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Legg-Calve-Perthes Disease: Etiology, Pathogenesis, and Biology

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

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Journal of Pediatric Orthopaedics: September 2011 - Volume 31 - Issue - p S141-S146
doi: 10.1097/BPO.0b013e318223b4bd
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Since the recognition of Legg-Calve-Perthes disease (LCPD) as a separate disease entity in 1910, numerous theories on the etiology of the disease have been proposed (Table 1). A challenge has been to find a single etiologic factor that would explain various clinical and epidemiologic features of LCPD. A possibility that LCPD may be caused by multiple etiologic factors that share a common final pathogenic pathway remains open. A prevailing view is that LCPD is a multifactorial disease caused by a combination of genetic and environmental factors. According to this view, genetic factors impart “susceptibility” to the disruption of the blood supply to the femoral head, whereas environmental factors, such as repeated subclinical trauma or mechanical overloading related to hyperactivity of the child, trigger the disease.

Proposed Etiologies

Type II Collagen Mutation

Recently, Asian families with multiple members affected with femoral head osteonecrosis in an autosomal dominant manner were found to have a missense mutation in the type II collagen gene (replacement of glycine with serine at codon 1170 of COL2A1).1–3 In contrast to other skeletal dysplasias and type II collagenopathies, the affected individuals with this mutation did not seem to have overt evidence of other skeletal abnormalities. In the affected individuals with open growth plates, radiographic changes similar to LCPD were observed.2,3 It is unclear at this time whether these changes are in fact due to an ischemic process or whether this is a form of skeletal dysplasia. It is speculated that the collagen mutation causes a weakening of the cartilage matrix3 leading to a compromise in the integrity of the blood vessels within the cartilage with mechanical loading. Even if the mutation is a cause of LCPD, it may only account for a small number of patients with bilateral familial LCPD, as it is yet to be reported in sporadic unilateral or nonfamilial bilateral cases of LCPD.4


Thrombophilia leading to thrombotic venous occlusion of the femoral head have been proposed as a cause of LCPD. In a case-control study that reported on the association between LCPD and coagulation abnormalities, Glueck et al5 found that 19 of the 44 patients with LCPD had protein-C deficiency and 4 of the 44 patients with Perthes disease had protein-S deficiency. Seven patients had elevated lipoprotein (a) and 3 had hypofibrinolysis. Altogether, 75% of the patients in the study had coagulation abnormalities. Although some studies also have reported on an increased rate of coagulation abnormalities in the patients with LCPD at lower rates than originally reported by Glueck et al,5–9 others have not found any association at all.10–13 It is difficult to decipher why such discrepancy exist; however, small sample size in some studies, retrospective study design, use of suboptimal controls, and nonstandardized range of laboratory values of what coagulation factor level is considered abnormal for different age groups may be some of the confounding factors.

In terms of a prospective study, a random series of 50 consecutive patients with LCPD did not have a difference in the prevalence of protein-C, protein-S, or antithrombin III deficiencies, or factor-V Leiden mutation between the study group and the estimated population frequency.14 More recent case-control study from Cincinnati consisting of 72 nonselected, consecutive series of patients with LCPD and 197 healthy controls also found no increase in the prevalence of protein-C, protein-S, and antithrombin-III deficiencies, hyperhomocysteinemia, and elevated plasminogen activator inhibitor-1 activity.15 However, this study did find a higher prevalence of factor-V Leiden (8 of 72 in the study group compared with 7 of 197 in the control group) and anticardiolipin antibodies (19 of 72 in the study group compared with 22 of 197 in the control group) in the patients with LCPD. In a larger case-control study reported recently from a group in the Netherlands, a higher prevalence of the factor V Leiden mutation (16 of 166 compared with 16 of 509 in the control group) was also observed along with a higher prevalence of the prothrombin G20210A mutation (9 of 169 compared with 11 of 512 in the control group).16 Another case-control study consisting of 119 patients with LCPD and 276 control participants from Israel, however, did not find a higher prevalence of the factor V Leiden mutation in the patients with LCPD (7 of 119 compared with 13 of 276 in the control group).4

Even in a few number of families studied with multigeneration transmission of factor V Leiden mutation, the rate of LCPD seems to be quite variable. In 1 family, only 1 of the 11 members found to be heterozygous for the factor V Leiden mutation (G1691A) was noted to have LCPD. In another family, 3 of the 10 members with either heterozygous or homozygous factor V mutation were noted to have LCPD.8 It is estimated that LCPD develops in 1 of 2777 children (0.036%) in whom the factor V Leiden mutation is present.15 As thrombotic events are uncommon during childhood, even in those patients with inherited thrombophilia,17 the significance of inherited or acquired thrombophilia to the pathogenesis of LCPD remains unclear at this time.

Abnormality in the Insulin-like Growth Factor-1 Pathway

Alteration of the insulin-like growth factor-1 (IGF-1) pathway as a cause of LCPD merits attention, as IGF-1 is known to affect the postnatal development of various tissues, including the brain and skeleton. Thus, dysfunction in the IGF-1 pathway can potentially explain the delayed skeletal maturation, hyperactive behavior, and minor congenital abnormalities seen in the patients with LCPD. Low levels of serum IGF-1 and IGF-1 binding protein 3 have been reported in patients with LCPD.18,19 These results conflict with another study, which reported normal IGF-1 binding protein levels.20

Other Associated Factors

Studies have reported increased association between a very low birth weight or short body length at birth with LCPD, suggesting that genetic or early developmental factors may be linked to the disease. An increased association has also been reported with maternal smoking and second-hand smoke exposure.21–23


Although the etiology of LCPD remains unknown, clinical and experimental evidence support the notion that the disruption of the blood supply to the femoral head is a key pathogenic event associated with the disease process. Selective angiography,24–26 bone scintigraphy,27 perfusion magnetic resonance imaging,28 and the biopsy studies29 from the early stages of the disease show evidence of a disruption of perfusion and tissue damage consistent with ischemic necrosis.

It is debatable whether a single episode or multiepisodes of ischemia are necessary to produce LCPD. The multiple infarction theory is based on the observations from an immature canine model, where a single surgical attempt at inducing femoral head infarction did not produce the femoral head deformity and the histologic features of LCPD.30,31 These findings were observed only after a second infarction surgery, leading to the conclusion that LCPD may be due to >1 episode of infarction.30 In contrast, a single infarction surgery produced a femoral head deformity and histologic changes resembling LCPD in a piglet model of ischemic necrosis.32

In a clinical study, 51% of 57 biopsy specimens from the femoral heads of patients with LCPD revealed dead-woven bone superimposed on dead lamellar bone with marrow space occupied by dead granulation tissue, suggesting 2 episodes of infarction in these specimens.33 A review of 6 whole femoral heads and 5 core biopsy specimens from the patients with LCPD by Catterall et al,34 found thickened trabeculae with multiple layers of cement lines, but no evidence of bone necrosis in a Catterall classification group 1 femoral head. In Catterall classification group 4 femoral heads, thickened trabeculae with many cement lines with bone necrosis were observed in the central area of the femoral heads. In the periphery, however, the researchers observed bony trabeculae showing 1 episode of infarction only. A prevailing interpretation of these findings is that multiple episodes of infarction are necessary to produce LCPD. This implies that if the cause of the infarction can be stopped or treated early, then the extent or the severity of the disease can be minimized. Another interpretation may be that the disease is due to 1 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 producing secondary episodes of infarctions. This implies that the avoidance of mechanical overloading would be beneficial to the healing process.

Limited availability of clinical specimens underscores the major obstacle in trying to understand the pathophysiology of a condition with so much variability. The findings from a histopathological review of 6 whole femoral heads, a few isolated necropsy reports, and some studies based on surgical biopsy specimens29,33–40 are all that are available at this time to gain understanding of the disease process. From these studies, it can be summarized that the pathologic process affects the articular cartilage, bony epiphysis, physis, and metaphysis (Fig. 1). Articular cartilage changes include increased thickness, chondrocyte necrosis in the deep layer of the cartilage, cessation of endochondral ossification, separation of cartilage from underlying subchondral bone, vascular invasion of the cartilage, and new accessory ossification. In the bony epiphysis, the necrosis of the marrow space and the trabecular bone, compression fracture of trabeculae, fibrovascular granulation tissue invasion, and osteoclastic resorption of the necrotic bone, and thickened trabeculae due to new bone formation have been reported. The physeal changes are most often seen in the anterior part of the femoral head with focal areas of growth cartilage extending into the metaphysis. Premature growth arrest of the growth plate is seen in 30% of patients with LCPD suggesting that in a majority of the patients the growth plate continues to function. Metaphyseal changes are commonly seen during the early stages of LCPD. Various tissue types have been reported.34 Some researchers have found an association between the presence of radiolucent metaphyseal changes and poor prognosis, whereas other researchers have not.

An illustration combining the described histopathological changes from the necropsy, biopsy, and experimental studies of Legg-Calve-Perthes disease. Important pathological changes include cartilage and bone necrosis, subchondral fracture and compaction of the necrotic bone, and revascularization of the necrotic epiphysis from the periphery. With the onset of ischemic necrosis, the mechanical properties of the femoral head decrease. It is proposed that when hip joint loading surpasses the weakened mechanical strength of the necrotic femoral head, the deformity is initiated and progresses. Resorption of the necrotic bone and asymmetric restoration of endochondral ossification at the periphery further contribute to the pathogenesis of the femoral head deformity.

The lack of availability of clinical samples for research has prompted alternative approaches to investigate the pathogenesis of LCPD. In particular, a piglet model has allowed more systematic investigation of ischemic damage, repair process, and pathogenesis of femoral head deformity after disruption of the epiphyseal blood supply. The key findings are that the induction of ischemia produces a decrease in the mechanical stiffness of the necrotic femoral head, making it soft in comparison to the normal femoral head from the early avascular necrotic phase of the model.41,42 In the necrotic phase, the decrease in the mechanical properties of the necrotic femoral head may be due to the necrosis of the deep layer of the articular cartilage,43 the changes in the material properties of the necrotic calcified cartilage and the trabecular bone,44 and possible accumulation of microfractures in the necrotic bone. Repetitive loading is known to produce microfractures in the bone, which are normally detected and repaired by bone cells.45 In the necrotic bone, however, no cells are available to detect and repair the microdamage related to repetitive loading.

Vascular invasion and osteoclastic resorption of the necrotic bone further compromise the mechanical properties of the infarcted head.41 The predominance of bone resorption produces areas of radiolucency within the necrotic epiphysis and a fragmented appearance.32 Inhibition of bone resorption using antiresorptive agents, such as bisphosphonates and a RANKL inhibitor, has been shown to decrease the deformity in the animal studies indicating that the resorptive process is an important component of the pathogenesis of the femoral head deformity.46,47

It is important to consider the development of the femoral head deformity in the context of loading, as the hip joint is a major load-bearing joint. Unfortunately, the relationship between hip joint loading and development of the femoral head deformity remains largely unstudied. In children, the hip contact pressures associated with various activities of daily living are unknown. In adults, a femoral head prosthesis equipped with a strain gauge has allowed collection of this data after total hip replacement (Table 2).48 The measurements indicate that significant forces act on the femoral head with certain daily activities. For activities that are performed in a repetitive manner, such as walking or running, the number of steps, or the frequency of loading should also be taken into consideration. For an individual, the magnitude and frequency of hip joint loading will depend on the list of activities the person performs, the frequency of each activity, and the body weight. In a disease where the femoral head deformity is produced due to mechanical weakening, avoidance of activities that generate a significant increase in the hip contact pressure seems reasonable. At this time it is unknown what the “significant” loading is and what the efficacy of restricting activities is on preventing the deformity.

Hip Contact Pressures in Adults Obtained Using Strain gauge-instrumented Total Hip Replacement

In contrast to the femoral head weakening and hip joint loading, which promote the development of the femoral head deformity, the healing or remodeling potential related to the age at onset of the disease seems to offset the deformity. Clinical studies consistently show a better outcome in terms of the femoral head shape in the patients with early-onset of LCPD.49 It is unclear what factors determine the healing and the remodeling potentials. One important biological factor to keep in mind is that LCPD affects a wide age range of children from preschool years to teenage years, and that the age range represents a growth period when significant changes are taking place in terms of the femoral head anatomy, size, and vascularity (Fig. 2).50–53 The size of the bony epiphysis increases while the thickness of the articular cartilage and its growth potential decrease with age. In addition, more subtle changes, such as the regression of cartilage vascularity (cartilage vascular canals) and the changes in the vascular anatomy of the proximal femur, are taking place. Given these changes, the onset of the disease at different ages implies that the disease is affecting a femoral head that may have significantly different growth and remodeling potentials. These factors are likely to affect the final outcome of the femoral head.

A drawing showing significant developmental changes occurring in the proximal femur from infancy to maturity. Notable changes included decreased cartilage thickness and cartilage vascularity, increased size of the bony epiphysis, and decreased growth potential. It is postulated that the onset of ischemic necrosis at different stages of femoral head development will have a significant implication in terms of the healing and the remodeling potentials of the femoral head due to these changes.

In summary, there is still much to learn about the etiology and the pathogenesis of LCPD. The pathogenesis of the femoral head deformity is complex with biological and mechanical factors playing a role. To be effective, treatment should take into consideration the mechanical and biological factors involved with the pathogenesis of deformity.


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Legg-Calve-Perthes disease; avascular necrosis; etiology; pathogenesis; femoral head deformity

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