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

1 Month
16 Years
Open (Enrolling)
Acute Lymphoblastic Leukemia, Nephrotic Syndrome, Rheumatism

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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.

Inclusion Criteria:

Inclusion Criteria

1. Children aged > or = 1 month to < or = 16 years at the time of enrolment.

2. Clinical diagnosis of one of the following three diseases:

1. Acute lymphoblastic leukemia OR

2. Rheumatic disease,OR

3. Nephrotic syndrome

3. Need for the first-time initiation of intravenous (IV) or oral glucocorticoid therapy
(regardless of the dose or duration) for the treatment of the leukemia, nephrotic
syndrome or rheumatic conditions, as determined by the attending physician. IV and
oral glucocorticoids used in current clinical practice for the treatment of leukemia,
nephrotic syndrome and rheumatic conditions include cortisone, hydrocortisone,
methylprednisolone, prednisolone, prednisone, dexamethasone, and deflazacorte. If
patients are receiving intra-articular, inhaled, intra-nasal or topical
corticosteroids, these agents alone do not meet the steroid criteria for enrolment in
the study. However, the use of such steroids will be captured as part of the Case
Report Form.

4. Only patients who are receiving glucocorticoids for the first time for the treatment
of their underlying leukemia, nephrotic syndrome or rheumatic condition, will be
included. Patients who have received glucocorticoids in the past for other
indications (e.g. asthma), may be included in the study, provided they have not
received more than 14 consecutive days of IV or oral steroids in the 12 months prior
to the first initiation of steroids for their underlying leukemia, nephrotic syndrome
or rheumatic condition. The pre-STOPP study use of glucocorticoids for 14 days or
less, for treatment of unrelated medical conditions in the 12 months prior to the
first initiation of steroids to treat the underlying leukemia, nephrotic syndrome or
rheumatic conditions, will be captured in the Case Report Form.

5. Informed consent.

6. Ability and willingness to maintain a "Glucocorticoid Dose Diary" throughout the

7. For menstruating females, a negative pregnancy test will be required prior to

Exclusion Criteria:

1. Inability to obtain baseline investigations within 30 days of the first-time
initiation of glucocorticoids for the treatment of the underlying leukemia, nephrotic
syndrome or rheumatic condition.

2. Complete immobilization (patient confined to bed except for toileting) for more than
14 consecutive days in the 12 months prior to the initiation of glucocorticoids for
the treatment of their underlying leukemia, nephrotic syndrome or rheumatic

3. Use of IV or oral glucocorticoids for more than 14 consecutive days, for the
treatment of unrelated medical conditions, in the 12 months prior to the first
initiation of steroids for the treatment of the underlying leukemia, nephrotic
syndrome or rheumatic condition.

4. Treatment of osteoporosis with medical therapy prior to the initial baseline visit
(treatment with, for example, a bisphosphonate, calcitonin, fluoride).

5. Unwillingness to utilize a medically approved method of birth control if menstruating
and sexually active.

Type of Study:


Study Design:

Observational Model: Cohort, Time Perspective: Prospective

Outcome Measure:

The magnitude and rate of total body, hip and lumbar spine bone mass deficits

Outcome Description:

We will determine the magnitude and rate of total body, hip and lumbar spine bone mass deficits following initiation of glucocorticoid therapy, in relation to glucocorticoid dose and duration, among children with leukemia, rheumatic conditions and nephrotic syndrome. The longitudinal pattern of deficits (or gains) in bone mass will be determined for each disease state by plotting bone mass measurements taken at 6 month intervals throughout the study, with an additional 3 month measurement being recorded for patients with nephrotic syndrome.

Outcome Time Frame:

up to 72 months (plus at 3 months post baseline visit for the Nephrotic Syndrome Group)

Safety Issue:


Principal Investigator

Leanne M Ward, MD FRCPC

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Hospital of Eastern Ontario


Canada: Health Canada

Study ID:




Start Date:

January 2005

Completion Date:

June 2014

Related Keywords:

  • Acute Lymphoblastic Leukemia
  • Nephrotic Syndrome
  • Rheumatism
  • Children
  • Osteoporosis
  • Vertebral Compression Fractures
  • Chronic Illness
  • Glucocorticoids
  • Bone Fragility
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Nephrotic Syndrome
  • Osteoporosis
  • Rheumatic Diseases