Cholecalciferol for Vitamin D in Adult Cystic Fibrosis (CF) Patients
Cholecalciferol for Vitamin D in Adult Cystic Fibrosis (CF) Patients
The main aim of the research question to test the primary hypothesis of this study, namely,
 Does 12 weeks of an additional 5000 IU daily of cholecalciferol increase serum 25OHD levels
 in adults with Cystic Fibrosis (CF) who have vitamin D deficiency relative to placebo?
Background and Significance Vitamin D is a fat-soluble vitamin necessary to maintain bone
 health as it maximizes calcium absorption from the gastrointestinal tract. Our primary source
 of vitamin D is through skin synthesis following exposure to solar UV-B irradiation. Natural
 dietary sources are limited which has led to the fortification of milk and baby formula with
 vitamin D.1 Vitamin D deficiency reduces dietary calcium absorption to 10-15% whereas 30 to
 40% is absorbed when vitamin D levels are adequate.2 Although the effect of vitamin D is
 primarily on calcium homeostasis, vitamin D receptors can be found on many different cells
 within the body suggesting vitamin D has an impact beyond bones. Several epidemiological
 studies have shown an association between vitamin D and the prevalence of multiple
 sclerosis3, type 1 diabetes4;5, and cancer6. More recently, low vitamin D has been associated
 with lower lung function7;8 raising the possibility that vitamin D may influence pulmonary
 status. The active metabolite, 1,25 dihydroxyvitamin D, has a number of actions that may be
 relevant to respiratory diseases. It inhibits the formation of matrix metalloproteinases,
 inhibits fibroblast proliferations and influences collagen synthesis, all of which could
 influence tissue remodelling in the pulmonary airways.

 Vitamin D deficiency: Definitions Vitamin D adequacy is traditionally assessed using
 circulating serum 25-hydroxyvitamin D (25OHD) levels. Concentrations below 25 nmol/L are
 associated with rickets and histologically evident osteomalacia indicating severe deficiency.
 Levels between 25 and 50 nmol/L are indicative of moderate deficiency and have been
 associated with mild elevations in parathyroid hormone(PTH) levels.9 However, there is a
 growing body of literature to suggest that levels below 75 nmol/L are inadequate. For
 example, healthy individuals on no vitamin D supplementation who live and work in sun-rich
 environments (i.e. lifeguards) have 25OHD levels between 100 and 158 nmol/L.10 Furthermore,
 vitamin D supplementation reduces fracture rates and improves bone mineral density (BMD) when
 serum 25OHD levels are > 100 nmol/L.11;12 And finally, 25OHD levels between 75 and 100 nmol/L
 result in maximal suppression of PTH and maximize calcium absorption from the
 gastrointestinal tract.13;14 This evidence supports the notion that the ideal target serum
 25OHD level approximates 75 nmol/L or higher.

 Vitamin D deficiency in Cystic Fibrosis Despite routine supplementation, the prevalence of
 vitamin D deficiency in cystic fibrosis (CF) is common ranging from 20 to over 80%, depending
 on the definition used to categorize the normal range.15-20 The etiology of low vitamin D in
 CF is poorly understood but contributing factors include decreased gastrointestinal
 absorption, impaired hydroxylation of vitamin D21, reduced sun exposure combined with
 increased use of sunscreens, seasonal influence as well as geographical location. Low bone
 mineral density has been well documented in CF and although bone disease in CF is likely
 multifactorial, vitamin D deficiency has been implicated as an etiologic factor15;17;19;22.
 Although few studies show a clear relationship between vitamin D and low bone density, it is
 plausible that sub-optimal serum vitamin D levels may aggravate bone disease in this
 population and that normalizing levels will maximize bone health. Furthermore, fracture risk
 appears to be increased in the CF population17;19;23. Vitamin D supplementation in elderly
 and osteoporotic subjects has been shown to reduce fractures, improve BMD and decrease
 falls11 but there are few studies examining the effect of vitamin D supplementation in
 CF16;18;24.

 Treatment of vitamin D deficiency in CF Several forms of vitamin D supplementation have been
 used in an attempt to improve calcium homeostasis and normalize serum vitamin D levels in CF
 including cholecalciferol (animal form), ergocalciferol (plant form), and calcitriol (active
 1,25-dihydroxyvitamin D). Which form of vitamin D and how much is needed to normalize serum
 levels most effectively in CF is unknown. Hanly et al assessed the response to 800 IU daily
 of cholecalciferol for a minimum of 4 weeks in twenty adolescents and young adults with CF.
 Serum levels of 25OHD increased although several subjects remained below the normal range
 despite supplementation.16 In the only published randomized placebo-controlled trial, Haworth
 et al studied 30 adults with CF and showed that calcium and cholecalciferol supplementation
 reduced the rate of bone turnover and bone loss although this did not reach statistical
 significance. Interestingly however, serum 25OHD levels were unchanged despite an additional
 800 IU of cholecalciferol daily for 12 months.24 Pilot work recently published on our CF
 population shows that additional cholecalciferol can successfully increased serum 25OHD
 levels.25 This study was a retrospective review and a randomized clinical trial is needed to
 confirm these results. With ergocalciferol, Lark et al found absorption to be significantly
 lower and highly variable in adults with CF compared to controls.26 Furthermore, these
 patients demonstrated poor conversion of ergocalciferol to 25OHD raising the possibility of
 impaired hydroxylation by the hepatic enzyme, 25-hydroxylase. In 2005, Boyle et al showed
 that even with high-dose ergocalciferol (50-100,000 IU weekly), serum levels did not correct
 vitamin D deficiency to the target level of 75 nmol/L in subjects with CF.18 Some studies
 have shown that cholecalciferol is more efficacious than ergocalciferol in correcting vitamin
 D deficiency in the non-CF population.27;28 Possible mechanisms for this differential
 response to supplemental vitamin D include differences in affinity of vitamin D-binding
 protein for the two calciferols or increased affinity for the hepatic 25-hydroxylase for
 cholecalciferol. Finally, one study published showed short-term use of calcitriol, (1,25
 dihydroxyvitamin D) increased calcium absorption in CF but serum 25OHD levels remained
 unchanged.29

 In summary, there are many studies documenting vitamin D deficiency in the CF population
 however there is a paucity of literature evaluating treatment regimens to correct this
 deficiency. One may ask why not study a more clinically relevant outcome such as fracture
 rate or change in bone mineral density rather than a biochemical marker. Although these are
 definitely important clinical outcomes to examine, we feel that the CF population has unique
 factors that affect absorption of fats therefore it is difficult to estimate the amount of
 supplementation needed to achieve optimal serum levels (i.e. > 75 nmol/L) of 25OHD. Changes
 in serum levels can be seen within 4-8 weeks whereas changes in bone mineral density can take
 years to be detected. If vitamin D supplementation is inadequate to achieve optimal serum
 levels, changes in BMD and fractures may not be seen and the study results may be falsely
 negative. By determining the dosage required to achieve optimal serum levels first, this
 study will provide important information to researchers that can be used in long-term
 controlled clinical trials.

 Research Question Aim The main aim of the research question to test the primary hypothesis of
 this study, namely, Does 12 weeks of an additional 5000 IU daily of cholecalciferol increase
 serum 25OHD levels in adults with CF who have vitamin D deficiency relative to placebo?
Inclusion Criteria:

 1. older than 18 years of age

 2. diagnosis of CF by sweat testing/genetics

 3. vitamin D deficiency defined as a serum 25OHD level < 75 nmol/L

 4. on stable baseline vitamin D supplementation for at least 2 months. Standard vitamin D
 supplementation (cholecalciferol) in CF includes 800 IU daily for individuals with
 pancreatic insufficiency and 400 IU daily for those with pancreatic sufficiency

 Exclusion Criteria:

 1. Individuals with known hypercalcemia or renal stones

 2. psychiatric history

 3. use of tanning beds/travel to sunny location within the last 2 months

 4. lung transplantation

 5. pregnancy or lactating women