The term heterotopic ossification (HO) describes bone formation at an abnormal anatomical site, usually in soft tissue. HO can be classified into the following 3 types:
Myositis ossificans progressiva (fibrodysplasia ossificans progressiva) - This disorder is among the rarest genetic conditions, with an incidence of 1 case per 2 million persons. Transmission is autosomal dominant with variable expression. The condition is characterized by (a) recurrent, painful soft-tissue swelling that leads to HO and (b) congenital malformation of the great toe. There is no treatment for this form of HO. Limited benefits have been reported using corticosteroids and etidronate. Most patients die early from restricted lung disease and pneumonia; however some patients live productive lives. 
Traumatic myositis ossificans - In this condition, a painful area develops in muscle or soft tissue following a single blow to the area, a muscle tear, or repeated minor trauma. The painful area gradually develops masses with a cartilaginous consistency; within 4-7 weeks, a solid mass of bone can be felt. Common sites include the pectoralis major, the biceps, and thigh muscles. A nontraumatic type of myositis ossificans also may exist.
Neurogenic heterotopic ossification - This condition is the one that comes to mind when the generic phrase heterotopic ossification is used. This type of HO is the subject of this article. The various terms mentioned at the outset all refer to this type of HO.
In 1918, Dejerine and Ceilier first described HO in patients with spinal cord injury (SCI) from the First World War. Now HO is recognized as a fairly common sequela of SCI, especially after traumatic cord injury. The condition has also been described with lesser frequency in other severe neurologic disorders (eg, traumatic brain injury, stroke, encephalitis, polio, tetanus, tabes dorsalis, syringomyelia, anoxic encephalopathy), as well as following severe burns. [2, 3]
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Despite many investigations, the etiology and pathogenesis of neurogenic heterotopic ossification remain unknown. [4, 5, 6] An extensive review of the problem in 1973 by Rossier and colleagues attempted to address the question of pathogenesis by investigating the following parameters  :
Lower limb angiography
Venous and arterial blood gas analyses
Serial serum calcium
Creatine kinase (CK) and alkaline phosphatase (AlkP)
Urine calcium and hydroxyproline
None of these observations explain the factors responsible for the development of HO. Although the etiology of HO remains unknown, clinical and experimental evidence supports the hypothesis that trauma is one of the most important initiating factors.  In the studies in which HO was induced experimentally, 2 factors were found to be prerequisites for ectopic ossification: (1) traumatic ischemic degeneration of involved muscle and (2) tissue expression of bone morphogenic proteins (BMPs).
It also has been shown that expression of many genes, including BMP, is regulated by mechanical stress. The target cells in the muscle for BMP are mesenchymal stem cells, also called satellite cells. These cells are precursors capable of differentiating into many cell types, including osteoblasts. Thus, BMP may play a role as a paracrine factor in the differentiation of satellite cells into bone-forming cells.
Most likely, other factors also are involved in the etiology of HO. Studies have shown that AlkP may have an important role in ectopic calcification and ossification of soft tissues. The major role of AlkP in soft tissue is to remove inhibitors of mineralization. An increased expression of AlkP was found in vascular smooth muscle cells in the presence of macrophages and inflammatory cytokines. These observations may have clinical importance, because inflammation and trauma have long been suggested by many investigators as possible etiologic factors.
Clinically, muscle trauma has been reported as a cause of HO after SCI by numerous investigators, including Bodley and colleagues,  as well as Snoecx and co-investigators.  The types of muscle trauma proposed as initiating HO are muscle tears, ruptures, edema, and bleeding.
It has also been suggested that factors such as intensive rehabilitation, transfer activities, and repeated minor trauma during activities of daily living can cause superimposed mechanical stress and initiate HO. The hypothesis that trauma is an important factor in HO formation after SCI also has been documented by ultrasonographic and histologic studies. Various degrees of muscular damage with evidence of tissue bleeding have been found in the early stage of HO.
During the formation of HO, initially immature connective tissue, fibroblasts, ground substance, and collagen fibers are seen. Eventually, usually within 7-14 days, osteoblasts are noted, located irregularly in osteoid. New bone formation may start in multiple foci within osteoid. As mineralization progresses, amorphous calcium phosphate is gradually replaced by hydroxyapatite crystals. Commonly, after approximately 6 months, the appearance of true bone is noted. Rossier noted that after approximately 30 months, the pattern in HO approached that of normal young adult bone.  Anatomically, HO is always extra-articular, but it may attach to the joint capsule without disrupting it. Occasionally, HO may attach to the cortex of adjacent bone, with or without cortical disruption.
The reported incidence of HO following SCI varies greatly from study to study. Incidence varies from a low of 3.4% to a high of 47% reported by Hassard, who found HO around the hips of 62 of 131 patients with SCI who were admitted to the Hot Springs Rehabilitation Center over a 2-year period.  Most studies cite a range between these 2 extremes. Peak incidence is noted from 4-12 weeks postinjury and can occur up to 5 months following trauma. Later onset has been reported but is very rare.
In 1954, Irving and LeBrun first documented HO in patients with hemiplegia. Roberts reported 6 cases of HO following intracranial lesions (3 traumatic, 2 vascular, and 1 neoplastic) in 1968, and subsequent studies cited the incidence of clinically significant HO following severe closed head injury (CHI) as being 11-76%. Incidence of HO following other neurologic disorders has not been delineated yet, but it appears to be lower than the incidence following SCI or head injury.
The following reasons may be postulated for the large variability in incidence seen in different studies:
Different authors use different criteria to define HO. For example, using a radiologic screening survey yields higher incidence figures than does reporting only clinically significant HO detected on physical examination.
Although neurogenic heterotopic ossification (NHO) generally occurs periarticularly (as noted in the European term paraosteoarthropathy), some authors include patients with calcification or bone formation, possibly secondary to other causes (eg, decubitus ulcers, septic arthritis, trauma, surgery), in their studies.
Various authors study different populations (eg, early vs late cord injured patients).
Approximately 10-35% of all patients with HO secondary to SCI have significant reduction of range of motion (ROM) at the affected joint or joints.  Wharton and Morgan found that 3% of patients with SCI have an ankylosed joint caused by HO. Effects on activities of daily living (ADL) and functional mobility (eg, transfers) are not difficult to imagine. In addition, abnormal weight distribution may lead to increased frequency of decubitus ulceration, as Hassard noted in 1975. 
No known correlation exists between race and incidence of HO.
No known correlation exists between sex and incidence of HO.
Age has no significant correlation with HO formation, although the condition is somewhat less frequent in pediatric and geriatric patients with SCI.
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