Steroid-Induced Osteoporosis in the Pediatric Population - Canadian Incidence Study

Overview

To determine the magnitude and rate of bone mass deficits following initiation of glucocorticoid therapy for the treatment of pediatric leukemia, rheumatic conditions and nephrotic syndrome, we propose a 6 year, prospective study in 12 academic, tertiary care centres across Canada. The investigators hypothesize that glucocorticoid-treated children with leukemia, rheumatic conditions and nephrotic syndrome will fail to accrue bone mass at a normal rate, and that deficits in mineral accrual will occur in a glucocorticoid dose- and duration-dependent fashion. We also hypothesize that the fracture incidence will increase with concomitant reductions in bone mass.

Leukemia and Bone Morbidity Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with an overall survival rate now exceeding 70%. As such, there is an increasing population of survivors who are at risk for long-term sequelae of childhood leukemia, including osteoporosis. In Canada, there are approximately 250 new cases of childhood ALL diagnosed per year. All children in Canada undergoing therapy for the treatment of ALL in tertiary care pediatric hospitals will receive high dose glucocorticoids as per one of three ALL protocols (the Children's Cancer Group protocol, the Pediatric Oncology Group protocol, or the Dana Farber Cancer Institute Consortium protocol), depending upon the standard of care at a given institution. Musculoskeletal pain and gait abnormalities have been reported in one third of children with ALL at diagnosis, a sub-set of whom also demonstrate fractures. Radiographs of painful regions show metaphyseal lucencies, sclerotic lesions and sites of periosteal reaction in many of the patients with bone pain at presentation. Lumbar spine areal bone mineral density (BMD) is reduced at diagnosis, while total body and volumetric BMD are within the normal range. Several groups have reported significant loss of bone mass during therapy for ALL, while studies of bone mass restitution following chemotherapy have led to inconsistent results. The most rapid reductions in bone mass have occurred in the first 6-8 months of therapy, similar to the observed glucocorticoid effect on bone in adults. Fractures have been present in as many as 13% of children at diagnosis, rising to 39% during chemotherapy. In addition to glucocorticoids, a number of other mechanisms have been proposed for the skeletal morbidity in ALL, including infiltration of bone by leukemic cells, paraneoplastic factors, other medications, physical inactivity, cranial irradiation, inadequate nutrition and disordered mineral metabolism. Rheumatic Conditions and Bone Morbidity Rheumatic diseases of childhood, including juvenile rheumatoid arthritis, systemic lupus erythematosis and juvenile dermatomyositis, are well-known to be associated with compromised skeletal health. Of these, juvenile rheumatoid arthritis has been evaluated the most extensively. Significant reductions in bone mass have been documented in a number of studies of pediatric patients with chronic rheumatic disease, and atraumatic fractures have been noted at an early age. Active arthritis may affect bone metabolism in areas adjacent to affected joints ("periarticular osteopenia"), and at more distant sites including the radius, spine, and femoral neck. In a recent study of pediatric patients with reductions in bone mass secondary to chronic rheumatic disease, 8/38 (21%) of patients had fragility fractures, primarily of the vertebrae. Similar to other osteoporotic conditions due to chronic illness, the pathogenesis of the bone morbidity in these cases is multi-factorial, with disease activity, muscle disease, physical inactivity, nutritional status and medical therapy playing significant roles. However, as in leukemia, glucocorticoid use has emerged as one of the strongest determinants of skeletal morbidity during treatment for juvenile rheumatoid arthritis and systemic lupus erythematosis. The role of glucocorticoids in bone morbidity associated with pediatric rheumatic diseases such as juvenile dermatomyositis and vasculitides has not been determined. Nephrotic Syndrome and Bone Morbidity Childhood nephrotic syndrome is an idiopathic disorder characterized by proteinuria, hypoproteinemia, edema and hyperlipidemia. The incidence of the syndrome varies between 1:15,000 to 1:50,000. Following the introduction of glucocorticoid therapy in the 1970's, the mortality from nephrotic syndrome decreased dramatically over the ensuing 15 years, from 35 to 3 per cent. The vast majority of patients with nephrotic syndrome have steroid-responsive disease. In Canada, the standard of care for children with their first episode of nephrotic syndrome is high-dose glucocorticoid therapy for 6 weeks, followed by gradual tapering over the next three to seven months. Only one-third of patients will enter into permanent remission with this regime, while another third will require pulse steroid therapy for up to six weeks' duration at infrequent intervals throughout the growing years. The final third of patients will either require frequent courses of pulse glucocorticoid therapy or chronic steroid administration in order to achieve remission. Children with nephrotic syndrome are typically well-nourished, fully ambulatory, and otherwise well between episodes. Furthermore, their treatment regime is more likely to be characterized by glucocorticoid therapy alone, compared to the polytherapy that is required for the treatment of leukemia and rheumatic conditions. As such, the greater homogeneity of the nephrotic syndrome population allows for a more "pure" assessment of glucocorticoid effect on pediatric bone. Small studies have demonstrated reductions in bone mass by dual energy x-ray absorptiometry (DXA) and an increase in biochemical markers of bone resorption among young, glucocorticoid-treated patients with nephrotic syndrome. Tenbrock et al. recently showed by peripheral quantitative computed tomography that 16 children with nephrotic syndrome, all previously treated with glucocorticoids, had reductions in cortical area at the distal radius, which correlated with reductions in grip strength. The fracture rate among children with nephrotic syndrome is presently unknown. Among adults with nephrotic syndrome, high-dose glucocorticoid administration led to rapid bone loss in the first few months of therapy, raising the question whether preventive therapy should be initiated in such adults after three months of glucocorticoid use, if measures of bone mass have fallen significantly below baseline.