Trial Information

Bone Microarchitecture at the Radius: a Pilot Comparison Between Children With Cystic Fibrosis and Healthy Controls

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.