Heterotopic Ossification (HO), also known as paraosteoarthopathy, myositis ossificans, and heterotopic calcification1 among others, is a commonly occurring condition that refers to ectopic bone formation in soft tissues. HO can be subdivided into two major types: acquired and genetic, with acquired being the most predominate. Acquired HO is closely related to tissue trauma and can be seen after joint surgery, musculoskeletal trauma, central nervous system injury, and even burns.2 HO develops in up to 44% of patients undergoing hip arthroscopy or replacement, 10-20% of those with CNS injury, and 4% of those with burns covering greater than 30% of body surface.3, 4, 5, 6, 7, 8, 9, 10 Many cases of HO lead an indolent course, however severe cases can cause inflammation, pain, immobility and functional impairment.11 Due to its potential to cause disability, it is imperative to be able to distinguish HO from other etiologies including tumoral calcinosis, osteosarcoma, or dystrophic calcification to provide adequate treatment.
Acquired HO can be broadly categorized in to three etiologic subtypes: neurogenic from central nervous system injury, orthopedic covering fractures, fixations, joint replacements,
Patients presenting with HO typically complain of inflammatory symptoms including pain, swelling, erythema, and warmth along with joint immobility, which appear anytime from 3 to 12 weeks after the precipitating event.11,25, 26, 27, 28 The most common sites of occurrence, in a decreasing order, are the hips, knees, shoulders, and elbows.25,27 The gold standard method for diagnosing HO is through imaging studies, mainly radiography and computerized tomography (CT).3 The downfall to these types of imaging is that they are not able to detect calcifications for at least 6 weeks after the inciting trauma.25,29 Three-phase bone scintigraphy is the most sensitive method for detecting HO, with the earliest detection being 2.5 weeks post trauma.25,30 It is also effective in monitoring HO progression and determining the appropriate time to stage surgical intervention.25,26,30 Activity on bone scans usually peaks a few months after the inciting event and returns to baseline by 12 months.25
Early screening methods used before imaging studies include serum alkaline phosphate levels and 24-hour urinary PGE2. Alkaline phosphate levels can increase two weeks after trauma, reaching 3.5 times baseline by 10 weeks, and then returning to baseline by 18 weeks. A rapid increase in 24-hour PGE2 urinary secretion has also been shown to suggest HO and would indicate further imaging studies.31,32
Upon suspicion of HO on imaging, it has been suggested to perform a biopsy to confirm the diagnosis; however, current recommendations are to follow up with imaging studies in four weeks, which together with the history of trauma can confirm the diagnosis.33
A soft tissue mass is the earliest finding of HO on imaging, it is often depicted as a peripheral zone of mineralization in acquired cases.33 With time, these outer regions can mature in to a peripheral cortex with a well-defined cancellous bone interior detectable by CT (Figures 1-2 and 3).29,33 Radiography (Figure 4) and CT scan remain the gold standard for diagnosis due to their ability to detect immature bone formation and the relatively cheap cost.3,29 In the acute phase of HO, there is increased tissue vascularization and density, which can be detected on Magnetic Resonance (MR).34 This region appears isointense or hyperintense to muscle on T1-weighted images and hyperintense on T2 weighted images with pronounced surrounding inflammation.34,35 As the rim of calcification forms, signal void begins to appear on the periphery on all sequences.35,36 During this maturing phase, MR imaging results in non-specific findings and heterogenous signal that mimics many other pathologic processes.29,37 Once mature, HO presents as cancellous fat that is hyperintense on T1 and T2 weighted images outlined by the hypointense cortical bone29 and this can be considered diagnostic. Therefore, when MR detects a mature HO, no further imaging is necessary. On the other hand, early MRI has a great advantage in excluding other differential diagnosis possibilities, as we can observe the “striate pattern” and “checkerboard-like pattern” appearance in T2-WI and contrast-enhanced MRI images38 or it can be detected by displacing the fascial planes, especially at the periphery of the lesion.39 Recognizing these MRI patterns in HO could be very beneficial in the early phases as the condition is commonly misdiagnosed for an osteomyelitis or even a malignancy, mostly sarcomas.40, 41, 42
Ultrasonography (US) is proved to be a sensitive imaging modality for soft tissues lesions and calcifications.43,44 It is also safe, of low-cost, and easy to perform and repeat.45 US has the great advantage of bedside application as well, which could be more feasible for bed-ridden patients.45,46 Qing Wang
Staging of HO is commonly done using the Brooker classification (Table 1), which was initially developed using anteroposterior radiographs of the hip.9 There has been some criticism of this classification as anteroposterior radiographs cannot distinguish between bridging or overlapping calcifications.48 To simplify and reduce variability, Della Valle
Brooker classification of heterotopic ossification9
Islands of bone within the soft tissues over the hip | |
Bone spurs from the pelvis or proximal end of the femur, leaving at least one centimeter between opposing bone surfaces. | |
Bone spurs from the pelvis or proximal end of the femur, reducing | |
the space between opposing bone surfaces to less than one centimeter. | |
Apparent bone ankylosis of the hip |
Della Valle classification of heterotopic ossification49
Absence of HO or islands measuring <1 cm in length | |
Islands >1 cm or spurs leaving at least 1 cm between femur and pelvis | |
Spurs leaving <1 cm between opposing surfaces or bony ankylosis |
Schmidt and Hackenbroch classification of heterotopic ossification50
Heterotopic ossifications strictly below tip of greater trochanter | |
Heterotopic ossifications below and above tip of greater trochanter | |
Heterotopic ossifications strictly above tip of greater trochanter | |
Single or multiple heterotopic ossifications < 10 mm in maximal extent without contact with pelvis or femur | |
Heterotopic ossifications > 10 mm without contact with pelvis but with possible contact with femur; no bridging from femur to proximal part of greater trochanter, with no evidence of ankylosis | |
Ankylosis by means of firm bridging from femur to pelvis |
Many pathologies can imitate HO clinically or radiographically. It is vital to understand the similarities and differences of these mimetics when considering the diagnosis of HO. A few differentials that should be considered are briefly discussed below.
Dystrophic calcification (DC) is the calcification that occurs in soft tissue post inflammation and damage. The mechanism is thought to be either disruption of cell membranes during cellular stress allowing calcium to enter and subsequently be concentrated in the mitochondria or by creating an acidic environment in the tissue that lacks calcification inhibitors.51
It is well documented to occur in cases of collagen vascular diseases like dermatomyositis (Figure 5), systemic lupus erythematosus, and scleroderma52, but has also been identified in other disease processes.51 On plain film, DC appears as amorphous calcification with a hazy ill-defined appearance that can increase in density over time.53 CT will similarly show peripheral amorphous hyperdensities, with MRI showing hypointense signals in T1 and T2 weighted images (Figure 6).54
The distinguishing difference between DC and HO is organization. DC and HO are virtually indistinguishable on plain films, CT, or MRI early in the disease process as mineralization occurs. HO will begin to organize and ossify over the course of months into lamellar bone while DC will remain as amorphous, non-ossified calcifications.55
Chondrocalcinosis is calcification within fibrous or cartilaginous structures and is frequently associated with calcium pyrophosphatase disease (CPPD).56 In cases of CPPD, there is usually acute, painful inflammation of a joint, often the knee, where calcium phosphate crystals are deposited.57 Microcrystals can then impregnate cartilage causing arthritic symptoms, which can range from mild to severe with joint destruction.57 On plain films, this appears as a dense line within hyaline cartilage that runs parallel to the articular surface.56 CT has excellent sensitivity and specificity for detecting chondrocalcinosis and can better visualize the linear hyperintense calcifications (Figure 7).56 There is often a concurrent degenerative joint disease with joint space narrowing and large osteophyte formation.58 The linear deposition contrasts with HO, which presents as a peripheral circumferential calcific mass on both plain films and CT with minimal intra-articular involvement. MRI has little utility in diagnosing Chondrocalcinosis, as the calcifications are not well visualized in tissues.56
Tumoral calcinosis (TC) refers to a syndrome characterized by calcium salt deposition in peri-articular soft tissue.59 A major component of TC is hyper-phosphatemia secondary to genetically acquired decrease in phosphate secretion59, 60, 61 or chronic renal failure and resulting hyperparathyroidism.59 Patients present with joint pain, swelling, or immobility most commonly in the hip, elbow, shoulder, foot, or wrist.59,62,63, 64 Unlike HO, TC lesions grow slowly over the course of several years.65 Plain radiographs, ultrasound and CT scan, all can be used for diagnosis and would show fluid filled, lobulated, cystic calcifications in peri-articular tissue.66
T1 and T2 weighted MRI show a hypointense lesion with septal enhancement (Figure 8). HO is not cystic in nature and lacks the lobulated pattern on both CT and MRI. HO also presents with hyperintense signal centrally with a hypointense cortical shell on MRI. Management of TC is clinically determined based on the symptoms and the size of calcinosis with surgical or needle decompression being most common interventions.66
An avulsion fracture (AF) is the separation of a bone fragment at the site of tendon attachment, often occurring after a traumatic injury. Patients with this injury typically have a definite history of trauma accompanied by pain, swelling, and loss of joint function.67 Findings on imaging can be seen immediately post trauma, depicting sharply delineated bone fragments (Figure 9). Large avulsed fragments can appear identical to matured HO, therefore having a clinical history is important. In addition, HO will not be visible on a plain film until weeks after the inciting trauma and will not mature into cortical bone for many months.25 CT of avulsion fractures helps delineate fracture sites and show displaced hyperdense cortical bone.67 HO can be distinguished from AF on CT, showing a ring of hyperdense cortical bone with a hypodense interior.29,33 MRI may be useful in detecting local tissue damage seen in avulsion fragments; however, findings are consistent with inflammation and are non-specific.67
Osteosarcomas (OS) are the most common primary bone tumor, developing from uninhibited osteoid production by malignant mesenchymal cells.68 Patients present with localized pain and swelling, which then proceeds to joint immobility. This type of tumor is commonly seen in the metaphysis of long bones, most commonly the distal femur, proximal tibia, and proximal humerus; in a descending fashion.68,69 On plain radiographs, it can present as osteoblastic, osteolytic, or with mixed appearances, and have patchy calcifications from the newly developing bone in the surrounding soft tissue.68 The imaging appearance is commonly described as a “sunburst” appearance or as having cloudlike density (Figure 10).70 CT scan is highly sensitive to calcification and is useful in showing the amorphous osteoid formation in OS, which can help distinguish it from organized circumferential osteoid formation in HO. MRI of OS shows heterogenous signal intensities on T1- and T2-weighted images due to a mixture of amorphous osteoid, hemorrhage, and necrosis.70,71 Radiographs can be correlated with a low signal intensity on T1-wieghted imaging and hyperintensity on STIR imaging indicating mineralized matrix deposition with small periosteal reaction. Other findings include cortical bone destruction and marrow invasion not typically seen with HO.71
Gout is a type of inflammatory arthritis caused by the deposition of monosodium urate crystals in joints and surrounding tissue.72 Clinically, this condition presents with an acute onset pain and swelling at the site of deposition, typically the feet and knees but can also be seen elsewhere.72 Early radiographic studies can often be negative, however in chronic gout patients, punched erosions with well-defined sclerotic borders can form extra marginally, articularly, or para-articularly with preservation of the joint space.72,73 In severe cases, extreme bone destruction can occur with large periarticular lesions, joint space widening, and concurring osteoarthritis.72, 73, 74 Tophi on CT are seen as discrete masses with a higher intensity than adjacent soft tissue.75 CT is also useful in defining well-demarcated erosions with overhanging osteophytes seen in gout.75 MRI is only beneficial in identifying soft tissue abnormalities around affected joints rather than tophi themselves, leading to low specificity and utility.75 When seen, tophi appear with decreased signal intensity on T1 weighted images and heterogeneous signal on T2.75 HO can be distinguished from tophaceous gout on x-ray and CT by lack of intraosseous erosions, peripheral calcifications in the soft tissue, and formation of cortical bone. MRI is not useful in distinguishing between the two unless the HO is mature, when complete lamellar bone is seen.
Calcific Tendonitis refers to the condition of calcium deposition in tendons.76 This is clinically depicted by chronic pain with activity, tenderness, swelling, and joint immobility that is commonly localized to the rotator cuff tendons.76,77 The etiology remains unknown; however, severity has been associated with endocrine diseases.78 Pathology can be noted by standard AP radiograph with internal and external rotation views showing dense homogenous calcification typically noted proximal to the greater tubercle (Figure 11).79 Ultrasound, used to evaluate a rotator cuff injury, can show a hyperechoic lesions with reproducible pain in palpation during the procedure.80 Calcific tendonitis can also be viewed with susceptibility-weighted imaging, which presents as a hyperintense lesion at tendon insertion site with occasional central hypointensity. It lacks the well-defined shape of HO and the hyperintense core seen on T1 weighted images.81
Fibrodysplasia Ossificans Progessiva is an extremely rare genetic form of HO in which patients repair mechanism ossifies the fibrous tissue at the trauma site, leaving the patient permanently frozen secondary to minor trauma.82 Patients initially present with characteristic malformations of the large toes at birth with painful soft tissue swelling and ectopic bone formation within the first decade of life.82, 83, 84 Laboratory changes include increased serum alkaline phosphatase and urinary basic fibroblast growth factor during acute episodes. Radiographic imaging shows extensive heterotopic bone formation diffusely with no specific pattern and ankylosis of adjacent joints with heterotopic bone formation.82 MRI can show heterotopic bone formation with underlying edema and subtle soft tissue changes indicating pre-osseous lesions, noted as hyperintense lesion on fat suppressed T2 imaging.85 CT imaging can be used for volumetric analysis of ossification that is unattainable via radiographs or MRI, showing the extent of joint ankylosis with 3D rendering and assessment of severity via Lederson grading scale. 85 This condition can be distinguished from traumatic HO by early onset and severe disseminated ossification.
Treatment for HO is divided into prophylaxis for high-risk patients and management of already formed HO. Due to the large variability in etiology and underlying mechanisms for HO and individualized patient risk factors, there is little agreement on appropriate treatment regimens. Commonly used prophylaxis includes NSAIDs, localized low dose radiation, or a combination there-of with the most popular being NSAID alone.86,87 Prophylactic NSAIDs have shown to reduce the occurrence of ectopic bone formation when given peri-operatively compared to placebo, but at the expense of medication side effects such as gastrointestinal ulcers, bleeding, and delayed bone healing.88,89 Although there is a decrease in HO formation, NSAIDs had no effect on pain or physical function compared to placebo.88,90,91 NSAIDs target pro-inflammatory prostaglandins, which have been shown to be integral to osteogenesis and are thought to have some effect by suppressing the migration and proliferation of mesenchymal cells.21,92,93 The NSAID of choice is the non-selective cox inhibitor indomethacin.94 Cox-2 specific inhibitors have been suggested to reduce side effects associated with nonselective cox inhibitors; however, their cardiovascular side effects and lack of safety with routine use limit their use.15
Coventry
Surgical management currently remains the only effective treatment for a preformed ectopic bone. Indications for surgery include symptomatic disabilities and radiographic evidence showing the cessation of bone growth.3 Surgery should not be performed until 12 to 18 months after HO formation to allow maturation of the lesion and patient’s tissue has had time to recover to decrease intraoperative complications and HO reoccurrence.28,100 Although efficacious, surgery inherently causes tissue trauma, which can simulate the same inflammatory conditions for HO formation and is therefore complicated by high reoccurrence rates.101
Heterotopic ossification is a commonly seen condition occurring secondary to trauma and may cause mild to severe disability. The exact pathogenesis of this disease remains unclear; however, there is an ongoing promising research to develop prophylactic and therapeutic treatments that is promising. Distinguishing HO from other mimics help clinicians better manage the disease and improve patient care.