The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 94, Issue 7

Current Concepts Review | April 04, 2012

Pathophysiology and New Strategies for the Treatment of Legg-Calvé-Perthes Disease

Harry K.W. Kim, MD, MS, FRCSC¹

¹ 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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Investigation performed at Texas Scottish Rite Hospital for Children, Dallas, Texas

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 Apr 04;94(7):659-669. doi: 10.2106/JBJS.J.01834

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Abstract

Legg-Calvé-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 Legg-Calvé-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.

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Introduction

Introduction | Current Treatments and Outcomes | Pathophysiology of Legg-Calvé-Perthes Disease | Pathogenesis of Femoral Head Deformity in Legg-Calvé-Perthes Disease | Role of Hip Loading on the Pathogenesis of Femoral Head Deformity | Antiresorptive Therapy To Inhibit Pathological Resorption of the Necrotic Bone | Bone Anabolic Therapy To Stimulate New Bone Formation | Clinical Studies on Bisphosphonate Therapy for Femoral Head Osteonecrosis | Overview

Legg-Calvé-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 world^1-4. Since the initial reports of this unique condition approximately 100 years ago by Legg⁵, Calvé⁶, and Perthes⁷, a number of studies have been published regarding its etiology^8-15, epidemiology^1,3,4, natural history^16-20, radiographic classifications^16,21-23, treatments^24-29, and outcomes^30-32. Despite the increase in knowledge, Legg-Calvé-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 purposes 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-Calvé-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-Calvé-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 acetabulum^33,34. 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, various nonoperative^28,35-39 and operative treatments^{24,27,29,40,41} 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 studies^42,43, 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 patients 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.

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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)	27% (3)	73% (8)
Range of motion (n = 44)	48% (21)	52% (23)
Brace (n = 79)	62% (49)	38% (30)
Innominate osteotomy (n = 39)	69% (27)	31% (12)
Femoral osteotomy (n = 31)	68% (21)	32% (10)
Age of ≥8 to 12 years at disease onset (n = 141)
No treatment (n = 8)	25% (2)	75% (6)
Range of motion (n = 33)	30% (10)	70% (23)
Brace (n = 50)	36% (18)	64% (32)
Innominate osteotomy (n = 29)	41% (12)	59% (17)
Femoral osteotomy (n = 21)	62% (13)	38% (8)

*The data are from Herring JA, Kim HT, Browne R. Legg-Calvé-Perthes disease. Part II: Prospective multicenter study of the effect of treatment on outcome. J Bone Joint Surg Am. 2004;86:2121-34.

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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)	27% (3)	73% (8)
Range of motion (n = 44)	48% (21)	52% (23)
Brace (n = 79)	62% (49)	38% (30)
Innominate osteotomy (n = 39)	69% (27)	31% (12)
Femoral osteotomy (n = 31)	68% (21)	32% (10)
Age of ≥8 to 12 years at disease onset (n = 141)
No treatment (n = 8)	25% (2)	75% (6)
Range of motion (n = 33)	30% (10)	70% (23)
Brace (n = 50)	36% (18)	64% (32)
Innominate osteotomy (n = 29)	41% (12)	59% (17)
Femoral osteotomy (n = 21)	62% (13)	38% (8)

*The data are from Herring JA, Kim HT, Browne R. Legg-Calvé-Perthes disease. Part II: Prospective multicenter study of the effect of treatment on outcome. J Bone Joint Surg Am. 2004;86:2121-34.

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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)	53% (65)	47% (58)
Scottish Rite orthosis (n = 22)	45.5% (10)	54.5% (12)
Femoral osteotomy (n = 23)	52% (12)	48% (11)
Age of ≥6 years at diagnosis (n = 146)
Physiotherapy (n = 51)	33% (17)	67% (34)
Scottish Rite orthosis (n = 25)	20% (5)	80% (20)
Femoral osteotomy (n = 70)	43% (30)	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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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)	53% (65)	47% (58)
Scottish Rite orthosis (n = 22)	45.5% (10)	54.5% (12)
Femoral osteotomy (n = 23)	52% (12)	48% (11)
Age of ≥6 years at diagnosis (n = 146)
Physiotherapy (n = 51)	33% (17)	67% (34)
Scottish Rite orthosis (n = 25)	20% (5)	80% (20)
Femoral osteotomy (n = 70)	43% (30)	57% (40)

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 head^42,45, they do not directly or specifically address the pathobiology of the disease and the impaired healing observed in the older children with Legg-Calvé-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-Calvé-Perthes disease is essential for the development of more effective treatments.

Pathophysiology of Legg-Calvé-Perthes Disease

Various theories on the etiology of Legg-Calvé-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 exposure^13,46-49, and, most recently, a subtle type-II collagen mutation^12,14,50. Most of these theories remain unsubstantiated. Thrombophilia as a cause of Legg-Calvé-Perthes disease remains controversial, with some studies having shown an association between the disease and various coagulation factor abnormalities^8,51-55, while other studies have shown no association at all^11,56-60. The prevailing opinion is that Legg-Calvé-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 angiography^61-63, 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-Calvé-Perthes disease are limited in number, they show changes consistent with ischemic necrosis of the bone and the deep layer of the articular cartilage^66,67. Animal studies also have shown that a disruption of the blood supply to the femoral head can produce radiographic and histological changes resembling Legg-Calvé-Perthes disease^68,69.

The question of whether Legg-Calvé-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-Calvé-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-Calvé-Perthes disease in some femoral heads^70,71. 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 Legg-Calvé-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-Calvé-Perthes Disease

Development of the femoral head deformity is the most important sequela of Legg-Calvé-Perthes disease since the extent of the deformity correlates with the long-term outcome^18-20. 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-Calvé-Perthes disease, various pathological changes from the proximal part of the femur that include the articular cartilage, osseous epiphysis, physis, and metaphysis have been reported^66,67,73-76. 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 deformity^68,77-80 (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 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-Calvé-Perthes disease.

Fig. 1

A flowchart depicting the pathogenesis of the femoral head deformity in Legg-Calvé-Perthes disease. VEGF = vascular endothelial growth factor.

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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-Calvé-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 tissue^66,67. The pathological repair process (imbalance of resorption and formation) 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 head^82-86.

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.)

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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 Legg-Calvé-Perthes disease^66,74,76 and the experimental models of ischemic necrosis^78,87,88 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 studies^89,90. 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.

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-Calvé-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 time^93,94. 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-Calvé-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)-κß ligand (RANKL)⁸³. It is well established that the interaction of the receptor activator of NF-κß (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.

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.)

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More extensive studies have been performed with use of bisphosphonates, which are well-known inhibitors of osteoclastic resorption^{82,84-86,98,99}. The mechanism of action of the aminobisphosphonates (the newer bisphosphonates) is to inhibit farnesyl pyrophosphatase, an enzyme in the HMG-CoA (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 rat^85,86 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 osteonecrosis^82,99. 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 surface^85,86. 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 groups^83,84 (Fig. 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.

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.)

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Currently, the use of bisphosphonate therapy to treat Legg-Calvé-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-Calvé-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 circumstances^101-103. 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 osteonecrosis^104,105 and femoral head defect¹⁰⁶. The animal studies have described improved bone healing and increased new bone formation with 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 fifty-three 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 resorption^108-111. 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 ibandronate and BMP-2. It is postulated that a leakage of BMP-2 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 Legg-Calvé-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.

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 + 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 μm. 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 + 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.)

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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 osteonecrosis^112-117. Most of those studies assessed short-term 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 head^112-115. 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 patients 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 Legg-Calvé-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-Calvé-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-Calvé-Perthes disease.

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head of femur ; legg-perthes disease ; necrosis

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Harry K.W. Kim; Pathophysiology and New Strategies for the Treatment of Legg-Calvé-Perthes Disease. The Journal of Bone & Joint Surgery. 2012 Apr;94(7):659-669.

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