REVIEW ARTICLE

Current concepts in the development of

heterotopic ossification
H. C. Pape,
S. Marsh,
J. R. Morley,
C. Krettek,
P. V. Giannoudis
From Hannover
Medical School,
Hannover, Germany
and St Jamess
University Hospital
and the University of
Leeds, Leeds,
England

H. C. Pape, MD, Professor

C. Krettek, Professor
Department of Trauma,
Hannover Medical School,
Unfallchirurgische Klinic,
Hannover 305625, Germany.

S. Marsh, MB, BS, House
Surgeon
Trauma & Orthopaedics, St
Jamess University Hospital,
Leeds, UK.

J. R. Morley, FRCS (Ed),
Lecturer

P. V. Giannoudis, MD, EEC
(Ortho), Professor
Trauma & Orthopaedics,
School of Medicine,
University of Leeds, St.
Jamess Hospital University
Hospital, Beckett Street,
Leeds LS9 7TF, UK.
Correspondence should be
sent to Professor P. V.
Giannoudis.
2004 British Editorial
Society of Bone and
Joint Surgery
doi:10.1302/0301-620X.86B6.
15356 $2.00
J Bone Joint Surg [Br]
2004;86-B:783-7.
VOL. 86-B, No. 6, AUGUST 2004

Heterotopic ossification can be defined as the

formation of bone in tissues which normally
exhibit no properties of ossification. It is characterised by the rapid development of calcified
bone in soft tissues. Ectopic bone can develop
from immature osteoid in a matter of weeks.
The development of heterotopic ossification
has been shown to be associated with many
predisposing factors including neurological
injury, both to the spinal cord and the brain,
major joint surgery and burns.1-4 Marked variation can occur in the incidence and location
of bone formed and in the resulting complications.
The first description of heterotopic ossification after neurological injury was by Dejerne
and Ceiller1 who detailed the clinical, anatomical and histological features of ectopic bone
formation in soldiers who sustained spinal
injuries during the First World War. Heterotopic ossification after traumatic brain injury
was first reported by Roberts2 who described
involvement of the elbow in patients with cerebral injury and a prolonged period of coma.
The incidence following brain injury has
been reported to vary between 11% and
22%.5,6 The most common joints to be
affected are the hip, elbow and shoulder. After
such injury an accelerated rate of fracture healing has also been reported with the formation
of exuberant callus at fracture sites.7,8
Since the original report of heterotopic ossification after traumatic brain injury,2 there
have been a number of papers describing the
incidence, location and management. This
review provides an analysis of the papers on
this topic published previously and discusses
the aetiology, pathophysiology and the current
concepts of treatment.

Heterotopic ossification
Aetiology. Although much has been written

about heterotopic ossification it is clear that as

yet there is no clearly defined mechanism for its
occurrence. It has a multi-factorial aetiology
with several risk factors identified which pre-

dispose to its formation. Trauma is a constant

feature and in the case of head injury, traumatic damage to the brain. Other general factors have been identified from studies of
patients undergoing total hip arthroplasty who
have developed heterotopic ossification (Table
I). It is uncertain whether these risk considerations play a significant role in patients with
head injuries.
Specific factors have been implicated in the
latter group of patients (Table II). Limb spasticity is associated with a greater risk of developing heterotopic ossification. Garland5 found
when studying patients with traumatic brain
injury that 89% of involved joints were in
spastic limbs, with the hip joint being most
commonly affected. Another related factor is
the decorticate and decerebrate postures which
may occur after such injury.9 The extent of
brain damage has also been linked to the formation of heterotopic bone. Gennarelli10 suggested that diffuse axonal injury may
predispose to the development of heterotopic
ossification more than focal brain injury, as
patients with the former injury tend to be
younger, may have a period of coma and often
develop limb spasticity. A long period of
immobilisation is also associated with the formation of heterotopic ossification.11 It thus
may occur after prolonged coma or the multiple long bone fractures which are often associated with a severe head injury.6
Many patients who suffer a head injury
require respiratory ventilation, sometimes to
assist in the control of intra-cranial pressure.
Ventilation is known to cause homeostatic
changes of systemic alkalosis which result in
the formation of heterotopic bone.12 The
changes in pH associated with alkalosis can
cause modification of the precipitation kinetics
of calcium and phosphate. Studies of the effect
of modifying the pH at fracture sites has
shown that as the local environment goes from
acidity to alkalinity more callus is deposited.12
There may also be a yet unidentified genetic
predisposition to the development of ossifica783

784

H. C. PAPE, S. MARSH, J. R. MORLEY, C. KRETTEK, P. V. GIANNOUDIS

Table I. Factors associated with the formation of heterotopic ossification after total
hip arthroplasty
Factor

Source

Male gender
Previous history of heterotopic ossification
Osteoarthritis with pre-existing heterotopic bone
Ankylosing spondylitis
Diffuse idiopathic skeletal hyperostosis

Ahrengart and Lindgren46

Ritter and Vaughan47
DeLee, Ferrari and Charnley48
Sundaram and Murphy49
Fahrer et al 50

Table II. Factors associated

ossification after head injury

with

heterotopic

Risk factor

Source

Spasticity of limbs
Decerebrate posture
Diffuse axonal injury
Prolonged immobilisation
Respiratory ventilation

Garland5
Flin et al9
Gennarelli10
Mielants et al11
Newman et al12

tion since it does not develop in all patients with head injuries.5
The location of heterotopic ossification after head injury.

Following head injury heterotopic bone tends to form in

para-articular sites. The most commonly affected joint is
the hip, then the shoulders, elbows and rarely the knee.13
Bone tends to be deposited anterolaterally, inferomedially
and posteriorly in contrast to after injury to the spinal cord
when ossification tends to occur in the anteromedial
plane.5,14
The distribution of ossification around the elbow is similar to that around the shoulder. In the elbow, it occurs most
commonly either anteriorly in the flexor muscles or posteriorly in the extensors. Of the joints affected by heterotopic
ossification after head injury, ankylosis is most likely to
occur in the elbow and it usually occurs posteriorly.13
Heterotopic ossification occurs rarely in the knee following
head injury. When present, the most common site is in the
inferomedial aspect of the distal femur, but it can occur in
any plane. In a study of 496 patients with head injury
heterotopic ossification was seen in three planes, medially,
laterally and posteriorly.13,14
Ankylosis of the knee is rare. However, the knee is the
second most common site for the formation of heterotopic
bone following a spinal cord injury.15
Clinical features. The development of heterotopic ossification may be detected in a number of ways. Clinical examination may reveal a swollen, warm painful joint. This is
often associated with a decreased range of movement and it
can be difficult initially to differentiate from infection, as
the patient often has an associated pyrexia.6,13,14
Accelerated bone healing and heterotopic ossification after
head injury. In the patient who has sustained a head injury

and an associated fracture, there is often the clinical perception that fracture heals more rapidly. Clinical and radiological findings of accelerated bone healing and the
formation of more callus have been reported.7,8

There is no universal agreement about this concept since

other studies have shown that fractures in these patients
heal at the same rate and frequency as similar injuries in
patients without a head injury.16-20 It has been proposed
that the accelerated fracture healing observed after head
injury is actually a variant of heterotopic ossification.16,21
Some histological evidence to support this is derived from
the unusual pattern of callus formation seen in patients
with head injuries.21 Such callus first matures peripherally
whereas in normal fracture callus maturation initially
occurs centrally. As yet the question of whether a head
injury genuinely results in accelerated fracture healing
rather than a form of heterotopic ossification occurring at
the fracture site remains unanswered.
Biochemical changes. Biochemical changes may also be
useful in making the diagnosis. The serum alkaline phosphatase level reflects osteoblastic activity and an increase
has been demonstrated up to seven weeks before the clinical
symptoms of heterotopic ossification become evident.14,22
However, it can be difficult to interpret the levels of serum
alkaline phosphatase following injury if the patient has
concomitant fractures or liver disease, as these conditions
will also produce an increase in levels, but it is a minimally
invasive, inexpensive screening tool to monitor the formation of heterotopic ossification.
Another useful biochemical assay in the assessment of
the development of heterotopic ossification is the excretion
of prostaglandin E2 (PGE2) in the urine. In a study of the
24-hour urinary excretion of PGE2 after acute spinal cord
injury, eight of 44 patients developed heterotopic ossification and an increase in the excretion of PGE2.15 The
increase only continued until the ossification reached maturity. The 24-hour urinary excretion of PGE2 can be a valuable indicator in the early diagnosis of heterotopic
ossification.
Radiological changes. Plain radiographs can confirm the
presence of heterotopic ossification although changes may
not be evident during the initial phases. It may take up to
six weeks for ossification to be evident on a radiograph and
it is not generally a confirmatory investigation until more
than two months after injury.14 However, radiographs are
an inexpensive and simple method of assessing the extent of
ossification.
For the early detection of ossification and assessment of
its maturity, plain radiographs have been largely superseded by three-phase bone scintigraphy6,13,14,22 using
99m
Tc-methylene disphosphonate. Flow studies and blood
THE JOURNAL OF BONE AND JOINT SURGERY

CURRENT CONCEPTS IN THE DEVELOPMENT OF HETEROTOPIC OSSIFICATION

Traumatic brain injury

Direct trauma (eg fracture)

Release of systemic factors

Bone morphogenetic proteins
Growth hormone (prolactin)
Growth factor type-1
Basic fibroblast growth factor
Other as yet unidentified factors

Release of
local stimulating factors

Local environmental changes

pH changes: alkalosis
Tissue hypoxia

Stimulation of
mesenchymal stem cells
to differentiate

Osteoblast formation

Heterotopic ossification

Fig. 1
Diagram demonstrating the potential mechanism for the interaction of
systemic and local factors on mesenchymal stem cells resulting in their
differentiation into osteoblasts and the formation of heterotopic ossification.

pool images are the first two phases and allow early detection of incipient ossification at approximately 2.5 weeks.
Phase three involves a delayed scintigram, with positive
findings at about one week after the first two phases. Bone
scans return to normal after approximately 12 months, the
activity peaking at around two months and then decreasing
progressively. However, the scan may remain positive even
when the ossification is mature.13,14,22

Pathophysiology of heterotopic ossification after

head injury
The ectopic bone is thought to originate from mesenchymal
stem cells which lie dormant in soft tissues and differentiate
into osteogenic cells under appropriate stimuli. Three conditions are thought to be needed for heterotopic ossification
to occur,23 namely a stimulating event, progenitor or mesenchymal stem cells and an environment that allows osteogenesis. It has been suggested that in some situations,
particularly after neurological injury, there is a neurogenic
factor contributing to the development of heterotopic ossification, but the mechanism for this is poorly understood.8,24 The conditions and stimulating factors involved
VOL. 86-B, No. 6, AUGUST 2004

785

and the possible interactions resulting in heterotopic ossification are illustrated in Figure 1.
Mesenchymal stem cells. The term mesenchymal refers to
the developing loose connective tissue of an embryo, mainly
derived from the mesoderm, which eventually gives rise to
most of the cells in adult connective tissue. The definition is
generally extended to include connective tissue cells in adult
tissues such as fibroblasts and the cells that form bone, cartilage, fat, tendon, muscle and nerve tissue. Many mesenchymal tissues contain committed, lineage-directed
mesenchymal precursor cells which participate in local
regeneration, such as the satellite cell in skeletal muscle or
the adipocyte progenitors of adipose tissue.
Mesenchymal stem cells or human bone marrow stromal stem cells are pluripotent progenitor cells with the
ability to generate cartilage, bone, muscle, tendon, ligament and fat. These primitive progenitors exist postnatally
and exhibit the characteristics of stem cells, namely a low
incidence and an extensive potential for renewal. Mesenchymal stem cells can give rise to other types of mesenchymal tissues than the one they represent,25 and are thought
to play a pivotal role in the development of heterotopic
ossification.
Stimulating agents. Mesenchymal stem cells alone cannot
produce heterotopic ossification. Stimulating agents are
also required. It has been thought that bone morphogenetic
proteins in the soft tissues may stimulate the development
of heterotopic ossification. In a study almost 30 years ago
by Urist et al,26 the effect of extracted non-collagenous proteins from bone matrix was assessed when cultured with
vascularised and avascular muscle tissue. In the vascular
system bone developed and in the avascular system cartilaginous tissue was formed. The conclusion was that a bone
morphogenetic protein was the stimulating agent, and in
the correct local environment this could cause the transition
of mesenchymal stem cells to bone.26
The addition of other stimulating factors such as interleukin-1 to bone morphogenetic proteins has been shown
to further enhance bone formation.27 Growth hormone,
prolactin, insulin-like growth factor type-I and basic
fibroblast growth factor have all been implicated in the formation of heterotopic ossification after head injury.28,29 It
would appear that a complex and as yet poorly understood
interaction of a wide variety of stimulating factors is
involved.
Stimulating factors related to head injury. Circulating factors which promote heterotopic ossification are thought to
be present in patients after head injury. The serum from
patients with head injuries has been shown to promote
mitogenesis and cell division in a rat osteoblast cell culture
model.30 It has been hypothesised that the circulating factors in these patients promote release of local stimulating
factors which promote heterotopic ossification, although
this specific interaction has not yet been shown.
Local tissue environment. Various factors in the local tissue
environment have been implicated in the development of

786

H. C. PAPE, S. MARSH, J. R. MORLEY, C. KRETTEK, P. V. GIANNOUDIS

heterotopic ossification. These include disturbances involving the microvasculature and changes in oxygen tension,
pH and blood flow. Punch biopsies of skin and soft tissue in
areas of heterotopic ossification in patients with injury to
the spinal cord and paraplegia have shown alterations in
the endothelial cells and basement membrane of capillaries
and small vessels.31 The resulting microvascular changes in
the skin and subcutaneous tissue led to the theory that vascular changes may induce hypoxaemic alterations in the
para-articular soft tissues, leading to metabolic changes
which may contribute to the development of heterotopic
ossification.
Callus is deposited at fracture sites as the local pH
changes from acid to alkaline, so enhancing the precipitation of bone salts such as calcium and phosphate. Mechanical respiratory ventilation may produce a systemic
alkalosis which can also affect the local tissue environment.
It is possible that the alkalosis seen in patients during prolonged respiratory ventilation may be a causative factor in
the development of heterotopic ossification, which has been
described in ventilated patients with acute respiratory distress syndrome after sustaining multiple injuries but no
head injury.8,32

Treatment of heterotopic ossification

The treatment of heterotopic ossification is largely dependant on the severity and extent of the ectopic bone and the
amount of associated functional disability. Clinical examination allows a crude assessment of the long-term outcome
and joint mobility. Patients with persistent spasticity and
poor neurological recovery have a high incidence of recurrent ossification and poor joint mobility. Treatment may
start with physiotherapy and joint mobilisation and pass
through a spectrum of medical therapy, radiotherapy and
surgical excision.
Physiotherapy. In the patient with heterotopic ossification,
careful physiotherapy has been shown to be of benefit.33
This should involve assisted range of movement exercises
with gentle stretch and terminal resistance training. Care
should be taken not to move the joint beyond its pain-free
range of movement as this can exacerbate the condition.34
Physiotherapy is often combined with other forms of treatment in order to provide maximum therapeutic benefit.
Medical management. Medical treatment aims to prevent
the formation of heterotopic ossification following injury
and to avoid recurrence after surgical excision.
The groups of drugs used in the medical management of
heterotopic ossification include non-steroidal anti-inflammatory drugs (NSAIDs) and bisphophonates. NSAIDs
and in particular indomethacin, have been shown to be of
benefit in preventing the formation of heterotopic bone
after total hip arthroplasty.35 They have been helpful in
preventing heterotopic ossification following injury to the
spinal cord and after excision of ectopic bone in those
with a head injury.36,37 However, some patients experience
side-effects. Recent work has studied the efficacy of Cox-

2 selective inhibitors, in particular meloxicam, compared

to indomethacin in the prevention of heterotopic ossification after hip arthroplasty. Meloxicam has been shown to
be a more expensive alternative, without reducing the
incidence of ossification and it may cause it to
increase.38,39
Bisphosphonates, in particular etidronate, have also been
used in the management of heterotopic ossification. One of
the pharmacological affects of etidronate disodium is to
block the aggregation, growth and mineralisation of calcium hydroxyapatite crystals. Despite extensive use in clinical practice, there has not been conclusive evidence to
show that etidronate causes significant arrest of the development of heterotopic ossification.6,14,22,40
Radiotherapy. Radiotherapy has been used successfully to
prevent heterotopic ossification after arthroplasty of the
hip.41,42 It is difficult to investigate its use in patients with
ossification after head injury. The site of the ectopic bone
after hip surgery is predictable, whereas that after head
injury is difficult to forecast. Prophylactic radiotherapy, the
only form shown to be of benefit in preventing heterotopic
ossification, is thus difficult to administer in these patients.
Radiotherapy has not been shown to be of benefit in reducing the volume of established ectopic bone but it may help
in controlling pain refractory to indomethacin in patients
with head injury.43
Surgical excision of heterotopic bone. Surgical intervention
is used either to alter the position of a joint or to improve its
range of movement. Garland14 recommended timetables
for the surgical removal of heterotopic ossification depending on the aetiology. He advised surgery after six months
following traumatic heterotopic ossification, one year following spinal cord injury and 18 months after head
injury.14 The long interval of 18 months is intended to
ensure the maturity of the ectopic bone and reduce the likelihood of recurrence. Another factor in the timing of surgical intervention is the neurological condition of the patient.
Patients with head injury commonly have some neurological impairment. Studies have shown that patients with
more severe cognitive and physical impairment have poor
results from surgery with a high rate of recurrence and that
those with good neuromuscular control before operation
have the best functional result.14,44,45 Continuous passive
motion after surgery has been shown to be beneficial in
improving the eventual range of movement and the administration of indomethacin is a useful adjunct to reduce the
incidence of recurrent ossification.37,45
Heterotopic ossification remains a poorly understood
condition with little known of the exact mechanisms
involved. Its development can be reduced by the judicious
use of treatment regimes including physiotherapy, NSAIDs
and occasionally radiotherapy. Excision may give good
results but there is a significant risk of recurrence. The old
adage is true in the management of heterotopic ossification,
as in many other conditions prevention is better than
cure.
THE JOURNAL OF BONE AND JOINT SURGERY

CURRENT CONCEPTS IN THE DEVELOPMENT OF HETEROTOPIC OSSIFICATION

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