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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified August 2012 by Children's Hospital of Eastern Ontario.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Dr. Leanne Ward, Children's Hospital of Eastern Ontario
ClinicalTrials.gov Identifier:
NCT01663129
First received: August 8, 2012
Last updated: August 10, 2012
Last verified: August 2012
  Purpose

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.


Condition
Acute Lymphoblastic Leukemia
Nephrotic Syndrome
Rheumatism

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Steroid-Induced Osteoporosis in the Pediatric Population - Canadian Incidence Study (STOPP-CIS)

Resource links provided by NLM:


Further study details as provided by Children's Hospital of Eastern Ontario:

Primary Outcome Measures:
  • The magnitude and rate of total body, hip and lumbar spine bone mass deficits [ Time Frame: up to 72 months (plus at 3 months post baseline visit for the Nephrotic Syndrome Group) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Glucocorticoid threshold dose [ Time Frame: At baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72-month visits ] [ Designated as safety issue: No ]
    To identify whether a glucocorticoid threshold dose exists for each of the three disease categories, above which significant deficits in bone mass are likely to occur.

  • Frequency of atraumatic fractures [ Time Frame: At baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72-month visits ] [ Designated as safety issue: No ]
    To assess the frequency of atraumatic fractures in relation to glucocorticoid dose and duration for each of the three chronic illnesses.

  • Fracture risk [ Time Frame: At baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72-month visits ] [ Designated as safety issue: No ]
    To determine the fracture risk associated with a given reduction in bone mass from baseline, for each of the three chronic diseases.

  • Magnitude of bone mass restitution [ Time Frame: At baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72-month visits ] [ Designated as safety issue: No ]
    To determine the magnitude of bone mass restitution when glucocorticoid therapy is withdrawn, and to evaluate whether recovery is age- and/or pubertal stage-dependent.

  • Handedness and lateralization of bone density [ Time Frame: Once during either the baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 or 72-month visits ] [ Designated as safety issue: No ]
    To investigate the relationship between handedness and lateralization of bone density.


Enrollment: 406
Study Start Date: January 2005
Estimated Study Completion Date: June 2014
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts
Leukemia Patient Group
Acute Lymphoblastic Leukemia (ALL)
Rheumatic Disease Patient Group
  • Juvenile Idiopathic Arthritis (JIA)
  • Systemic Lupus Erythematosis
  • Juvenile Dermatomyositis
  • Scleroderma
  • Overlap Syndromes
  • Sjogren's syndrome
  • Sarcoidosis
  • Systemic Vasculitis (excluding Kawasaki's disease and Henoch-Schonlein Purpura)
  • Systemic vasculitis as defined by the Chapel Hill Concensus Conference on Nomenclature. Other forms of systemic vasculitis, including Giant cell (temporal) arteritis, Takayasu's arteritis, Polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, Microscopic polyangiitis, Essential cryoglobulinemic vasculitis, Cutaneous leukocytoclastic angiitis, Behcet's disease, Other vasculitis
  • Other rheumatic disease
Nephrotic Syndrome Patient Group

Nephrotic syndrome will be classified according to the following categories:

Idiopathic nephrotic syndrome, without renal biopsy histology, presumed minimal change disease (MCD), Focal segmental glomerulosclerosis (FSGS), confirmed on biopsy, Minimal change disease, confirmed on biopsy Nephrotic syndrome with Henoch-Schonlein Purpura (HSP).


  Hide Detailed Description

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   1 Month to 16 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Children will be recruited into the study following a clinical diagnosis of glucocorticoid-requiring leukemia, rheumatic disease or nephrotic syndrome, as determined by the study collaborators in each of the three sub-specialties according to their usual clinical practice. Potential participants will be identified by the attending physician (oncologist, rheumatologist or nephrologist) who will then refer the patient to the site bone designee. The bone designee (or his/her research assistant) will be responsible for determining patient eligibility and for carrying out the requirements of the study.

Criteria

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

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 condition.
  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01663129

Locations
Canada, Alberta
Alberta Children's Hospital
Calgary, Alberta, Canada, T3B 6A8
Stollery Children's Hospital
Edmonton, Alberta, Canada, T6G 2B7
Canada, British Columbia
BC Children's Hospital
Vancouver, British Columbia, Canada, V6H 3V4
Canada, Manitoba
Winnipeg Children's Hospital
Winnipeg, Manitoba, Canada, R3E 3P4
Canada, Nova Scotia
IWK Health Centre
Halifax, Nova Scotia, Canada, B3K 6R8
Canada, Ontario
McMaster Children's Hospital
Hamilton, Ontario, Canada, L8N 3Z5
London Health Sciences Centre
London, Ontario, Canada, N6C 2V5
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada, K1H 8L1
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Shriners Hospital for Children
Montreal, Quebec, Canada, H3G 1A6
Hopital Sainte Justine
Montreal, Quebec, Canada, H3T 1C5
Montreal Children's Hospital
Montreal, Quebec, Canada, H3H 1P3
Sponsors and Collaborators
Children's Hospital of Eastern Ontario
Canadian Institutes of Health Research (CIHR)
Investigators
Principal Investigator: Leanne M Ward, MD FRCPC Children's Hospital of Eastern Ontario
  More Information

Publications:

Responsible Party: Dr. Leanne Ward, Director, Pediatric Bone Health Clinical and Research Programs, Children's Hospital of Eastern Ontario
ClinicalTrials.gov Identifier: NCT01663129     History of Changes
Other Study ID Numbers: 03-07e, 03-07e
Study First Received: August 8, 2012
Last Updated: August 10, 2012
Health Authority: Canada: Health Canada

Keywords provided by Children's Hospital of Eastern Ontario:
Children
Osteoporosis
Vertebral Compression Fractures
Chronic Illness
Glucocorticoids
Bone Fragility

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Nephrotic Syndrome
Osteoporosis
Rheumatic Diseases
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Nephrosis
Kidney Diseases
Urologic Diseases
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Connective Tissue Diseases

ClinicalTrials.gov processed this record on August 19, 2014