early detection of heterotopic ossification (HO). Triple-phase technetium-99m (^99mTc) bone scanning detects early increases in vascularity and is a reliable indicator in making a diagnosis.¹ The first and second phases of the triple-phase bone scan show increased uptake. Areas demonstrating increased blood flow and soft-tissue concentration of the tracer on early imaging (blood flow phase) correlate with sites of subsequent HO development. The optimal timing of the imaging for accurate assessment of the presence of ectopic bone has not been established, but 3 weeks or more following the injury should be sufficient for early detection.

Procedures

• Various authors who have reviewed the association between the human leukocyte antigen (HLA) system and heterotopic ossification (HO) have suggested that a genetic predisposition to an associated systemic factor exists; thus, an antigenic marker should be available to mark susceptible patients. Others have found no evidence of any association between the HLA system and HO. An association between HLA-B 18 and patients with neurologic disorders, as well as with patients who develop HO, has been described. However, 75% of patients with HO lack this marker.

Histologic Findings

Histologic examination demonstrates that tissue developed through heterotopic ossification (HO) is composed of true osseous tissue rather than of calcified soft tissue. Heterotopic bone is metabolically active and exhibits approximately triple the normal rate of bone formation and double the normal number of osteoclasts.

TREATMENT

Section 6 of 11  

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Rehabilitation Program

Physical Therapy

The treatment of heterotopic ossification (HO) often is quite challenging and, in many cases, unsatisfactory. Therefore, emphasis should be placed on the importance of understanding the natural history of HO in developing treatment strategies. Most cases of HO occur within 3 months after spinal cord injury. Most roentgenographic evaluation occurs during a 6-month period, and the progress of HO is related to the severity of injury. In patients with severe injuries, roentgenographic progression has been found to subside by 6 months and serum alkaline phosphatase and bone scan activity to become normal or significantly decreased. In patients with more severe deficits, larger amounts of bone formation that progressed for more than 1 year has been seen, and elevated alkaline phosphatase levels and increased bone scan activity have been observed for up to 2 years or longer.

The role of physical therapy in patients with HO is controversial. The major goal of treatment is to maintain ROM and thereby preserve function; however, opinions differ regarding ROM exercises for patients with HO.

Several authors have reviewed the literature that compares opposing philosophies. One theory is that an aggressive regimen of passive ROM exercises may predispose the patient to the development of HO because of microtrauma or local hemorrhage. Several authors suggest that passive stretching and ROM exercises are contraindicated after HO is suggested, but they recommend active exercise within the pain-free range. Other authors stress the importance of ROM exercises to maintain joint mobility and to prevent or retard fibrous ankylosis. They found no evidence for increased HO or decreased ROM with passive ROM exercises.

Forceful manipulation of joints with preexisting HO under anesthesia helps to maintain useful joint ROM and to prevent ankylosis. A study by Garland and colleagues found that 64% of affected joints maintained or gained ROM with rehabilitation after manipulation.⁵ Some patients required repeated manipulations; none had a detectable increase in HO. The literature generally supports the common use of active ROM exercises and gentle, passive ROM exercises to maintain available joint motion and to avoid progressive contractures. If ankylosis seems inevitable despite exercises, it is best for the patient if it occurs in the most functional position.

Medical Issues/Complications

In a patient with a severe head injury, problems (such as deforming spasticity and contracture) often have time to develop because of the time needed to handle prolonged complications in acute care (eg, craniotomy facial bone surgeries, cholecystitis, pneumonia or other infections). In addition, if the head-injury patient displays a low level of responsiveness during much of the hospital course, this often casts doubt in the mind of acute care personnel about the individual's suitability for rehabilitation. Aggressive measures to prevent deformities may be given a lesser priority, especially if staff members are dealing with complications that have a greater medical priority. The resulting deformities may be quite advanced by the time the patient reaches acute rehabilitation, making intervention more difficult.

Surgical Intervention

In cases of heterotopic ossification (HO), surgery for removal of ectopic bone should be undertaken only for clear functional goals, such as for improved standing posture or ambulation or for independent dressing and feeding. In general, surgery is not undertaken earlier than 18 months after injury.

Excision should be considered for patients in whom shoulder motion is severely limited by extensive heterotopic bone, especially if dynamic electromyography studies reveal volitional capacity for the various shoulder muscles. Excision also may be undertaken to improve passive shoulder functions.

HO that restricts elbow motion is excised surgically at maturation. Maturation of HO is determined by the radiographic appearance of a defined cortex and by a normal level of serum alkaline phosphatase. Additional prognostic indicators for successful HO excision are good cognitive recovery (Rancho scale level VI or greater) and selective motor control in the extremity. Time since onset of brain injury alone is not an accurate prognosticator.^{6, 7}

lf joint deformity from HO results in significant functional limitations, such as difficulty with hygiene, sitting, or ambulation, surgical resection of HO may be indicated. Surgery also may be appropriate if an underlying bone mass contributes to repeated pressure sores. Various recommendations have been made for the timing of surgery. Surgery is contraindicated in patients with clinical, laboratory, or radiographic evidence of active ossification. Waiting for the maturation of heterotopic bone before operating may take 1-2 years. Heterotopic bone should be excised when it significantly restricts joint ROM and limits function and rehabilitation. Other authors have said that the process is stabilized after 6-8 months and that surgery is of benefit after that time, although the authors did not state whether radiation treatments were given to the patients studied.

Traditionally, surgery should be delayed for 18 months after brain injury. Patients with good neurologic recovery, good motor control, normal or slightly elevated levels of alkaline phosphatase, and a mature lesion may be candidates for surgery before the 18 months. In more severely compromised patients, if motor control is still improving and laboratory test values still indicate abnormalities, surgery should be delayed longer than 18 months. With such patients, the major indication for surgery is limb positioning. Once HO has matured, at 12-18 months or more after injury, it can be removed surgically or partially resected if clinically indicated. Postexcision, low-dose radiation or the use of etidronate disodium (EHDP) can prevent its recurrence.^{8, 9, 10, 11, 12, 13}

However, several case series suggest that earlier resection results in improved function without significant risk of recurrence. Although diphosphonates are an effective means of prophylaxis if initiated shortly after the trauma, mineralization of the bone matrix resumes after drug discontinuation, making this traditional practice also controversial.

Consultations

• Physiatrists - To plan the best rehabilitative approach
• Neurologists - To rule out other neurologic impairments
• Orthopedic surgeons - If any surgical treatment is necessary

Other Treatment

Forceful joint manipulation appeared to enhance formation of HO, and it has been postulated that the force generated by muscle spasticity may promote its development.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.^{11, 14, 15, 16, 17, 18, 19, 20, 21}

Drug Category: Bisphosphonate derivatives

Analogs of pyrophosphate, these act by binding to hydroxyapatite in bone-matrix, thereby inhibiting the dissolution of crystals. Bisphosphonate derivatives prevent osteoclast attachment to the bone matrix and inhibit osteoclast recruitment and viability.⁸

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• If, at discharge from acute care, the residual impairments are of such severity that the patient remains dependent, options include an acute or a subacute rehabilitation program.²² The typical candidate for a TBI acute rehabilitation unit is the patient who consistently is able to follow a 1-step command but who often is confused, disoriented, and restless, if not overtly agitated; many patients have a combination of physical limitations or medical complications.
  
  The ideal goal of this phase of rehabilitation is to assist the patient during the period ranging from the late stages of unconsciousness through the clearing of posttraumatic amnesia, resolution of agitation, and at least minimal independence in activities of daily living (ADL). For the patient and his/her family, the most salient goal of the acute rehabilitation phase is to regain optimal independence in ADL. To remain in this rehabilitation environment, the patient must be able to tolerate and benefit from a minimum of 3 hours of therapy, 5 days per week.
• Subacute rehabilitation programs are largely based in nursing homes. Such programs do not require that the patient tolerate 8 hours of therapy per day. Consequently, subacute rehabilitation programs are most appropriate for patients who remain in the coma stages, inconsistently respond to simple commands, or show a low rate of progress. The typical length of stay is considerably longer than the present national average of approximately 30 days in acute rehabilitation. Largely because of staffing and overhead, subacute rehabilitation offers health care providers a less expensive form of specialized intervention. Although data support the importance of early rehabilitation interventions to outcome, virtually no data compare the outcome of acute intervention with that of subacute intervention.

Further Outpatient Care

• After documenting the extent of impairment and estimating functional outcome, the physiatrist should determine the most appropriate rehabilitation interventions. Early rehabilitation is initiated while the patient remains on the trauma or neurosurgical service unit. Rehabilitation options after this early stage are predicated on the nature of residual impairments. In the unlikely event that a patient with severe TBI recovers sufficiently during acute care to permit rehabilitation management on an outpatient basis, individual outpatient services or a day treatment program may be recommended. Day treatment rehabilitation typically offers integrated programs of physical therapy, occupational therapy, speech therapy, cognitive remediation, and psychological services up to 8 hours per day, 5 days per week.

Transfer

• Once the patient is ready to be transferred from inpatient rehabilitation, a number of postacute management strategies are available. If the patient can be given effective treatment at home, then rehabilitation options include individual in-home or outpatient therapy or comprehensive day treatment services. If the patient in an acute rehabilitation setting fails to achieve basic functional independence in a timely fashion, transfer to a subacute rehabilitation program may be warranted. In the event that behavioral problems, such as agitation, preclude discharge to the home, more specialized inpatient behavioral treatment programs are indicated. Another level in the continuum of rehabilitation includes transitional living programs, which typically are residential community–based alternatives for patients with primarily cognitive and neurobehavioral deficits.

Deterrence

• Various recommendations have been made to prevent recurrence of heterotopic ossification (HO). Low-dose radiation is thought to be effective in the immediate postoperative phase. Low-dose radiation also has been used to prevent HO. The recommended dose is 2000 rads over 12 days for extensive HO lesions and 1000 rads over 5-7 days for small HO lesions. Radiation is thought to prevent the conversion of mesenchymal cells to bone precursor cells. As a result, concerns about neoplasia limit its application in younger patient groups.
• Evidence indicates that a short course of perioperative NSAIDs can substantially limit the development of ectopic bone.¹⁵

Complications

• Once developed, heterotopic ossification (HO) may cause complications through pressure on surrounding anatomic structures. Peripheral nerve compression and vascular compression with subsequent thrombophlebitis and lymphedema may result from HO. As a result, serial evaluation of deep tendon reflexes is recommended to track peripheral nerve function. The most common complication is decreased ROM, which in rare cases may progress to joint ankylosis.

Prognosis

• A recurrence of heterotopic ossification (HO) is less likely in patients who have higher functional abilities and exhibit normal alkaline phosphatase levels.

Patient Education

• At 3 months after injury, families often have high hopes for recovery, especially if certain milestone signs have recently appeared. The patient recently may have begun to speak and follow some voluntary commands. Family members are elated to see these signs, which give them hope for future recovery and possible avoidance of many other problems. Moreover, because speech seems to be returning spontaneously, the family could hope for spontaneous remission of deformities.
• Expectations tend to color the family's perception and understanding of the limits of recovery, the nature of the various pathologies, and the effects and side effects of medical intervention. For example, spasticity of a muscle may give way to voluntary activity as neurologic recovery unfolds during the first 9-18 months after head injury. Families may therefore think that contracture of the same spastic muscle also disappears when voluntary movement recovers. Aggressive interventions for contracture in the spastic state, therefore, may not make sense to the family. Education of the family clearly is needed, but what they need to know may well depend on drawing out their beliefs, hopes, and expectations. The education campaign is designed to promote compliance with clinical goals.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Surgery for heterotopic ossification (HO) is challenging, because the ossified mass is highly vascular; postoperative bleeding, hematoma, and infection are common complications. Trauma to nerves also may occur. Preoperative CT scans may guide the surgeon and lower the rate of complications. Active ROM exercises may be initiated 2-3 days after surgery. More active exercises may begin about 10-14 days after pain and swelling have subsided. Patients with more severe cognitive and motor deficits may require several months of postoperative physical therapy to maintain ROM. If HO recurs, it becomes evident within 3 months after surgery.

Special Concerns

• Indications for the treatment of increased muscle tone include the following:
• • Interference with active movement
  • Contracture formation or progression in a posturing limb
  • Interference with appropriate positioning or hygiene
  • Self-inflicted trauma during muscle spasms
  • Excessive pain with ROM exercises or during muscle spasms
  • Excessive therapy time devoted to contracture prevention rather than to functional activities
  • Prevention of heterotopic ossification (HO)

MULTIMEDIA

Section 10 of 11  

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Media file 1:  This radiograph clearly demonstrates fairly extensive heterotopic ossification at the bilateral hip regions. The extensive bone formation shown here makes it easy for the viewer to understand why a patient with HO could present with complaints such as pain, swelling, palpable mass, and decreased range of motion.
	View Full Size Image
Media type:  X-RAY

REFERENCES

Section 11 of 11

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25. Finlayson MAJ, Garner SH, eds. Brain Injury Rehabilitation: Clinical Considerations. Baltimore, Md: Williams & Wilkins; 1994.
26. Buschbacher R. Heterotopic ossification: a review. Crit Rev Phys Med. 1992;4:199.
27. Chestnut RM. Medical complications of the head injured patient. In: Cooper PR, ed. Head Injury. 3^rd ed. Baltimore, Md: Williams & Wilkins; 1993.
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Article Last Updated: Jul 28, 2008