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
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, or joint arthroplasty.
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 20-30% patients develop HO
- TBI patients: Hips, elbows, shoulders, and knees commonly affected and 10-20% develop HO
- Cerebrovascular accident (CVA) or Severe Burn: Elbows commonly affected
While not conclusively established, the following may have a role in primary prevention:
- Passive joint mobilization
- Control of spasticity
- Pre-operative radiation in total hip arthroplasty patients
- Non steroidal anti-inflammatory drugs
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 a disruption of the normal balance of bone formation and inhibition, perhaps by inducing a cascade of inflammatory factors promotes mesenchymal cell differentiation to osteoblasts, which in turn deposit new bone matrix in non-skeletal soft tissue.
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.2
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- Osteoblasts lay down osteoid matrix in non-skeletal tissue
- Primitive osteoid develops by 7-10 days
- Primitive cartilage and woven bone seen by 14 days
- 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 warmth, swelling, pain, and restricted motion in peri-articular regions can occur 1 week post-injury
- Maturity defined by normalization of alkaline phosphatase levels, normal uptake in triple phase bone scan, organized bone on radiographs.
- Associated with possible contracture deformities, joint ankylosis, pressure ulcers, pain, nerve/vascular compression, and lymphedema.
- HO has the potential to resorb but mostly seen in the pediatric population.3
Specific secondary or associated conditions and complications
Heterotopic bone impairs joint range of motion (ROM) affecting mobility, hygiene, and other activities of daily living (ADL). As ectopic bone matures, the underlying bone mass may cause worsening spasticity, skin breakdown with resultant soft tissue infection, nerve entrapment, and contracture deformities leading to end-stage joint ankylosis and severe disability.
2. ESSENTIALS OF ASSESSMENT
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).
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 ADL. 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.
- Alkaline phosphatase
- Elevated in early HO but not specific for diagnosis
- Normalizes by maturity
- Useful to monitor therapy efficacy.
- C-reactive protein
- Erythrocyte sedimentation rate.
- Creatinine Kinase
Urinary markers used for detection of HO (less commonly ordered):
- prostaglandin E2.
Triple phase bone scan is the current gold standard for diagnosis.1 It is sensitive for early HO, and can detect ectopic bone within 2-4 weeks during first and second flow phases. Radiographic films can detect HO within 3 weeks to 2 months of ectopic bone formation, but is more useful to confirm mature HO. The appearance of mature HO on radiographs is often described as a “fluffy” or “pop-corn-like” appearance of bone. Ultrasound may have a role as a screening tool, and may be obtained during DVT screening exam.
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. This combination can be used to evaluate a patient’s candidacy for surgical resection. HO can also be visualized by ultrasound and magnetic resonance imaging (MRI).
Early prediction of outcomes
Patients most at risk for contracture and ankylosis due to HO are those who are immobilized and/or have a predilection to spasticity. It is important to develop treatment strategies in these populations that include frequent ROM exercises as well as other appropriate prevention measures discussed in the management section.
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 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 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.
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.
3. 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
- Should occur at all stages in disease
- May prevent HO occurrence and progression
Control Spasticity and Pain
- Should occur symptomatically at all stages
- May arrest early bone formation in post-operative patient.4
- Indomethacin shown in controlled trials to lower incidence of HO in the SCI population. Recommended dose 25 mg three times daily for 6 weeks as effective prophylaxis.5
- 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.5
- Useful to treat early stage HO
- Oral dosing depends on pathology
- Hip Arthroplasty: 20 mg/kg/day for 1 month before and 3 months following surgery.
- SCI patients: 20 mg/kd/day for 2 weeks and then 10 mg/kd/day for 10 weeks
- TBI patients: 20 mg/kg/day for 3 months, then 10 mg/kg/day for 3 months.
- Combination therapy with indomethacin may cause gastro-intestinal upset, diarrhea, myalgias, and infrequently osteonecrosis.
- Reserved for cases where functional gains can be made with mobility and/or self-care.
- Surgery is generally delayed until HO is mature (after 12-18 months) to decrease chance of recurrence. However, some data suggests early resection in the elbow before HO maturity was associated with improved upper extremity function in the case of burn patients.5,6
- Surgery has a high risk of recurrence status post-HO resection without prophylactic treatment.
- Post-operative radiation may prevent HO after a total hip arthroplasty and HO recurrence after surgical resection.2,4,7
Coordination of care
A team approach for medical management may include a primary care physician, physiatrist, surgeon, occupational therapist, physical therapist, and psychologist. 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, potential complications, functional limitations, 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
- ADL, functional improvement, and prevention of functional decline
- Maintenance of joint ROM (as measured on goniometer)
- Prevention of occurrence of HO radiographically
- Most applicable to post-surgical outcome measurements
- The Brooker classification for example uses 4 classes of radiographic findings of HO after THA where class I and II are usually considered clinically insignificant and class III and IV are significant in correlation to physical findings. 2
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 judgement.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
Emerging aspects of management of HO include:
- Bone morphogenic protein receptor inhibition
- Ex vivo delivery of noggin to cells with known noggin gene mutation
- Manipulation of the retinoic acid receptor (RAR) pathway, which inhibits chondrogenesis
- Limited data indicate that allopurinol and N-acetylcysteine in combination are effective at preventing experimentally induced HO.2
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Controversies and 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.1,5,6
- Mavrogenis AF, Soucacos PN, Papagelopoulos PJ. Heterotopic Ossification Revisited. Orthopedics. 2011 Mar 11; 34 (3): 177.
- Pavlou G, Kyrkos M, Tsialogiannis E, Et al. Pharmacological treatment of heterotopic ossification following hip surgery: an update [editorial]. Expert Opinion on Pharmacoptherapy. 2012;13(5):619-622.
- Garland DE, Shimoyama ST, Lugo C, et al. Spinal cord insults and heterotopic ossification in the pediatric population. Clinical Orthopaedics and Related Research. 1989;(245): 303-310.
- Strauss JB, Wysocki RW; Shah A, et al. Radiation therapy for heterotopic ossification prophylaxis after high-risk elbow surgery. American Journal of Orthopedics. 2011; 40 (8): 400-405.
- Aubut J, Mehta S, Cullen N, et al. A comparison of heterotopic ossification treatment within the traumatic brain- and spinal cord-injured population: An evidence-based systematic review. NeuroRehabilitation. 2001;28(2):151-160.
- Tsionos I, Leclercq C, Rochet J-M. Heterotopic ossification of the elbow in patients with burns. Journal of Bone and Joint Surgery. 2004;86-B:396-403.
- Mishra MV, Austin L, Parvizi J, et al. Safety and efficacy of radiation therapy as secondary prophylaxis for heterotopic ossification of non-hip joints. Journal of Medical Imaging and Radiation Oncology. 2011; 55(3):333-336.
- Bering-Sorensen S, Burns AS, Curt A, et al. International spinal cord injury musculoskeletal data set, Spinal Cord. 2012;Sep 4 [Epub ahead of print]
- Harrington AL, Blount PJ, Bockenek WL. Heterotopic Ossification. In: Frontera WR, Silver JK, Rizzo TD Jr , eds. Essentials of Physical Medicine and Rehabilitation. 2nd ed. Philadelphia, PA: Elsevier; 2008:691-695.
- Tan JC. Practical Manual of Physical Medicine and Rehabilitation. 2nd ed. Philadelphia, PA: Elsevier; 2005:402-403.
- Braddom RL, ed. Physical Medicine and Rehabilitation. 4th ed. Philadelphia, PA: Saunders; 2010.
Original Version of the Topic:
Patricia W. Nance, MD, Jennifer W. Tsoi, MD. Heterotopic ossifications. Publication Date: 2012/11/05.
Patricia W. Nance, MD
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Ravi Mirpuri, DO
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