Heterotopic Ossification

Etiology

Heterotopic ossification can be classified into 3 main categories: traumatic, neurogenic, and genetic. The most common is traumatic, which occurs after injuries such as fractures, arthroplasty, muscular trauma, joint dislocations, or burns. In total joint arthroplasty, heterotopic ossification is most frequently observed after hip, knee, elbow, and shoulder replacements. Chronic muscular trauma can lead to traumatic myositis ossificans, with the quadriceps femoris and brachialis muscles being the most commonly affected.

The second category is neurogenic, associated with neurologic insults such as stroke, SCI, traumatic brain injury, and brain tumors.[5] Neurogenic heterotopic ossification most commonly involves the hips, the extensor side of the elbows, shoulders, and knees, though rare sites include incisions, kidneys, the uterus, the corpora cavernosum, and the gastrointestinal tract. The exact mechanism is not fully understood and is discussed further in the Pathophysiology section. Risk factors include spasticity, older age, pressure ulcers, deep vein thrombosis, tracheostomy, long bone fractures, prior injury to the same area, edema, immobility, long-term coma, and severity of trauma, TBI, SCI, or stroke. In the THA population, high- and moderate-risk factors include men with bilateral THA, prior history of heterotopic ossification, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, or Paget disease.[6] 

The third and rarest category is genetic, including fibrodysplasia ossificans progressiva, a disorder characterized by abnormal, progressive bone formation in soft tissues following injury. This condition manifests at birth with malformations of the great toe and leads to widespread skeletal immobilization due to progressive ectopic bone formation. Minor trauma, intramuscular injections, and surgical procedures can precipitate flare-ups, making early recognition and avoidance of unnecessary interventions essential to prevent irreversible functional decline.[4]

Epidemiology

The prevalence of heterotopic ossification varies widely depending on the underlying clinical context.[1] In patients undergoing THA, reported incidence rates range from 8% to 90%, with an overall average prevalence estimated around 53%, particularly in those with high-risk factors such as men, cemented components, and older age.[2] Heterotopic ossification is approximately twice as common in men as in women; however, women aged 65 and older may also have an elevated risk.

Following acetabular fractures, the incidence ranges from 17% to 100%, whereas in burn injuries, the incidence is lower, with rates reported at 0.2% to 4%.[7][8] Among patients with neurological injury, neurogenic heterotopic ossification occurs in 10% to 20% of cases. More specifically, adult patients with SCI  have a 20% to 30% incidence, whereas patients with TBI demonstrate a 10% to 20% incidence. In pediatric TBI populations, the prevalence ranges from 3% to 20%.[9] Clinically, heterotopic ossification can result in substantial morbidity due to pain, joint contracture, ankylosis, limited mobility, and secondary complications such as disuse osteopenia and fracture risk.

Pathophysiology

The exact mechanism of heterotopic ossification in traumatic and neurogenic cases is unknown, but 2 common factors precede its formation—the first being trauma or an inciting neurological event.[10] In the SCI population, it is hypothesised that acute rehabilitation, transfer activities, and repeated microtrauma during activities of daily living can accumulate mechanical stress, predisposing individuals to heterotopic ossification. Second, after trauma or neurological injury, tissue expression of bone morphogenetic proteins (BMPs) changes. BMPS stimulate mesenchymal spindle stem cells, also known as satellite cells, to migrate to the injured area, where they differentiate into fibroblasts and, eventually, osteoblasts.

Evidence indicates that alkaline phosphatase also contributes to ectopic bone formation. Alkaline phosphatase suppresses inhibitors of bone formation and is known to be elevated in vascular smooth muscle tissue in the presence of inflammatory cytokines and macrophages.[10] After migration, mesenchymal spindle cells differentiate into fibroblasts, which then secrete immature connective tissue composed of collagen and extracellular matrix. With continued tissue irritation, fibroblastic metaplasia is activated, transforming fibroblasts into chondrocytes through a process similar to endochondral ossification. Some of the chondrocytes continue to deposit collagen into the cartilage matrix while the remaining chondrocytes transform into osteoblasts. By 1 to 2 weeks, new osteoid is present within the tissue, and new bone formation starts to form within the osteoid. Osteoblasts then begin to degrade and replace the cartilage with bone. Calcium pyrophosphate within the osteoid is slowly replaced by hydroxyapatite crystals as the bone mineralises and matures.[11]

The pathogenesis of neurogenic heterotopic ossification following SCI has been investigated in murine models. Heterotopic bone formation occurs after combined injury to the central nervous system and skeletal muscle. This process results from dysregulation of normal muscle repair. Under physiological conditions, fibro-adipogenic progenitor cells undergo tumor necrosis factor-induced apoptosis by inflammatory macrophages, thereby preventing fibrosis.[12] 

Following SCI, these progenitors escape apoptosis, accumulate, and differentiate into osteoblasts.[13] This shift toward osteogenesis is driven by stress-induced adrenal glucocorticoid release, particularly corticosterone, which amplifies local inflammation and promotes excessive secretion of oncostatin M and interleukin-1β in injured muscle.[14] These bind to their receptors and promote osteogenic proliferation, explaining the higher incidence of neurogenic heterotopic ossification observed in patients with traumatic brain or SCI who develop gram-negative infections. Lipopolysaccharides from gram-negative organisms induce heterotopic bone formation by activating Toll-like receptor 4 on macrophages and muscle fibro-adipogenic progenitors, thereby increasing macrophage secretion of oncostatin M and interleukin-1β.[15][16]

Heterotopic ossification is a complex, multifactorial process. Rooted in mechanisms similar to fibrodysplasia ossificans progressiva, involving mutations in activin receptor–like kinase 2 (activin A receptor type I) that cause aberrant BMP signalling. Trauma-induced heterotopic ossification is characterized by increased BMP-2 and BMP-4 activity, leading to downstream Smad1/5/8 phosphorylation and osteogenic gene activation. Additional contributors include tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2–positive progenitor cells, fibroblasts capable of transdifferentiation, and environmental factors such as hypoxia and pH.[17][18]

Histopathology

Microscopic examination of the biopsy in myositis ossificans revealed an outer zone of hypercellular spindle cells and woven bone surrounding an inner zone of trapped muscle with normal osteoblasts continuing to lay down bone. Heterotopic ossification can be distinguished from osteosarcoma by its characteristic zonation pattern, which progresses from central immature fibrous tissue to peripheral mature bone. In contrast, osteosarcoma demonstrates mature bone formation within the central zone.[5] 

Histologically, heterotopic ossification is characterized by lamellar bone formation within soft tissue, frequently via an endochondral ossification pathway. At initial injury, there is a proliferation of hypercellular spindle cells. Cartilage and woven bone start to form 2 weeks after injury. Trabecular bone starts to form from weeks 2 to 5 with mature fatty bone marrow. After 6 weeks, lamellar bone matures.[19]

History and Physical

Heterotopic ossification usually occurs 3 to 12 weeks after the inciting injury, but it can take up to 6 months to present.[20] Look for a history of recent arthroplasty (eg, THA or total knee replacement), as well as stroke, SCI, TBI, or burns. The most common presentation is pain and decreased range of motion. Patients often complain of joint stiffness. Other common signs to look for are local edema, effusion, erythema, warmth, and tenderness in the tissue or joint.[5]

Localized soft-tissue swelling may mimic a deep vein thrombosis. The patient may also present with a low-grade fever. Since spasticity is a risk factor, the patient may present with spasticity near the affected joint. Other risk factors to look for in the history are prolonged coma, tracheostomy or gastric tube, immobility, pressure ulcers, and associated long bone fractures.[21] The greatest risk of developing heterotopic ossification also occurs during the 3- to 4-month post-injury period.

Evaluation

Laboratory Studies

Alkaline phosphatase has historically been the most commonly ordered laboratory test for heterotopic ossification; however, levels may remain normal in the early stages of bone formation.[22] Elevation may not occur until up to 2 weeks after injury and can increase to as much as 3.5 times the normal value by 10 weeks post-injury. In the THA population, serum alkaline phosphatase levels greater than 250 have been shown to correlate with heterotopic ossification and injury severity. Clinicians should note that alkaline phosphatase levels may also be falsely elevated in the presence of associated long-bone injuries.

Erythrocyte sedimentation rate (ESR) is another inflammatory marker that is used. ESR greater than 35 mm/hr can indicate the development of heterotopic ossification.[23] C-reactive protein is another inflammatory marker that can be elevated in earlyheterotopic ossification. Both are nonspecific. Creatine kinase can be used to assess the severity of heterotopic ossification; however, it is not highly specific.[5] Results from a study of 18 patients with SCI determined that an elevated creatine kinase may be associated with a more aggressive course of heterotopic ossification and may show possible resistance to etidronate therapy.[24]

Imaging

Plain radiographs

Plain radiographs are first-line but have poor early sensitivity; they are generally used for grading. Radiographs show circumferential bone formation around or near a joint with a radiolucent center (see Images. Heterotopic Ossification of the Elbow, Radiograph and Heterotopic Ossification, Radiograph). Radiographs are specific for heterotopic ossification but not sensitive in early disease. Plain films may not be positive until 3 to 4 weeks after heterotopic ossification is detected on a bone scan. Therefore, the triple-phase bone scan is the most sensitive. A bone scan can reveal heterotopic ossification as early as 2.5 weeks after injury.[5]

MRI

In the acute or early phase of disease, MRI remains the gold standard for detecting soft-tissue masses.[25]

Computed tomography

This imaging may be used to delineate the area of bone formation prior to surgery, but its role in the evaluation/diagnosis of heterotopic ossification is not established.[10] MRI may also be used, but it is not cost-effective unless the bone encompasses neurologic structures. Other imaging techniques that are uncommonly used include ultrasound and 3-dimensional stereolithography. Computed tomography may be used preoperatively to better define the extent and location of mature bone prior to surgical resection; however, its role in the initial evaluation and diagnosis of heterotopic ossification is limited.[10] MRI may also assist with surgical planning, but it is generally not cost-effective unless heterotopic bone involves or threatens neurologic structures.

Ultrasound

Ultrasound detects early lesions preoperatively.[26]

Positron emission tomography, single-photon emission computed tomography, and Raman spectroscopy

Advanced imaging modalities, including positron emission tomography, single-photon emission computed tomography, and Raman spectroscopy, are considered experimental but show promise for early detection and assessment of disease activity.[27][28]

Treatment / Management

Prophylaxis

The approach to prophylaxis involves identifying patients at high risk of developing heterotopic ossification. Routine prophylaxis is not recommended. Preventive treatment strategies for heterotopic ossification remain largely undefined, primarily because the cellular and molecular pathways underlying the condition are not yet fully understood. Early passive ROM exercises should be initiated once heterotopic ossification is confirmed to prevent joint ankylosis. 

• Nonsteroidal anti-inflammatory drugs 
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of pharmacologic prophylaxis. Indomethacin, administered at 25 mg 3 times daily for 3 to 6 weeks postoperatively, has been the historical standard.[29][30] NSAIDs inhibit cyclooxygenase (COX)-1 and COX-2, thereby reducing prostaglandin-mediated osteogenesis.[29] Other NSAIDs that have been proven effective are meloxicam, celecoxib, rofecoxib, and ibuprofen.
  • Selective COX-2 inhibitors such as etoricoxib have demonstrated equivalent efficacy to non-selective NSAIDs in preventing heterotopic ossification, while reducing gastrointestinal side effects and risk of bleeding. Etoricoxib has been effective when administered at 90 mg daily in patients with THA.[31][32]
  • Limitations: Risk of gastrointestinal irritation, renal dysfunction, and impaired bone healing—especially concerning in fracture settings.[33]
  • Careful monitoring must be done for the risk of bleeding, especially with concurrent chemoprophylaxis for venous thromboembolism. Concurrent prophylaxis is advised for gastrointestinal ulcers. 
• Bisphosphonates
  • These antiresorptive agents inhibit osteoclast-mediated bone turnover and mineralisation. While etidronate and alendronate have shown some efficacy in reducing the development of heterotopic ossification, clinical results remain inconsistent. Some study results support their use in high-risk individuals, while others advise against routine prophylaxis due to a lack of reproducible benefit.
  • For SCI-associated heterotopic ossification, the recommended treatment is 20 mg/kg per day for 2 weeks, followed by 10 mg/kg per day for 10 weeks, for a total treatment period of 12 weeks. For THA, the recommended treatment is 20 mg/kg per day for 1 month preoperatively, followed by the same dose for 3 months postoperatively.[30]
  • External-beam radiation therapy is most commonly used after total joint arthroplasty. A single dose of 700 to 800 g (centigray) is administered up to 24 hours preoperatively or within 72 hours postoperatively.[34]
• Radiotherapy
  • Low-dose external-beam radiotherapy (700–800 cGy) delivered within 24 hours preoperatively or within 3 days postoperatively reduces the incidence of heterotopic ossification, particularly after THA and SCI. Radiotherapy is especially useful in NSAID-intolerant patients or those at very high risk of recurrence.[35][36] 
  • The adverse effects of radiotherapy include delayed wound healing, soft-tissue fibrosis, and potential interference with implant osseointegration, especially in cementless THA.
(A1)

Surgical Treatment

Surgical excision of heterotopic ossification is indicated in patients with functionally limiting joint ankylosis, persistent pain or reduced range of motion, and in cases where there is interference with prosthetic function or personal hygiene

Timing is crucial to minimize recurrence risk, with resection ideally delayed until radiological and clinical signs of ossification maturity:

• ≥6 months after trauma-related heterotopic ossification
• ≥12 months after SCI
• ≥18 months after traumatic brain injury 

Risks and complications of surgical intervention:

• Infection
• Wound breakdown
• Neurovascular injury (eg, sciatic nerve in hip heterotopic ossification)
• Recurrence of heterotopic ossification
  • In some series (eg, acetabular heterotopic ossification), complication rates after excision have reached 33%.

Differential Diagnosis

In the SCI population, deep vein thrombosis (DVT), cellulitis, abscess, hematoma, and tumor (osteosarcoma, osteochondroma) are the most common differential diagnoses to consider, particularly when plain film x-ray is negative. Other common differential diagnoses are hardware infection, thrombophlebitis, and osteomyelitis.[5] A venous Doppler should be ordered to rule out a DVT. Cellulitis and abscesses can be difficult to assess because white blood cell counts and inflammatory markers can be elevated in the setting of heterotopic ossification.

Elevated alkaline phosphatase can help distinguish heterotopic ossification from other infectious conditions. Computed tomography/MRI with contrast can help differentiate heterotopic ossification from hematoma, thrombophlebitis, osteomyelitis, and tumor, but it is not the most cost-effective modality. Triple-phase bone scan remains the most sensitive for detecting heterotopic ossification, especially early on, because it may take up to 6 weeks from the initial presentation of symptoms for heterotopic ossification to appear on an x-ray.

Radiation Oncology

Radiation therapy is more effective than NSAIDs in multiple trials. The effectiveness of indomethacin versus radiation therapy for heterotopic ossification prevention was compared in a prospective randomized trial comparing post-open reduction/internal fixation surgery for patients with an acetabular fracture. Radiation therapy was given as 8 Gy in 1 fraction within 72 hours of surgery, and indomethacin was given for 6 weeks. There was a greater risk of nonunion of long-bone fractures among those who received indomethacin compared with radiation therapy (26% vs 7%, P = 0.004).[37] A subsequent meta-analysis by Pakos et al analyzed 7 randomized trials for 1143 patients and found that radiation therapy was almost twice as effective as NSAIDs. Still, the absolute benefit was less than 2%, with efficacy being dose-dependent.[38]

Radiation Dosing and Fractionation

Radiation oncologists have evaluated numerous radiotherapy fractionation regimens to find the optimal total therapeutic dose for preventing heterotopic ossification in high-risk individuals. In 1987, Anthony et al compared 20 Gy in 10 fractions with 10 Gy in 5 fractions, favouring the higher-dose regimen as marginally more effective in reducing heterotopic ossification, but at the cost of increased radiation-related toxicity (19.4% vs 7.3%).[39] Subsequently, Sylvester et al analyzed outcomes in 28 patients treated with the same fractionation regimen and concluded that both were equally effective when radiotherapy was delivered within 4 days postoperatively.[40] More recently, Ruo Redda et al evaluated the prophylactic role of x-rays in high-risk patients and demonstrated superior outcomes with a single 7 Gy fraction, achieving complete pathological response in 76% of patients.[34]

Radiation Timing

Radiation therapy is typically given preoperatively within 24 hours or postoperatively within 72 hours. If surgery is planned, it is ideal that the patient be consulted and consented to before surgery, since the anesthesia may render the patient unable to give informed consent. Also, the patient could be in more pain postoperatively and may not be able to lie still during treatment. However, in trauma or emergencies, the radiation would be given postoperatively.

A randomized, multi-institutional trial by Gregoritch et al compared patients treated with preoperative vs postoperative 7 to 8 Gy in 1 fraction and found that radiographic and clinical failure rates between the 2 groups were not significantly different.[41] This was examined in another randomized study of 161 patients, who were treated either preoperatively (less than 4 hours before surgery) or postoperatively (less than 72 hours after surgery). There was no significant difference among patients with Brooker grades 0 to 2; however, treatment failures in the overall cohort were significantly lower in the postoperative group. This was likely due to a higher biological equivalent dose as the preoperative group received 7 Gy in 1 fraction, while the postoperative group received 17.5 Gy in 5 fractions. Despite these findings, the current standard is to use a single fraction of 7 to 8 Gy at a single dose, administered preoperatively within 24 hours or postoperatively within 72 hours.

Treatment Planning

The general principles of treatment planning include the use of standard techniques, the use of immobilization devices when needed, and patient positioning to ensure consistent, reproducible daily treatments. Target volumes should encompass the bone surfaces most commonly involved in heterotopic ossification, particularly periarticular regions. Heterotopic ossification frequently develops between the femoral head and pelvis, extending from the greater trochanter to the ilium or from the lesser trochanter to the ischium; therefore, these surfaces should be included within the radiation field.

Radiation techniques for treating heterotopic ossification of the hip have been well described, as this is the most commonly treated site. The patient is treated in a comfortable, reproducible supine position. Each field is customized to the patient’s anatomy. Still, generally, the cranial border is about 3 cm above the acetabulum, the inferior border about 3 cm below the lesser trochanter of the femoral head, or could include the upper third of the implant shaft (if used), with a field size of about 14 x 10 cm. Soft tissue can be blocked by collimating the field to use the field edges, or by using multi-leaf collimators to shape the field, allowing about a 1.5 to 2 cm margin on the bone and prior areas of heterotopic ossification. Three-dimensional conformal radiotherapy using anterior-posterior/posterior-anterior fields with 6 to 15 megavoltage photons is often used to create a homogeneous plan that covers the target to at least the 95% isodose line while minimizing dose to the surrounding soft tissue and skin (see Image. Heterotopic Ossification of the Hip).

The hip is the most common site of heterotopic ossification and the most common site of treatment. However, other joints are also susceptible to heterotopic ossification. Radiation therapy has also been effective in these areas, particularly with the elbow. Results from a study of 36 patients treated at the Cleveland Clinic with 7 Gy in 1 fraction following elbow surgery found that radiation therapy was associated with favorable functional and radiographic outcomes.[42] 

Furthermore, results from a retrospective study by Strauss et al of 44 patients found radiographic evidence of heterotopic ossification in 48%, with no complications after high-risk elbow surgery.[43] Favorable outcomes were reported from a case series of 9 patients with clinically significant heterotopic ossification at the elbow. Fractionation consisted of 5 Gy in 2 fractions and 6 to 7 Gy in 1 fraction, with a median follow-up of 7.7 months; there were no failures, and most patients showed clinical improvement.[44]

Toxicity and Adverse Effect Management

Heterotopic ossification is not a malignant condition, but it can cause pain, limited mobility, and negatively affect quality of life. Thus, the benefits of treatment must be weighed against the risks. Patients are often counseled that the low radiation therapy dose used for heterotopic ossification prophylaxis significantly reduces the risk of heterotopic ossification, with minimal adverse effects, and is considered a safe treatment overall. Potential side effects are rare but include fatigue, wound healing delays, joint swelling, and an extremely low chance of secondary cancer from the radiation therapy.

Secondary malignancies from radiation can develop in the bone or tissues included in a previous radiation therapy field. Since the total dose for heterotopic ossification prophylaxis is very low, the risk of secondary malignancies is also extremely low, but not 0. At least 2 case reports have described secondary malignancies after a single fraction. The first case described a 51-year-old patient who received 7 Gy x 1 for heterotopic ossification 15 years earlier. He underwent a second course of 7 Gy x 1 for debilitating heterotopic ossification but developed high-grade undifferentiated sarcoma of the proximal thigh 16 months after his second treatment.[45] 

Another case described a 26-year-old man who underwent surgery for an acetabular fracture and received 7 Gy in 1 fraction postoperatively for heterotopic ossification prophylaxis. He presented 11 years later with osteosarcoma of the treated area, which was treated definitively with neoadjuvant cisplatin and doxorubicin (Adriamycin), with plans for surgical resection at the time of the report.[46] Otherwise, there are no other reported cases of secondary malignancies from radiation therapy given for heterotopic ossification prophylaxis treatment.

Trochanteric nonunion and wound healing complications are also potential toxicities from radiation therapy. Results from one study showed that the nonunion rate ranged from 12% to 30% after radiation therapy, whereas it was 2% to 15% lower in those who did not receive radiation therapy.[47] Since modern THA hardware is cementless and porous, it may rely on bony ingrowth at the acetabular or proximal femoral surfaces. There is concern that radiation therapy may inhibit the necessary bony ingrowth and lead to prosthesis failure, which has prompted some clinicians to use shielding of the acetabular cup to prevent this complication. However, a clinical study of patients who received preoperative and postoperative radiation therapy found no evidence of prosthesis failure, even without shielding.[48]

For young men, infertility can also be an adverse effect of radiation therapy. A dosage of 70 to 100 cGy of radiation may cause oligospermia during treatment of the pelvic disease, whereas higher doses may cause azoospermia. Moreover, wearing a lead testicular shield during radiation therapy may help prevent infertility. Patients should also be advised about the possible effects of radiation therapy on fertility.[49]

Staging

Staging is most often used for surgical planning and less commonly for rehabilitation management. The Brooker Classification System, used to assess the severity of heterotopic ossification in the hip, is the most commonly employed staging system and relies on plain radiographs to visually evaluate the presence and extent of bone deposition.[20] A simplified version, called the Della Valle classification system, has been proposed.[50] None of the most commonly used rating systems account for patient function or range of motion, so a modified Brooker classification scale has been proposed that does.

The Brooker Classification divides the extent of heterotopic ossification formation in the hip into 4 classes:

• Class 1: Islands of bone within the soft tissues around the hip
• Class 2: Bone spurs that originate from the pelvis or proximal end of the femur, leaving at least 1 cm between opposing bone surfaces
• Class 3: Bone spurs originating from the pelvis or proximal end of the femur, with a reduced space between opposing bone surfaces of less than 1 cm
• Class 4: Ankylosis of the hip

The Della Valle Classification system: 

• Grade A: Absence of heterotopic ossification (or if bone is present, it may be greater than or equal to 1 island of bone of less than 1 cm in length
• Grade B: Presence of greater than or equal to 1 islands of bone at least 1 cm in length, with 1 cm distance between opposing surfaces of bone
• Grade C: Bone spurs arising from the pelvis or femur with less than 1 cm between opposing surfaces or bone ankylosis [50]

Prognosis

Complications of heterotopic ossification include decreased function and mobility, peripheral nerve entrapment, and pressure ulcers. Up to 70% of cases involving heterotopic ossification are asymptomatic. Ankylosis, vascular compression, and lymphedema can occur with heterotopic ossification.[51] Prognosis is generally good after surgery. The mean time from injury to surgery is 3.6 years.

Following surgical resection of heterotopic ossification around the hip joint, hip range of motion has been shown to improve from 24.3° to approximately 98.5 °. Range of motion is maintained at follow-up 6 months post-surgery. Complications from surgical resection of heterotopic ossification, such as infection, severe hematoma, and deep vein thrombosis, have been reported.[10]