Heterotopic Ossification in Spinal Cord Injury 

Heterotopic ossification following spinal cord injury (SCI) was first described by Dejerine and Ceillier in 1918 as paraosteoarthropathy. The ossification process involves the formation of mature lamellar bone, which is indistinguishable from normal bone, in soft tissues surrounding paralyzed joints (see the following image). The bone is not connected to periosteum and becomes encapsulated as it matures.

The pathology is similar to that of fracture callus, except that bone forms in the connective tissue between the muscle planes (histologic findings in neurogenic heterotopic ossification are similar to those in healing fracture callus). Heterotopic ossification is also seen after other neurologic insults, such as traumatic brain injury (TBI) and stroke, as well as after thermal injuries and orthopedic procedures (eg, total hip replacement).

In experimental models of heterotopic ossification formation, ischemia and tissue expression of bone morphogenic proteins have been shown to play important roles. Bone morphogenic proteins likely act on mesenchymal stem cells present in tissue, activating the cells to differentiate into osteoblasts.^[1]

The incidence of heterotopic ossification in spinal cord injury is between 16% and 53%, depending on the incidence reports from various institutions. Once present, neurogenic heterotopic ossification is clinically significant in 18-27% of cases. Fortunately, only 3-5% of cases involve joint ankylosis.

There is no known race or sex predilection for neurogenic heterotopic ossification; however, the incidence of neurogenic heterotopic ossification after spinal cord injury is lower in pediatric patients than in adults, ranging from 3% to 10%. In addition, spontaneous resorption of the neurogenic heterotopic ossification is frequently seen in pediatric patients.^[2]

The following image depicts 3 common locations of heterotopic ossification in the hip.

See also Spinal Cord Injuries, Autonomic Dysreflexia in Spinal Cord Injury, Functional Outcomes per level of Spinal Cord Injury, Hypercalcemia in Spinal Cord Injury, Osteoporosis and Spinal Cord Injury, Prevention of Thromboembolism in Spinal Cord Injury, Rehabilitation of Persons with Spinal Cord Injuries, and Spinal Cord Injury and Aging.

Debate continues on whether there is migration of distant mesenchymal cells or transformation of existing mesenchymal cells into osteoblasts. Osteoinductive factors have been studied, including circulating biochemicals and local factors (eg, venous thrombosis, venous insufficiency, decubitus ulcers, edema, tissue hypoxia). None of these factors has been proven to play a pivotal role in neurogenic heterotopic ossification.

Genetic predisposition for neurogenic heterotopic ossification has also not been confirmed.

Patients with limb spasticity have a greater risk of developing neurogenic heterotopic ossification, and patients with extensive amounts of neurogenic heterotopic ossification have severe spasticity.

The pathophysiology of heterotopic ossification involves an inflammatory process, with increased blood flow in soft tissue. Bone matrix is laid down and mineralized, and this sequence reaches completion in 6-18 months. As noted above, local, systemic, neural, and hormonal causes for the heterotopic ossification process have been hypothesized but have not been proven.

The adult patient with neurogenic heterotopic ossification gives a history of progressive loss of range of motion (ROM) accompanied by pain or swelling in the involved area. Most pediatric patients present with decreased ROM but are less likely to have physical symptoms.

The average length of time reported between spinal cord injury and diagnosis of neurogenic heterotopic ossification in the adult population is 6 months, which is in contrast to 14 months after injury in the pediatric population. The use of 3-phase bone scanning to detect heterotopic ossification may result in a shorter average reporting time between injury and diagnosis.

Limited ROM is seen at the involved joint, possibly accompanied by redness, warmth, or swelling.

Differential diagnosis

Other conditions to consider when evaluating a patient with spinal cord injury and suspected heterotopic ossification include cellulitis, deep venous thrombosis (DVT) , benign effusion, fracture, hematoma , and tumor.

The serum alkaline phosphatase (AP) level can be used to detect early onset of heterotopic ossification, because it is a marker of osteoblastic and osteogenic activity that increases with bone deposition.^[3] With heterotopic ossification, the AP level rises at 2 weeks, exceeds normal values at 3 weeks, peaks at 10 weeks, and then returns to normal after the heterotopic ossification is mature. However, AP levels are nonspecific for this condition: levels are also elevated with trauma and fractures.

Serum calcium levels are transiently depressed in heterotopic ossification.

In animal models, prostaglandin E2 (PGE2) has been shown to induce subperiosteal lamellar bone formation^[4] ; PGE2 may be an inducer of bone formation in humans. PGE2 urinary excretion has been measured over a 24-hour period in patients with acute spinal cord injury (SCI), and excretion was shown to increase in patients who developed heterotopic ossification.^[5] Excretion continued until the bone reached maturity.

Plain film radiographs detect neurogenic heterotopic ossification 5-7 weeks after spinal cord injury (SCI), a relatively late finding (see the following image).

Computed tomograph (CT) scanning is used to determine the volume of bone needed when planning surgical resection.

Magnetic resonance imaging (MRI) has been shown to demonstrated increased T2 signal (edema) in muscles, fascia, and subcutaneous tissue during acute onset of heterotopic ossification.^[6]

Ultrasonography permits an early diagnosis of heterotopic ossification (before radiography).^[7] A typical zone phenomenon that depends on the age of the lesion and the degree of mineralization takes place, characterized by the following:

• An echolucent zone of surrounding muscle enclosing a broader reflective zone, which in turn surrounds an amorphous, echolucent zone
• A reflective zone containing foci of echogenic islands, which rapidly become confluent and increasingly reflective due to increased mineralization

This imaging modality is also useful because it can differentiate heterotopic ossification from abscess or deep vein thrombosis (DVT).

Bone scintigraphy is performed using a 3-phase test involving the injection of technetium-99m (^99m Tc)–labeled methylene diphosphonate. This procedure permits an early diagnosis of neurogenic heterotopic ossification.^[3] The first 2 phases (blood flow and blood pool) are the most sensitive indicators, but they are less specific; the third phase is positive 4 weeks before the appearance of findings on plain radiographs.

The 3-phase bone scan returns to normal as the neurogenic heterotopic ossification matures in 6-18 months after injury. False negative studies can occur, so follow-up studies are indicated for patients with clinically suspicious heterotopic ossification but negative initial bone scans.^[8]

Quantitative radionuclide scans compare the ratio of uptake in heterotopic bone versus normal bone. This ratio decreases over time, and a steady state is noted as the bone reaches maturity.^[9] This steady state, however, has not been shown to be a good predictor of recurrence of HO.

Experimental studies in animals suggest that forcible stretching and hematoma induce new bone formation and heterotopic ossification. This conclusion has not been substantiated in humans.

Physical therapists (PTs) work on range-of-motion (ROM) exercises, which are important in maintaining joint function. Once heterotopic ossification is identified, the ROM exercises should be withheld until the inflammatory signs (eg, warmth, erythema) have subsided. Active-assistive range of motion (AAROM) should then be prescribed, and gentle passive range of motion (PROM) should be initiated for completely paralyzed joints.

The occupational therapist (OT) works on activities of daily living (ADLs) and functional transfers to compensate for lost ROM due to heterotopic ossification. In addition, the OT and PT work on customizing seating systems to minimize pressure over heterotopic bony prominences.

Bisphosphonates prevent the formation of hydroxyapatite crystals. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the inflammatory process that precedes the formation of the collagenous bony matrix.

Bisphosphonates

Analogues of pyrophosphate act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals and blocking the formation of hydroxyapatite crystals. Bisphosphonates prevent osteoclast attachment to the bone matrix, as well as osteoclast recruitment and viability.

Etidronate disodium

When Finerman and Stover treated patients with spinal cord injury (SCI) with etidronate disodium for 12 weeks, starting at 20 mg/kg/d PO for 2 weeks and then 10 mg/kg/d PO for 10 weeks, the final incidence of heterotopic ossification in the etidronate disodium group was reduced and the amount of heterotopic ossification laid down was smaller.^[10]

In subsequent research, patients given higher doses of etidronate—administered intravenously (300 mg/d x 3d), followed by 20 mg/kg taken orally for 6 months and started early (before radiographic evidence of heterotopic ossification was apparent)—showed a significant reduction in the incidence of heterotopic ossification.^[11] Etidronate disodium also prevents the recurrence of neurogenic heterotopic ossification that has been resected in patients with spinal cord injury.

Etidronate is a relatively safe drug. Gastrointestinal (GI) symptoms are the most common adverse effect (eg, nausea, diarrhea, abdominal distress), but these effects can be limited if the daily dose is split into several doses.

Pamidronate

A newer bisphosphonate, pamidronate, may have pronounced beneficial effects in high-risk patients with established heterotopic ossification who are undergoing excision surgery, but the timing of dosing has not been established.^[12]

Nonsteroidal anti-inflammatory drugs

NSAIDs have not been studied in the population of individuals with spinal cord injury. In the literature on total hip replacement, NSAIDs are described as possible inhibitors of neurogenic heterotopic ossification in the early stages.

The mechanism of action behind the NSAIDs is probably the inhibition of prostaglandins and related inflammatory substances during the initial phase of osteoid formation. Indomethacin was the most common drug studied.^[13]

In this population of patients with spinal cord injury, who is already at risk for GI bleeding, there is obviously a relative contraindication to NSAID use.

Orthopedic surgical consultation is recommended for patients with neurogenic heterotopic ossification who require surgical resection of the bone, such as those who have loss of function at a joint or if other complications exist.

Surgery is also indicated in those patients with seating problems, skin breakdown, pain, or loss of function.^[14]

Traditional thought has been that the surgery must be delayed until the bone scan ratio is at steady state and the serum alkaline phosphatase level returns to normal, which is usually 12-18 months after injury.

However, several investigators have published good results that were achieved with early wedge resection of heterotopic ossification that had not reached maturity.^[15] Etidronate disodium and/or radiation therapy is warranted after surgery to prevent the recurrence of neurogenic heterotopic ossification.

No direct mortality is associated with neurogenic heterotopic ossification. Morbidity is associated primarily with loss of range of motion (ROM) and the consequent loss of joint function.

If prophylactic measures are not taken, surgically resected neurogenic heterotopic ossification has a high rate of recurrence.

Complications

Complications may include the following:

• Joint ankylosis
• Skin breakdown over the area of neurogenic heterotopic ossification: This is a significant sequela over the sites of bone formation and an indication for surgical resection of the heterotopic ossification
• Peripheral nerve entrapment: This has been documented as a possible complication of heterotopic ossification; the ulnar and femoral nerves are most frequently involved, and in such instances, entrapment can result in further neurologic loss of function in incomplete injuries; computed tomography (CT) scanning is useful for planning surgical resection of an entrapped peripheral nerve.
• Deep vein thrombosis (DVT) from compression of the veins by the neurogenic heterotopic ossification
• Pain is another complication of heterotopic ossification in patients with neurologically incomplete spinal cord injury.

Patient education, a lifelong process for individuals with spinal cord injury (SCI), should include the possible complication of heterotopic ossification. If this condition develops, patients need to be informed thoroughly about the condition and the various means of treatment. A range-of-motion (ROM) program needs to be presented to the patient and family members to prevent a loss of motion, contractures, and a possible loss of function.