Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neurogenic heterotopic ossification in spinal cord injury


Neurogenic heterotopic ossification (NHO) is a frequent complication in spinal cord injury (SCI) that is often difficult to treat. This review emphasizes the incidence, risk factors and clinical signs of NHO in SCI patients. Although the exact pathophysiology underlying NHO in neurologic patients is not yet understood, different pathogenic mechanisms have been proposed in the literature. A selection of the most important theories will be given and discussed. Moreover the different diagnostic, therapeutic, and preventive methods currently used in NHO management after SCI will be reviewed.


Neurogenic heterotopic ossification (NHO) is a frequent complication in spinal cord injury (SCI). It is characterized by the formation of new extra osseous (ectopic) bone in soft tissue surrounding peripheral joints in patients with neurologic disorders. In SCI patients, the incidence ranges from 10–53% depending on the study design, the methods of detection (radiologically or by clinical symptoms), and the diagnostic criteria used.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28 Moreover, in the early literature, no attempt was made to separate cases with ectopic bone formation associated with trauma or decubitus from true ectopic ossification not associated with a history of (local) trauma or infection. In non-traumatic myelopathies the incidence of NHO seems less compared to traumatic SCI ranging somewhere between 6–15%.6,14,19,29,30 NHO is less common in children than in adults with an incidence generally reported between 3–10%.31,32 The clinical symptoms in children do not differ from those reported in adults, but are less pronounced compared to adult patients. Moreover, spontaneous regression of NHO is more often reported in children and young adults than in older adults.31,32

The clinical spectrum of NHO ranges from an incidental finding on X-rays to severe limitation of the range of motion and even complete ankylosis of peripheral joints. In the majority of cases, the extent of NHO is minimal and only diagnosed as a radiographic finding. However, in 20–30% of the SCI patients clinically significant NHO is present with a reduction of joint range of motion, whereas in 3–8% of the SCI patients ankylosis develops.7,8,10,12,19,20,22,23,24,27,29,33 NHO always occurs below the level of the SCI, most commonly at the hip (70–97%).4,5,7,8,10,12,14,15,18,19,22,24,26,28,34,35,36,37 Other body segments including the knee, elbow, shoulder, hand and spine (in decreasing incidence) may be involved.7,10,12,14,22,23,33,36,38,39,40,41,42 Incidentally, NHO has been reported after soft tissue surgery in SCI patients.43,44

Although NHO may develop even several years after SCI, it is generally diagnosed between 1 to 6 months post-injury with a peak incidence at 2 months7,8,10,12,19,22,45,46,47,48,49,50 Although NHO may begin well before the clinical signs become evident, the initial signs are often seen within the first 3 weeks after SCI.3,4,7,9,39,51 The most common clinical findings are a decreased joint range of motion and a peri-articular swelling due to interstitial oedema of the soft tissues.1,7,8,10,30,36,39,45,52,53 In patients with sensory sparing, the first symptom may be pain in the affected area.10,54 Peri-articular erythema and warmth may also occur, sometimes accompanied by a low-grade fever.55 Spasticity may increase secondary to the NHO development.53 Reduction of hip joint movement and spasticity may lead to loss of an adequate sitting position,51 pressure sores, and related pain complaints52 and may also compromise transfers and activities of daily living. Although not commonly reported in SCI patients, ectopic ossification has been associated with compression of vascular structures and nearby peripheral nerves.56,57,58,59,60,61 The relatively low incidence of neuropathies found in SCI patients may be due to the sensory loss in (complete) SCI patients, so that they will not experience painful paraesthesias associated with nerve compression. Moreover, progression of NHO sufficient to compress nerves and nearby vascular structures and thereby causing clinical symptoms may result in ankylosis prior to possible neurovascular compression.


NHO originates in the connective tissues and may be contiguous with the skeleton, but does not involve the periosteum. When near a joint, it leaves the joint space and capsule preserved.34,35,36,48,62 Muscle fibres are not primarily involved in the process, but can be incorporated in or compressed by the fibrosing and calcifying soft tissues leading to local muscle necrosis.8,34,48

NHO begins as an area of oedematous, inflammatory reaction coinciding with an increased bloodflow in the affected soft-tissues.48 First, an exsudative cellular infiltration is seen, then fibroblastic proliferation occurs followed by osteoid formation, and subsequent deposition of bone matrix. Primitive osteoid is deposited as small masses within an area of fibroblastic mesenchymal reaction early within the first 2 weeks at first in the periphery. Osteoblasts produce tropocollagen, which polymerizes to form collagen, and secrete alkaline phosphatase (AP). The AP lyses pyrophosphate, a compound that prevents calcium deposition. Thus, by inactivating the pyrophosphate near the developing ectopic bone matrix, AP allows calcium to precipitate and the bone matrix to mineralize.63,64,65

The mineralization process of the soft tissues consists of an amorphous calcium phosphate phase, which is gradually replaced by enlarging hydroxyapatite crystals.48 The centripetal pattern of maturation that is seen in the following weeks is the basis of the zone phenomenon described by Ackerman.66 The zone phenomenon is characterized by a thin outer zone in the surrounding muscle that encloses a broader intermediate zone. In the intermediate zone, areas of immature bone are lined by osteoblasts, while in the outer margins of this zone mature bone forming a well-demarcated outer trabecular rim is already present. The intermediate zone surrounds the central zone that consists of an undifferentiated highly cellular proliferation of fibroblasts with haemorrhage and muscle necrosis. As the lesion matures, the peripheral rim of the intermediate zone becomes radiographically opaque due to progressive mineralization.67,68,69 The entire sequence of bone maturation is usually completed within 6–18 months.10,35,52,70 Mature NHO resembles normal bone, both histologically and radiologically.71,72 and consists of cancellous bone with Haversian canals, cortex, blood vessels and bone marrow, although with a minor amount of hematopoesis.34,36,39,48,73

According to Chalmers et al74 three conditions must be met for the formation of ectopic ossification: the presence of osteogenic percursor cells, an inducing agent, and a permissive environment. Although the precise causal mechanism for NHO is still unknown, humoral, neural and local factors probably all play a role in its pathophysiology (Figure 1). There is either a migration of distant mesenchymal cells to the area involved, with subsequent transformation of these cells into osteoblasts, or a transformation of the local mesenchymal cells directly into osteoblasts.52,63,75,76,77 Whether these cells migrate at random or in response to some chemotactic factor is still not known, but the importance of several factors has been suggested in the transformation of mesenchymal cells into osteoblasts.77,78

Figure 1

Visual approach to the pathophysiology of NHO in SCI patients. OAC: oral anti-coagulant. DVT: deep venous thrombosis

Humoral factors

Recent work with the serum of traumatic brain injured (TBI) and SCI patients seems to indicate that humoral mechanisms may be involved.79,80 In the study of Binder,79 the serum of a TBI patient increased the osteoblast growth factor activity in foetal rats. Kurer et al80 incubated sera from SCI patients with and without NHO 4–7 months post injury and sera from healthy control subjects with human osteoblasts in tissue culture. An increase in osteoblast stimulating factors was found only in the SCI groups and the activity was more pronounced in the group of SCI patients with NHO compared to patients without NHO. Renfree et al26 incubated sera from SCI and TBI patients throughout the first 12 weeks post-injury with osteoblasts from foetal rats. They observed a significant rise in serum mitogenic activity during the period after the injury in both patient groups. However, no significant differences were seen when patients who developed NHO were compared to other patients and healthy control subjects. Because their findings did not support the existence of a humoral factor that directly stimulates osteoblast proliferation within the first 12 weeks post injury, Renfree et al26 hypothesized that the rise in mitogenic activity seen in their patients may indirectly play a role in the bone inductive process.

Although humoral factors may play a role in the osteo-inductive process their origin and their biological characteristics have not actually been identified in SCI patients. Yet, in experimental studies concerning the in vitro induction of ectopic bone, an osteo-inductive protein released from demineralized bone tissue could be identified.81 This factor was called bone morphogenic protein (BMP).77,82,83,84 It is, therefore, possible that bone resorption and collagen degradation in acute SCI patients may well release (still unidentified) osteo-inductive factors.85

Neuro-immunological factors

The neural influence on NHO development cannot be disregarded taking into account its high incidence in neurologic disorders and the confinement of the NHO to the body regions with neurologic deficits. Dejerine1 was one of the first to suggest that damage to the intermedio-lateral sympathetic columns of the traumatized spinal cord might predispose to NHO through autonomic dysregulation. Secondary to an altered balance within the autonomic nervous system, a diversity of metabolic and vascular changes may occur.1,3,36,46,48,73,86 Indeed, several studies have shown that the initial stage of NHO is characterized by local microvascular alterations such as an increased vascularity, venous haemostasis and arterio-venous shunting in the involved tissues.36,48,87 These modifications in the blood perfusion and oxygen levels of the soft tissues might play a critical role in the formation of NHO,36,87,88 although it remains unclear whether these changes are secondary to or a causal factor in the NHO. Whether a disruption of the neuro-immunological pathways could result in an abnormal balance between osteoblast and osteoclasts and the subsequent induction of NHO is also still hypothetical.89 Yet the presence of interstitial oedema by itself, whether due to autonomic dysregulation,1 hypersensitivity, or hypoproteinemia6 may add to a permissive environment by facilitating pathological calcification of the osteoid.

Local factors

The local factors that may predispose to NHO are venous thrombosis or haemostasis, (local) infection, decubitus ulcers and (micro) trauma. These factors may lead to tissue damage and subsequent inflammatory reactions causing oedema and tissue hypoxia12 and may predispose to ectopic bone formation either by providing a permissive environment or by releasing humoral factors through the inflammatory process. In animal studies it has been suggested that eg prostaglandin E2 (PGE2) and interleukin-1 can induce a dose dependent increase in the subperiostal lamellar bone formation90 and that subcutaneous injections of PGE2 in growing rats can induce heterotopic bone formation.91,92 Measurement of 24-h PGE in SCI patients with NHO showed abnormal 24-h PGE2 urinary excretion as long as the bone-scan had not stabilized.27 However, the mechanism by which prostaglandins may induce ectopic bone formation in SCI patients remains unclear and there are well-known difficulties in the interpretation of PGE2 urinary excretion measurements in men presenting with a positive urinary sperm count or in patients with lower urinary tract infections. Both groups account for a substantial amount of the SCI population.

Risk factors

Several risk factors have been associated with NHO. In general, no association was found between NHO and race or gender,13,19 although in some studies a slightly higher incidence has been suggested for (young) male patients.10,13,14,17,24,47 A genetic predisposition for NHO based on human lymphocyte antigen (HLA)-typing has also been suggested. The human leukocyte antigen system (HLA) consists of a series of glycoprotein molecules that appear on the surface of virtually all nucleated cells. The major histocompatibility complex (MHC) is located on the short arm of the sixth chromosome and regulates a large and complex portion of the body's immune system and possibly other aspects of cell proliferation. The MHC contains a number of loci, more specifically the classic HLA-antigens (HLA-A, HLA-B, and HLA-C).93 Some authors have suggested an association between HLA B18 and HLA B27 on the one hand and NHO on the other hand,94,95,96 whereas others could not corroborate this association.93,97,98,99

The degree of completeness of SCI seems to be more important than the level of the lesion. Although Catz et al37 did not find a relationship between radiologically diagnosed NHO and the severity of the motor deficits, other authors have reported that complete transverse SCI is more commonly associated with NHO than incomplete SCI with relative risks (RR) reported between 2.0–4.2.1,13,14,19,21,22,24,88 Also, NHO is less frequently reported (<5%) in patients with lumbosacral or conus-cauda lesions, which regain or retain ambulation.88

Other clinical factors associated with NHO are the presence of pressure sores,6,21,22,24,30,47 urinary tract infections or renal stones,3,4,6,24,100 deep venous thrombosis (DVT),24 severe spasticity,22 and (micro) trauma. An area of soft tissue damage due to pressure ulceration with subsequent oedema may predispose to the development of ectopic ossification.101 On the other hand, pressure sores may occur secondary to NHO due to a decrease in eg hip range of motion that affects sitting position and alters pressure patterns. As a result, body weight is unequally distributed among the tubera and pressure ulceration may evolve, mostly contralateral to the NHO affected side.11

An infected urinary tract could serve as a source of antigenic material precipitating an immune response that triggers subsequent NHO.89 On the other hand, it may be that demineralization of bone accompanied by a loss of calcium and a subsequent loss of collagen as is seen in the acute phase of SCI102,103 is associated with an increased risk of developing both urinary tract stones, osteoporosis and NHO.3,4,17,100 As yet, the conclusion seems justified that the relatively high incidence of urinary tract infection and stone formation in SCI patients with NHO is not well understood from a pathophysiological perspective.21,22

Patients in the acute phase of traumatic SCI are known to be hypercoagulable and at risk of developing thromboembolic complications. In several studies an association was found between DVT and NHO, with RR reported between 1.8 and 2.0 for patients with DVT compared to patients without DVT. Colachis et al25 found a 5.3% co-incidence of DVT and NHO. Although the authors routinely screened all SCI patients on admission for DVT, they did not routinely screen for NHO at the same time and hence, there may have been an underestimation of the real incidence of NHO in this study. In all cases the DVT was diagnosed prior to the NHO and the NHO activity was present at the same side of the body. Although these findings suggest that DVT may be a possible risk factor for NHO, Perkash et al104 emphasized in their report of three chronic SCI patients with acute NHO the possibility of a secondary hypercoagulable state. They reported that the NHO activity correlated well with the increased coagulation parameters. As the NHO activity decreased, the coagulation parameters returned to near baseline values suggesting that NHO may alter blood coagulation and thereby predispose to DVT. Another possible mechanism by which NHO may predispose to DVT is a compression of vascular structures by local oedema as well as by the expanding ectopic bone mass.56,57,59,61,105,106 As a consequence, it can also be concluded that the precise pathophysiological relationship between DVT and NHO has yet to be established.

Controversy also exists regarding the possible association between NHO and spasticity. In some studies NHO is more commonly seen in SCI patients with spasticity and more extensively in those with severe spasticity (RR 0.17–2.0).21,22,30 Moreover, ectopic ossification seems to be rare in flaccid limbs or in limbs not affected by spasticity.17,21,52 Although such observations may suggest that spasticity predisposes to the development of ectopic ossification, the direction of this putative causality may easily be reversed such that a developing ectopic mass leads to an increase in spasticity.6,7,10,14

As for the role of (micro) trauma, mechanical stress to the musculotendinous apparatus may arise either from vigorous passive exercises9,17,46 or from loss of mobility and muscle imbalance causing peak pressure on soft tissue areas. Mechanical stress causes local micro-trauma that may induce ossification either indirectly through an inflammatory response or directly by releasing osteoblast-stimulating factors. Results from several case series revealed that the time-interval between the SCI and the beginning of passive movement exercises plays a vital role in the risk of developing NHO.6,9,51,107 In the study of Daud,107 clinically apparent NHO only occurred in SCI patients in whom the start of passive motion exercises was delayed until 7 or more days after the SCI. These results were supported by animal studies.108,109 Studies performed by Izumi110 and Michelson108,109 demonstrated that heterotopic bone could be produced in rabbits by forced passive movements in paralytic limbs that had been immobilized for a certain period. It is, therefore, tempting to speculate that (forced) passive movements following a period of immobilization may easily result in shear and tear of soft tissues leading to an increased risk of developing NHO.111,112

In conclusion, apart from the existence and completeness of SCI and the probable role of (micro) trauma, the reports of other possible risk factors and their presumed causal relationship with NHO are still inconclusive.


NHO is primarily diagnosed based on clinical signs and likelihood. The early symptoms must be differentiated from arthritis,113 thrombophlebitis, DVT, cellulitis, soft-tissue haematoma, complex regional pain syndrome (CRPS),114 and soft tissue tumour.8,35,36,105,115,116,117,118 Elevated serum alkaline phosphatase (SAP) levels may be of value in differentiating early NHO from other inflammations, as SAP may be markedly elevated during active osteogenesis.16 Ultrasonography can be used for the early identification of clinically suspected NHO and for differentiating NHO from DVT, a developing pressure sore, infection, or tumor.60,65,69,112,119 The use of phlebography to differentiate between NHO and DVT can be misleading. A large mass of ectopic bone can distort and compress vascular structures, causing venographic findings that mimic venous thrombosis.60,61,106 In order to differentiate between NHO and arthritis due to rheumatic disease, synovial fluid analyses can be performed. In contrast with arthritis due to rheumatic disease, synovial fluid analysis in NHO reveals a low white blood cell count, high protein levels, low viscosity and no crystals.39,48,113,120

Laboratory examinations

It has been shown that routine blood chemistry, eg the determination of isolated urinary and serum calcium, is of little value in the diagnosis and monitoring of NHO.16,48,65,72,100,121,122,123 Also an elevated erythrocyte sedimentation rate may reflect the initial ‘inflammatory’ phase of NHO, but is very aspecific.

The SAP consists of a series of iso-enzymes which are sensitive, but non-specific indicators of heterotopic ossification. They are found in several human tissues including the skeleton, the liver, the intestinal mucosa, and the placenta.64 The various iso-enzymes can be separated by electrophoresis. Electrophoretical studies performed with the sera of NHO patients revealed that elevated SAP levels reflect the activity of the ossification process.16,116,124 When new bone is actively deposited, the SAP levels are elevated. As soon as the ossification has stopped, the enzyme levels return to normal.16,48,70,72,125 In general, SAP levels start to rise on average 7 weeks before the first clinical signs of NHO become apparent, exceed normal levels 1 week later and reach peak levels 3 weeks after the appearance of the first clinical signs.65,70 Thereafter, the SAP levels gradually decline to reach normal values at about 5 months post onset. However, extensive bone formation may lead to prolonged elevation of SAP levels,39,48 whereas a minor amount of bone formation may not lead to SAP elevation at all. Normalization of the SAP levels does not constitute adequate proof of stabilization of the osteogenic process45,48,49,52,62 nor does the height of the SAP levels accurately correlate with either the peak activity in the bone formation or the number or amount of NHO lesions.100 Therefore, SAP levels are generally considered of limited value for judging NHO maturity, as well as for detecting possible recurrence or reactivation. Nonetheless, SAP levels may play a role in diagnosing NHO, since the persistent elevation of both inorganic phosphate and SAP levels increases the likelihood of active heterotopic bone formation.122

The determination of urinary collagen metabolite excretion has also been advocated in SCI patients with NHO. Normally, the urinary excretion of collagen related glycosides is an indication of the tissue origin of the collagen being currently degraded. A degradation of bone collagen will produce a large increase in the excretion of gal-hydroxylysine and a smaller increase in the glu-gal hydroxylysine excretion. The reverse will be true in the case of skin collagen degradation as seen in decubitus.100 In SCI patients with NHO the gal-hydroxylysine excretion in urine was found to be higher than in SCI patients with NHO, and did not return to control values until the bone turnover had stabilized.

Also the urinary concentration of hydroxyproline, which is another collagen metabolite, was found to parallel the level of SAP in SCI patients with NHO.72,48 The peak in the hydroxyproline excretion is related to a specific polypeptide fraction that reflects the collagen degradation.48,122 Yet, the urinary hydroxyproline levels appear to be elevated in nearly all tetra en paraplegic SCI patients, which makes it difficult to differentiate between the general influence of SCI and the specific influence of bone formation in patients with early NHO development. Moreover, although urine hydroxyproline levels are associated with SAP levels, they are unreliable parameters in determining NHO maturation.48

Longitudinal studies are necessary to determine the precise temporal relationship between an increase in the characteristic urinary glycoside excretion and the appearance of clinical signs of bone formation. Until now, measurements of collagen metabolites derived from bone, connective tissue, or muscles have been abandoned, because of their unspecificity and methodological difficulty.36

Radiological examination

In the early stages of NHO, the bone formation mainly consists of osteoid that shows a high uptake of osteotropic radionuclides through which it is readily detectable by three-phase 99m Technetium bone scanning.15,16,28,39,70,126,127,128,129,130,131,132 The first phase of the three-phase bone scan is the period immediately after the intravenous injection of the radionuclides and detects areas of increased blood blow, which is an early indicator of the inflammation process (the dynamic blood flow phase). The second phase (the static blood pool phase), identifies areas of increased blood pooling several minutes after the injection. The third phase (the static bone phase) determines the degree of osseous uptake of the labelled radionuclides several hours after the injection. The blood flow and blood pool phases of the bone scan are able to detect NHO as early as 2.5 weeks after SCI and are followed by a positive static bone phase 1–4 weeks later.28,129 Bone scans return to normal as the NHO matures usually within 6–18 months after its first clinical signs.70 Compared to plain radiography, bone scanning is a more sensitive diagnostic test for early NHO, but radiography is more specific. A disadvantage of the three-phase bone scan is its low specificity leading to potential difficulty in discriminating NHO from other inflammatory, traumatic, or degenerative processes of the skeleton, eg fracture, bone tumor, metastasis, or osteomyelitis which all show increased osteoblastic activity and thereby increased uptake of osteotropic radionuclides.126,127,132,133,134 Moreover, it requires expensive specialist equipment and the use of ionising radiation. Yet bone scanning may reach a fair specificity once clinical signs and likelihood have given rise to reasonable suspicion of NHO.28 In monitoring NHO maturation, the three-phase bone scan seems the most sensitive tool and currently the ‘golden standard’.49,126,129,132 Nonetheless, the criteria for maturity rating on the bone scans remains a topic of discussion. Whether a qualitative assessment eg a continuous decrease in the uptake or a steady state in the radionuclide accumulation, or a quantitative assessment such as specific uptake ratios should be considered as the best maturity index remains unclear.

The sonographic diagnosis of NHO depends on the age of the lesion, the rate of bone formation and the degree of mineralization.133 The first finding on ultra-sound (US) examination of a focal, elongated hypoechoic mass is unspecific and is also seen in muscle tears, abscess, and soft tissue tumor. The muscle fibres and soft tissues surrounding the lesion may appear compressed, but the interface is smooth and there is no evidence of invasion. Thereafter, the development of a centripetal pattern of maturation can be seen. Initially, the intermediate zone contains foci of echodense islands and will not be uniformly reflective. Later, the foci of echodense islands rapidly become confluent68,69,135 and the complete zone phenomena can be seen sonographically. As the NHO matures, the peripheral rim of the intermediate zone becomes more reflective on US due to increased mineralization67,68,69 and 4–6 weeks after the first clinical signs the NHO behaves like corticated bone. At that time, the US beam is totally reflected and the NHO can also be seen radiographically.133,69 Mechanical forces can modify the appearance of the zone phenomena. Therefore, the sensitivity and specificity of US for diagnosing NHO strongly depend on the experience of the radiologist. Serial sonography allows differentiation from muscle tears, soft tissue haematoma, abscess, thrombosis and soft tissue tumor.67,68,119,135,136 Sonography has the advantage of the possibility of bedside application, is relatively cheap, and requires no radiation.

The earliest radiographic sign of NHO is an increased density of the peri-articular soft tissues due to oedema.39,47,48 Gradually, the image shows flocculent densities as calcium precipitates. The maturation process proceeds rapidly with increased delineation of the soft tissue mass and the formation of bony cortex and trabeculations. The skeleton underlying the NHO may show variable degrees of demineralization, but the underlying bone configuration and the joint surfaces remain unaffected.18 NHO will become evident on plain radiography upon accumulation of minerals about 2–6 weeks after the three-phase bone scan first becomes positive.70,129,137 In several studies radiographic signs of NHO were found on average 1–10 weeks after the first clinical signs.19,36,47 Plain radiography may be positive even in asymptomatic patients as early as 4.5 weeks after the SCI. For monitoring NHO activity, plain radiography may be valuable as long as the X-rays show modification from one examination to the next.48 However, with a large block of ectopic bone, interpretation of the X-rays is difficult because immature elements may be obscured by mature bone.47 Therefore, radiography is generally considered of little value for judging NHO maturity,47 as well as for detecting possible recurrence or reactivation.49

CT scanning allows a better visualization of the ectopic bone in relation to the soft tissues.118,138 The CT scan may aid in the development of a surgical plan,139 especially three-dimensional tomography, eg in order to avoid areas of immature bone.140 MRI scanning is the best technique to define the extent of the soft tissue oedema, but has no role in the early diagnosis of NHO. The appearance of soft tissue swelling is aspecific and the lack of signal from calcification prevents differentiation from other inflammatory processes.118

The vascular changes seen immediately after SCI and more frequently in the case of concomitant NHO can be visualized by angiography. They consist of opening of the arteriovenous shunts, early venous return, and locally increased vascularity, which can easily be determined by angiography.48,141 However, the persistence or absence of venous return is not a valid indication of the degree of maturity. As ectopic bone matures, the pathological angiographic findings regress, in particular the vasodilatation and blood pooling without necessarily returning to normal.48,141 Complications of angiography are haematoma and subsequent scar tissue formation. As yet, angiography has no role in diagnosing or monitoring NHO.


Disodium etidronate (EHDP)

Once NHO has been diagnosed, patients can be treated with sodium etidronate, which is a disphosphonate. Diphosphonates are structural analogues of the naturally occurring inorganic pyrophosphates, which play an important role in the calcium-phosphate metabolism. Unlike the natural pyrophosphates, diphosphonates are almost completely stable to biochemical degradation. EHDP has been most widely used in patients with ectopic bone formation. In vitro EHDP strongly binds with hydroxyapatite, the main inorganic constituent of bone, thereby blocking the transformation of amorphous calcium phosphate into hydroxyapatite crystals, without inhibiting the formation of bone matrix.142,143,144,145 In animal studies and experimental models of ectopic ossification, it has also been demonstrated that EHDP can reduce the number of bone forming cells and alter their cell morphology.146,147 EDHP might also have an anti-inflammatory effect probably by affecting the production of interleukin-1.148

In SCI patients EDHP has mainly been used to block ectopic bone formation in the early phase after the clinical diagnosis of NHO. Stover62 treated patients on average 56 days post-SCI with EHDP 20 mg/kg/day for the first 2 weeks, followed by 10 mg/kg/day for the next 10 weeks. At the start of the EHDP treatment radiographic evidence of NHO was found in 25% of the placebo-group and in 22% of the EHDP group. After the treatment 41% of the placebo group and 30% of the EHDP group showed radiographic evidence of NHO. At its best EHDP may have slowed down the mineralization process. The authors suggested that for an optimal effect EHDP should be started at an earlier phase of NHO before significant amounts of ectopic bone have been formed. Finerman et al29 treated patients with clinical signs but without radiographic evidence of NHO according to Stover's62 treatment protocol on average 112 days post-SCI. At the end of the treatment period of 12 weeks, 6% of the EHDP group demonstrated NHO on X-rays, of which only 2% was clinically significant. In the placebo group, 27% demonstrated radiographic evidence of NHO, of which 13% was clinically significant. However, after cessation of treatment, the incidence of NHO increased in the EHDP group, although the lesions were less extensive than in the placebo group. Since the majority of NHO is radiographically diagnosed within the first 6 months after SCI,52,149,70 Garland et al20 stated that EHDP should be administered for at least a 6-month period. Although EHDP seems to block the mineralization process to a certain extent, it does not influence the formation of the osteoid matrix. After cessation of EHDP administration, the bone matrix already formed may undergo an uninhibited mineralization, the so-called ‘rebound ossification’.52,65

Some of the differences seen in therapeutic response to EHDP between patients may be due to variations in the bioavailability of EHDP after absorption by the gut. Because of the low solubility of EHDP in water, absorption in the intestinal tract can fluctuate from 1–10%. To avoid such variations and to improve the bioavailability of EHDP, Banovac et al137 administered EHDP intravenously in SCI patients with early clinical signs of NHO and a positive I and II phase on the bone scan on average 28 days post-SCI using high dosages over a prolonged time period: 300 mg for 3 days, followed by 20 mg/kg/day orally for 6 months. A prompt reduction in the peri-articular swelling was seen during the first 48 h. However, after the treatment period, no radiographic differences with regard to extent of NHO were found between the EHDP patients and a control group treated with 20 mg/kg/day orally for 2 weeks followed by 10 mg/kg/day for 6 months. In the subgroup without radiographic evidence of NHO (N=12), only two patients (15%) developed minimal radiographic evidence of NHO at the end of the follow-up period on average 11 months post onset of therapy. Banovac28,150 repeated his study in asymptomatic patients with a positive third phase on the three-phase bone scan. Only one patient developed NHO to a minimal extent.

Side effects of EHDP include hyperphosphatemia. In animal studies EHDP induced osteomalacia and spontaneous fractures have been reported. However, these complications have not been found in patients after total hip arthroplasty (THA) nor in SCI patients. Moreover, animal studies suggest that three to five times higher dosages are needed to induce such complications compared to the dosages currently used in SCI patients.151 The main reasons for patients to discontinue EHDP treatment are gastro-intestinal symptoms such as nausea, diarrhoea, and abdominal distress.

Non-steroidal anti-inflammatory drugs (NSAID)

The basic knowledge about the prophylactic treatment of ectopic bone formation by NSAID comes from animal studies and studies in patients undergoing THA.152,153,154,155,156,157 The effect of NSAID has been attributed to the inhibition of the inflammation process and the suppression of mesenchymal cell proliferation.52 Anti-inflammatory drugs inhibit the release of prostaglandins and related substances, thereby reducing the stimulation of the formative and resorptive phases of the bone remodelling.152,153,154,155,156,157 Moreover, NSAID are known to inhibit the differentiation of the mesenchymal cells into osteogenic cells and to reduce ectopic ossification in soft tissues in experimental conditions.

In the only randomised clinical trial (RCT) performed in SCI patients, Banovac et al158 allocated patients to either indomethacin 75 mg/day or placebo for 3 weeks from admission to a rehabilitation centre on average 20 days after their injury. There was a significantly higher incidence of NHO diagnosed by bone scan in the placebo group (65%) compared to the indomethacin treated group (25%). In the indomethacin treated patients with NHO the onset of symptoms was delayed on average 31.7 days compared to the placebo treated patients with NHO on average 19.2 days. Also, the inflammatory symptoms, ie swelling, erythema, and fever were less pronounced.

No side effects were reported, although gastro-intestinal complications eg dyspepsia and gastric ulceration or bleeding, and delayed fracture healing have been reported in other studies.152,153 Moreover indomethacin is also known to have an anti-thrombotic effect and may alter blood coagulation especially with the concomitant use of other anticoagulants to prevent deep vein thrombosis (DVT).

Other types of medication

Two other types of medication have been used in the treatment of NHO after SCI. Calcitonin has been used in an uncontrolled study with inconclusive results.159

Warfarin, which is an anti-coagulant that inhibits vitamin-K-dependent synthesis of calcium binding proteins such as osteocalcin has been used in a historic cohort of 227 SCI patients, of whom 33 had been treated with a low dose (prothrombin time 1.5–2) for the prevention of DVT.23 The authors did not observe clinically significant NHO as long as 10 years after SCI in the Warfarin treated group, whereas in the other patients clinically significant NHO developed in 15%. Although methodologically non-optimal, this study suggests a possible inhibiting effect of Warfarin on NHO, yet the nature of this effect remains to be elucidated.

Glucocorticoids, such as prednisolone can decrease the formation of bone and scar tissue in vitro. Animal studies showed that prednisolone decreased the inflammatory changes and fibrosis in rabbits caused by forceful manipulation after prolonged immobilization and therefore, also decreased ectopic bone formation.154 However, until now, glucocorticoids have not been used in the treatment of NHO in SCI patients.

Low-field irradiation

The exact mechanism by which irradiation affects NHO formation remains unknown, although it is suggested that irradiation may disrupt the differentiation process of pluripotent mesenchymal cells into osteoblasts.160,161,162,163,164 Irradiation may also decrease pain perception associated with the tissue inflammation surrounding the NHO, or it may induce the ablation of pain receptors.164 Sautter-Bihl et al165 treated 20 SCI patients with low field irradiation with 10 Gy in single fractions of 2 to 2.5 Gy. In 15 patients irradiation was given as a primary treatment to prevent NHO, whereas in seven patients it was used after operative NHO resection to prevent NHO recurrence. Four of the seven operated SCI patients, received a THA. During the follow-up period of 12 weeks, none of the 22 patients showed progression of their NHO. In the five patients followed for 44 months, the hip joint range of motion and sitting position did not deteriorate. In a second study, the same author166 treated 49 SCI (70 joints) with low field irradiation with 8 to 10 Gy in 2–25 single dose fractions. In 58 joints, irradiation was the primary treatment after the first clinical signs of NHO, whereas in 12 joints irradiation was performed after surgical resection of the NHO. In 71% no progression of the incipient ossification or post-operative recurrence of NHO was seen during a follow-up period of on average 11 months.

Complications of radiation therapy include delayed wound and bone healing, osteonecrosis,167 as well as the risk of developing radiation-induced sarcoma. Although these complications are not mentioned in relation to dosages less than 30 Gy delivered within a 3-week period,168,169 they certainly limit the use of radiation therapy as the primary prevention of NHO, when a relatively long life expectancy and the frequent involvement of multiple joints in SCI patients are taken into account.170

Surgical resection

The indications for surgical resection of NHO are improvement of joint motion, eg to achieve an adequate sitting or standing position,49,116,171 reduction of spasms, and prevention of pressure sores.172,173,174,175 However, operative resection of NHO has been associated with severe complications and poor outcome.171 These complications include deep (2–5%)174,175 or superficial infection (7–38%),45,49,174,175 post-operative haemorrhage (5–38%),45,173 and excessive intra-operative bleeding requiring (multiple) blood transfusions (9–83%).49,174,175,176 Moreover, intra- and post-operative fracturation of bone may occur in the case of severe osteoporosis. Stover174 has reported intra-operative fracturation of the femoral head in 5% and post-operative (spontaneous) fracturation in 3–16% of the SCI patients operated for NHO around the hip joint. Since other authors mention a higher percentage (29%)175 of SCI patients with femoral heads too brittle to preserve during operation, the real incidence of this problem may be even higher. NHO resection is also associated with a poor outcome due to a high recurrence rate. The post-operative recurrence of NHO depends on the definition used and the follow-up period. Radiographic signs of NHO recurrence have been mentioned in 82–100% of the operated SCI patients,45,49,173,174 although clinically significant NHO would develop in only 17–58% of the cases.10,45,49,173,174,176 It has been suggested that the recurrence after resection can be reduced if NHO is removed only once the first and second phase of the bone scan have normalized.10,52,115,129,132 However, such a maturity rating does not guarantee that NHO recurrence is unlikely. Garland et al49 reported that still 36% recurrence of clinically significant NHO was found in SCI patients with mature NHO on the bone scan. It was not so much the maturity that was associated with the risk of NHO recurrence, but rather the extent of the NHO preoperatively. There was also no correlation between NHO recurrence and the time post SCI or NHO onset.49,174,177 Recently McAuliffe et al170 and Freebourn177 reported three patients that had successfully undergone early resection of NHO, that is within 7–11 months post SCI. Earlier surgery may be warranted to prevent fibrous ankylosis, muscle contractures, and severe disuse osteoporosis to decrease the intra-operative fracturation rate. Hence, although many experts advise a time period of 12–18 months between NHO diagnosis and resection, no adequate studies are available to corroborate this advice or to give an indication of the most effective timing for the surgery.

Different prophylactic measures have been advocated to reduced the NHO recurrence post surgery. As for THA, both irradiation and indomethacin seem to be effective in reducing the occurrence of heterotropic ossification after THA,152,153,160,161,162,163 whereas EHDP has been abandoned due to its ineffectiveness on bone matrix formation and the high risk of ‘rebound’ ossification.142,146 In SCI patients EHDP,174 NSAID, irradiation,163,165,166,170,175 or a combination of treatments177,178,179 have all been recommended to reduce the NHO recurrence after surgery, however, no controlled studies are available.163,165,166,170,174,175,176,177,178,179

Primary prevention

Since the pathophysiology of NHO is poorly understood, the only preventive treatment possible is the early identification and adequate treatment of the putative risk factors. Through adequate nursing management the incidence of urinary tract infections, decubitus ulcers, and DVT may be reduced, and thus, the risk of developing NHO. Although in the early literature aggressive passive physiotherapy has been recommended to improve joint mobility and to counteract ankylosis in the case of contractures, it is now generally accepted that SCI patients profit from early, regular, and cautious joint mobilization to prevent more rigorous exercises with the risk of (micro) trauma to the peri-articular tissues becoming necessary. When gentle passive movements of the large peripheral joints are started and maintained from the day of the injury, the joint capsules are kept as supple as possible, muscles will not easily shorten and contractures will not readily develop, so that NHO may be prevented. This insight takes into account the highly ‘vascular’ state of the paralysed area and the concomitant use of anticoagulants (to prevent DVT), that may predispose to haematoma and secondary NHO, particularly during the rehabilitation phase after SCI.19

Various, more specific prophylactic measures have been proposed to prevent NHO, including the use of diphosphonates, NSAID, and more recently irradiation. The latter two methods have been successful to some degree in preventing heterotopic ossification eg after THA,142,152,153,160,161,162,163,180 but no controlled studies are available in SCI patients.


NHO is a frequent complication in SCI. Although the precise pathophysiology of NHO is still unknown, humoral,26,79,80,81,82,83,84,85 neural,1,3,6,36,46,48,73,86,87,88,89 and local factors12,27,90,91,92 probably all play a role in the formation of ectopic bone. Apart from the completeness of SCI1,13,14,19,21,22,24,88 and the possible role of (micro) trauma,6,9,17,46,51,107,108,109,110,111,112 reports of possible risk factors like DVT, pressure ulceration, infection, and spasticity6,7,10,14,21,22,24,30,47,89 and their presumed causal relationship with NHO are inconclusive. Studies on experimental bone induction have emphasized the role of neuro-immunological and humoral factors. The role of these factors is currently also studied in the pathophysiology of CRPS and shoulder–hand syndrome and seems to be a promising area of further research in the pathophysiology of NHO. Until now, most studies on experimental bone induction have been performed in animal models without SCI. To enhance our knowledge of the pathophysiology of NHO in SCI, research needs to be done in SCI patients as well as in animal models with SCI.

The diagnosis of NHO is primarily based on clinical signs and likelihood. It is the concurrence of persistent elevated SAP levels with characteristic clinical signs and, ultimately, positive radiographic findings that is essential for definitively diagnosing NHO.122 Sonography may also play a role in the early diagnosis of NHO, however its sensitivity and specificity greatly depend on the experience of the radiologist.67,68,69,133 The three-phase bone scanning is the most sensitive technique for diagnosing NHO and, although generally aspecific, may reach a fair degree of specificity once clinical signs and likelihood have given rise to reasonable clinical suspicion.28,49,70,126,129,132 For monitoring NHO activity, plain radiographs and elevated SAP levels may be valuable as long as they show modification from one examination to the next, but currently the three-phase bone scan seems to be the ‘golden standard’. CT and MRI scanning are mainly used to aid in the development of a surgical plan.118,138,140

Several studies have documented that early diagnosis is of crucial importance in the treatment of NHO.29,65 Waiting for late clinical or radiographic symptoms of NHO may allow a significant amount of ectopic bone to be deposited before treatment is initiated. Although EHDP inhibits the mineralization of bone, it does not influence the formation of osteoid.142,143,144,145 Hence, after cessation of EHDP, the bone matrix already formed may still undergo mineralization as soon as the drug has been cleared from the tissues, especially in the first 6 months after SCI, the so-called ‘rebound’ ossification.52,65 Therefore, in the treatment with diphosphonates prolonged administration up to 6 months seems to be of crucial importance.20,28,137,150 Yet, there is also some evidence that with the late application of EHDP, the severity of the lesions remains less compared to placebo treatment.29,62 More recently, NSAID and irradiation have been used in SCI to prevent NHO occurrence. The effects of both NSAID and irradiation have been attributed to the suppression of the differentiation process of the mesenchymal cells into osteoblasts.52,152,153,154,155,156,157,160,161,162,163,164 Irradiation may also decrease pain perception association with the soft tissue inflammatory reaction surrounding the NHO, or it may result in the ablation of pain receptors.164 NSAID may also exert an effect through the inhibition of the inflammatory response.152,153,154,155,156,157 However, the exact mechanisms by which NSAID or irradiation prevent NHO development remain unknown. Both treatments, however, do not influence the ectopic bone already formed, and are, therefore, effective only in the early stages of NHO.158,165,166 More controlled studies are needed to determine the effectiveness and complication rates of different (prophylactic) treatments for NHO in SCI patients.

The indication for surgery is to improve joint range of motion to achieve adequate posture, reduction in spasms, and prevention of pressure sores.49,116,171,175 Operative resection of NHO is generally associated with severe complications and poor outcome.45,49,71,173,174,175,176 It has been suggested that the recurrence of NHO after resection can be reduced, if the NHO is removed during a radionuclide steady stage, however, this policy is not supported by unequivocal clinical evidence.10,52,115,129,132 Although most authors advise a delay of 12 to 18 months between NHO diagnosis and surgical resection, until now no adequate controlled studies are available to corroborate such advice. Hence, there is no consensus on the most effective timing for surgery.

To date there is no satisfactory prevention of NHO and its prophylaxis is mainly based on the early identification and adequate treatment of putative risk factors, such as DVT, pressure ulcers, urinary tract infection and spasticity. Yet, there is ample empirical evidence that regular and cautious mobilization of the large peripheral joints should be recommended, from the day of the injury, to keep the joint capsules as supple as possible and to maintain adequate muscle length. With such an approach contractures will not readily develop and NHO related to traumatizing mobilization might be prevented.


  1. 1

    Dejerine A, Ceillier MA . Para-ostéo-arthropathies des paraplégiques par lésion médullaire: Étude clinique et radiographique Ann Méd 1918 5: 497–535

    Google Scholar 

  2. 2

    Heilbrun N, Kuhn WG . Erosive bone lesions and soft tissue ossifications associated with spinal cord injuries (Paraplegia) Radiology 1947 48: 579–593

    Google Scholar 

  3. 3

    Abramason AS . Bone disturbances in injuries to the spinal cord and cauda equina. Their prevention by ambulation J Bone Joint Surg 1948 30(A): 982–988

    Google Scholar 

  4. 4

    Liberson M . Soft tissue calcifications in cord lesions JAMA 1953 11: 1010–1013

    Google Scholar 

  5. 5

    Lodge T . Bone, joint and soft tissue changes following paraplegia Acta Radiol 1956 46: 435–445

    CAS  PubMed  Google Scholar 

  6. 6

    Damanski M . Heterotopic ossification in paraplegia: A clinical study J Bone Joint Surg 1961 43(B): 286–299

    Google Scholar 

  7. 7

    Hardy AG, Dickson JW . Pathological ossification in traumatic paraplegia J Bone Joint Surg 1963 45(B): 76–87

    Google Scholar 

  8. 8

    Freehafer AA, Yurick R, Mast WA . Para-articular ossification in spinal cord injury Med Serv J Can 1966 22: 471–478

    CAS  PubMed  Google Scholar 

  9. 9

    Silver JR . Heterotropic ossification. A clinical study of its possible relationship to trauma Paraplegia 1969 7: 220–230

    CAS  PubMed  Google Scholar 

  10. 10

    Wharton GW, Morgan TH . Ankylosis in the paralyzed patient J Bone Joint Surg 1970 52A: 105–112

    Google Scholar 

  11. 11

    Hassard GH . Heterotropic bone formation about the hip and unilateral decubitus ulcers in spinal cord injury Arch Phys Med Rehabil 1975 56: 355–358

    CAS  PubMed  Google Scholar 

  12. 12

    Stover SL, Hataway CJ, Zeiger HE . Heterotopic ossification in spinal cord injured patients Arch Phys Med Rehabil 1975 56: 199–204

    CAS  PubMed  Google Scholar 

  13. 13

    Scher AT . The incidence of ectopic bone formation in posttraumatic paraplegic patients of different racial groups Paraplegia 1976 14: 202–206

    CAS  PubMed  Google Scholar 

  14. 14

    Hernandez AM et al. The para-articular ossifications on our paraplegics and tetraplegics. A survey of 704 patients Paraplegia 1978 16: 272–275

    CAS  PubMed  Google Scholar 

  15. 15

    Prakash V, Lin MS, Perkash I . Detection of heterotopic calcification with 99m Tc Pyrophosphate in spinal cord injury patients Clin Nucl Med 1978 3: 167–169

    CAS  PubMed  Google Scholar 

  16. 16

    Furman R, Nicholas JJ, Jivoff L . Elevation of the serum alkaline phosphatase coincident with ectopic bone formation in paraplegic patients J Bone Joint Surg 1970 52(A): 1131–1137

    Google Scholar 

  17. 17

    Goldman J . Heterotopic ossification in spinal cord injuries Physiotherapy 1980 66: 219–220

    CAS  PubMed  Google Scholar 

  18. 18

    Blane CE, Perkash I . True heterotopic bone in the paralyzed patient Skeletal Radiol 1981 7: 21–25

    CAS  PubMed  Google Scholar 

  19. 19

    Knudsen L, Lundberg D, Ericsson G . Myositis ossificans circumscripta in para-/tetraplegics Scand J Rheum 1982 11: 27–31

    CAS  PubMed  Google Scholar 

  20. 20

    Garland DE, Alday B, Venos KG, Vogt JC . Diphosphonate treatment for heterotopic ossification in spinal cord injury patients Clin Orthop 1983 176: 197–200

    Google Scholar 

  21. 21

    Lal S, Hamilton BB, Heineman A, Betts HB . Risk factors for heterotopic ossification in spinal cord injury Arch Phys Med rehabilitation 1989 70: 387–390

    CAS  Google Scholar 

  22. 22

    Bravo-Payno P et al. Incidence and risk factors in the appearance of heterotopic ossification in spinal cord injury Paraplegia 1992 30: 740–745

    CAS  PubMed  Google Scholar 

  23. 23

    Buschbacher R et al. Warfarin in prevention of heterotopic ossification Am J Phys Med Rehabil 1992 71: 86–91

    CAS  PubMed  Google Scholar 

  24. 24

    Wittenberg RH, Peschke U, Bötel U . Heterotopic ossification after spinal cord injury; epidemiology and risk factors J Bone Joint Surg 1992 74(B): 215–218

    Google Scholar 

  25. 25

    Colachis SC, Clinchot DM . The association between deep venous thrombosis and heterotopic ossification in patients with acute traumatic spinal cord injury Paraplegia 1993 31: 507–512

    PubMed  PubMed Central  Google Scholar 

  26. 26

    Renfree KJ et al. Evaluation of serum osteoblast mitogenic activity in spinal cord and head injury patients with acute heterotopic ossification Spine 1994 19: 740–746

    CAS  PubMed  Google Scholar 

  27. 27

    Schurch B, Capaul M, Vallotton MB, Rossier AB . Prostaglandin E2 measurements: Their value in the early diagnosis of heterotopic ossification in spinal cord patients Arch Phys Med Rehabil 1997 78: 687–691

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Banovac K, Gonzalez F . Evaluation and management of heterotopic ossification in patients with spinal cord injury Spinal Cord 1997 35: 158–162

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Finerman GAM, Stover SL . Heterotopic ossification following hip replacement or spinal cord injury. Two clinical studies with EHDP Metabl Bone Dis Rel Res 1981 4/5: 337–342

    Google Scholar 

  30. 30

    Taly AB et al. Heterotopic ossification in non-traumatic myelopathies Spinal Cord 1999 37: 47–49

    CAS  PubMed  Google Scholar 

  31. 31

    Garland DE et al. Spinal cord insults and heterotopic ossification in the pediatric population Clin Orthop 1989 245: 303–310

    Google Scholar 

  32. 32

    Kluger G, Kochs A, Holthausen H . Heterotopic ossification in childhood and adolescence J Child Neurol 2000 15: 406–413

    CAS  PubMed  Google Scholar 

  33. 33

    Frankel HL . Traumatic quadriplegia with ectopic ossification Proc R Soc Med 1971 64: 222–223

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Miller LF, O'Neill CJ . Myositis ossificans in paraplegics J Bone Joint Surg 1949 31(A): 283–294

    Google Scholar 

  35. 35

    Venier LH, Dutunno JF . Heterotopic ossification in the paraplegic patient Arch Phys Med Rehabil 1971 52: 475–479

    CAS  PubMed  Google Scholar 

  36. 36

    Chantraine A, Minaire P . Para-osteo-arthropathies. A new theory and mode of treatment Scand J Rehabil Med 1981 13: 31–37

    CAS  PubMed  Google Scholar 

  37. 37

    Catz A et al. Is the appearance of peri-articular new bone formation related to local neurological disability? Paraplegia 1992 30: 361–365

    CAS  PubMed  Google Scholar 

  38. 38

    Lynch C, Point A, Weingarden SI . Heterotopic ossification in the hand of a patient with spinal cord injury Arch Phys Med Rehabil 1981 62: 291–293

    CAS  PubMed  Google Scholar 

  39. 39

    Nicholas JJ . Ectopic bone formation in patients with spinal cord injury Arch Phys Med Rehabil 1973 54: 354–359

    CAS  PubMed  Google Scholar 

  40. 40

    Cope R . Heterotopic ossification South Med J 1990 83: 1058–1064

    CAS  PubMed  Google Scholar 

  41. 41

    Bell RB, Wallace CJ, Swanson HA, Brownell AKW . Ossification of the lumbosacral dura and arachnoid following spinal cord trauma. Case report Paraplegia 1995 33: 543–546

    CAS  PubMed  Google Scholar 

  42. 42

    Good AE, Solsky MA, Gulati SM . Heterotopic ossification simulating acute arthritis. A patient with stable, chronic neurologic disease J Rheumatol 1983 10: 124–127

    CAS  PubMed  Google Scholar 

  43. 43

    Röhl K, Bosse A, Bötel U . Ungewöhnliche lokalisation einer heterotopen Ossifikation im bereich einer Laparotomienarbe Unfallchirung 1993 96: 662–664

    Google Scholar 

  44. 44

    Rubayai S, Ambe MK, Garland DE, Capen D . Heterotopic ossification as a complication of the staged total thigh muscles flap in spinal cord injury patients Annals Plast Surg 1992 29: 41–46

    Google Scholar 

  45. 45

    Hsu JD, Sakimura I, Stauffer ES . Heterotopic ossification around the hip joint in spinal cord injured patients Clin Orthop 1975 112: 165–169

    Google Scholar 

  46. 46

    Nechwatal E . Die Vermeidung Heterotoper Ossifikationen. Ein zentrales Problem bei der Fruehbehandlung von Querschnittgelaehmten Z Orthop 1972 110: 590–596

    CAS  PubMed  Google Scholar 

  47. 47

    Tibone J, Sakimura I, Nickel VL, Hsu JD . Heterotopic Ossification around the hip in spinal cord-injured patients. A long term follow-up study J Bone Joint Surg 1978 60(A): 769–775

    Google Scholar 

  48. 48

    Rossier AB et al. Current facts on para-osteo-arthropathy (POA) Paraplegia 1973 11: 36–78

    Google Scholar 

  49. 49

    Garland DE, Orwin JF . Resection of heterotopic ossification in patients with spinal cord injuries Clin Orthop 1989 242: 169–176

    Google Scholar 

  50. 50

    Kim SW, Wu SY, Kim RC . Computerized quantitative radionuclide assessment of heterotopic ossification in spinal cord patients Paraplegia 1992 30: 803–807

    CAS  PubMed  Google Scholar 

  51. 51

    Roche MB, Jostes FA . Ectopic bone deposits. A paraplegic complication Am J Surg 1948 75: 633–636

    CAS  PubMed  Google Scholar 

  52. 52

    Garland DE . A clinical perspective on common forms of acquired heterotopic ossification Clin Orthop 1991 263: 13–29

    Google Scholar 

  53. 53

    Blankenship LD, Strommen JA . 27-year-old man with a swollen leg Mayo Clin Proc 2000 75: 977–980

    CAS  PubMed  Google Scholar 

  54. 54

    Rosin AJ . Ectopic calcification around joint of paralyzed limbs in hemiplegia, diffuse brain damage and other diseases Ann Rheum Dis 1975 34: 499–505

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Tow AP, Kong KH . Prolonged fever and heterotopic ossification in a C4 tetraplegic patient. Case report Paraplegia 1995 33: 170–174

    CAS  PubMed  Google Scholar 

  56. 56

    Colachis SC, Clinchot DM, Venesy MD . Neurovascular complications of heterotopic ossification following spinal cord injury Paraplegia 1993 31: 51–57

    PubMed  Google Scholar 

  57. 57

    Varghese G, Williams K, Desmet A, Redford JB . Nonarticular complication of heterotopic ossification: a clinical review Arch Phys Med Rehabil 1991 72: 1009–1013

    CAS  PubMed  Google Scholar 

  58. 58

    Bradleigh LH et al. Deep venous thrombosis associated with heterotopic ossification Arch Phys Med Rehabil 1992 73: 293–294

    CAS  PubMed  Google Scholar 

  59. 59

    Haselkorn J, Britell CW, Cardenas DD . Diagnostic imaging of heterotopic ossification with coexistent deep-venous thrombosis in flaccid paraplegia Arch Phys Med Rehabil 1991 72: 227–229

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Yarkony GM, Lee MY, Green D, Roth EJ . Heterotopic ossification pseudophlebitis Am J Med 1989 87: 342–344

    CAS  PubMed  Google Scholar 

  61. 61

    Paul SM, Hammerman A, Stoddard E . Heterotopic ossification causing extrinsic compression of the deep venous system of the lower extremity (abstract) Arch Phys Med Rehabil 1988 69: 760

    Google Scholar 

  62. 62

    Stover SL, Niemann KMW, Miller III JM . Disodium Etidronate in the prevention of postoperative recurrence of heterotopic ossification in spinal cord injury patients J Bone Joint Surg 1976 58(A): 683–688

    Google Scholar 

  63. 63

    Jensen LL, Halar E, Little JW, Brooke MM . Neurogenic heterotopic ossification Am J Phys Med 1987 66: 351–363

    CAS  PubMed  Google Scholar 

  64. 64

    Bolger JT . Heterotopic bone formation and alkaline phosphate Arch Phys Med Rehabil 1975 56: 36–39

    CAS  PubMed  Google Scholar 

  65. 65

    Buschbacher R . Heterotopic ossification. A review Crit Rev Phys Rehabil Med 1992 4: 199–213

    Google Scholar 

  66. 66

    Ackerman LV . Extra osseous localized non-neoplastic bone and cartilage formation J Bone Joint Surg 1958 40(A): 279–298

    Google Scholar 

  67. 67

    Peck RJ, Metreweli C . Early myositis ossificans: a new echographic sign Clin Radiol 1988 39: 586–588

    CAS  PubMed  Google Scholar 

  68. 68

    Fornage BD, Eftekhari F . Sonographic diagnosis of myositis ossificans J Ultrasound Med 1989 8: 463–466

    CAS  PubMed  Google Scholar 

  69. 69

    Cassar-Pullincino VN et al. Sonographic diagnosis of heterotopic bone formation in spinal cord patients Paraplegia 1993 31: 40–50

    Google Scholar 

  70. 70

    Orzel JA, Rudd TG . Heterotopic bone formation. Clinical, laboratory, and imaging correlation J Nucl Med 1985 26: 125–132

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Nollen AJG . Effects of ethylhydroxydiphosphonate (EHDP) on heterotopic ossification Acta Orthop Scand 1986 57: 358–361

    CAS  PubMed  Google Scholar 

  72. 72

    Kewalramani LS, Orth MS . Ectopic ossification Am J Phys Med 1977 56: 99–121

    CAS  PubMed  Google Scholar 

  73. 73

    Benassy J, Mazabraud A, Diverres J . L'ostéogenésè neurogène Rev Chir Orthop 1963 49: 95–116

    CAS  PubMed  Google Scholar 

  74. 74

    Chalmers J, Gray DH, Rush J . Observations on the induction of bone in soft tissues J Bone Joint Surg 1975 57(B): 36–45

    Google Scholar 

  75. 75

    Buring K . On the origin of cells in heterotopic bone formation Clin Orthop 1975 110: 293–302

    Google Scholar 

  76. 76

    Wlodarski KH . Bone histogenesis mediated by nonsteogenic cells Clin Orthop 1991 272: 8–15

    Google Scholar 

  77. 77

    Puzas JE, Miller MD, Rossier RN . Pathologic bone formation Clin Orthop 1989 245: 259–281

    Google Scholar 

  78. 78

    Urist MR, Hay P, Dubuc F, Buring K . Osteogenic competence Clin Orthop 1969 64: 194–220

    CAS  PubMed  Google Scholar 

  79. 79

    Binder SM et al. Evidence for a humoral mechanism for enhanced osteogenesis after head injury J Bone Joint Surg 1990 72(A): 1144–1149

    Google Scholar 

  80. 80

    Kurer MHJ, Kohker MA, Dandona P . Human osteoblast stimulation by sera from paraplegic patients with heterotopic ossification Paraplegia 1992 30: 165–168

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Bridges JB, Pritchard JJ . Bone and cartilage induction in the rabbit J Anatomy 1958 92: 28–38

    CAS  Google Scholar 

  82. 82

    Ekelund A, Brosjö O, Nillson SS . Experimental induction of heterotopic bone Clin Orthop 1991 263: 102–112

    Google Scholar 

  83. 83

    Mohan S, Baylink DJ . Bone growth factors Clin Orthop 1991 263: 30–48

    Google Scholar 

  84. 84

    Sawyer JR, Myers MA, Rosier RN, Puzas JE . Heterotopic ossification. Clinical and cellular aspects Calcif Tissue Int 1991 49: 208–215

    CAS  PubMed  Google Scholar 

  85. 85

    Smith R, Triffit T . Bones in muscles. The problem of soft tissue ossification Q J Med 1986 61: 985–990

    CAS  PubMed  Google Scholar 

  86. 86

    Major P, Resnick D, Greenway G . Heterotopic ossification in paraplegia: A possible disturbance of the paravertebral venous plexus Radiology 1980 136: 797–799

    CAS  PubMed  Google Scholar 

  87. 87

    Lotta S, Scelsi L, Scelsi R . Microvascular changes in the lower extremities of paraplegics with heterotopic ossification Spinal Cord 2001 39: 595–598

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Abramson DJ, Kamberg S . Spondylitis, pathological ossification, and calcification associated with spinal cord injury J Bone Joint Surg 1949 31(A): 275–283

    Google Scholar 

  89. 89

    Rush PJ . The rheumatic manifestations of traumatic spinal cord injury Semin Arthritis Rheum 1989 19: 77–89

    CAS  PubMed  Google Scholar 

  90. 90

    High WB . Effects of orally administered prostaglandin E2 on cortical bone turn over in adult dogs; a histomorphometric study Bone 1987 8: 363–373

    CAS  PubMed  Google Scholar 

  91. 91

    Jee WSS, Ueno K, Deng YP, Woodbury DM . The effects of prostaglandin E2 in growing rats; increased metaphyseal hard tissue and cortico-endosteal bone formation Calcif Tissue Int 1985 37: 148–157

    CAS  PubMed  Google Scholar 

  92. 92

    Jee WSS et al. The role of bone cells in increasing metaphyseal hard tissue in rapidly growing rats treated with prostaglandin E2 Bone 1987 4: 171–178

    Google Scholar 

  93. 93

    Garland DE, Alday B, Venos KG . Heterotopic ossification and HLA antigens Arch Phys Med Rehabil 1984 65: 531–532

    CAS  PubMed  Google Scholar 

  94. 94

    Minaire P, Betuel H, Girard R, Pilonchery G . Neurologic injuries, paraosteoarthropathies, and human leukocyte antigens Arch Phys Med Rehabil 1980 61: 214–215

    CAS  PubMed  Google Scholar 

  95. 95

    Minaire P, Betuel H, Pilonchery G . Syteme HLA chez les blesses medullaires atteints de para osteo-arthropathies neurogenes Nouv Presse Med 1978 7: 3044

    CAS  PubMed  Google Scholar 

  96. 96

    Larson JM et al. Increased prevalence of HLA-B27 in patients with ectopic ossification following traumatic spinal cord injury Rheum Rehabil 1981 20: 193–197

    CAS  Google Scholar 

  97. 97

    Hunter T et al. Histocompatibility antigens in patients with spinal cord injury or cerebral damage complicated by heterotopic ossification Rheumatol Rehabil 1980 19: 97–99

    CAS  PubMed  Google Scholar 

  98. 98

    Weiss S et al. Histocompatibility (HLA) antigens in heterotopic ossification associated with neurological injury J Rheumatol 1979 6: 88–91

    CAS  PubMed  Google Scholar 

  99. 99

    Seignalet J et al. HLA and neurogenic paraosteoarthropathies Tissue antigens 1983 21: 268–269

    CAS  PubMed  Google Scholar 

  100. 100

    Rodriguez GP, Claus-Walker J, Kent MC, Garza HM . Collagen metabolite excretion as a predictor of bone- and skin-related complications in spinal cord injury Arch Phys Med Rehabil 1989 70: 442–444

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Heilbrun N, Kuhn WG . Erosive bone lesions and soft tissue ossifications associated with spinal cord injuries (Paraplegia) Radiology 1947 48: 579–593

    Google Scholar 

  102. 102

    Pilonchery G, Minaire P, Milan JJ, Revol A . Urinary elimination of glycosaminoglycans during the immobilisation osteoporosis of spinal cord injury patients Clin Orthop 1983 174: 230–235

    Google Scholar 

  103. 103

    Pietschmann P et al. Increased serum osteoclacin levels in patients with paraplegia Paraplegia 1992 30: 204–209

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Perkash A et al. Persistent hypercoagulation associated with heterotopic ossification in patients with spinal cord injury long after injury has occurred Paraplegia 1993 31: 653–659

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Orzel JA, Rudd TG, Nelp WB . Heterotopic bone formation and lower extremity swelling mimicking deep-venous disease J Nucl Med 1984 25: 1105–1107

    CAS  PubMed  Google Scholar 

  106. 106

    Gutknecht DR . Heterotopic ossification and deep venous thrombosis: Concurrence (?), bleeding complications, and caval interruption South Med J 1992 85: 1244–1246

    CAS  PubMed  Google Scholar 

  107. 107

    Daud O, Sett P, Burr RG, Silver JR . The relationship of heterotopic ossification to passive movements in paraplegic patients Disab Rehabil 1993 15: 114–118

    CAS  Google Scholar 

  108. 108

    Michelsson JE, Rauschning W . Pathogenesis of experimental heterotopic bone formation following temporary forcible exercising of immobilised limbs Clin Orthop Rel Res 1983 178: 265–272

    Google Scholar 

  109. 109

    Michelsson JE, Granroth G, Andersson LC . Myositis ossificans following forcible manipulation of the leg. A rabbit model for the study of heterotopic bone formation J Bone Joint Surg 1980 62(A): 811–815

    Google Scholar 

  110. 110

    Izumi K . Study of ectopic bone formation in experimental spinal cord injured rabbits Paraplegia 1983 21: 351–363

    CAS  PubMed  Google Scholar 

  111. 111

    Hossack DW, King A . Neurogenic heterotopic ossification Med J Aust 1967 7: 326–328

    Google Scholar 

  112. 112

    Snoecx M, De Muynck M, Van Laere M . Association between muscle trauma and heterotopic ossification in spinal cord injured patients. Reflections on causal relationships and diagnostic value of ultrasonography Paraplegia 1995 33: 464–468

    CAS  PubMed  Google Scholar 

  113. 113

    Yue CC, Regier A, Kushner I . Heterotopic ossification presenting as arthritis J Rheum 1985 12: 769–772

    CAS  PubMed  Google Scholar 

  114. 114

    Lefkoe TP, Cardenas DD . Reflex sympathetic dystrophy of the lower extremity in tetraplegia: case report Spinal Cord 1996 4: 239–242

    Google Scholar 

  115. 115

    Wharton G . Heterotopic ossification Clin Orthop 1975 112: 142–149

    Google Scholar 

  116. 116

    Couvée LMJ . Heterotropic ossification and the surgical treatment of serious contractures Paraplegia 1971 9: 89–93

    PubMed  Google Scholar 

  117. 117

    Yarkony GM, Bass LM, Keenan III V, Meyer PR . Contractures complicating spinal cord injury: Incidence and comparison between spinal cord center and general hospital acute car Paraplegia 1985 23: 265–271

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Laurin NR, Powe JE, Pavlovsky WF, Driedger AA . Multimodality imaging of early heterotopic bone formation Can Assoc Radiol J 1990 1: 93–95

    Google Scholar 

  119. 119

    Bodley R, Jamous A, Short D . Ultrasound in the early diagnosis of heterotopic ossification in patients with spinal injuries Paraplegia 1993 31: 500–506

    CAS  PubMed  Google Scholar 

  120. 120

    Baron M, Stern J, Lander P . Heterotopic ossification heralded by knee effusion J Rheum 1983 10: 961–964

    CAS  PubMed  Google Scholar 

  121. 121

    Kim SW et al. Serum alkaline phosphatase and inorganic phosphorus values in spinal cord injury patients with heterotopic ossification Paraplegia 1990 28: 441–447

    CAS  PubMed  Google Scholar 

  122. 122

    Chantraine A, Nusgens B, Lapiere CM . Biochemical analysis of heterotopic ossification in spinal cord injury patients Paraplegia 1995 33: 398–401

    CAS  PubMed  Google Scholar 

  123. 123

    Chantraine A, Very JM, Baud CA . A biophysical study of posttraumatic ectopic ossification. A case report Clin Orthop 1990 255: 289–292

    Google Scholar 

  124. 124

    Mead S, Cain HD, Kelly RE, Liebgold H . Periarticular calcification in paraplegics: attempted treatment with disodium edetate Paraplegia 1963 1: 62–68

    CAS  PubMed  Google Scholar 

  125. 125

    Nechwatal E . Early recognition of heterotopic calcifications by means of alkaline phosphatase Paraplegia 1973 11: 79–85

    CAS  PubMed  Google Scholar 

  126. 126

    Tanaka T et al. Quantitative assessment of para-osteo-arthropathy and its maturation on serial radionuclide bone images Radiology 1977 123: 217–221

    CAS  PubMed  Google Scholar 

  127. 127

    Suzuki Y, Hisada K, Takeda M . Demonstration of myositis ossificans by 99m Tc pyrophosphate bone scanning Radiology 1974 31: 663–664

    Google Scholar 

  128. 128

    Tyler JL, Derbekyan V, Lisbona R . Early diagnosis of myositis ossificans with Tc-99m diphosphonate imaging Clin Nucl Med 1984 9: 256–258

    CAS  PubMed  Google Scholar 

  129. 129

    Freed JH, Hahn H, Menter R, Dillon T . The use of three phase bone scan in the early diagnosis of heterotopic ossification and in the evaluation of Didronel therapy Paraplegia 1982 20: 208–216

    CAS  PubMed  Google Scholar 

  130. 130

    Drane WE . Myositis ossificans and the three-phase bone scan Am J Roentgenol 1983 142: 179–180

    Google Scholar 

  131. 131

    Nagaraj N, Elgazzar AH, Fernandez-Ulloa M . Heterotopic ossification mimicking infection. Scintigraphic evaluation Clin Nucl Med 1995 20: 763–766

    CAS  PubMed  Google Scholar 

  132. 132

    Muheim G, Donath A, Rossier AB . Serial scintigrams in the course of ectopic bone formation in paraplegic patients Am J Roentgenol 1973 118: 865–869

    CAS  Google Scholar 

  133. 133

    Thomas EA, Cassar-Pullicino VN, McCall IW . The role of ultrasound in the early diagnosis and management of heterotopic bone formation Clin Radiol 1991 43: 190–196

    CAS  PubMed  Google Scholar 

  134. 134

    Vento JA, Sziklas JJ, Spencer RP, Rosenberg RJ . Reactivation of Tc-99 MDP uptake in heterotopic bone Clin Nucl Med 1985 10: 206–207

    CAS  PubMed  Google Scholar 

  135. 135

    Kramer FL, Kurtz AB, Rubin C, Goldberg BB . Ultrasound appearance of myositis ossificans Skeletal Radiol 1979 4: 19–20

    CAS  PubMed  Google Scholar 

  136. 136

    Scola FH, Parzaile JR . Ultrasonographic diagnosis of heterotopic ossification mimicking deep vein thrombosis J Clin Ultrasound 1991 19: 55–57

    CAS  PubMed  Google Scholar 

  137. 137

    Banovac K, Gonzalez F, Wade N, Bowker JJ . Intravenous disodium etidronate therapy in spinal cord injury patients with heterotopic ossification Paraplegia 1993 31: 660–666

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Zeanah WR, Hudson TM . Myositis ossificans. Radiologic evaluation of two cases with diagnostic computed tomograms Clin Orthop 1982 168: 187–191

    Google Scholar 

  139. 139

    Amendola MA et al. Myositis ossificans circumscripta. Computer tomographic diagnosis Radiology 1983 149: 775–779

    CAS  PubMed  Google Scholar 

  140. 140

    Bressler EL, Marn CS, Gore RM, Hendrix RW . Evaluation of ectopic bone by CT Am J Roent 1987 148: 931–935

    CAS  Google Scholar 

  141. 141

    Yaghmai I . Myositis ossificans. Diagnostic value of arteriography Am J Roent 1977 128: 811–816

    CAS  Google Scholar 

  142. 142

    Lindholm TS, Bauer FCH, Rindell K . High doses of the diphosphonate EHDP for the prevention of heterotopic ossification. An experimental and clinical study Scand J Rheumatol 1987 18: 33–39

    Google Scholar 

  143. 143

    Russell RGG . Diphosphonates and polyphosphates in medicine Br J Hosp Med 1975 297–313

  144. 144

    Russell RGG, Fleish H . Pyrophosphate and diphosphonates in skeletal metabolism. Therapeutic, clinical and therapeutic aspects Clin Orthop Rel Res 1975 108: 241–263

    CAS  Google Scholar 

  145. 145

    Russell RGG, Smith R . Diphosphonates. Experimental and clinical aspects J Bone Joint Surg 1973 55(B): 66–86

    Google Scholar 

  146. 146

    Plasmans CM, Kuypers W, Slooff TJJH . The effect of Ethane-1-hydroxy-1, 1-disphosphonic acid (EHDP) on matric induced ectopic bone formation Clin Orthop 1978 132: 233–243

    CAS  Google Scholar 

  147. 147

    Hu HP et al. The effect of biphosphonate on induced heterotopic bone Clin Orthop 1991 272: 259–267

    Google Scholar 

  148. 148

    Mahay PR, Urist MR . Experimental heterotopic bone formation induced by bone morphogenic protein and recombinant human interleukin-1b Clin Orthop 1988 237: 236–244

    Google Scholar 

  149. 149

    Garland DE . Clinical observations on fracture and heterotopic ossification in the spinal cord and brain injured populations Clin Orthop 1988 233: 86–101

    Google Scholar 

  150. 150

    Banovac K . The effect of etidronate on late development of heterotopic ossification after spinal cord injury J Spinal Cord Med 2000 23: 40–44

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Flora et al. The long-term skeletal effects of EHDP in dogs Metab Bone Dis Rel Res 1981 4/5: 289–300

    Google Scholar 

  152. 152

    Kjaersgaard-Andersen P et al. Indomethacin for prevention of heterotopic ossification Acta Othop Scand 1993 64: 639–642

    CAS  Google Scholar 

  153. 153

    Kjaersgaard-Andersen P, Schmidt SA . Total hip arthroplasty. The role of anti-inflammatory medications in the prevention of heterotopic ossification Acta Orthop Scand 1990 263: 78–86

    Google Scholar 

  154. 154

    Ahrengart L, Lindgren U, Reinholt FP . Comparative study on the effects of radiation, indomethacin, prednisolone, and ethane-1-hydroxy-1,1-disphosphanate (EHDP) in the prevention of ectopic bone formation Clin Orthop 1988 229: 265–273

    CAS  Google Scholar 

  155. 155

    Nilsson OS, Bauer HCF, Brosjö O, Törnkvist H . Influence of indomethacin on induced heterotopic bone formation in rats. Importance of length of treatment and of age Clin Orthop 1986 207: 239–245

    CAS  Google Scholar 

  156. 156

    Törnkvist H, Nilsson OS, Bauer HCF, Lindholm TS . Experimentally induced heterotopic ossification in rats influenced by anti-inflammatory drugs Scand J Rheumatol 1983 12: 177–180

    PubMed  Google Scholar 

  157. 157

    Sudmann E, Bang G . Indomethacin induced inhibition of Haversian remodelling in rabbits Acta Orthop Scand 1979 50: 621–627

    CAS  PubMed  Google Scholar 

  158. 158

    Banovac K, Williams JM, Patrick LD, Haniff YM . Prevention of heterotopic ossification after spinal cord injury with indomethacin Spinal cord 2001 39: 370–374

    CAS  PubMed  Google Scholar 

  159. 159

    Naftchi NE, Viau AT, Sell GH, Lowman EW . Spinal cord injury: effect of thyrocalcitonin on periartricular bone formation in three subjects Arch Phys Med Rehabil 1979 60: 280–283

    CAS  PubMed  Google Scholar 

  160. 160

    Ayers DC, Pelligrini VD, Evarts CM . Prevention of heterotopic ossification in high-risk patients by radiation therapy Clin Orthop 1991 263: 87–93

    Google Scholar 

  161. 161

    Coventry MB, Scalon PW . The use of radiation to discourage ectopic bone. A nine-year study in surgery about the hip J Bone Joint Surg 1981 64(A): 201–208

    Google Scholar 

  162. 162

    Deflitch CJ, Stryker JA . Postoperative hip irradiation in prevention of heterotopic ossification. Causes of treatment failure Radiology 1993 188: 265–270

    CAS  PubMed  Google Scholar 

  163. 163

    Pelligrini VD, Gregoritch SJ . Preoperative irradiation for prevention of heterotopic ossification J Bone Joint Surg 1996 78(A): 870–881

    Google Scholar 

  164. 164

    Schaeffer MA, Sosner J . Heterotopic ossification: Treatment of established bone with radiation therapy Arch Phys Med Rehabil 1995 76: 284–286

    CAS  PubMed  Google Scholar 

  165. 165

    Sautter-Bihl ML et al. The radiotherapy of heterotopic ossification in paraplegics Strahlenther Onkol 1995 171: 454–459

    CAS  PubMed  Google Scholar 

  166. 166

    Sautter-Bihl ML, Hültenschmidt B, Liebermeister E, Nanassy A . Fractionated and single-dose radiotherapy for heterotopic bone formation in patients with spinal cord injury. A phase-I/II study Strahlenther Onkol 2001 177: 200–205

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Van Kuijk AA, Van Kuppevelt HJM, Van der Schaaf DB . Osteonecrosis after treatment for heterotopic ossification in spinal cord injury with the combination of surgery, irradiation, and an NSAID Spinal Cord 2000 38: 319–324

    CAS  PubMed  Google Scholar 

  168. 168

    Brady LW . Radiation induced sarcomas of bone Skel Radiol 1972 4: 72–78

    Google Scholar 

  169. 169

    Kim JH et al. Radiation induced soft tissue and bone sarcoma Radiology 1978 129: 501–508

    CAS  PubMed  Google Scholar 

  170. 170

    McAuliffe JA, Wolfson AH . Early excision of heterotopic ossification about the elbow followed by radiation therapy J Bone Joint Surg 1997 79(A): 749–755

    Google Scholar 

  171. 171

    Armstrong-Ressy CT, Weiss AR, Ebel A . Results of surgical treatment of extraosseous ossification in paraplegia New York State Med 1959 59: 2548–2553

    CAS  Google Scholar 

  172. 172

    Aanholt van PCTh, Martina JD, Eisma WHE . Ectopische botvorming, diagnostiek en behandeling NTvG 1991 9: 380–384

    Google Scholar 

  173. 173

    Stover SL, Hahn HR, Miller III JM . Disodium etidronate in the prevention of heterotopic ossification following spinal cord injury (preliminary report) Paraplegia 1976 14: 146–156

    CAS  PubMed  Google Scholar 

  174. 174

    Stover SL, Niemann KMW, Tulos J . Experience with surgical resection of heterotopic bone in spinal cord injury patients Clin Orthop 1991 263: 71–77

    Google Scholar 

  175. 175

    Meiners T, Abel R, Böhm V, Gerner HJ . Resection of heterotopic ossification of the hip in spinal cord injured patients Spin Cord 1997 35: 443–445

    CAS  Google Scholar 

  176. 176

    Gacon G, Deidier CH, Rhenter JL, Minaire P . Possibilités du traitement chirurgícal des para-ostéoarthropathies neurogènes. Étued critique de 70 cas opérés Rev Chir Orthop 1978 64: 373–390

    Google Scholar 

  177. 177

    Freebourn TM, Barber DB, Able AC . The treatment of immature heterotopic ossification in spinal cord injury with the combination surgery, radiation therapy and NSAID Spinal Cord 1999 37: 50–53

    CAS  PubMed  Google Scholar 

  178. 178

    Biering-Sørensen F, Tøndevold E . Indomethacine and disodium etidronate for the prevention of recurrence of heterotopic ossification after surgical resection Paraplegia 1993 31: 513–515

    PubMed  Google Scholar 

  179. 179

    Ellerin BE et al. Current therapy in the management of heterotopic ossification of the elbow: a review with case studies Am J Phys Med Rehabil 1999 78: 259–271

    CAS  PubMed  Google Scholar 

  180. 180

    Nilsson OS . Heterotopic ossification Acta Orthop Scand 1998 69: 103–106

    CAS  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to AA van Kuijk.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

van Kuijk, A., Geurts, A. & van Kuppevelt, H. Neurogenic heterotopic ossification in spinal cord injury. Spinal Cord 40, 313–326 (2002).

Download citation


  • neurogenic heterotopic ossification
  • spinal cord injury

Further reading


Quick links