Injury, Int. J.

Care Injured 47S6 (2016) S16–S26

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Injury
j o u r n a l h o m e p a g e : w w w. e l s e v i e r . c o m / l o c at e / I n j u r y

The physiopathology of avascular necrosis of the femoral head: an update

Enrique Gueradoa,*, Enrique Casob
a
Department of Orthopaedic Surgery and Traumatology, Hospital Universitario Costa del Sol. University of Malaga, Spain
b
Research Unit, Hospital Universitario Costa del Sol. University of Malaga, Spain

K E Y W O R D S A B S T R A C T

Bone necrosis The physiopathology of the femoral head bone necrosis is similar for children and for adults. The disease is
Avascular necrosis characterized by apoptosis of bone cells – bone marrow and bone forming cells-resulting in head collapse with a
Femoral head subsequent lesion of the overlying cartilage, and therefore flattening of the rounded surface shape of the head
Hip Fracture articulating with the acetabulum, provoking, eventually, secondary osteoarthritis. When the disease becomes
Cartilage disruption clinically evident already destructive phenomena have occurred and collapse will eventually ensue. In children,
Growth cartilage
because epiphyseal cartilage has growth capabilities, lost epiphyseal height can be recovered, however in adults
Perthes’ Disease
collapse is irreversible. In this paper the physiopathology of this disease is examined as well as its implication for
Genomics
treatment. Prevention by genetic studies is discussed.
© 2016 Elsevier Ltd. All rights reserved.

Introduction Aetiology of the ANFH

Avascular necrosis of the femoral head (ANFH) is not an uncommon Bone necrosis can be grouped according to its etiology in traumatic
disease characterized by apoptosis of bone cells – bone marrow, bone and non-traumatic cases, and also within these two groups, as
forming, and bone destroying cells-resulting in bone collapse with a pediatric or adult.
subsequent involvement of the overlying cartilage, provoking flatten- Many diseases, medicaments, and conditions are classified under
ing of the head surface with, eventually, development of secondary non-traumatic cases, as a complication of the original disease.
osteoarthritis [1–10]. In children, since most of the head cartilage has Traumatic cases are usually the result of a femoral neck fracture, and
growth properties – the so called epiphyseal cartilage-restoration of although the most common denomination for atraumatic ANFH has
head height and shape is possible and arthritis avoidance may be a been idiopathic, a metabolic disorder background is the most common
fact. The younger the child is the greater the capacity of growth and, keystone in every patient. The hepatic metabolism is usually altered
consequently the regeneration potential [11–14]. either by a primary syndrome, by alcohol intake or by the adminis-
The denomination “avascular” is very peculiar as the femoral tration of steroid medication for an immunogenic or autoimmune
head blood supplying vessels do not disappear; rather they suffer a disease.
pathological process which results in blood flow interruption. Alcohol is the most common etiology in adults; its intake is dose-
Although the nature of ANFH is basically defined upon the death of dependent being demonstrated that the relative risk of the disease is
cells, in the adult as well as in children, the diagnosis is normally made 3.3 if the intake is over 400 ml per week, 9.8 if the intake increases to 1
by images obtained through a non-invasive method, either with x-rays liter and up to 17.9 if more than this amount per week is consumed
or magnetic resonance (MRI). Therefore, what usually characterizes [15]. What alcohol disturbs is phospholipid and cytokines metabolism
the disease is the augmentation of bone density under x-rays, with a [16] but the final mechanism of how the blood supply interrupts and
subsequent disturbance of the femoral head shape in a limping patient the bone cells of the femoral head die is unknown [17]. That is why
with groin, thigh or even knee pain. Since the disease is usually silent patients developing antiphospholipid antibodies have threefold higher
for an undetermined time, former physiopathological events are risk of presenting an ANFH than control population as well as some
ignored by the time the clinician receives the patient. other metabolic diseases such as Gaucher’s disease [18].
Other disorders such as sickle cell hemoglobinopathies, mainly
homozygous sickle cell disease, present bone necrosis as a complica-
* Corresponding author at: Department of Orthopaedic Surgery and Traumatology, Hospital
tion. It has been estimated that after 35 years of the disease onset, 50%
Costa del Sol, University of Malaga, Autovía A-7. Km 187. 29603 Marbella (Malaga). Spain.
Tel: +34 951976224; Fax: +34 952823219. of the patients have developed bone necrosis [19]. Haematopoietic cell
E-mail address: [email protected] (E. Guerado). transplantation also can provoke bone necrosis which might be based

0020-1383 / © 2016 Elsevier Ltd. All rights reserved.

 Guerado and Caso / Injury, Int. J. Care Injured 47S6 (2016) S16–S26 S17

on a similar mechanism as hemoglobinopathies [20]. Some other

blood diseases such as inherited thrombophilia and hypofibrinolysis
have also been related with the onset of bone necrosis with a gene
mutation mechanism suggested [21–29].
Steroid administration and diseases treated with steroids are
also one of the main etiologies of ANFH. Similarly to alcohol, steroids
are also dose-dependent in their role of etiology agent of femoral
head bone necrosis. Higher doses than 20–40 mg per day, mainly
in prolonged treatments, have more chance of developing the
disease [30].
Autoimmune disease such as Systemic Lupus Erythematosus (SLE)
can be associated with ANFH [31]. Its association with glucocorticoids
administration further increases the risk of the necrosis provoked by
vasculitis; duration and doses of treatment influence the proclivity of
developing bone necrosis [32–34]. Those patients having associated
conditions because of SLE disease develop more bone necrosis than the
rest [32–34]. Fig. 1. Femoral head of a 5 week old rabbit. The bony epiphysis can be seen sur-
Other diseases that have been related to bone necrosis include rounded by the epiphyseal cartilage which is pierced by canals for vascular supply to
Human Immunodeficiency Virus (HIV) infection [35,36] via fat the bone.

testosterone mechanism but apparently not related to antiretroviral

therapy [36], radiation, heritable COL2A1, or bisphosphonate use. A
instances worse fracture patterns do not end in an ANFH whereas some
thorough updated review of diseases and conditions provoking ANFH
more benign cases develop the disease remains unknown.
can be found elsewhere [19,37].
In non-traumatic pediatric cases the theories on its etiopatho-
Although what has been described above is known to have the
genesis were developed between the fifties to the nineties, and still
hazard of provoking ANFH the intimate mechanism of how the
it is not clear if the origin of the ischemia is in the vessels nourishing
vascular flow ceases remains obscure. Microangeitis can easily provoke
the epiphysis [39–44], in the blood they transport [45] or in the
thrombosis and ensuing necrosis but that has not been proven in the
cartilaginous matrix surrounding the cartilage piercing vessels [46–
role of the disease. Therefore, the denomination of idiopathic or
50]; this last hypothesis is mainly supported by pathological findings
essential for the phenomena triggering the bone necrosis and its
[51–53], and also by studies on either prenatal [54–57] or postnatal
physiopathology is appropriate. We just know associations but not
periods [58–61].
etiological events correlation with physiopathology.
According to this constitutional theory, the altered growth cartilage
Children can also have necrosis of the femoral head bone epiphysis,
composition would facilitate breakdown of the blood supplier canals to
and, as the adults, the disease can be either traumatic or not. Many
the bony epiphysis [38,62,63] (Figures 1 and 2). Then as the blood flow
diseases have also been described to provoke bone necrosis in the child
to the head is interrupted with subsequent ischemia of the bony
but they are mainly metabolic in origin. Cultural, geographical and
epiphysis, it would be expected that child complains of pain. Yet, we
genetic circumstances have also been related with idiopathic cases, the
know that either pediatric or adults cases do not come to the doctor in
so-called Legg Calvé Perthes’ Disease (LCPD). Studies from the eighties
this early situation, rather they do when the regeneration phase is well
onwards have elucidated many situations related with this disease but
in progress. Since long, studies on transient synovitis of pediatric hips
nothing is clear so far in relation to its etipathogenesis.
in non-traumatic cases, -characterized by hip pain of unknown origin
during a short period- have failed in relating this disease with early
Physiopathology of ANFH
onset of LCPD [44]. Hence, it can be thought that bone ischemia does
not always provoke pain, at least in early phases. The same comes true
Bone necrosis physiopathology is very similar in children and
for adults.
adults. What differentiates both age groups is cartilage maturity. Since
For image-pathology correlation, the majority of imaginings
children have epiphyseal growth cartilage capable of repairing femoral
studies on this early ischemia phase mainly come from animal
head height, loss occurred during disease evolution can be restored;
however, matured patients cannot compensate that because the thin
epiphyseal cartilage is just articular and has not growth aptitudes.
Growth potential is so important. The younger the child is the better
the prognosis will be [13,14].
The sequence of events occurring in the physiopathology of bone
necrosis in adults as well as in children has been constructed by
interacting knowledge from animal experimentation with human
clinical and images observations, and bone biopsies. Therefore,
conclusions about whether events here described are for sure or not,
is not yet supported by very strong arguments. According to them,
bone necrosis evolution can be divided into two successive phases:
ischemia and regeneration [3,7,8,10,38].

Ischemia phase

The timing as to when ischemia starts is very difficult to know, since

once the disease clinically onsets, it has usually been silent for long.
Also the background, in adults and in children, is unknown in many
Fig. 2. Femoral head of an 11 week old rabbit treated with oxytetracyline. A vascular
cases. This is applicable for non-traumatic cases and also in traumatic tunnel piercing through the epiphyseal cartilage of the femoral head can be seen.
ones as although a fracture is the origin of ANFH, why in many Blood flows through it.
S18 Guerado and Caso / Injury, Int. J. Care Injured 47S6 (2016) S16–S26

experimentation, as human specimen collections during this stage

is very difficult [38,53,64–66]. Anyhow seemingly experimentation
animal images and humans would be very similar.
It is believed that along this phase, as vascular supply is interrupted,
no changes in the mineralized bone tissue occurs [1–3,5]; therefore
x-rays images will be normal whereas more dynamic studies such as
scintigraphy will show a decreased up-take in the infarcted area
because of cessation of vascular flow [38,65,67] (Figure 3). MRI will
early detect bone marrow disturbances [68]. Since only the ischemic
phase can be considered to be an early one in bone necrosis
physiopathology, it can be said that no early x-ray disease signs exists.
For radiological signs to occur, it is necessary that the dead bone
segment receives revascularization giving chance to Mesenchyme
Stem Cells (MSCs) of migration to the necrotic area [69,70]. Then MSCs
multiply and differentiate to bone forming osteoblasts so that new
appositional bone can take place with an ensuing bone resorption by
osteoclasts [1–3,5–8,10]. These events constitute the first steps of the Fig. 4. The same specimen. Bone tissue lacuna with a dead osteocyte within.
regeneration phase. Although this osteocyte can be seen under light and electron microscopy, its dis-
rupted membrane with part of the cytoplasmatic substance out of the cells shows
Although bone necrosis diagnosis is mainly made by images, proper that it is unviable.
confirmation is accepted to be, by definition, under histology
[1–3,5,6,10]. Observation, under light microscopy, of dead bone cells
is the key sign for necrosis definition. Bone marrow cells are the first travel to the necrotic area [69–74]. For that purpose new vessels pierce
population to die, followed by osteoblasts and osteocytes. The again the epiphyseal cartilage and follow the same posterolateral
histological diagnosis of osteocyte necrosis is made when cells have direction as the medial circumflex artery had before the disease started
disappear from the lacuna or, alternatively, are shrunk within it [1– [38,75–78] (Figure 5). This physiopathological phenomena provides
3,5,6,10]. Nonetheless, further studies carried out previously have the foundation for some new therapies [79,80].
demonstrated that disappearance of cells from the lacunae, under light Studies in immature animal experimentation on blood flow
microscopy, make take up to 4 years [6]. Electron microscopy regeneration by using Rhinelander technique have shown that
preparations, DNA stains and some other current laboratory methods revascularization is exaggerated in relation to the normal blood flow
have shown that although the osteocyte could be within the lacuna, it before ischemia took place [38] (Figures 5 and 6). Reasons for that are
may be unviable [38] (Figure 4). unknown but what is known is that cartilage repair will also be
Apparently the ischemia phase is similar for adults and children. overstated in such a way that the femoral head will grow bigger than
In adults whereas some authors speculate for a primary heritable the acetabular socket, resulting in an eventual subluxation which is
thrombophilia or hypofibrinolysis causing a thrombotic venous known to be a bad prognosis sign of head at risk [81,82] (Figures 7–11).
occlusion within the femur head leading to venous hypertension and This new vascularization brings new cells: MSCs derived bone
hypoxic death of bone [71], seemingly endothelial progenitor cells forming cells, and monocytes bone destroying cells [1–3,5,6,10]. From
population is reduced, compromising angiogenesis and regeneration the beginning of this regeneration phase, two different phenomena
[72]. Therefore non-traumatic ANFH should not be associated occur within the bone necrotic femoral head. On the one hand the
to thrombophilic disorder, but rather related to endothelial dysfunc- compact subchondral bone will sustain a negative apposition-
tion [73]. resorption balance; osteoclasts originate from monocytes coalescence
expressing the phenotype of a multinucleated giant cell and remove
Regeneration phase this hard cartilage supporting compact bone, known, since more 80
years ago, as “creeping substitution” [1] (Figure 12); on the other hand,
As in common traumatic fractures, once ischemia and necrosis the cancellous bone situated in the core of the head will have a positive
occur, some molecular mediators mobilize and encourage MSCs to appositional balance [1–3,5–10] (Figure 13), thanks to active

Fig. 5. The same specimen. Vascularization penetrating through the lateral part of
Fig. 3. The same specimen. Scintigraphy with decreased uptake on the left hip. the epiphyseal cartilage substituting the subchondral compact bone. Rhinelander
Posteroanterior image. technique.
 Guerado and Caso / Injury, Int. J. Care Injured 47S6 (2016) S16–S26 S19

Fig. 9. The former case. A coxa magna with subluxation can be seen. In lateral projec-
tion (hip abduction and lateral rotation) centering of the head is evident.

Fig. 6. The same specimen and preparation. Vascularization underlying the epiphys-
eal cartilage substituting the subchondral compact bone.

Fig. 10. The former case. The right femoral head is well covered by the acetabulum
Fig. 7. Femoral head of an 11 week old rabbit treated with oxytetracyline. Femoral after Dega acetabular osteotomy. Anteroposterior x-ray projection.
head epiphysis height restitution thanks to cartilage proliferation. Still the vascular-
ization penetrating through the lateral part of the epiphyseal cartilage, substituting
the subchondral compact bone, can be seen.

Fig. 8. Right hip Legg-Calve-Perthes’ disease in a 7 year old male child. A coxa magna
with subluxation can be seen. Anteroposterior x-ray projection. Fig. 11. The former case. Lateral projection.
S20 Guerado and Caso / Injury, Int. J. Care Injured 47S6 (2016) S16–S26

Fig. 12. Femoral head of an 11 week old rabbit treated with oxytetracyline.
Substitution of the compact subchondral bone is evident. Fig. 15. Femoral head of a 59 year old man diagnosed of ANFH. A subchondral frac-
ture can be easily seen. A rod is drawn in order to show the difficulties of drilling
and buttressing the hole affected volume of bone necrosis.

Fig. 16. Femoral head of an 11 week old rabbit treated with oxytetracyline. Lateral
Fig. 13. The same specimen. Cancellous dead bone trabeculi with osteogenetic prolif- flattening of the femoral head after bone collapse.
eration in a formerly necrotic femoral head.

populations, features x-ray diagnosis of adult ANFH and is known in

LCPD as the condensation phase. From then on, the events occurring in
the necrotic femoral head, will influence the future of the joint.
The weaken subchondral bone will no longer be able of holding the
overlying cartilage and, consequently, the head articular surface will
collapse (Figure 16). It is interesting to emphasize that cartilage is not
primarily disturbed; It is affected only when the subchondral bone
substitution takes place and collapses occur [1–3,5,6,38,83].
Adult hips will eventually evolution to osteoarthritis whereas in
children, recovery of the height of this collapsed epiphysis will depend
on the potential capability of the epiphyseal cartilage for synthetizing
new cartilage matrix (Figure 17); moreover, depending on age,
pediatric hips will obtain a “restitutio ad integrum” or, conversely,
will also evolution to joint destruction. As a general rule, it is supposed
that femoral head of children younger than 4 years of age will recover
roundness shape whereas those older than 8–9 years will get a bad
result whatever treatment is applied. Results between age range of
Fig. 14. The same specimen. Active osteoblast onto a dead trabeculae synthetizing 4–8 years, would depend on the amount of head involved and the
new bone matrix. It can be seen a very active endoplasmic reticulum. treatment applied [11,12,38]. According to different authors the limit
age may have little changes, but not the concept [13]. This capability of
epiphyseal height for restitution and shape recovery is known as
osteoblasts (Figure 14). An x-ray view of the femoral head at the biological plasticity. For a good hip remodeling the femoral head
beginning of this phase could show a subchondral radiolucent line with requires to be covered as much as possible by the acetabulum together
an underlying condensation. The subchondral line has been described with the maintenance of full range of motion in all directions [11,12].
for both children and adults as a subchondral fracture [1–3,5,6,10,83] The treatment of LCPD as that of the any hip epiphyseal bone necrosis
(Figure 15) and the appositional image of the core, also for both in pediatric ages consists of facilitating that capability of remodeling
 Guerado and Caso / Injury, Int. J. Care Injured 47S6 (2016) S16–S26 S21

Fig. 17. The same specimen. This lateral epiphyseal growth cartilage surface shows Fig. 19. Bone necrosis of the femoral head of a 57 year old patient, who had under-
chondroblasts proliferation in order to repair femoral head height loss. See Figure 7. gone a varization osteotomy for the treatment of avascular necrosis of the femoral
head. The articular cartilage has a step off defect overlying the necrotic area.

either by conservative or surgical methods; this principle is named

as “containment treatment” because the femoral head is contained
ischemic event with a subsequent early regeneration stage. That
within the acetabular cavity avoiding subluxation and does not require
emphasizes the fact that early stages under x-rays does not exists as
weight bearing release (Figures 8–11). Along the last 40 years, the
once the disease can be observed under x-rays is because it has been in
principle of containment achievement has been alternatively favoured
progress, although silent, for long, and histological events – revascu-
either for conservative or for surgical methods.
larization mediated-need to occur.
In the adult, the primary causes of ischemia are very much
The same conclusions can be reached after reading a report using
under discussion, but apparently clearer events occur at the point
MRI. The authors observed that diffuse femoral head and neck
that regeneration starts (Fig. 18). They appear to be similar to the
medullary impairment with fat cell replacement by fibroblastic
phenomena occurred in children, unless, as stated above, the
tissue were found without evidence of trabecular bone necrosis in
regeneration of the collapsed cartilage [1–3,5,6,10,83] (Figure 19).
what they believed to be the early stages of idiopathic osteonecrosis.
In a very interesting research, a superselective angiography of the
Core biopsy showed that fibroblastic tissue and edema replaced the
medial circumflex artery was carried out in sixteen adult hips with,
bone marrow but without detectable trabecular bone impairment.
according to the authors, early stage osteonecrosis diagnosed by bone
Classical radiographic, CT, and MRI abnormalities of osteonecrosis of
scintigraphy; also 22 contralateral hips, in unilateral cases, were used
the femoral head were present 14 months later [85]. These findings are
as a control group; the authors included 22 further normal cases in
in accordance with what is nowadays known: bone marrow is affected
patients on corticosteroids also studied under x-rays and scintigraphy.
early after ischemia and changes in bone matrix are provoked only
They found that small arteries were penetrating into those heads,
during the regeneration phase, as new appositional bone and dead
which later developed necrosis under x-rays studies but were silent by
bone resorption requires the action of cells blood transported through
the time of scintigraphy was performed. Conclusions reached included
new vessels (Figures 13 and 14).
that revascularization was found not only in necrotic head but also in
This new vascular penetration occupies the subchondral bone and
those which had not yet developed the necrosis under x-ray studies
collapse occurs when this weight-bearing zone of the femoral head is
[84], but according to the findings, they already had been involved in an
substituted by fibrous tissue, as stated above (Figures 16 and 19).
Subsequent flatness of the head can be easily seen as a secondary event
to collapse [86]. Then the overlying articular cartilage, primarily
healthy results injured and osteoarthritis can eventually develop. Deep
into the core of the femoral head revascularization features more bone
apposition than resorption in a process of enchondral bone callus
formation. In a histopathologic study of a series of 346 resected femoral
heads subarticular fracture clefts were commonly present in speci-
mens with severe osteonecrosis secondary to either trauma, steroid
therapy, idiopathic or other disease processes; the enchondral callus
occurs only when at least one of the two opposing surfaces at the
fracture cleft contain viable bone [87]. We know that this enchondral
ossification is the physiological way of forming bone when fracture
ends are well vascularized.

Physiopathological implications for treatment

Whereas mechanical principles of treatment-based on growth

capabilities – in children look clear, in adult femoral heads, as cartilage
does not have growth properties, collapse will not be restored and the
Fig. 18. MRI of a 47 year old man with the diagnosis of posttraumatic ANFH.
femoral head will remain flattened, developing late osteoarthritis.
Subchondral bone substitution can be seen although bone collapse has not occurred
yet. Difficulties for collapse prevention or even rod buttressing is evident as the bone Many treatments have been tried in adult femoral head necrosis before
necrosis volume is very large. and after collapse but none of them have proven to have any value.
S22 Guerado and Caso / Injury, Int. J. Care Injured 47S6 (2016) S16–S26

Since it looks worldwide accepted that once collapse occurs the clearer the etiopathogenesis of LCPD and its relation with the
progression to osteoarthritis cannot be stopped [7–9], core decom- “intravascular theory”.
pression of the head has been claimed to be effective in incipient bone Other studies have pointed that there is a constitutional problem in
necrosis before the articular cartilage is affected and the head flattens children developing LCPD and the cause of the epiphyseal ischemia
(Figure 15). Nonetheless according to basic science studies, by drilling is not intravascular, but extravascular. The observation of concurrent
into the necrotic zone regenerative phase would accelerate and bone diseases related to mesenchyme growth has been, since long, the base
collapse could occur even earlier. Therefore, although several patients for that hypothesis [57,58,106,107]. Congenital genitourinary and
may feel some pain relief after core decompression, as pathological ilioinguinal hernia had been studied during the eighties, and recently
high venous pressure is drastically diminished, no differences in terms shown after studying large databases [108]. These studies have also
of disease outcome have been found between core decompression and shown regional distribution of the disease even within the same
abstention, and collapse will occur without delay whether or not core country [107]. However, declining incidence of LCPD suggests that
decompression is performed. So far, no well-designed study has found environment may also be determinant for the disease onset [108].
differences in relation to collapse between femoral head undergoing The “extravascular –constitutional-theory” based on an epiphyseal
core decompression and abstention [88,89]. cartilage collagen alteration and consequently a disruption of the
Proximal femur osteotomies have also been used for the treatment vascular canals piercing the cartilage, has also been explained by
of the ANFH in the adult, but the aim of it is to change the necrotic area genetic aetiology. Type II collagenopathies, including LCPD and ANFH
from loading, therefore it is assumed that collapse has or is going to would consist of the replacement of the triple helical (Gly-X-Y) of the
ensue (Figure 19). Varization osteotomy alone or in combination with extracellular matrix by other amino acids. Since type II collagen is
derotation is aimed to release the pressure from the necrotic area, by encoded by the COL2A1 gene and contains N- and C-terminal regions,
loading a healthy part of the head instead of the affected one. mutation of COL2A1 would result in a collagenopathy [109,110] and
Nevertheless, so far no methodological well designed study has been therefore an alteration of the biomechanical properties of the vessels-
made on the effectiveness of femoral osteotomy for the treatment of containing epiphyseal cartilage. Medical literature reports on abundant
ANFH and this treatment, very popular among orthopaedic surgeons in private mutations in COL2A1 associated with diverse clinical pheno-
the eighties, is currently not very much in use as anatomy of the types of chondrogenesis alteration [111]. Therefore, DNA mutation
proximal femur is very much altered, compromising the technique of a analysis might be valuable for identifying other at-risk family members
secondary joint replacement. Variables such as age, necrotic volume, when a diagnosis of LCPD has been made [111,112].
osteotomy types and others make osteotomies outcome very uncer- In a very interesting study, Gly1170Ser mutation of COL2A1has also
tain, and nowadays only joint replacement may guarantee – provided been found in several families with an inherited disease of the hip
there are no complications- a satisfactory result. Single or combined joint, including ANFH and LCPD. Histological studies showed that the
proximal femoral or acetabular osteotomies are of current use in LCPD hierarchical structure of the transmuted cartilage and the imbedded
[90,91] with very long term good results [14,92] (Figure 10 and 11). chondrocytes were significantly abnormal. The expression and
Some others attempt to help regeneration by introducing either distribution of type II collagen was not uniform in sections of the
artificial stems [93] (Figure 15), growth factors or MSCs have not shown cartilage. Studies under electron microscopy also showed clearly
to improve abstention [74]. Old techniques are reborn with some abnormal chondrocytes as well as an abnormal arrangement of collagen
modifications [94], and mixtures of therapies have also been published. fibers in the transmuted chondral matrix. Likewise, the predicted
Medline bibliography search in current data bases combining different stability of type II collagen greatly decreased with the substitution of
therapies obtains an overwhelming amount of references nearly all of serine by glycine. The authors concluded that Gly1170Ser mutation of
them with “promising results”. Therefore, disease prevention programs COL2A1 can cause significant structural alterations in articular cartilage,
are essentials as once the disease has triggered, no reliable therapy is which are responsible for the new type II collagenopathy [113].
available. Studies on this alteration have also been carried out in dogs [114],
and also nearly thirty years ago we had created an animal experimental
Genetics determination as a future prevention tool of the ANFH model of LCPD inducing a chondrogenesis alteration during growth by
the administration of high doses of oxytetracycline – an antibiotic
Genetics is a very useful tool in order to know susceptibility of interfering with proteins’ synthesis- [38]. We also observed, years later,
people to suffering from ANFH. Prevention programs could be that patients having LCPD during childhood had also developed some
instituted for anticipating risks of diseases, benefits and risks of others chondrogenesis-related alterations, clinically silent, during
therapies and habits in relation to ANFH. their growth period [115].
Differential expression of genes encoding for proteins involved in A group of authors claim a relation between the appearance of
thrombus formation in the microvasculature, coagulation pathway, LCPD and genetic protheathesis but do not support either theory, being
ischemia, angiogenesis, apoptosis, lipid biosynthesis and bone remod- intra or extravascular; they just discuss on that correlation [116].
elling have been suggested to be responsible for the progression to Although some authors found evidence of family proclivity to suffer
the end stage of ANFH in adults [95]. In children the hypothesis that LCPD, some others failed in founding a genetic component, even
LCPD is caused by intravascular thrombosis causing epiphyseal between monozygotic twin pairs [117]. Likewise, it has been found that
ischemia, has been empirically studied [96–98]. However, although children heterozygous for IL-6 G-174C/G-597A polymorphisms pre-
according to coagulation parameters the role of thrombophilia can sented a lower probability of presenting LCPD than those being
develop the disease [71,99–101], no effect has been demonstrated on homozygote [118].
the severity of it [98]. By PCR-RFLP analysis, proapoptotic Bax factor and Bax/Bcl-2
The “intravascular aetiology” and its relation with genetics has also ratio have shown overexpression also in LCPD patients [119]. Children
been discussed for LCPD. Some authors have found that a factor V with heterozygous IL-6 G-174C/g-597A polymorphism have lower
Leiden mutation is very much related to this disease, and that by risk of developing LCPD [118]. But no overall association between
screening this mutation, children under risk could be identified in MTHER gene polymorphisms and ANFH has been suggested in LCPD
advance [12,22–29]. Some other authors have failed to find that patients [120].
association [102,103], nor even any coagulopathy associated to LCPD Whether LCPD is related or triggered by either intra or extravascular
[104]. Alterations of thrombogenesis such as a beta fibrinogen gene G- causes is not well known as one of the problem starts since the own
455-A polymorphism have related LCPD with passive smoke exposure definition of the disease. Many concurrent diseases have been
[105]. Therefore, genetics have not found definitive hints making described to be associated with LCPD, based just on the simple
 Guerado and Caso / Injury, Int. J. Care Injured 47S6 (2016) S16–S26 S23

observation of x-rays resembling the usual images for LCPD [21,103, questions about reporting incidental findings (IF) derived from WES
121–144]. analysis, such as identifying medically relevant mutations in genes
Recent results from genome-wide (GW) transcriptomics on unrelated to the diagnostic question and sex chromosome abnormal-
immature articular cartilage of piglets following osteonecrosis of ities that need to be addressed.
femoral head (ANFH) have shown upregulation of several hundred of
protein-coding genes compared to the normal controls, reinforcing the Conflict of interest
role of the immature articular cartilage following ANFH [145]. The
encoded proteins upregulated along the phases of ANFH are involved No benefits in any form have been received or will be received from
in different molecular pathways, including HIF-1, PI3K-Akt, MAPK, a commercial party related directly or indirectly to the subject of this
focal adhesion and TNF-a signalling pathway. These pathways article.
participate in oxidoreductive, cell-survival, angiogenic and inflamma-
tory responses, throughout secretory and chemokine signalling Acknowledgments
proteins. The differential gene expression of relevant genes (HIF-1A,
The researches illustrating this paper were carried out during the
VEGFA, IL-6, IL6R, IL-8, CCL2, FGF2, TGFB2, MMP1, MMP3, ITGA5, FN
middle of the eighties at the Nuffield Orthopaedic Centre (NOC) while
and Col6A1) was confirmed by quantitative reverse-transcriptase
one of the authors (EG) stayed in Oxford; also during the late eighties
polymerase change reaction (qRTPCR) analysis.
studies were performed at the University Autonoma of Madrid by the
Genotyping studies on adult ANFH have suggested an association of
same author, and along the last twenty years, the Ministry of Health of
gene-encoding protein polymorphisms with ANFH. A recent meta-
the Spanish Government, together with the regional government of
analysis [146] has found increased risk of ANFH after focusing the
Andalusia, supported the University of Malaga, and the Hospital Costa
studies on VEGF, eNOS and ABCB1. Genetic variations in angiogenesis
del Sol with several generous grants. Thanks are given to these
and hypoxia-related genes may be considered as a susceptibility factor
Institutions.
for the development of ANFH since the IGFBP3 gene polymorphism
was significantly associated with a higher risk of ANFH [147]. A recent
systematic review on VEGF protein, highly expressed around the References
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