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Physical Medicine and Rehabilitation > SPINAL CORD INJURY
Heterotopic Ossification in Spinal Cord Injury
Article Last Updated: Oct 4, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Denise I Campagnolo, MD, MS, Director of Multiple Sclerosis Clinical Research and Staff Physiatrist, Barrow Neurology Clinics, St. Joseph's Hospital and Medical Center; Investigator for Barrow Neurology Clinics; Director, NARCOMS Project for Consortium of MS Centers, Phoenix
Denise I Campagnolo is a member of the following medical societies: Alpha Omega Alpha, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, Association of Academic Physiatrists, and Consortium of Multiple Sclerosis Centers
Editors: Robert L Sheridan, MD, Assistant Chief of Staff, Chief of Burn Surgery, Shriners Burns Hospital; Associate Professor of Surgery, Department of Surgery, Division of Trauma and Burns, Massachusetts General Hospital and Harvard Medical School; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Kat Kolaski, MD, Assistant Professor, Departments of Orthopedics and Pediatrics, Wake Forest University School of Medicine; Kelly L Allen, MD, Consulting Staff, Department of Physical Medicine and Rehabilitation, Lourdes Regional Rehabilitation Center, Our Lady of Lourdes Medical Center; Robert H Meier III, MD, Director, Amputee Services of America, Presbyterian St Luke's Hospital; Consulting Staff, North Valley Rehabilitation Hospital, Kindred Hospital, North Suburban Hospital
Author and Editor Disclosure
Synonyms and related keywords:
heterotopic ossification, HO, spinal cord injury, SCI, traumatic brain injury, TBI, ectopic calcification, neurogenic heterotopic ossification, paraosteoarthropathy of paraplegia
Background
Heterotopic ossification (HO) following spinal cord injury (SCI) was described first by Dejerine and Ceillier in 1918 as paraosteoarthropathy. The process is one of formation of mature lamellar bone, which is indistinguishable from normal bone, in soft tissues surrounding paralyzed joints. 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. HO also is 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 HO 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 and, thus, activate them to differentiate into osteoblasts (Banovac, 2004).
Pathophysiology
The pathophysiology 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. Local, systemic, neural, and hormonal causes for this process have been hypothesized but not proven (see Causes). Debate continues on whether there is migration of distant mesenchymal cells or transformation of existing mesenchymal cells into osteoblasts.
Frequency
United States
The incidence of HO in SCI is from 16-53%. The incidence of clinically significant cases is 18-27%. Fortunately, only 3-5% of joints involved ankylosis.
Mortality/Morbidity
No direct mortality is associated with neurogenic heterotopic ossification (NHO). Morbidity is associated primarily with loss of range of motion (ROM) and the consequent loss of function of the joint.
Race
No racial association with NHO is known.
Sex
The male-to-female ratio is 1:1.
Age
The incidence of NHO after SCI is lower in pediatric patients than in adults, ranging from 3-10%. In addition, spontaneous resorption of the NHO frequently is seen in pediatric patients.
History
The adult patient gives a history of progressive loss of 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 injury and diagnosis of NHO in the adult population is 6 months, in contrast to 14 months after injury in the pediatric population. Use of 3-phase bone scan to detect HO may result in shorter average reporting times between injury and diagnosis.
Physical
Limited ROM is seen at the involved joint, possibly accompanied by redness, warmth, or swelling.
Causes
- 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 NHO.
- Genetic predisposition for NHO has not been confirmed.
- Patients with limb spasticity have a greater risk of developing NHO, and patients with extensive amounts of NHO have severe spasticity.
Other Problems to be Considered
Deep venous thrombosis
Benign effusion
Cellulitis
Fracture
Hematoma
Tumor
Lab Studies
- Serum alkaline phosphatase (AP) level can detect early onset of HO, since it is a marker of osteoblastic and osteogenic activity that increases with bone deposition. With HO, AP rises at 2 weeks, exceeds normal values at 3 weeks, peaks at 10 weeks, and then returns to normal after HO is mature; however, AP levels are nonspecific for HO. Levels also are elevated with trauma and fractures.
- Serum calcium levels are depressed transiently.
- In animal models, prostaglandin E2 (PGE2) has been shown to induce subperiosteal lamellar bone formation. PGE2 may be an inducer of bone formation in humans. PGE2 urinary excretion has been measured over 24 hours in patients with acute SCI, and excretion was shown to increase in patients who formed HO. Excretion continued as long as the bone was not mature.
Imaging Studies
- Bone scintigraphy is performed using a 3-phase test involving the injection of technetium Tc 99–labeled methylene diphosphonate. This procedure permits an early diagnosis. 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 prior to the appearance of findings on plain radiographs. The 3-phase bone scan returns to normal as the NHO matures in 6-18 months after injury. 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. This steady state, however, has not been shown to be a good predictor of recurrence of HO.
- Plain film detects NHO 5-7 weeks after injury, a relatively late finding.
- CT scan is used to determine the volume of bone needed for planning surgical resection.
- Ultrasonography permits an early diagnosis of HO (before radiography).
- 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 also is useful because it can differentiate HO from abscess or deep vein thrombosis (DVT).
- MRI has been shown to increase T2 signal (edema) in muscles, fascia, and subcutaneous tissue during acute onset HO (Wick, 2005).
Histologic Findings
Histologic findings are similar to those in healing fracture callus.
Rehabilitation Program
Physical Therapy
Experimental studies in animals suggest that forcible stretching and hematoma induce new bone formation and HO. This conclusion has not been substantiated in humans. The physical therapists (PTs) work on ROM exercises, which are important in maintaining joint function. Once HO is identified, the ROM should be with held until the inflammatory signs (eg, warmth, erythema) have subsided. Then, active-assistive range of motion (AAROM) should be prescribed, and gentle passive range of motion (PROM) should be initiated for completely paralyzed joints.
Occupational Therapy
The occupational therapist (OT) works on activities of daily living (ADL) and functional transfers to compensate for lost ROM due to HO. Both the OT and PT work on customizing seating systems to minimize pressure over heterotopic bony prominences.
Medical Issues/Complications
- Skin breakdown over the sites of bone formation is a significant sequela and an indication for surgical resection of the HO.
- Pain is another complication of HO in patients with neurologically incomplete SCI.
- Peripheral nerve entrapment has been documented as a possible complication of HO. The ulnar and femoral nerves most frequently are involved and can result in further neurologic loss of function in incomplete injuries. CT scanning is useful for planning surgical resection of an entrapped peripheral nerve.
Surgical Intervention
Surgery is indicated in those patients with seating problems, skin breakdown, pain, or loss of function. Surgery is performed on NHO if there is loss of function at a joint or other complications exist.
- Traditional thought is that the surgery must be delayed until the bone scan ratio is at steady state and serum alkaline phosphatase (SAP) returns to normal, which is usually 12-18 months after injury.
- More recently, several investigators have published reports good results of early wedge resection of HO that has not reached maturity. Etidronate disodium and/or radiation therapy is warranted after surgery to prevent the recurrence of NHO.
Consultations
Orthopedic surgical consultation is recommended for patients who require surgical resection of the bone.
Bisphosphonates prevent formation of hydroxyapatite crystals. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the inflammatory process that precedes formation of the collagenous bony matrix.
Drug Category: Bisphosphonates
Analogs of pyrophosphate act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals and blocking formation of hydroxyapatite crystals. Bisphosphonates prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.
Finerman and Stover in 1981 treated patients with SCI with etidronate for 12 wks starting at 20 mg/kg/d PO for 2 wks then 10 mg/kg/d PO for 10 wks. The final incidence is the same, but the amount HO laid down in the etidronate disodium group was smaller. Recently, higher doses administered IV (300 mg/d x 3 d) followed by 20 mg/kg PO for 6 mo started early (before x-ray evidence of HO is apparent) showed significant reduction of incidence. Etidronate disodium also prevents recurrence of NHO resected in SCI patients.
This is a relatively safe drug. GI symptoms are the most common adverse effect (eg, nausea, diarrhea, abdominal distress) and can be limited if the dose is split to several times daily. Should be taken as a single oral dose; however, the dose may be divided should GI discomfort occur.
A newer bisphosphonate, pamidronate, may have pronounced beneficial effects in high-risk patients with established HO who are undergoing excision surgery, but timing of dosing has not been established (Schuetz, 2005).
| Drug Name | Etidronate disodium (Didronel) |
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| Description | Similar to an inorganic pyrophosphate. Pyrophosphates inhibit calcium deposition and thereby inhibit precipitation of calcium phosphate from solution. The actual mechanism is the blockage of transformation of calcium phosphate to hydroxyapatite crystals. Thus, there is a delay in aggregation of hydroxyapatite crystals into larger clusters. |
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| Adult Dose | 20 mg/kg/d PO for 2 wk initially, followed by 10 mg/kg/d for 10 wk; alternatively,
300 mg/d for 3 d IV, followed by 20 mg/kg PO for 6 mo (has been shown to be more effective) |
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| Pediatric Dose | Not established; pediatric patients have been treated with etidronate disodium, at doses recommended for adults, to prevent HO or soft tissue calcifications |
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| Contraindications | Documented hypersensitivity, hypocalcemia, or renal impairment; in patients with Class Dc and higher renal functional impairment (serum creatinine > 5 mg/dL), IV infusion should be withheld |
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| Interactions | Coadministration with calcium containing products (eg, milk, milk products, vitamin supplements, antacids) and other multivalent cations (eg, iron, magnesium, aluminum) decrease absorption when ingested within 2 hours of dose; there have been isolated reports of patients experiencing increases in PT when etidronate was added to warfarin therapy; patients on warfarin and receiving etidronate should have PT monitored |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | In teratology and developmental toxicity studies conducted in rats and rabbits treated with dosages of up to 100 mg/kg (5-20 times the clinical dose), no adverse or teratogenic effects have been observed in the offspring; etidronate disodium has been shown to cause skeletal abnormalities in rats when given at oral dose levels of 300 mg/kg (15-60 times the human dose); other effects on the offspring (including decreased live births) are at dosages that cause significant toxicity in the parent generation and are 25-200 times the human dose; skeletal effects are thought to be the result of pharmacologic effects of the drug on bone; no adequate and well-controlled studies have been conducted in pregnant women; etidronate disodium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus; not known whether this drug is excreted in human milk; caution when administering to a woman who is breastfeeding
Incidence of GI complaints (eg, diarrhea, nausea) is the same for etidronate disodium at 5 mg/kg/d as for placebo, about 1 patient in 15; at 10 to 20 mg/kg/d, incidence may increase to 2-3 in 10; these complaints often are alleviated by dividing total daily dose; not metabolized and is excreted intact via kidney; hyperphosphatemia may occur at doses of 10-20 mg/kg/d, apparently as a result of drug-related increases in tubular reabsorption of phosphate; serum phosphate levels generally return to normal in 2-4 wk following therapy; there is no experience to guide specific treatment in patients with impaired renal function; etidronate disodium dosage should be reduced when reductions in glomerular filtration rates are noted
Safety and effectiveness in pediatric patients have not been established; a rachitic syndrome has been reported infrequently at doses of 10 mg/kg/d and more for prolonged periods (ie, >9-12 mo); the epiphyseal radiologic changes associated with retarded mineralization of new osteoid and cartilage, and occasional symptoms reported, have been reversible when medication is discontinued |
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Drug Category: Nonsteroidal anti-inflammatory drugs
Have not been studied in the SCI population. In the literature on total hip replacement, NSAIDs are described as possible inhibitors of NHO 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. Obviously, in this population who are already at risk for GI bleeding, there is a relative contraindication to NSAID use.
| Drug Name | Indomethacin (Indocin) |
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| Description | Has been shown to be effective in preventing HO formation following total hip replacement. Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation; inhibits prostaglandin synthesis.
As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. |
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| Adult Dose | 25 mg PO tid |
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| Pediatric Dose | Not established; 2 mg/kg/d PO in divided doses suggested; not to exceed 4 mg/kg/d or 150-200 mg/d, whichever is less |
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| Contraindications | Documented hypersensitivity; GI bleeding or renal insufficiency; patients in whom asthmatic attacks, urticaria, or rhinitis have been precipitated by aspirin or other NSAIDs; suppositories are contraindicated in patients with history of proctitis or recent rectal bleeding; concomitant use with diflunisal may decrease renal clearance and significantly increase plasma levels; in some patients, combined use with diflunisal has been associated with fatal GI hemorrhage |
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| Interactions | Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; may decrease effects of beta-blockers, hydralazine, and captopril; may decrease diuretic effects of furosemide and thiazides; coadministration with anticoagulants may prolong PT (monitor and watch for signs of bleeding); may increase risk of methotrexate toxicity, which can manifest as stomatitis, bone marrow suppression, or nephrotoxicity; coadministration may increase phenytoin levels; probenecid may increase toxicity of NSAIDS |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | GI bleeding is a risk; concomitant use of indomethacin with other NSAIDs is not recommended due to increased possibility of GI toxicity, with little or no increase in efficacy; not for use by breastfeeding mothers; effectiveness of indomethacin in pediatric patients has not been established; should not be prescribed for pediatric patients aged 14 years and younger unless toxicity or lack of efficacy associated with other drugs warrants risk |
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Complications
- Joint ankylosis
- Skin breakdown over the area of NHO
- Peripheral nerve entrapment
- DVT from compression of the veins by the NHO
Prognosis
- Surgically resected NHO has a high rate of recurrence, if prophylactic measures are not taken (see Surgical Intervention).
Patient Education
- Patient education is a lifelong process for individuals with SCI. Patients with SCI need to be educated about the possible complication of HO. If the condition develops, patients need to be informed thoroughly about the condition and the various means of treatment. An ROM program needs to be presented to the patient and family members to prevent loss of motion, contractures, and possible loss of function.
Medical/Legal Pitfalls
- Vague symptoms of discomfort surrounding a paralyzed joint may be dismissed initially by a health care provider. Be sure to evaluate aggressively any discomfort associated with a loss of ROM.
| Media file 1:
Three common locations of heterotopic ossification around the hip joint. A is anterolateral/anteromedial, B is inferior and medial, and C is around the femoral neck and posterior. |
 |  View Full Size Image | |
Media type: Graph
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| Media file 2:
Extensive heterotopic ossification at the medial aspect of the left knee. |
 | View Full Size Image | |
Media type: X-RAY
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Heterotopic Ossification in Spinal Cord Injury excerpt Article Last Updated: Oct 4, 2006
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