Bone Microarchitecture at the Radius: a Pilot Comparison Between Children With Cystic Fibrosis and Healthy Controls
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis
Study type: Observational

Summary: 
      Cystic fibrosis (CF) affects an estimated 30,000 people in the United States and is caused by
      a mutation in the gene encoding a protein called CF transmembrane regulator (CFTR). The
      hallmarks of CF are recurrent pulmonary exacerbations and declining pulmonary function.
      However, there are other problems in CF that affect both health and quality of life. These
      include CF related diabetes, liver disease, and bone disease. The median age of survival for
      patients with CF has been increasing steadily and is currently more than 37 years. With this
      improvement in life expectancy, it has become increasingly important to address the long-term
      complications of CF.

      Currently, patients with CF are evaluated annually for bone disease with dual X-ray
      absorptiometry (DXA), and screening usually starts at age 12. However, this may not be
      sufficient to detect early bone changes that may impact fracture risk. Furthermore, bone
      disease in children may manifest earlier than adolescence, which would suggest that screening
      should start at an earlier age in these vulnerable patients. The following study is therefore
      proposed to examine the potential role of peripheral quantitative computed tomography (pQCT)
      as a screening approach for bone disease in children with CF. The investigators expect to
      find bone problems by pQCT but not DXA.
    

Detailed description: 
      This is a single-center study

        1. STUDY OBJECTIVES

           1.1 Primary Objective Compare bone measurements (by pQCT of the radius and DXA scan of
           the lumbar spine and total body) in children with CF 6-12 years of age to healthy
           children. Measurements by pQCT to be compared will include cortex width, trabecular bone
           mineral density (BMD), and volumetric BMD. Measurements by DXA to be compared will
           include total body bone mineral density and lumbar spine (L1-L4) BMD.

           1.2 Secondary Objectives Compare Z-scores of pQCT parameters to Z-scores of BMD as
           measured by DXA in children with CF 6-12 years of age. The Z-scores for each CF subject
           for pQCT measurements (cortex width, trabecular BMD, volumetric BMD) and DXA
           measurements (total body BMD and lumbar spine BMD) will be compared.

           Compare correlation of pQCT parameters and BMD as measured by DXA to markers of bone
           turnover and inflammation (serum propeptide of type I collagen (PICP), total serum
           deoxypyridinoline, C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis
           factor (TNF)-alpha) in children with CF 6-12 years of age and healthy controls. As an
           exploratory specific aim, the correlation between these serum markers and the bone
           measurements in Specific Aim 1 will be evaluated.

        2. BACKGROUND AND RATIONALE

      Cystic fibrosis (CF) affects an estimated 30,000 people in the United States1 and is caused
      by a mutation in the gene encoding a protein called CF transmembrane regulator (CFTR). This
      protein functions as a chloride channel in epithelial cells of multiple organ systems. The
      mutation results in a dysfunctional or absent CFTR channel and a decrease in chloride
      secretion, which ultimately results in increased viscosity of secretions. Children with CF
      are less able to clear pulmonary secretions and become colonized with bacterial pathogens
      that regularly cause exacerbation of lung disease. The hallmarks of CF are recurrent
      pulmonary exacerbations and declining pulmonary function. Respiratory failure is the cause of
      death in more than 90% of people with CF. However, there are also extrapulmonary
      manifestations of CF that affect both health and quality of life. These include CF related
      diabetes, liver disease, and bone disease. The median age of survival for patients with CF
      has been increasing steadily and is currently more than 37 years.1 With this improvement in
      life expectancy, it has become increasingly important to address the long-term complications
      of CF.

      There is a high prevalence of osteopenia and osteoporosis among both adult and pediatric
      patients with CF and this steadily increases with age. There is also an associated increase
      in fracture rate and kyphosis in adults. Studies evaluating fracture risk in children with CF
      have generated mixed results. Henderson et al reported an increased rate of fracture in girls
      with CF, but not boys, in comparison to healthy controls. A more recent study by Rovner et al
      showed no increase in fracture risk among children with mild to moderate lung disease.
      Bisphosphonates have been used to treat osteopenia and osteoporosis in adults with CF and
      clinical trials have shown that there is an increase in bone mineral density (BMD) with
      therapy. However, there is no published data demonstrating a reduced fracture rate with
      bisphosphonate therapy. Furthermore, there is currently no consensus on how to treat
      osteopenia or osteoporosis in children with CF other than to ensure adequate nutrition and
      vitamin D levels. Although CF bone disease is considerably more prevalent in the adults than
      in children, screening for bone disease must be addressed in childhood to maximize peak bone
      mass and potentially minimize bone related disease in these patients.

      Biochemical markers of bone turnover may be used to evaluate derangements in bone formation
      and/or resorption. Studies conducted in CF patients have shown in general a decrease in
      markers of bone formation and increase in markers of bone resorption. Conway et al reported
      correlation between markers of bone turnover and both spinal and total body BMD; however, no
      studies have evaluated whether bone turnover markers correlate with pQCT parameters. Serum
      PICP is a peptide cleaved from the carboxy-terminal end of collagen type I and is a marker of
      bone formation. Deoxypyridinoline is a cross-linking amino acid that is released from the
      bone matrix by resorption, and thus is a marker of bone resorption.

      The etiology of bone disease in patients with CF is multifactorial and contributing factors
      include poor nutrition, decreased activity levels, poor absorption of vitamin D, chronic
      inflammation, and therapy with corticosteroids. Multiple studies have correlated BMD with
      clinical factors such as lung function, nutritional status, inflammation markers, clinical
      score, and frequency of antibiotic courses. Studies evaluating the relationship between
      inflammation markers and bone in CF patients have been somewhat mixed, although in general
      have shown an inverse relationship between inflammation and BMD, and a direct correlation
      between inflammation and increased bone resorption markers. Inflammation markers evaluated
      have included both acute-phase cytokines such as IL-6 and TNF-alpha, and the general marker
      CRP. There is some evidence that CFTR is expressed in bone cells such as osteoclasts,
      osteoblasts, and osteocytes, suggesting the potential for a bone phenotype in patients with
      CF. Most studies utilize DXA and demonstrate reduced BMD in patients with CF that is usually
      detectable starting in adolescence. Low BMD is nearly universal among adults with CF;
      however, results from studies evaluating BMD in children with CF have been variable.

      A study conducted in adolescents and young adults with CF utilized pQCT to evaluate bone
      geometry of the radius. Although BMD was normal for these subjects, pQCT data indicated that
      the subjects had a reduced cortical thickness. Reduced cortical thickness has been shown in
      cadaveric studies to be predictive of mechanical strength. Currently, patients with CF are
      evaluated annually for bone disease with DXA, and screening usually starts at approximately
      age. However, the above study suggests that this approach may not be sufficient to detect
      early bone changes that may impact fracture risk. Furthermore, bone disease in children may
      manifest earlier than adolescence, which would suggest that screening should start at an
      earlier age in these vulnerable patients. The following study is therefore proposed as a
      translational pilot study to examine the potential role of pQCT as a screening approach for
      bone disease in children with CF. The investigators expect to find bone deficits by pQCT but
      not DXA, and better correlation of inflammation and bone turnover markers with pQCT
      measurements than with DXA measurements.
    

Intervention name(s): Peripheral quantitative computed tomography (pQCT); Dual X-ray absorptiometry (DXA)
Intervention type(s): Device; Device
Intervention description(s): A pQCT scan of the non-dominant radius at the 4% and 65% sites will be conducted at a single study visit; A total body DXA scan will be conducted at a single study visit
Other intervention name(s): Stratec XCT 2000 series pQCT; Hologic QDR 4500A
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Participants for the cystic fibrosis (CF) group will be recruited from the pulmonary clinic
        at Arkansas Children's Hospital. Healthy controls will be recruited from Arkansas
        Children's Hospital outpatient clinics and the community.
      
Biospecimen description: 
      Serum samples will be frozen and assayed together.
    
Keywords: cystic fibrosis; bone