Pathophysiology Puenting

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C OPYRIGHT 2012
BY
T HE J OURNAL
OF
B ONE
AND J OINT
S URGERY, I NCORPORATED
Current Concepts Review
Pathophysiology and New Strategies for the

Treatment of Legg-Calve -Perthes Disease
Harry K.W. Kim, MD, MS, FRCSC
Investigation performed at Texas Scottish Rite Hospital for Children, Dallas, Texas
Legg-Calve -Perthes disease is a juvenile form of idiopathic osteonecrosis of the femoral head that can lead to
permanent femoral head deformity and premature osteoarthritis.
According to two recent multicenter, prospective cohort studies, current nonoperative and operative treatments
have modest success rates of producing a good outcome with a spherical femoral head in older children with LeggCalve -Perthes disease.
Experimental studies have revealed that the immature femoral head is mechanically weakened following ischemic
necrosis.
Increased bone resorption and delayed new bone formation, in combination with continued mechanical loading of
the hip, contribute to the pathogenesis of the femoral head deformity.
Biological treatment strategies to improve the healing process by decreasing bone resorption and stimulating
bone formation appear promising in nonhuman preclinical studies.
Legg-Calve -Perthes disease is a juvenile form of idiopathic

osteonecrosis of the femoral head that affects children between
the ages of two and fourteen years. It is considered one of the
most common forms of pediatric femoral head osteonecrosis,
with the prevalence ranging from 5.1 to 16.9 per 100,000 in
various regions of the world1-4. Since the initial reports of this
unique condition approximately 100 years ago by Legg5, Calve 6,
and Perthes7, a number of studies have been published regarding its etiology 8-15, epidemiology1,3,4, natural history16-20,
radiographic classifications16,21-23, treatments24-29, and outcomes30-32.
Despite the increase in knowledge, Legg-Calve -Perthes disease remains one of the most controversial conditions in
pediatric orthopaedics. Many aspects of the disease remain
unknown or unclear, including the etiology and pathophysiology of the disease and the best methods to treat the patients
in different age groups affected with the disease. The pur-
poses of this review are threefold: to provide an update on the

outcomes of current treatments according to the results of
recent prospective studies, to provide an update on the pathophysiology of Legg-Calve -Perthes disease on the basis of the
knowledge gained from recent experimental investigations, and
to summarize the rationale, results, and concerns of new biological therapeutic strategies that are being explored as possible
treatments for the disease.
Current Treatments and Outcomes
Current treatments for Legg-Calve -Perthes disease are largely
based on the principles of obtaining and maintaining good hip
range of motion, and obtaining and maintaining containment
of the femoral head in the acetabulum33,34. It is believed that, if
these principles are followed, a soft femoral head will be molded
into a spherical shape by the acetabular socket. Over the years,
Disclosure: The author did not receive payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any aspect
of this work. Neither the author nor his institution has had any financial relationship, in the thirty-six months prior to submission of this work, with any
entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. The author has had a
relationship, or has engaged in another activity, that could be perceived to influence or have the potential to influence what is written in this work. The
complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
J Bone Joint Surg Am. 2012;94:659-69
http://dx.doi.org/10.2106/JBJS.J.01834
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TABLE I Stulberg Radiographic Outcome of Three Treatments

in the Study by Herring et al.*
Radiographic Outcome
According to Stulberg
Class
I or II
III, IV, or V
Age of 6 to 8 years at disease

onset (n = 204)
No treatment (n = 11)
Range of motion (n = 44)
Brace (n = 79)
Innominate osteotomy (n = 39)
Femoral osteotomy (n = 31)
27% (3)
48% (21)
62% (49)
69% (27)
68% (21)
73% (8)
52% (23)
38% (30)
31% (12)
32% (10)
Age of 8 to 12 years at disease

onset (n = 141)
No treatment (n = 8)
Range of motion (n = 33)
Brace (n = 50)
Innominate osteotomy (n = 29)
25% (2)
30% (10)
36% (18)
41% (12)
62% (13)
75% (6)
70% (23)
64% (32)
59% (17)
38% (8)
*The data are from Herring JA, Kim HT, Browne R. Legg-CalvePerthes disease. Part II: Prospective multicenter study of the effect
of treatment on outcome. J Bone Joint Surg Am. 2004;86:2121-34.
various nonoperative28,35-39 and operative treatments24,27,29,40,41

were introduced on the basis of this concept. One of the criticisms of this concept has been the inability to accurately
quantify femoral head containment and to establish a direct
relationship between the amount of containment of the femoral head and the ultimate outcome. According to hip modeling studies42,43, a clinical impression of containment based on
radiographic assessment of the femoral head coverage may not
accurately represent the degree of containment of the femoral
head.
The effectiveness of current treatments based on the
concept of containment has been investigated in two multicenter prospective investigations (level-II prospective cohort
studies)30,44. In the study by Herring et al.30 (Table I), the success
rate of achieving a spherical femoral head (Stulberg class-I
or II hips)20 after one of the five treatments (no treatment,
physiotherapy, Scottish Rite orthosis, femoral osteotomy, or
Salter innominate osteotomy29) ranged from 27% to 69% in
the 204 patients with the onset of the disease between the ages
of six and eight years and from 25% to 62% in the 141 patients
with the onset of the disease between the ages of eight and
twelve years. The operative treatments, as a treatment group,
produced better results than the nonoperative treatments
for the older age group; however, the effectiveness of these
treatments in achieving a spherical femoral head was modest. In the study by Wiig et al.44 (Table II), the success rate of
achieving a spherical femoral head after one of the three
treatments (physiotherapy, Scottish Rite orthosis, or femoral
varus osteotomy) ranged from 46% to 53% in the 168 pa-
P AT H O P H Y S I O L O G Y A N D N E W S T R AT E G I E S F O R T H E
T R E AT M E N T O F L E G G -C A LV E - P E R T H E S D I S E A S E
tients with the onset of the disease before the age of six years
and from 20% to 43% in the 146 patients with the onset of the
disease after the age of six years. While that study found that a
femoral osteotomy was beneficial in the patients who were
more than six years old at the onset of the disease, the effectiveness of a femoral osteotomy in achieving a spherical femoral
head was also modest.
The results of these studies raise a question regarding
why a femoral or Salter innominate osteotomy produces good
results in some patients and not in the others. One theory is
that while these osteotomies do provide some load-relieving
effects on the necrotic femoral head42,45, they do not directly or
specifically address the pathobiology of the disease and the
impaired healing observed in the older children with LeggCalve -Perthes disease. These results also clearly indicate a need
to develop more effective treatments for the disease that prevent the femoral head deformity. It is generally agreed that a
better understanding of the pathophysiology of the femoral
head deformity in Legg-Calve -Perthes disease is essential for
the development of more effective treatments.
Pathophysiology of Legg-Calve-Perthes Disease
Various theories on the etiology of Legg-Calve -Perthes disease
have been proposed. These include trauma, an inflammatory
process, vascular occlusion, thrombophilia, insulin-like growth
factor-1 pathway abnormality, maternal smoking, second-hand
smoke exposure13,46-49, and, most recently, a subtle type-II collagen mutation12,14,50. Most of these theories remain unsubstantiated. Thrombophilia as a cause of Legg-Calve -Perthes
disease remains controversial, with some studies having shown
an association between the disease and various coagulation factor
abnormalities8,51-55, while other studies have shown no association
TABLE II Stulberg Radiographic Outcome of Three Treatments

Studied by Wiig et al.*
Radiographic Outcome
According to Stulberg Class
I or II
III, IV, or V
Age of <6 years at diagnosis

(n = 168)
Physiotherapy (n = 123)
Scottish Rite orthosis (n = 22)
53% (65)
45.5% (10)
52% (12)
47% (58)
54.5% (12)
48% (11)
Age of 6 years at diagnosis

(n = 146)
Physiotherapy (n = 51)
Scottish Rite orthosis (n = 25)
33% (17)
20% (5)
43% (30)
67% (34)
80% (20)
57% (40)
*Data are from Wiig O, Terjesen T, Svenningsen S. Prognostic

factors and outcome of treatment in Perthes disease. A prospective study of 368 patients with five-year follow-up. J Bone Joint
Surg Br. 2008;90:1364-71.
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at all11,56-60. The prevailing opinion is that Legg-Calve -Perthes disease is a multifactorial disease with genetic and environmental
factors playing a role. There is also the possibility that the disease is
caused by several etiological factors that share a common pathological and clinical presentation.
Regardless of the cause, a disruption of blood supply to
the femoral head, producing ischemic necrosis, appears to be a
key pathogenic event, leading to the pathological and subsequent structural changes to the growing femoral head. Diagnostic imaging studies, such as selective angiography61-63, bone
scintigraphy64, and gadolinium-enhanced magnetic resonance
imaging65, provide evidence of absent blood flow to the affected
femoral head. Although histological studies of the femoral head
and biopsy specimens from the patients with Legg-Calve -Perthes
disease are limited in number, they show changes consistent with
ischemic necrosis of the bone and the deep layer of the articular
cartilage66,67. Animal studies also have shown that a disruption of
the blood supply to the femoral head can produce radiographic
and histological changes resembling Legg-Calve -Perthes disease68,69.
The question of whether Legg-Calve -Perthes disease is
due to a single episode of infarction or multiple episodes of
infarction remains controversial. The evidence for the single
infarction theory comes from studies of immature pigs in
which one episode of ischemia induction surgery produced
radiographic and histological changes resembling Legg-Calve Perthes disease. The evidence for the multiple infarction theory
comes from studies on immature dogs in which a single episode of infarction did not produce femoral head necrosis or
deformity, while consecutive interruptions of the blood supply
produced changes resembling Legg-Calve -Perthes disease in
some femoral heads70,71. In a subsequent clinical study, 51% of
fifty-seven biopsy specimens from the femoral heads of patients
with the disease revealed dead woven bone superimposed on
dead lamellar bone with the marrow space occupied by dead
granulation tissue, suggesting two episodes of infarction72.
Catterall et al. also observed thickened trabeculae with many
cement lines in the central area of two femoral heads with total
head involvement (Group 4 in the Catterall classification)66.
However, in the periphery of the specimens with less femoral
head involvement (Group 1 in the Catterall classification), the
authors observed osseous trabeculae showing only one episode
of infarction. One interpretation of these findings is that
multiple episodes of infarction are necessary to produce LeggCalve -Perthes disease. This interpretation suggests that, if the
cause of the infarction episodes can be identified, and if intervention can be initiated early in the course of the disease
process, then a full-blown disease may be prevented or the
severity of the disease can be reduced. Another interpretation
of these findings is that the disease is due to one infarction
episode, but subsequent mechanical overloading may injure
the vessels in the healing areas of the femoral head or produce
intermittent compression of the blood vessels traversing the
cartilage in the area of high loading, producing secondary
episodes of infarction. This interpretation suggests that the
prevention of mechanical overloading and a femoral head deformity would be beneficial to the healing process.
Pathogenesis of Femoral Head Deformity

in Legg-Calve-Perthes Disease
Development of the femoral head deformity is the most important sequela of Legg-Calve -Perthes disease since the extent
of the deformity correlates with the long-term outcome18-20. A
serial radiographic examination of patients with the disease
demonstrates that the development of the deformity begins in
the initial stage of the disease (the stage of increased radiodensity) and progresses during the resorptive stage (the stage of
fragmentation). From the limited number of biopsy and necropsy studies of Legg-Calve -Perthes disease, various pathological changes from the proximal part of the femur that
include the articular cartilage, osseous epiphysis, physis, and
metaphysis have been reported66,67,73-76. The temporal sequence
of the pathological changes and the functional importance of
the changes are difficult to appreciate from these few studies
as they only examined a limited number of specimens and in
various stages of the disease.
The lack of availability of clinical samples for research has
prompted an alternative approach, the use of experimental
models, to investigate the pathogenesis of the femoral head
deformity. In particular, a piglet model has allowed more systematic and in-depth investigation. This model of ischemic
necrosis of the immature femoral head is created by applying a
ligature (resorbable suture) around the femoral neck to disrupt
the blood flow to the femoral head. The femoral head becomes
necrotic and remains avascular in the first two weeks (the
avascular stage). Revascularization and resorption of the necrotic head are initiated by three to four weeks after ischemia
induction (the vascular repair stage), and moderate to severe
femoral head deformity is observed at eight weeks after ischemia induction68. The studies of this model have revealed
that the pathogenesis of the femoral head deformity following
ischemic necrosis is complex, and multiple factors contribute
to the development of the deformity68,77-80 (Fig. 1). Mechanical
testing of the normal and the infarcted femoral heads from
immature pigs has revealed a significant and persistent decrease
in the mechanical properties of the infarcted head from the
early avascular stage to the later vascular repair stage in this
model80. Further studies have revealed that the mechanical
properties of the articular cartilage and the bone from the infarcted heads were decreased79. Proposed explanations for the
early compromise of the mechanical properties have included
the necrosis of the deep layer of the articular cartilage as a result
of the ischemic injury, the inability of the necrotic bone to
repair the microdamage incurred during normal loading of the
hip, and the changes in the material properties of the calcified
cartilage and the subchondral bone associated with the ischemic damage. A recent study on the mineral content of the necrotic trabecular bone, with use of a technique called quantitative
backscatter electron imaging, showed a significant increase in
the calcium content of the calcified cartilage and the subchondral bone (p < 0.05), making the bone more homogeneous in the calcium content and, likely, more brittle77. It is
postulated that since brittle bone is more prone to microdamage and since there are no osteoclasts and osteoblasts in
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Fig. 1
A flowchart depicting the pathogenesis of the femoral head deformity in Legg-Calve-Perthes disease. VEGF = vascular endothelial growth factor.
the necrotic regions of bone to repair the microdamage incurred with the normal activities, this microdamage accumulates and results in a subchondral fracture or a compaction
fracture with continued loading of the hip in the early stages
of Legg-Calve -Perthes disease.
In the vascular repair stage of the piglet model, a pathological repair process marked by a predominance of osteoclastic resorption and delayed bone formation contributes to
the pathogenesis of the deformity68 (Fig. 2). The uncoupling of
bone resorption and formation, and the replacement of the
necrotic bone by a fibrovascular granulation tissue, impart
further weakening to the femoral head. The repair process is
clearly not creeping substitution, as defined by Phemister, in
which dead bone is substituted by new bone in the infarcted
segment of adult femoral heads81. The uncoupling of bone
resorption and formation observed in the piglet model is also
observable in the patients with Legg-Calve -Perthes disease. The
resorptive stage or the stage of fragmentation in the disease
demonstrates increased bone resorption seen as radiolucent
areas on serial radiographs prior to the femoral head entering
the stage of reossification several months or more after the
appearance of the radiolucent areas. Femoral head specimens
obtained from the patients at the stage of fragmentation indeed
show an increased presence of osteoclasts in the areas of repair
and replacement of the bone with a fibrovascular tissue66,67. The
pathological repair process (imbalance of resorption and for-
mation) has been recognized by several investigators as a potential therapeutic target to improve the remodeling of the
necrotic bone and to prevent the development of the deformity
in the immature femoral head82-86.
In addition to these mechanisms, ischemic necrosis of
the immature femoral head produces a growth arrest of the
spherical growth plate surrounding the osseous epiphysis,
which can potentially worsen the femoral head deformity (Fig.
2). Histological studies of specimens from patients with LeggCalve -Perthes disease66,74,76 and the experimental models of
ischemic necrosis78,87,88 have shown necrosis of the deep layer
of the articular cartilage, where endochondral ossification
of the osseous epiphysis occurs. To obtain normal spherical
growth of the epiphysis, endochondral ossification of the osseous epiphysis must be restored in a symmetric, circumferential
fashion as distorted, asymmetric growth may further contribute
to the head deformity. At the present time, the mechanisms
involved with the restoration of the epiphyseal growth are
poorly understood; however, vascular endothelial growth
factor appears to be involved in this process as it is increased
in the cartilage overlying the necrosis in the experimental
studies89,90. It is also known to play an important role in angiogenesis and endochondral ossification91. A recent experimental
study has suggested that exogenous bone morphogenetic
protein (BMP)-2 administration may hasten the restorative
process92.
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Fig. 2
A drawing representing a normal femoral head and an infarcted femoral head in an early stage of revascularization. Ischemic necrosis produces extensive
cell death in the deep layer of the articular cartilage. This is the growth cartilage responsible for the circumferential growth of the secondary center of
ossification. The ischemic damage produces a growth arrest of the secondary center, which may not be restored symmetrically during the healing process
and produces growth disturbance of the secondary center. Revascularization of the infarcted femoral head is associated with a predominance of resorptive
activity, as shown in the drawing. (Reproduced, with permission, from: the Texas Scottish Rite Hospital for Children, Dallas, Texas.)
Role of Hip Loading on the Pathogenesis of Femoral

Head Deformity
Since the hip is a major load-bearing joint, the contribution of
mechanical loading to the pathogenesis of the deformity in
Legg-Calve -Perthes disease must be considered. Unfortunately,
very little is known about the hip forces associated with various
activities of daily living in children. In adults, however, the hip
contact pressures have been measured in a limited number of
patients who had implantation of a strain gauge-instrumented
hip replacement with a telemetric capability to transmit hip
contact forces in real time93,94. These studies have shown that
substantial loading of the hip occurs with normal daily activities. For instance, walking at a normal rate can produce hip
forces of approximately 2.5 times the body weight with each
step, while running can produce hip contact pressure of approximately five times the body weight with each stride. Along
with the magnitude of loading, the frequency of loading may
be important as an active child can take >7500 steps per day
on average95. While it is reasonable to postulate that loading
of the necrotic head contributes to the worsening of the deformity, the efficacy of restricting activities to prevent progression of the deformity is not well studied and it remains
controversial.
Antiresorptive Therapy To Inhibit Pathological
Resorption of the Necrotic Bone
Recognition of Legg-Calve -Perthes disease as having an important resorptive component contributing to the femoral
head deformity has led investigators to study the effects of

inhibiting osteoclast-mediated bone resorption on preventing
the deformity. The most direct evidence that osteoclastic resorption plays an important role in the development of the
deformity comes from a large-animal study that used exogenous osteoprotegerin (OPG), a natural soluble decoy receptor
of the receptor activator of nuclear factor (NF)-k ligand
(RANKL)83. It is well established that the interaction of the
receptor activator of NF-k (RANK) and its ligand, RANKL, is
essential for osteoclast formation, function, and activation96.
The binding of OPG to RANKL prevents the RANK-RANKL
interaction and effectively inhibits osteoclast formation, activation, and survival. In a piglet model of ischemic necrosis,
exogenous OPG therapy significantly decreased osteoclast
number (p < 0.001), bone resorption (p < 0.001), and femoral
head deformity (p < 0.001), providing evidence that specific
targeting of osteoclastogenesis and osteoclastic function can
positively modulate the outcome in this model (Fig. 3)68.
Recently, a RANKL inhibitor called denosumab, a monoclonal antibody to RANKL, has become clinically available
for the treatment of postmenopausal osteoporosis97. Its effect on femoral head osteonecrosis, however, has not been
investigated.
More extensive studies have been performed with use of
bisphosphonates, which are well-known inhibitors of osteoclastic resorption82,84-86,98,99. The mechanism of action of the
aminobisphosphonates (the newer bisphosphonates) is to inhibit farnesyl pyrophosphatase, an enzyme in the HMG-CoA
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Fig. 3
Fig. 3-A Radiographs of the central region of immature femoral heads showing a progression of the femoral head deformity in the piglet model. w = weeks
following the induction of ischemic necrosis. Fig. 3-B A microcomputed tomographic image of a central region of the femoral head obtained at three weeks
after the induction of ischemia, showing a circular area of bone resorption in the necrotic epiphysis. A radiodense, intravascular contrast material (Microfil;
Flow Tech, Carver, Massachusetts) was infused into the distal aorta before imaging to detect revascularization in the necrotic epiphysis. The arrow is
pointing to a vessel with multiple small branches within the area of resorption. Fig. 3-C A photomicrograph of a peripheral area of revascularization showing
the increased presence of multinucleated cells (osteoclasts) and resorption of the trabecular bone (hematoxylin and eosin staining, 20). Fig. 3-D A
photomicrograph of a central area of revascularization showing fibrovascular tissue. The resorbed bone was not replaced by new bone (hematoxylin and
eosin staining, 10). (Figs. 3-A and 3-C are reproduced from Kim HK, Su PH. Development of flattening and apparent fragmentation following ischemic
necrosis of the capital femoral epiphysis in a piglet model. J Bone Joint Surg Am. 2002;84:1329-34.)
(3-hydroxy-3-methylglutaryl-coenyzyme A) reductase pathway, which interferes with prenylation of small GTPase proteins98. The uptake of these drugs by osteoclasts inhibits their
resorptive activity and accelerates apoptosis. Unlike RANKL
inhibitors, bisphosphonates do not inhibit osteoclast formation. Experimental studies in immature rat85,86 and pig models
of ischemic necrosis84 have shown that systemically administered bisphosphonates can decrease bone resorption and
femoral head deformity. In those studies, multiple dosing
regimens were used as only a small portion of each dose was
thought to access the necrotic femoral head. A study with use of
14C-labeled-ibandronate in immature pigs showed that the
local bioavailability and distribution of this bisphosphonate in
the necrotic head depended on the vascular status of the head99.
In the early avascular stage of the piglet model, very little radioactivity was detected in the necrotic head following an intravenous dose of 14C-labeled ibandronate. A significant
increase in the radioactivity was observed when the dose was
administered at a later stage when revascularization of the
femoral head had occurred (p < 0.05). These findings imply
that oral or intravenous administration of a bisphosphonate
has very limited access to the necrotic bone in the early stages of
the disease. Because of this limitation, a multiple-dosing regimen is thought to be required to allow accumulation of the
drug in the necrotic region with each dose100. The repeated

dosing over time is also thought to provide a greater opportunity for the drug to access the necrotic bone since the vascular
status of the necrotic head improves over time.
A concern for a wide distribution of bisphosphonate with
its long half-life on the immature skeleton and the limited
accessibility of the systemically administered bisphosphonate
on the infarcted head have led to an experimental investigation
on the retention, distribution, and effects of a local, intraosseous administration of bisphosphonate for the treatment of
femoral head osteonecrosis82,99. A single, local administration
was shown to be effective and substantially decreased the total
amount of bisphosphonate required to decrease the deformity
in immature pigs82. Only 5% of the systemic dose was required
in the local administration study compared with the systemic
administration study. While antiresorptive drugs were found to
be effective in preserving the necrotic bone in these studies,
their effect on bone remodeling and new bone formation has
been mixed. In rat models of osteonecrosis, new bone formation has been shown to occur on the necrotic bone surface85,86.
This has not been demonstrated in the piglet model. The osteoblast surface was significantly lower in the OPG (88%; p <
0.01) and the ibandronate treatment (93%; p < 0.05) groups
compared with their respective normal control groups83,84 (Fig.
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Fig. 4
Fig. 4-A Radiographs of infarcted femoral heads in the animals treated with subcutaneous saline solution or osteoprotegerin (OPG-Fc), which inhibits
osteoclast formation, function, and activation. The treatments were initiated two weeks after the induction of ischemic necrosis. The OPG group had a
significantly better preservation of the femoral head, as indicated by the bar graph representing the mean epiphyseal quotient (ratio of femoral head height
to its diameter) and the standard deviation. *p < 0.001 compared with the other groups. Fig. 4-B Low-magnification (0.5) photomicrographs of the femoral
heads from the control, saline solution, and OPG groups. The femoral heads from the saline solution group had areas of bone resorption (arrows) and
femoral head deformity. The femoral heads from the OPG group had significantly less bone resorption and better preservation of the femoral head shape
(McNeal tetrachromium staining). Fig. 4-C Higher-magnification (10) photomicrographs of the femoral heads from the control, saline solution, and OPG
groups stained for osteoclasts (red stain) (tartrate-resistant acid phosphatase staining). The mean osteoclast number (and standard deviation) was
significantly lower in the OPG group, as shown on the bar graph. *p < 0.0001 compared with the other groups. (Reproduced, with permission, from: Kim HK,
Morgan-Bagley S, Kostenuik P. RANKL inhibition: a novel strategy to decrease femoral head deformity after ischemic osteonecrosis. J Bone Miner Res.
2006;21:1946-54. 2006 American Society for Bone and Mineral Research.)
4). At this point, it is unclear whether this is an issue of the

duration of follow-up or an issue of the antiresorptive agents
having an inhibitory effect on new bone formation due to a
coupling of the two processes.
Currently, the use of bisphosphonate therapy to treat
Legg-Calve -Perthes disease is investigational. A randomized
clinical trial comparing intravenous administration of zoledronic acid and standard care (weight-bearing restriction and
current treatments) for Legg-Calve -Perthes disease (clinical
trial registration ACTRN12610000407099) is under way in
Australia.
Bone Anabolic Therapy To Stimulate New

Bone Formation
The effects of BMP administration on bone formation in the
context of femoral head osteonecrosis are being investigated
since BMP-2 and BMP-7 are potent osteoinductive agents
shown to promote bone healing under difficult clinical circumstances101-103. The use of BMP-2 to stimulate healing as an
adjunct to core decompression or a strut graft has been investigated in adult animal models of osteonecrosis104,105 and
femoral head defect106. The animal studies have described improved bone healing and increased new bone formation with
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Fig. 5
Fig. 5-A Radiographs of the femoral head of animals treated with intraosseous saline solution, ibandronate (IB), or IB and bone morphogenetic protein
(BMP)-2. A single injection of the respective agent(s) was rendered one week following the induction of ischemic necrosis. Fig. 5-B Photomicrographs
showing osteoblasts (black arrows) on the surface of the trabecular bone in the IB 1 BMP-2 group and the normal, control group (red arrows). The femoral
heads from the saline and the IB groups had a lack of osteoblasts on the trabecular surfaces. Bars = 100 mm. Fig. 5-C A bar graph showing the mean
percentage (and standard deviation) of trabecular bone surface on which osteoblasts were attached, with a significantly greater osteoblast surface, an
indicator of bone formation, in the IB 1 BMP-2 group than in the saline solution and the IB groups. (Reproduced from: Vandermeer JS, Kamiya N, Aya-ay J,
Garces A, Browne R, Kim HKW. Local administration of ibandronate and bone morphogenetic protein-2 stimulates bone formation and decreases femoral
head deformity following ischemic osteonecrosis of the immature femoral head. J Bone Joint Surg Am. 2011;93:905-13.)
the BMP treatment. BMP-2 has also been used clinically to treat
femoral head osteonecrosis in adults as an adjunct to core
decompression107. In a case series of seventeen hips (sixteen
Ficat Stage-II hips and one Ficat Stage-III hip), three hips
progressed and required total hip replacement, while fourteen
hips had good results at an average follow-up duration of fiftythree months107. Since the study was retrospective in nature
without a control group, the true efficacy of BMP-2 treatment
could not be determined.
The use of BMPs to treat femoral head osteonecrosis in a
pediatric population has not been reported, as far as we know.
However, a combined treatment of bisphosphonate (ibandronate) and BMP-2 with use of a local intraosseous injection
technique has been reported in a large-animal study92 (Fig. 5).
The rationale for using bisphosphonate and BMP-2 together in
the study was that, along with osteoinductive properties,

BMP-2 is known to transiently stimulate osteoclastogenesis
and bone resorption108-111. In comparison with the group that
had local administration of ibandronate alone, the group that
had local administration of ibandronate and BMP-2 showed a
significantly greater percent of osteoblast surface on the trabecular bone (p < 0.0001), greater bone volume (p < 0.0001),
and remodeling of the necrotic femoral head92. Furthermore, in
three of the six femoral heads treated with ibandronate and
BMP-2, a restoration of growth of the epiphysis was observed.
Along with improved bone healing, the round shape of the
femoral heads was better preserved in the ibandronate and
BMP-2 treatment group compared with the saline solution
group. In that study, however, heterotopic ossification was
observed in the hip joint capsule of the animals treated with the
667
d
ibandronate and BMP-2. It is postulated that a leakage of BMP2 into the joint on removal of the injection needle and injection
of BMP-2 shortly after the surgical trauma to create the femoral
head ischemia may have predisposed the soft tissues around the
hip to heterotopic ossification. The use of BMPs to treat LeggCalve -Perthes disease is still experimental at this time, and
further studies are warranted prior to the use of BMPs to treat
children with femoral head osteonecrosis.
Clinical Studies on Bisphosphonate Therapy for Femoral
Head Osteonecrosis
To date, only a small number of studies have investigated the
effects of bisphosphonate therapy for the treatment of femoral
head osteonecrosis112-117. Most of those studies assessed shortterm outcomes in adults with nontraumatic femoral head
osteonecrosis. Four clinical studies on nontraumatic osteonecrosis in adults have shown some beneficial effects of bisphosphonate therapy on pain, function, and preservation of
the femoral head112-115. It is of note that, in the randomized
clinical trial reported by Lai et al., only two of twenty-nine hips
required total hip replacement following oral alendronate
therapy for six months compared with nineteen of twenty-five
hips in the nontreatment group at the minimum follow-up
period of two years114. A study by Agarwala et al. showed that
oral bisphosphonate therapy produced the best results when
initiated in the early stage of osteonecrosis (stage-1 disease). At
the mean follow-up interval of four years, 56% (seventy-two)
of 129 patients with stage-2 disease had a radiographic evidence
of collapse, whereas only 13% (twenty-seven) of 215 patients
with stage-1 disease had a collapse113. Limitations of that study
were that the extent of the head involvement was not assessed
and that there were no controls.
A prospective case series of adolescent patients who had
traumatic osteonecrosis because of unstable slipped capital
femoral epiphysis, hip fracture, or dislocation showed that
those who had a cold bone scan and who were treated with
intermittent intravenous bisphosphonate therapy over an average period of twenty months did reasonably well at the
minimum follow-up of two years116. Nine of seventeen patients
had a spherical femoral head, and fourteen of seventeen pa-
tients were pain-free. That study, however, did not have a

control group. A small study of seventeen patients with osteonecrosis as a complication of chemotherapy for childhood
leukemia has also been reported117. In general, improvements
in the pain scores, analgesic requirement, and function were
observed in the nine patients who received bisphosphonate
therapy; however, a radiographic benefit of the therapy could
not be demonstrated. In a small number of patients with LeggCalve -Perthes disease, the systemic effects of intravenous bisphosphonate have been reported recently100; however, its effect on the preservation of the femoral head has yet to be
reported.
Overview
Multicenter prospective cohort studies (level-II evidence) have
shown that the benefits of treatment for older children affected
with Legg-Calve -Perthes disease are modest, even with operative treatments. A better understanding of the pathogenesis of
the femoral head deformity is required to develop more effective treatments. Experimental studies have revealed that an
imbalance of bone resorption and bone formation plays an
important role in the development of the deformity. Further
studies are needed to address the questions about why there is
uncoupling of bone resorption and formation during the
remodeling of the necrotic femoral head, what molecular
mechanisms are involved, and how we can therapeutically
target them more effectively. While recent experimental studies
have shown that antiresorptive and anabolic agents can effectively modulate the pathological repair process, further studies
are needed to address the clinical efficacy and safety of these
agents for the treatment of Legg-Calve -Perthes disease. n
Harry K.W. Kim, MD, MS, FRCSC

Center for Excellence in Hip Disorders,
Department of Orthopaedic Surgery,
Texas Scottish Rite Hospital for Children,
UT Southwestern Medical Center, 2222 Welborn Street,
Dallas, TX 75218. E-mail address: Harry.kim@tsrh.org
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659

Current Concepts Review

Pathophysiology and New Strategies for the

Legg-Calve -Perthes disease is a juvenile form of idiopathic

poses of this review are threefold: to provide an update on the

J Bone Joint Surg Am. 2012;94:659-69

TABLE I Stulberg Radiographic Outcome of Three Treatments

Age of 6 to 8 years at disease

Age of 8 to 12 years at disease

various nonoperative28,35-39 and operative treatments24,27,29,40,41

TABLE II Stulberg Radiographic Outcome of Three Treatments

Age of <6 years at diagnosis

Age of 6 years at diagnosis

*Data are from Wiig O, Terjesen T, Svenningsen S. Prognostic

Pathogenesis of Femoral Head Deformity

Role of Hip Loading on the Pathogenesis of Femoral

head deformity has led investigators to study the effects of

drug in the necrotic region with each dose100. The repeated

4). At this point, it is unclear whether this is an issue of the

Bone Anabolic Therapy To Stimulate New

the study was that, along with osteoinductive properties,

tients were pain-free. That study, however, did not have a

Harry K.W. Kim, MD, MS, FRCSC

45. Heikkinen E, Puranen J. Evaluation of femoral osteotomy in the treatment of

72. Inoue A, Freeman MA, Vernon-Roberts B, Mizuno S. The pathogenesis of

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