Heterotopic Ossification

Heterotopic ossification (HO) refers to abnormal formation of mature lamellar bone within extraskeletal, peri-articular soft tissue. It differs from other disorders of bone mineralization in that HO occurs outside of the joint capsule, in planes not connected to periosteum. It is also known as myositis ossificans. 1

Etiology

HO occurs following spinal cord injury (SCI), traumatic brain injury (TBI), and less commonly after other neurological disorders such as stroke or anoxic encephalopathy. It also occurs after severe burns, fractures (particularly acetabular and elbow fracture), or joint arthroplasty (particularly of the hip). 2

Epidemiology including risk factors and primary prevention

Risk factors for HO include long bone fracture, immobility, coma >2 weeks, edema, trauma and pressure ulceration.

Common locations of HO after injury:

• SCI patients: Hips and knees commonly affected and 20-29% patients develop HO 3
• TBI patients: Hips, elbows, shoulders, and knees commonly affected and 5-20% develop HO 3
• Cerebrovascular accident (CVA) or Severe Burn: Elbows commonly affected; increased probability when burned area more than 20% of body surface area 4

While not conclusively established, the following may have a role in primary prevention:

• Passive joint mobilization (though increased incidence of HO could be seen at the elbow with excessive passive ROM) 5
• Control of spasticity
• Pre-operative radiation in total hip arthroplasty patients
• Non-steroidal anti-inflammatory drugs
• Bisphosphonates

Patho-anatomy/physiology

The pathogenesis of HO is still largely unknown. Putatively, it is triggered by edema, tissue ischemia/hypoxia, trauma, and other local inflammatory processes. It is postulated that trauma-induced HO occurs through endochondral osteogenesis, such that cartilage formation occurs followed ultimately by ossification. 6,7 However, direct differentiation of mesenchymal stem cells into osteoblasts has been demonstrated. 8

Several studies have focused on the pathogenesis through local and systemic inducers of HO such as bone morphogenic proteins (BMPs) and prostaglandin-E2. Disruption of both these mediators has shown to reduce the incidence of HO. 9 Histocompatibility (HLA) antigens have been studied in patients with heterotopic ossification. There is a strong correlation between the presence of the antigens HLA-A2 and HLA-B18 in patients with HO Brooker grades 3 and 4 following total hip replacement. 10 However, no significant differences in the frequency of any HLA antigens were found in patients with HO and SCI or TBI. 11,12 There has also been discussion of tissue hypoxia causing hypoxia-inducible factor activation ultimately leading to pathological bone tissue formation. 5,13,14

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

• Trauma or inciting neurological event occurs in tissues with abnormally heightened or prolonged inflammatory response to injury. 15
• Tissue expression of bone morphogenic proteins (BMPs) with subsequent activation of activin type-1 receptor (ACVR1), leading to mesenchymal spindle stem cells (satellite cells) migrating to the injured area and transforming into fibroblasts. 2
• Fibroblasts secrete immature connective tissue composed of collagen and extracellular matrix.
• Fibroblastic metaplasia occurs with fibroblasts transforming into chondrocytes; some chondrocytes deposit collagen into the cartilage matrix, but others transform into osteoblasts. 16
• Primitive osteoid develops by 1-2 weeks, and new bone formation starts to form within the osteoid.
• Trabecular bone forms 2-5 weeks after inciting trauma.
• Zonal phenomenon occurs with immature, undifferentiated central tissue and mature lamellar bone peripherally at 6 weeks.
• Symptoms of localized pain, tenderness, and swelling with rapid increase in size of the tissue affected. 5

• Mature HO demonstrates cancellous bone and mature lamellar bone, vessels, and bone marrow with a minor amount of hematopoeisis. 17
• Swelling becomes more localized, firm, and when adjacent to a joint may restrict motion. 5
• Associated with increased limb spasticity, bony ankylosis, pressure ulcers, pain, nerve/vascular compression, and lymphedema.
• HO has the potential to resorb but mostly seen in the pediatric population. 18

Specific secondary or associated conditions and complications

Heterotopic bone reduces joint range of motion (ROM), resulting in ankylosis, as well as soft tissue contractures of the surrounding skin, muscles, ligaments, and neurovascular bundles. Consequently, the patients’ ability to perform activities of daily living (ADLs), sitting, and transfers declines, and the lack of joint motion further contributes to increased likelihood of pathologic fractures of osteoporotic bone during positioning or lifting of the patient. Beside affecting range of motion, HO can cause peripheral neuropathy by impinging adjacent nerve structures, with chronic nerve ischemia and compression potentially leading to nerve scarring and fibrosis. 19

Essentials of Assessment

History

The temporal relationship of HO onset varies with disease. Symptoms usually arise between two weeks and 12 months from inciting injury. Patients may complain of restricted ROM with peri-articular pain, swelling, warmth, erythema (often without antecedent trauma in the case of neurogenic HO).

Physical examination

HO can be asymptomatic, but some common exam findings can show:

• Restricted ROM in the adjacent joint(s)
• Pain or tenderness during joint movement in the sensate patient
• Erythema, swelling, and warmth on the skin overlying the area of ectopic bone
• Low-grade fever may be present

Early HO presentation is very similar to occult fracture, deep venous thrombosis (DVT), cellulitis, and superficial thrombophlebitis.

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

Restricted ROM, pain, skin breakdown, and possible nerve entrapment due to HO adversely affects mobility, hygiene, and ADLs. These secondary consequences compound the disabling impairments already seen in common HO populations: SCI, TBI, and burn victims. This further contributes to reduced function, increased caregiver burden, and decreased quality of life.

Laboratory studies

• Alkaline phosphatase,an enzyme that suppresses inhibitors of bone formation, is often elevated early in the clinical course of HO and can be useful to distinguish suspected heterotopic ossification from other conditions that may present similarly with erythema, edema, or warmth such as DVT, hematoma, or cellulitis. It can take up to 2 weeks to be elevated after clinical signs and symptoms of HO appear and can be up to 3.5 times the normal value by 10 weeks after the injury. An elevated alkaline phosphatase is not specific to HO, as it can be elevated in other conditions such as long bone injury. It is not a sensitive test either, as some studies have shown it to be elevated in only 58% of patients with HO. 20 Alkaline phosphatase levels normalize as HO matures.
• Erythrocyte sedimentation rate and C-reactive protein are inflammatory markers that can be elevated in early HO but are non-specific. ESR greater than 35 mm/hr could signify HO development. 21
• Osteocalcin, a protein hormone that is produced by bone-forming osteoblasts, is often used as a biomarker to determine the effectiveness of medications for osteoporosis on bone formation. It is not useful in confirming mature HO, however, as the value is within normal limits in the majority of patients. 20
• Creatinine kinase can be used to predict the severity of HO but it is not specific, and further studies are needed to determine if it can be used as a marker for early HO. 22

Urinary markers used for detection of HO (less commonly ordered):

• Elevated urine Hydroxyproline is fairly sensitive in mature HO but has not been proven to be useful at the time of diagnosis or in serial measurements. 20 This may be due in part to the fact that it is typically elevated from the onset of paraplegia in SCI patients before HO begins to form due to bone loss from immobilization. 23
• A 24hr urine Prostaglandin E2 can be elevated in early HO. One study of spinal cord injury patients recommended measuring this value once a week from the initial injury to 3 to 4 months post-injury for screening. A sudden increase should prompt an initial bone scan. This number can be falsely elevated if there is sperm in the urine or if there is inflammation of the lower urinary tract. 24

Imaging

• X ray is specific but not sensitive in early HO. It may take 3-8 weeks for heterotopic bone to show up on an X ray. The heterotopic bone is often described as “fluffy” or “popcorn-like” in appearance.
  • The classification system proposed by Brooker categorizes the degree HO into four classes: (A) Class 1 denotes discrete islands of bone within the soft tissues surrounding the hip; (B) Class 2 involves bone spurs emerging from the pelvis or proximal femur, with a minimum of 1 cm separation between bone surfaces; (C) Class 3 encompasses bone spurs originating from the pelvis or proximal femur, reducing the space between opposing bone surfaces to less than 1 cm; and (D) Class 4 exhibits apparent bone fusion (ankylosis) of the hip joint. 25
  • The classification outlined by Hastings and Graham divides HO specifically at the elbow into three grades based on clinical and radiographic data. Category I includes cases where there is radiological evidence without any observed functional limitations. Category II encompasses instances where radiological evidence is accompanied by functional limitations. This category is further subdivided into subcategories: IIA, involving limitations in flexion-extension; IIB, involving limitations in pronation-supination; and IIC, involving limitations in both. Category III refers to cases characterized by ankylosis. 26

  Supplemental assessment tools

  The combination of normalized alkaline phosphatase levels and the appearance of mature, organized bone on x-ray indicate maturity of heterotopic bone.

  Early prediction of outcomes

  Patients at highest risk for contracture and ankylosis due to HO are those with spasticity or are immobilized. See the management section for treatment strategies and prevention measures that should be used in this population.

  Environmental

  Given the potential functional limitation of HO, it is important to remove environmental fall risk hazards. Durable medical equipment for ambulation should be evaluated.

  Additionally ground floor habitation or elevator access should be encouraged for those with hip HO or other injuries affecting the lower extremities.

  Social role and social support system

  HO commonly occurs in patients with other impairing condition such as fracture, SCI, TBI, and severe burns. Thus, functional limitations may extend beyond HO causation. It is important to determine if each patient has adequate social support from family, friends, caregivers, community groups, and/or a psychologist. 2,26

  Professional issues

  Patients considering surgical resection should be fully informed about the potential benefits, risks, and limitations of surgery, including the potential of recurrent ossification post-resection. Since surgery is mainly offered to restore ROM and functional skills, a patient should have a clear functional goal before receiving a surgical consultation.

  Rehabilitation Management and Treatments

  Available or current treatment guidelines

  There is no well-established algorithmic guideline for treatment of heterotopic ossification although individual treatments do exist for different phases of the disease.

  At different disease stages

  Passive and Active Range of Motion

  • Literature is currently mixed regarding the role of ROM and joint mobilization in the prevention and treatment of HO, though it should be considered an adjunct therapy for HO prevention at all stages of HO progression and occurrence. 5,19
  • Some specific patient populations seem to benefit more from ROM, such as TBI patients. 27

  Control Spasticity and Pain

  • Should occur symptomatically at all stages, in conjunction with other therapeutic modalities, such as IM phenol, botulinum toxin, and oral medications such as baclofen. 28

  NSAIDs

  • May arrest early bone formation in post-operative patient. 29
  • While no NSAID has shown superior efficacy to another, Indomethacin is the historical gold standard and has been shown in controlled trials to lower incidence of HO in the SCI population. 5
  • Indomethacin at 75 mg daily for 3 weeks has been shown to decrease the incidence of HO in patients with SCI. 30
  • For post-operative prophylaxis, indomethacin has been proven equally as efficacious as peri-operative single dose radiation therapy. 31
  • A recent meta-analysis demonstrated significant reductions in post-SCI HO formation when prophylactic NSAIDs were used. 32
  • Cyclooxygenase 2 (COX-2) selective inhibitors may be an effective drug in the prevention of HO after SCI with 2.5 times lower incidence of HO based on clinical and scintigraphy diagnosis. 33
  • However, in a meta-analysis assessing the effectiveness of non-selective versus COX-2 selective inhibitors for the prevention of HO following total hip arthroplasty, there was no significant reduction in HO formation noted between the two groups. 34
  • The optimal dose of any NSAID therapy has not been definitively proven. 15

  Bisphosphonates

  • Inhibits bone mineralization by interfering with aggregation of calcium hydroxyapatite, the crystal substrate of bone.
  • Delays bone mineralization after surgery. 1
  • Slows progression of HO in the SCI population. 35
  • Useful to treat early-stage HO.
  • Combination therapy with indomethacin may cause gastro-intestinal upset, diarrhea, myalgias, and infrequently osteonecrosis.
  • Early studies demonstrated the benefits of etidronate therapy in SCI populations when used within 60 days of injury. However, a more recent meta-analysis has failed to demonstrate the effectiveness of any one bisphosphonate on the incidence of HO following SCI. 32

  Surgical Resection

  • Invasive surgical resection stands out as the sole clinically proven method to effectively address neurological HO. Nevertheless, it is advised that surgical intervention be contemplated solely under specific conditions in neurological HO patients: (1) noticeable limitation in range of motion (ROM) attributed to joint ankylosis, (2) absence of acute inflammatory reaction, and (3) maturity of the lesion, ensuring it is adequately mineralized for excision. 6
  • The goal of surgical resection is to achieve improvements in function, posture, ambulation, ADLs, and prevent recurrent pressure injuries, particularly when these cannot be achieved through non-operative management. 6
  • The timing of surgery is controversial, and no definitive guidelines exist. A risk-benefit analysis of early vs late surgery will likely be required. Historically, surgery has been delayed until HO was thought fully mature (after 12-18 months) to minimize the risk of recurrence. However, early surgery (after 6 months) may allow for sufficient maturity and can prevent prolonged exposure to pain, progressive ROM loss, pressure injuries and continued functional decline. Thus, early surgery may ultimately lead to improved neurologic recovery. Surgery prior to 6 months is associated with a higher rate of HO recurrence. 6,17,36
  • Surgical resection of HO carries a high risk of recurrence without prophylactic treatment.
  • Incomplete resection of HO should be avoided, as the risk for recurrence with incomplete resection is significantly higher. 37

  Localized radiation

  • Hypothesized to prevent and treat HO by altering the differentiation of mesenchymal stem cells into osteoblasts. 38
  • Peri-operative radiation within 24 hours pre-op to 72 hours post-op may prevent HO after a total hip arthroplasty. 39 Peri-operative radiation given outside the above range may increase the risk for HO formation. 40
  • The superiority of pre-operative radiation vs early post-op is not yet known.
  • Post-operative radiation may prevent HO recurrence after surgical resection. 9,29,41 In patients with SCI, a single dose of radiation at 700 cGy may prevent progression of early HO. 42
  • Low dose radiation therapy (4-5.5 Gy) may be less effective than intermediate dose (7-8 Gy). Higher doses provide no additional effectiveness. 43

  Coordination of care

  A team approach for medical management may include a primary care physician, physiatrist, surgeon, occupational therapist, physical therapist, and psychologist. If radiation is considered for prevention/management of heterotopic ossification, a radiation oncologist would be involved as well. 15 Coordination of care should occur with the patient and caregiver, if applicable.

  Patient & family education

  Both the patient and family should be educated about the progression of HO and its potential complications, including reduced range of motion with subsequent functional limitations as well as peripheral neuropathy. They also should be aware of preventive and treatment options at each stage of the disease.

  Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally-based.

  It can be difficult to measure treatment outcomes in HO since most treatments focus on prophylaxis. However, several measurements can be used

  • Ability to perform ADL’s and functional improvement as determined by the functional independence measure (FIM) vs. section GG, and prevention of functional decline after surgical management of HO
  • Maintenance of joint ROM (as measured on goniometer)
  • Prevention of occurrence of HO radiographically
    • Most applicable to cases of surgical removal of HO followed by prophylactic measures, or when prophylaxis is performed in the setting of patient having a history of HO or after acetabular fracture
    • The Brooker classification for example uses 4 classes of radiographic findings of HO specifically after THA. While classes I and II are usually considered clinically insignificant given that symptoms rarely manifest with this extent of HO, classes III and IV are significant given that symptoms are typically present. 44

    Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

    In practice, it is important to recognize signs and symptoms of heterotopic ossification particularly in the early phase where more treatments are available. Early HO presents similar to occult fracture, deep venous thrombosis (DVT), cellulitis, and superficial thrombophlebitis. Thus, clinical suspicion should be high when symptoms present after 1 week in the presence of recent trauma, recent surgery, SCI, TBI, or burn injury. However similar presenting conditions should be ruled out using ultrasound, radiographs, laboratory markers, and clinical judgment.

    Cutting Edge/Emerging and Unique Concepts and Practice

    Emerging aspects of management of HO include:

    • Bone morphogenic protein receptor antagonism, as both genetic and traumatic forms of HO are mediated by the BMP Pathway. 45
    • Rapamycin through modulation of the mTOR pathway and its subsequent effect on lepton signaling. 46
    • Limited data indicate that allopurinol and N-acetylcysteine in combination are effective at preventing experimentally induced HO. 9
    • A retinoic acid receptor agonist, such as palovarotene, has demonstrated effectiveness in thwarting the initial stages of NHO by hindering the expansion and differentiation of OPCs into chondrocytes. However, caution is advised in administering RAR-γ agonists to children due to their potential to delay growth plate development. Yet, in adults, intermittent RAR-γ treatment may offer a viable option, allowing for adequate recovery time for the growth plate. Moreover, while promising in preventing NHO progression, palovarotene’s inhibition of fracture healing warrants careful consideration, especially in patients with ongoing fracture repair. 6

    Gaps in the Evidence-Based Knowledge

    Currently our understanding of HO is limited by our understanding of the pathogenesis. Additionally, the timing for surgical resection still presents controversy. Traditionally surgical intervention is reserved after HO has completely matured, but some studies have suggested benefit from early resection as soon as 4 to 8 months after injury. 9,17,18 Future investigations should explore new underlying pathophysiological mechanisms, prognostic biomarkers, and preventive therapies suitable for complex trauma patients with CNS injuries, employing a translational approach that combines advanced animal models with thorough clinical studies. This integrated strategy holds the potential to advance the development of biomarkers and preventive strategies, ultimately enhancing outcomes for individuals affected by neurologic HO. 6

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    Original Version of the Topic:

    Patricia W. Nance, MD, Jennifer W. Tsoi, MD. Heterotopic ossifications. 11/5/2012

    Previous Revision of the Topic:

    Patricia W. Nance, MD, Ravi Mirpuri, DO. Heterotopic ossifications. 4/8/2016

    Justin Weppner, DO, Justin Tu, MD, Emily Hillaker, DO, Michael Bova, MD, Taylor Lee Lonjin, OMS-IV. Heterotopic Ossification. 3/11/2021

    Author Disclosure

    Justin Weppner, DO
    Nothing to Disclose

    Michael Bova, MD
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    Justin Tu, MD
    Nothing to Disclose