Steroid-Induced Osteoporosis in the Pediatric Population - Canadian Incidence Study
Condition: Acute Lymphoblastic Leukemia; Nephrotic Syndrome; Rheumatism
MeSH terms: Precursor Cell Lymphoblastic Leukemia-Lymphoma; Osteoporosis; Rheumatic Diseases; Nephrotic Syndrome; Nephrosis
Study type: Observational

Summary: 
      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.
    

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.
    

Observational model: Cohort
Time perspective: Prospective
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.
      
Keywords: Children; Osteoporosis; Vertebral Compression Fractures; Chronic Illness; Glucocorticoids; Bone Fragility