Heterotopic Ossification

Heterotopic ossification (HO) is the formation of mature lamellar bone in soft tissue where bone does not normally exist. It occurs in three settings: after trauma or surgery (most often total hip replacement, acetabular fracture and elbow trauma), after neurological injury (spinal cord injury, traumatic brain injury, stroke), and rarely as a genetic disorder (fibrodysplasia ossificans progressiva, progressive osseous heteroplasia).

After total hip replacement, radiographic HO occurs in 15 to 90% (clinically significant in 5 to 10%) without prophylaxis. After acetabular fractures through a posterior approach, rates reach 25 to 90%. After spinal cord injury, 10 to 53% of patients develop HO distal to the level of injury, most often at the hip, usually 1 to 4 months after injury. After traumatic brain injury, 10 to 20%, usually at the hip, elbow and shoulder.

Risk factors are male sex, previous HO, hypertrophic osteoarthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, burns (elbow), prolonged ventilation, spasticity, delayed fracture fixation, severe polytrauma, and prolonged operating time.

The Brooker classification grades hip HO.

• Class I: islands of bone within soft tissue.
• Class II: bone spurs from the pelvis or femur with a gap of 1 cm or more between opposing surfaces.
• Class III: spurs with less than 1 cm between surfaces.
• Class IV: apparent ankylosis.

Complications are loss of range of motion, ankylosis, pain, nerve entrapment (sciatic, ulnar), pressure sores, difficulty with sitting and hygiene, and functional loss.

Pathophysiology.

Pluripotent mesenchymal stem cells differentiate into osteoblasts under the influence of inflammation, bone morphogenetic proteins and prostaglandins, with hypoxia and tissue injury. Neurogenic HO follows central nervous system injury through changes in sympathetic activity, hypercalcaemia and local factors. The process progresses from an inflammatory phase to bone formation (4 to 12 weeks), and maturation takes 6 to 18 months.

Early signs (within 3 to 12 weeks) mimic infection or deep vein thrombosis: pain, swelling, warmth, erythema and a low grade fever around a joint, with loss of range of motion. Later a firm mass and progressive stiffness develop, and in spinal cord injury, increased spasticity and autonomic dysreflexia may be triggers.

Examine the joint range of motion (reduced), warmth and swelling, neurovascular state (sciatic and ulnar nerves), and skin integrity. The commonest locations are the hip (abduction, flexion), elbow (flexion and extension, forearm rotation), knee and shoulder.

• Serum alkaline phosphatase is raised early (peaks at 2 to 3 months), and creatine kinase and C-reactive protein can be elevated. Normal alkaline phosphatase does not exclude HO.
• Three phase technetium bone scan is the most sensitive for early detection (positive at 2 to 4 weeks, before radiographic changes). The blood pool phase shows active disease.
• Radiographs show calcification 4 to 6 weeks after onset, and the lesion matures by 6 to 12 months with a well defined cortex.
• CT for surgical planning to show the relation to nerves and joints. Ultrasound shows early lesions.
• Duplex ultrasound to exclude deep vein thrombosis, and culture and blood tests to exclude infection.

Differential diagnosis.

• Deep vein thrombosis and septic arthritis or periprosthetic infection.
• Cellulitis and myositis ossificans.
• Osteomyelitis and tumoural calcinosis.
• Soft tissue sarcoma and fracture nonunion.

Prophylaxis (high risk patients).

• NSAID: indomethacin 25 mg orally three times daily for 6 weeks (hip surgery, started within 24 hours after surgery).
• Or ibuprofen 400 mg orally every 8 hours with food for 2 to 6 weeks, or celecoxib 200 mg orally twice daily for 2 to 6 weeks (maximum 400 mg daily).
• Give omeprazole 20 mg orally daily for gastric protection. Avoid with eGFR under 30 mL/min/1.73 m2, peptic ulcer, heart failure, or anticoagulant use, and with fracture healing concerns.
• Radiotherapy: a single dose of 7 to 8 Gy to the hip within 4 hours before to 72 hours after surgery (cost and centre availability limit use; avoid in young patients and in pelvic cemented components when marrow is exposed). Effective in over 90% of cases.
• Meticulous surgical technique: minimise muscle trauma and irrigate bone debris.

Established HO (neurogenic or post-traumatic).

• Early physiotherapy: gentle passive range of motion within the pain free range, avoiding forceful manipulation that increases bleeding and inflammation.
• Etidronate 20 mg/kg orally daily for 2 weeks, then 10 mg/kg daily for 10 weeks (maximum 20 mg/kg daily), taken on an empty stomach; monitor calcium, phosphate and creatinine; avoid with eGFR under 30 mL/min/1.73 m2. It delays mineralisation but does not stop osteoid formation, so rebound ossification occurs when stopped.
• Use an NSAID for acute symptoms (indomethacin 25 mg orally three times daily, with omeprazole 20 mg orally daily). Treat spasticity (baclofen) and the underlying cause.
• Surgical excision when the lesion is mature (usually 6 to 12 months, confirmed by a normal alkaline phosphatase and a quiescent bone scan) and causes functional loss, nerve compression or pressure sores. Perioperative prophylaxis (radiotherapy or NSAID) reduces recurrence.
• Fibrodysplasia ossificans progressiva: avoid trauma, injections and biopsy; palovarotene or other disease specific treatments through specialist centres.

Operative antibiotic prophylaxis. Cefazolin 2 g intravenously (3 g when weight is 120 kg or over) within 60 minutes before incision as a single dose (repeat after 4 hours or blood loss over 1500 mL). With severe penicillin allergy, vancomycin 15 mg/kg intravenously starting 90 to 120 minutes before incision as a single dose, with levels and creatinine checked in prolonged cases.

Analgesia.

• Paracetamol 1 g orally every 6 hours as needed for up to 5 to 7 days (maximum 4 g daily; 3 g daily when weight is under 50 kg, with chronic alcohol use or hepatic impairment).
• Oral morphine 5 to 10 mg every 4 hours as needed for severe pain for up to 3 days (start 2.5 to 5 mg with age over 75 or eGFR under 30 mL/min/1.73 m2; avoid exceeding 60 mg in 24 hours without senior review). Monitor sedation and respiration and prescribe a laxative.

Monitoring. Range of motion, swelling and pain every 2 weeks in the high risk period (first 3 months). Alkaline phosphatase every 2 to 4 weeks until it normalises. Radiographs at 6 weeks, 3 months, 6 months and 12 months. Repeat bone scan before excision. Nerve function (sciatic, ulnar) and skin.

Referral and escalation. Refer loss of range of motion, nerve entrapment or pressure sores to orthopaedics or rehabilitation medicine. Urgent referral for a hot swollen joint that may be infected, or suspected deep vein thrombosis.

Special groups.

• Spinal cord injury and brain injury: high risk; start range-of-motion therapy early and screen with alkaline phosphatase; prophylactic NSAID for 4 to 6 weeks.
• Previous HO or ankylosing spondylitis: give prophylaxis routinely.
• Young adults and children: avoid radiotherapy where possible.
• Kidney impairment: avoid NSAIDs and etidronate; reduce morphine doses.