Trial Information

Steroid-Induced Osteoporosis in the Pediatric Population - Canadian Incidence Study (STOPP-CIS)

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.