243
AUSTRALIAN PAEDIATRIC JOURNAL
Aust. paediat. J. (1975) 11:243 246
corticosteroids and avascular necrosis of the femoral head in childhood by W.G. COLE' and B.W. NEAL' from the R o y a l Children's Hospital, Melbourne. Cole, W.G.and Neal, B.W. (197 ). A u s t . paediat. I., 11, 243-246. Corticosteroids and avascular necrosis of the femoral head in childhood. Avascular necrosis of the femoral head is a common disorder of childhood, but despite careful assessment of each child, a cause for the necrosis is not usually found. In adults, however, it has been shown that approximately one third of patients with idiopathic avascular necrosis of the femoral head have received drugs such as corticosteroids (Fisher & Bickel, 1971). These patients are now classified as having drug-induced avascular necrosis. Such a group has not been previously described in children. In this paper we present the histories of 3 children in whom avascular necrosis of the femoral head probably resulted from corticosteroid therapy. Patients
Drug Treatment
The details concerning the 3 children are listed in Table I. Each child was severely affected by his disease and corticosteroid therapy was an essential part of the treatment.
The corticosteroid therapy given is listed in Table 11. Where it will be noted that the dosage of prednisolone vaned widely in accord with the activity of the disease, and each child showed clinical and radiological evidence of hypercortisonism at the time of developing pain in the hip. The child with bronchial asthma had also received elixophyllin, ephedrobarbital, Intal@ and Tedral@. The child with rheumatoid disease had also received Indocid@, PrirnabQlin@and aspirin.
TABLE I Patients Disease
Sex
Ageof Age of onset of onset of Disease hip sym(Years) ptoms
TABLE I1 Corticosteroid Therapy
(Urns)
Bronchial Asthma Idiopathic thrombocytopenia Rheumatoid disease
M M F
2
11
4 4
7 11
Disease
Type of Corticosteroid
Dose Duration (mg/day ) before onset hip pain (Years)
Bronchial asthma
Prednisolone
7.5- 10 (oral)
3
5-40 (oral)
0.6
5-30 (oral)
7
Idiopathic thrombocytopenia purpura. Prednisolone Received 10 September, 1975 1. Orthopaedic Registrar. 2. Physician and Head of Unit.
Rheumatoid disease.
Prednisolone
244
AUSTRALIAN PAEDIATRIC JOURNAL
Clinical Features Both the child with bronchial asthma and the child with idiopathic thrombocytopenia presented because of ache in the groin and a limp. These symptoms became progressively worse and both children showed marked muscle spasm on all movements of the hip. In the child with idiopathic thrombocytopenia the left hip was affected; the child with bronchial asthma, while receiving treatment for the affected right hip, developed the same symptoms and signs 6 weeks later in the left hip. The child with Still’s disease had rapid onset of pain and stiffness in both hips, which worsened over the following 3 months. Examination showed painful restriction of all movements of the hip joint. Radiological Features All children showed evidence of osteoporosis of the femoral neck. The right hip joint of the child with bronchial asthma showed very marked subchondral destruction of bone with adjacent areas of dense bone. The left hip initially showed only minimal subchondral osteoporosis, but 6 weeks later when the child had pain in that hip, there was evidence of subchondral bone destruction ( Fig. 1). The child with idiopathic thrombocytopenia had a normal right hip, but subchondral bone destruction with adjacent areas of dense bone in the left femoral head with flattening of the femoral head (Fig. 2). The child with Still’s disease showed destruction of the femoral head, such that there was only a small portion of the head visible on the x-ray. The features were similar in both hips (Fig. 3). Treatment and Results The child with idiopathic thrombocytopenia was treated in a bilateral hip spica, and one month later the cast was removed and he was fitted with a Trumble-top weight-relieving caliper which he wore for 19 months. Serial x-rays showed that the flattening of the femoral head epiphysis persisted and after 19 months of treatment, the head had healed but with persistence of the flattening. In addition, he was found to have persistent limitation of internal rotation of the left hip, but he was able to play sport without functional disability. It was necessary for the prednisolone to be continued during the course of treatment of his avascular necrosis.
In contrast, the boy with bronchial asthma developed clinical and radiological features of avascular necrosis of the left femoral head while receiving treatment for avascular necrosis of the right femoral head. His treatment had consisted of preventing weight-bearing on the right leg. By supporting the leg in an abduction splint. Because of marked irritability of the left hip, he had a period of bilateral skin traction as an inpatient, and was subsequently allowed to use a wheelchair. Weight-bearing was not encouraged because of the severe destruction of the right femoral head. Because of the severity of his bronchial asthma it was necessary to continue prednisolone, despite attempts to withdraw it. Serial x-rays have shown severe destructive changes with little evidence of healing. The child with Still’s disease was severely handicapped by the pain, stiffness and deformity in her hips. Because of these problems bilateral hip arthroplasties were planned, but due to her small size it was not possible to perform a total hip joint replacement, so an excisional arthroplasty consisting of the excision of the remains of the femoral head was performed. She showed marked improvement in the deformity, movement, and pain in the hips, and because of the general improvement in her rheumatoid arthritis, prednisolone was later ceased. Discussion It was not possible for us to show that corticosteroid therapy was directly related to the development of avascular necrosis of the femoral head in these children, but many of the features are similar to those reported in adults with drug-induced avascular necrosis. These children did not show any other obvious cause for their avascular necrosis, although in rheumatoid disease avascular necrosis of the femoral heads may sometimes occur as part of the disease. However, bronchial asthma and idiopathic thrombocytopenia cannot be related to avascular necrosis of the femoral head. The first report of the association between administration of corticosteroid and avascular necrosis was by Pietrograndi e t al. (1957). Comprehensive accounts of corticosteroid-induced avascular necrosis in adults are given by Fisher & Bicket (1971), Patterson e t al. (1964), and Solomon (1973). In these reports corticosteroids had been given for a wide variety of disorders, including bronchial asthma, rheumatoid disease
W. G. Cole & B. W. Neal
and thrombocytopenia. The dose of corticosteroids varied considerably, but doses exceeding physiological requirements were given for some period. Although treatment for period as short as 30 days has been associated with development of bone necrosis, the average interval between the initiation of treatment and the onset of symptoms in the hip joint, was 2 years 9 months. The dosage and duration of corticosteroid treatment recorded in this study is in accord with these reports. Furthermore, prednisolone, which was given to our children, was the commonest type of corticosteroid used in the adults. Our children showed the same clinical features of avascular necrosis of the femoral head as were found in the adult series. In the latter the earliest radiological abnormality was subchondral osteoporosis, followed by marked subchondral bone destruction with flattening of the femoral head. Increased radiological density of the femoral head occurred at a later stage. Untreated adults usually showed progressive destruction and deformation of the femoral head. In addition some adults showed porosis of the acetabulum, occasionally leading t o a protrusio deformity. Bone necrosis was frequently found in both hips, and occasionally in other sites such as the humeral heads and femoral condyles. It is apparent that the radiological abnormalities seen in our children had many similarities to these reported changes, in particular the marked subchondral bone destruction occurring in both femoral heads. Pathological studies of affected adult femoral heads showed that the articular cartilage was often intact, although fragmentation and complete loss of the cartilage may be present in long-standing cases. The area of bone necrosis occurs immediately beneath the articular cartilage, and is often present in the weight-bearing area of the head of the femur. The extent of the necrosis vanes from a few millimeters in depth to involvement of approximately half the head. An extreme example was seen in our child with rheumatoid disease. Surrounding the necrotic area there is a zone of vascular granulation tissue, and beyond this an area of new bone formation which produces the increased density seen on x-ray. Normal trabeculae of the femoral head are present outside the area of new bone formation. The process by which corticosteroids lead to the development of avascular necrosis is uncertain, but two hypotheses exist. The first is that corticosteroids produce subchondral osteoporosis,
Corticosteroids & Avdsular Necrosis in Childhood
245
leading to microfractures in the subchondral weight-bearing area of the femoral head, with collapse of the trabeculae and localised aseptic bone necrosis. The second hypothesis is that the corticosteroids produce a fatty liver which leads to fat embolism and the obstruction of subchondral vessels of the femoral head, with subsequent bone necrosis. Analgesic drugs such as Indomethacin@, used in the treatment of the child with Still’s disease, have also been implicated in the production of bone necrosis. It has been suggested that Indomethacin@ decreases the synovitis, and because the patient does not protect his hip to the same degree, a greater stress is placed on the femoral head, with consequent increase in the number of fractures in the osteoporotic subchondral bone trabeculae. Adult studies show that surgicaI treatment, usually consisting of replacement of the femoral head with a prosthesis, has been necessary because of the poor results obtained with conservative treatment. This was found to be so in the child with Still’s disease, but the child with idiopathic thrombocytopenia shows that the femoral capital epiphysis can reform, although with some deformity and ultimately some limitation of hip movement. The outcome in the asthmatic child in whom both femoral heads were involved is uncertain, but conservative treatment should be continued in the expectation that the femoral heads are more likely to heal than may be the case in adults. From our study of these children and the reports of the adults with corticosteroid-induced avascular necrosis, it can be concluded that this is a serious condition which is frequently bilateral, and often leads to progressive destruction of the femoral heads. In children who are already severely handicapped with diseases such as rheumatoid disease or bronchial asthma, the development of avascular necrosis of the femoral head is a severe additional disability. Such an association should be considered when avascular necrosis develops in a child receiving such treatment. There are however, many unknown facts about this association, including the practical ones of whether stopping the drug will lead to a better end-result for the femoral head, and whether it is the total dose of the drug used or the magnitude of the dosages used for short periods during the severe stages of the disease which are important.
246
AUSTRALIAN PAEDIATRIC JOURNAL
Summary This paper reports 3 children in whom the administration of corticosteroids may have been responsible for the development of avascular necrosis of the femoral head. The corticosteroids were given in the form of oral prednisolone in variable doses over periods of 6 months to 7 years. The children presented with pain in the groin, a limp, irritability, and restriction of all hip joint movement. The characteristic radiological changes included porosis and marked subchrondal bone destruction of the femoral head, more marked in the 2 children with bilateral abnormalities. Because of severe destruction of the femoral head, pain and limited movement, one child required excision of the remains of the femoral heads, while the others have been treated with periods of non weight-bearing, but have some continuing abnormalities. This severe form of necrosis shares many features with those in adults reported to have corticosteroid-induced avascular necrosis of the femoral head. Because of these similarities, it is likely that corticosteroids played an important part in the production of femoral head necrosis in these children, and this association should be considered in any child developing femoral head necrosis while receiving this treatment.
REFERENCES Fischer, D.E. and Bickel, W.H. (1971). Corticosteroid Induced Avascular Necrosis. Journal of Bone &Joint Surgery 53-A: 859-873. Patterson, R.J., Bickel, W.H. and Dahlin, D.C. (1964). Idiopathic Avascular Necrosis of the Head of the Femur. Journal of Bone & Joint Surgery 46-A: 267-282. Pietrograndi, V. and Mastromarine, R.C. (1957). Osteopatia da Prolungato Trattamento Cortisonico. Otop. e TraumatoL dell 'Apparato Motore, 25: 791-810. Solomon, L. (1973). Drug - Induced Arthropathy and Necrosis of the Femoral Head. Journal of Bone &Joint Surgery, 55B: 246-261.
Acknowledgments We wish to thank Dr. S.W. Williams and Dr. J.M. Court for allowing us to report two children under their care, and the members of the Orthopaedic Unit for their advice.
Correspondence to: Dr. W.G. Cole, Royal Children's Hospital, Flemington Road, Parkville, Vic. 3052.
AUSTRALIAN PAEDIATRIC JOURNAL
Aust. paediat. J. (1975) 11:243 246
corticosteroids and avascular necrosis of the femoral head in childhood by W.G. COLE' and B.W. NEAL' from the R o y a l Children's Hospital, Melbourne. Cole, W.G.and Neal, B.W. (197 ). A u s t . paediat. I., 11, 243-246. Corticosteroids and avascular necrosis of the femoral head in childhood. Avascular necrosis of the femoral head is a common disorder of childhood, but despite careful assessment of each child, a cause for the necrosis is not usually found. In adults, however, it has been shown that approximately one third of patients with idiopathic avascular necrosis of the femoral head have received drugs such as corticosteroids (Fisher & Bickel, 1971). These patients are now classified as having drug-induced avascular necrosis. Such a group has not been previously described in children. In this paper we present the histories of 3 children in whom avascular necrosis of the femoral head probably resulted from corticosteroid therapy. Patients
Drug Treatment
The details concerning the 3 children are listed in Table I. Each child was severely affected by his disease and corticosteroid therapy was an essential part of the treatment.
The corticosteroid therapy given is listed in Table 11. Where it will be noted that the dosage of prednisolone vaned widely in accord with the activity of the disease, and each child showed clinical and radiological evidence of hypercortisonism at the time of developing pain in the hip. The child with bronchial asthma had also received elixophyllin, ephedrobarbital, Intal@ and Tedral@. The child with rheumatoid disease had also received Indocid@, PrirnabQlin@and aspirin.
TABLE I Patients Disease
Sex
Ageof Age of onset of onset of Disease hip sym(Years) ptoms
TABLE I1 Corticosteroid Therapy
(Urns)
Bronchial Asthma Idiopathic thrombocytopenia Rheumatoid disease
M M F
2
11
4 4
7 11
Disease
Type of Corticosteroid
Dose Duration (mg/day ) before onset hip pain (Years)
Bronchial asthma
Prednisolone
7.5- 10 (oral)
3
5-40 (oral)
0.6
5-30 (oral)
7
Idiopathic thrombocytopenia purpura. Prednisolone Received 10 September, 1975 1. Orthopaedic Registrar. 2. Physician and Head of Unit.
Rheumatoid disease.
Prednisolone
244
AUSTRALIAN PAEDIATRIC JOURNAL
Clinical Features Both the child with bronchial asthma and the child with idiopathic thrombocytopenia presented because of ache in the groin and a limp. These symptoms became progressively worse and both children showed marked muscle spasm on all movements of the hip. In the child with idiopathic thrombocytopenia the left hip was affected; the child with bronchial asthma, while receiving treatment for the affected right hip, developed the same symptoms and signs 6 weeks later in the left hip. The child with Still’s disease had rapid onset of pain and stiffness in both hips, which worsened over the following 3 months. Examination showed painful restriction of all movements of the hip joint. Radiological Features All children showed evidence of osteoporosis of the femoral neck. The right hip joint of the child with bronchial asthma showed very marked subchondral destruction of bone with adjacent areas of dense bone. The left hip initially showed only minimal subchondral osteoporosis, but 6 weeks later when the child had pain in that hip, there was evidence of subchondral bone destruction ( Fig. 1). The child with idiopathic thrombocytopenia had a normal right hip, but subchondral bone destruction with adjacent areas of dense bone in the left femoral head with flattening of the femoral head (Fig. 2). The child with Still’s disease showed destruction of the femoral head, such that there was only a small portion of the head visible on the x-ray. The features were similar in both hips (Fig. 3). Treatment and Results The child with idiopathic thrombocytopenia was treated in a bilateral hip spica, and one month later the cast was removed and he was fitted with a Trumble-top weight-relieving caliper which he wore for 19 months. Serial x-rays showed that the flattening of the femoral head epiphysis persisted and after 19 months of treatment, the head had healed but with persistence of the flattening. In addition, he was found to have persistent limitation of internal rotation of the left hip, but he was able to play sport without functional disability. It was necessary for the prednisolone to be continued during the course of treatment of his avascular necrosis.
In contrast, the boy with bronchial asthma developed clinical and radiological features of avascular necrosis of the left femoral head while receiving treatment for avascular necrosis of the right femoral head. His treatment had consisted of preventing weight-bearing on the right leg. By supporting the leg in an abduction splint. Because of marked irritability of the left hip, he had a period of bilateral skin traction as an inpatient, and was subsequently allowed to use a wheelchair. Weight-bearing was not encouraged because of the severe destruction of the right femoral head. Because of the severity of his bronchial asthma it was necessary to continue prednisolone, despite attempts to withdraw it. Serial x-rays have shown severe destructive changes with little evidence of healing. The child with Still’s disease was severely handicapped by the pain, stiffness and deformity in her hips. Because of these problems bilateral hip arthroplasties were planned, but due to her small size it was not possible to perform a total hip joint replacement, so an excisional arthroplasty consisting of the excision of the remains of the femoral head was performed. She showed marked improvement in the deformity, movement, and pain in the hips, and because of the general improvement in her rheumatoid arthritis, prednisolone was later ceased. Discussion It was not possible for us to show that corticosteroid therapy was directly related to the development of avascular necrosis of the femoral head in these children, but many of the features are similar to those reported in adults with drug-induced avascular necrosis. These children did not show any other obvious cause for their avascular necrosis, although in rheumatoid disease avascular necrosis of the femoral heads may sometimes occur as part of the disease. However, bronchial asthma and idiopathic thrombocytopenia cannot be related to avascular necrosis of the femoral head. The first report of the association between administration of corticosteroid and avascular necrosis was by Pietrograndi e t al. (1957). Comprehensive accounts of corticosteroid-induced avascular necrosis in adults are given by Fisher & Bicket (1971), Patterson e t al. (1964), and Solomon (1973). In these reports corticosteroids had been given for a wide variety of disorders, including bronchial asthma, rheumatoid disease
W. G. Cole & B. W. Neal
and thrombocytopenia. The dose of corticosteroids varied considerably, but doses exceeding physiological requirements were given for some period. Although treatment for period as short as 30 days has been associated with development of bone necrosis, the average interval between the initiation of treatment and the onset of symptoms in the hip joint, was 2 years 9 months. The dosage and duration of corticosteroid treatment recorded in this study is in accord with these reports. Furthermore, prednisolone, which was given to our children, was the commonest type of corticosteroid used in the adults. Our children showed the same clinical features of avascular necrosis of the femoral head as were found in the adult series. In the latter the earliest radiological abnormality was subchondral osteoporosis, followed by marked subchondral bone destruction with flattening of the femoral head. Increased radiological density of the femoral head occurred at a later stage. Untreated adults usually showed progressive destruction and deformation of the femoral head. In addition some adults showed porosis of the acetabulum, occasionally leading t o a protrusio deformity. Bone necrosis was frequently found in both hips, and occasionally in other sites such as the humeral heads and femoral condyles. It is apparent that the radiological abnormalities seen in our children had many similarities to these reported changes, in particular the marked subchondral bone destruction occurring in both femoral heads. Pathological studies of affected adult femoral heads showed that the articular cartilage was often intact, although fragmentation and complete loss of the cartilage may be present in long-standing cases. The area of bone necrosis occurs immediately beneath the articular cartilage, and is often present in the weight-bearing area of the head of the femur. The extent of the necrosis vanes from a few millimeters in depth to involvement of approximately half the head. An extreme example was seen in our child with rheumatoid disease. Surrounding the necrotic area there is a zone of vascular granulation tissue, and beyond this an area of new bone formation which produces the increased density seen on x-ray. Normal trabeculae of the femoral head are present outside the area of new bone formation. The process by which corticosteroids lead to the development of avascular necrosis is uncertain, but two hypotheses exist. The first is that corticosteroids produce subchondral osteoporosis,
Corticosteroids & Avdsular Necrosis in Childhood
245
leading to microfractures in the subchondral weight-bearing area of the femoral head, with collapse of the trabeculae and localised aseptic bone necrosis. The second hypothesis is that the corticosteroids produce a fatty liver which leads to fat embolism and the obstruction of subchondral vessels of the femoral head, with subsequent bone necrosis. Analgesic drugs such as Indomethacin@, used in the treatment of the child with Still’s disease, have also been implicated in the production of bone necrosis. It has been suggested that Indomethacin@ decreases the synovitis, and because the patient does not protect his hip to the same degree, a greater stress is placed on the femoral head, with consequent increase in the number of fractures in the osteoporotic subchondral bone trabeculae. Adult studies show that surgicaI treatment, usually consisting of replacement of the femoral head with a prosthesis, has been necessary because of the poor results obtained with conservative treatment. This was found to be so in the child with Still’s disease, but the child with idiopathic thrombocytopenia shows that the femoral capital epiphysis can reform, although with some deformity and ultimately some limitation of hip movement. The outcome in the asthmatic child in whom both femoral heads were involved is uncertain, but conservative treatment should be continued in the expectation that the femoral heads are more likely to heal than may be the case in adults. From our study of these children and the reports of the adults with corticosteroid-induced avascular necrosis, it can be concluded that this is a serious condition which is frequently bilateral, and often leads to progressive destruction of the femoral heads. In children who are already severely handicapped with diseases such as rheumatoid disease or bronchial asthma, the development of avascular necrosis of the femoral head is a severe additional disability. Such an association should be considered when avascular necrosis develops in a child receiving such treatment. There are however, many unknown facts about this association, including the practical ones of whether stopping the drug will lead to a better end-result for the femoral head, and whether it is the total dose of the drug used or the magnitude of the dosages used for short periods during the severe stages of the disease which are important.
246
AUSTRALIAN PAEDIATRIC JOURNAL
Summary This paper reports 3 children in whom the administration of corticosteroids may have been responsible for the development of avascular necrosis of the femoral head. The corticosteroids were given in the form of oral prednisolone in variable doses over periods of 6 months to 7 years. The children presented with pain in the groin, a limp, irritability, and restriction of all hip joint movement. The characteristic radiological changes included porosis and marked subchrondal bone destruction of the femoral head, more marked in the 2 children with bilateral abnormalities. Because of severe destruction of the femoral head, pain and limited movement, one child required excision of the remains of the femoral heads, while the others have been treated with periods of non weight-bearing, but have some continuing abnormalities. This severe form of necrosis shares many features with those in adults reported to have corticosteroid-induced avascular necrosis of the femoral head. Because of these similarities, it is likely that corticosteroids played an important part in the production of femoral head necrosis in these children, and this association should be considered in any child developing femoral head necrosis while receiving this treatment.
REFERENCES Fischer, D.E. and Bickel, W.H. (1971). Corticosteroid Induced Avascular Necrosis. Journal of Bone &Joint Surgery 53-A: 859-873. Patterson, R.J., Bickel, W.H. and Dahlin, D.C. (1964). Idiopathic Avascular Necrosis of the Head of the Femur. Journal of Bone & Joint Surgery 46-A: 267-282. Pietrograndi, V. and Mastromarine, R.C. (1957). Osteopatia da Prolungato Trattamento Cortisonico. Otop. e TraumatoL dell 'Apparato Motore, 25: 791-810. Solomon, L. (1973). Drug - Induced Arthropathy and Necrosis of the Femoral Head. Journal of Bone &Joint Surgery, 55B: 246-261.
Acknowledgments We wish to thank Dr. S.W. Williams and Dr. J.M. Court for allowing us to report two children under their care, and the members of the Orthopaedic Unit for their advice.
Correspondence to: Dr. W.G. Cole, Royal Children's Hospital, Flemington Road, Parkville, Vic. 3052.
