About this Journal Submit a Manuscript Table of Contents
International Journal of Endocrinology
Volume 2010 (2010), Article ID 218691, 9 pages
http://dx.doi.org/10.1155/2010/218691
Review Article

Vitamin D Deficiency in Cystic Fibrosis

Division of Pulmonary and Critical Care Medicine and the School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

Received 26 May 2009; Revised 1 September 2009; Accepted 23 October 2009

Academic Editor: Vin Tangpricha

Copyright © 2010 William B. Hall et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Cystic Fibrosis is the most common inherited genetic respiratory disorder in the Western World. Hypovitaminosis D is almost universal in CF patients, likely due to a combination of inadequate absorption, impaired metabolism, and lack of sun exposure. Inadequate levels are associated with the high prevalence of bone disease or osteoporosis in CF patients, which is associated with increased morbidity including fractures, kyphosis, and worsening pulmonary status. Treatment goals include regular monitoring 25 hydroxyvitamin D (25OHD) levels with aggressive treatment for those with levels <75 nmol/L (<30 ng/mL). More research is needed to determine optimal supplementation goals and strategies.

1. Cystic Fibrosis

With an estimated incidence of 1 per 3000 live births cystic fibrosis (CF) is the most common inherited respiratory disease in the western world [1, 2]. CF is caused by dysfunction of the CF transmembrane conductance regulator (CFTR), a chloride channel present on epithelial cells. Thus, CFTR mutations affect the respiratory, gastrointestinal, hepatobiliary, and reproductive systems as well as sweat glands. Most patients with CF succumb to respiratory failure from chronic pulmonary infection. Environmental, nutritional, and socioeconomic factors as well as modifier genes may affect the clinical manifestations of the disorder. Although a single gene deletion, F508del, is responsible for a majority of the mutations causing CF worldwide, more than 1600 mutations in CFTR have been described [3]. While there is great geographic and ethnic variation in the frequency of the disorder, CF remains predominantly a disease in Caucasians. The mean survival age in CF patients continues to improve from 2 in the 1950s to 37 years currently with roughly half of all CF individuals being of adult age. Survival is closely associated with both pulmonary and nutritional status [47].

2. Diagnosis of Vitamin D Deficiency

Like with non-CF individuals, the 25 hydroxyvitamin D (25OHD) level determines the degree of vitamin D insufficiency and, following data published outside CF, a 25OHD level 75 nmol/L (30 ng/mL) is considered insufficient. All CF patients should have vitamin D levels checked annually, ideally by high-performance liquid chromatography (HPLC) mass spectrometry test. Serum concentrations of 1–25 dihydroxyvitamin D have little impact on the management of vitamin D problems in CF. These levels are often normal or elevated in the setting of vitamin D deficiency due to increased activity of renal 1-hydroxylase under the influence of elevated PTH [8]. As in the general population, serum 25OHD levels may display variability based on the time of year and latitude and should be checked in late fall or winter to determine the degree of deficiency.

3. Magnitude and Causes of Vitamin D Deficiency in CF

CF represents the “perfect storm” for vitamin D deficiency. More than 20 studies have documented low levels of 25OHD from around the world and at many different latitudes. In recent studies from large CF Centers, 90% of patients have 25OHD levels 75 nmol/L (30 ng/mL) [9, 10]. Table 1 summarizes many of the documented 25OHD levels over the last few decades. These data suggest a trend toward higher 25OHD levels over recent years (especially among larger studies), which likely reflects increased attention to 25OHD levels by most large CF centers. The continued presence of low 25OHD emphasizes the continued inadequate supplementation despite increased awareness.

tab1
Table 1: 25OH vitamin D levels in CF patients.

The multifactorial etiology of low vitamin D levels in CF patients is illustrated in Figure 1. Despite routine oral supplementation, intake of vitamin D is often inadequate [10]. Ingested vitamin D is often not absorbed due to exocrine pancreatic insufficiency, present in 85% to 90% of individuals with CF [12]. Exocrine pancreatic insufficiency causes intestinal malabsorption of all fat soluble vitamins. Cystic fibrosis patients have impaired absorption of vitamin D from both plant sources (vitamin D2) and animal sources (vitamin D3) [8]. Figure 2 obtained from Lark et al. illustrates the decreased absorption from a single 2500 ug dose of vitamin D2 in CF patients despite pancreatic enzyme supplementation. Both decreased serum levels of vitamin D2 and 25OHD were noted [13]. With chronic supplementation, however, 25OHD levels do show some improvement with pancreatic enzyme and vitamin supplementation [14].

218691.fig.001
Figure 1: Causes of Vitamin D insufficiency in CF Patients [11].
fig2
Figure 2: Impaired absorption of Vitamin D following a 2500 ug dose in in CF patients and controls [13].

In addition to vitamin D malabsorption, CF patients exhibit impaired hepatic hydroxylation, which may affect metabolism of manufactured vitamin D and vitamin D absorbed through the gastrointestinal tract [1525]. The kinetics of vitamin D metabolism have not been studied in CF in detail (i.e., tracer studies), but indirect data suggest that there may be accelerated excretion of vitamin D, possibly through enterohepatic dumping, before exposure to the hepatic 25-hydroxylase enzyme [13].

Decreased storage of both produced and consumed vitamin D may also be due to decreased levels of vitamin D binding protein (DBP) in CF patients, a phenomenon known to exist for 3 decades [26]. DBP shuttles vitamin D from the intestine to fat beds. The effects of low DBP on vitamin D levels and metabolism are not entirely clear. However, most 25OHD is carried by DBP and very little is free in serum. High concentrations of unbound DBP in normal patients may function as a reservoir for 25OHD [27].

It is likely that CF patients have decreased vitamin D synthesis. In the normal population, 90% to 95% of the vitamin D requirement comes from exposure to sunlight. Healthy individuals can obtain their vitamin D requirement by exposing either their hands, face, and arms, or arms and legs to sunlight. The amount needed is 2 or 3 times a week in the spring, summer, and fall to about 20% to 25% of the amount of sunlight it would take to cause a mild pinkness to the skin [8, 28]. Many CF patients actively avoid sunlight exposure due to photosensitivity from some antibiotics. Though normal individuals store vitamin D produced in the skin to be released during the winter, cystic fibrosis patients who are exposed to the sun may have little body fat and may store less vitamin D, further exacerbating the problem.

4. Manifestations of Vitamin D Deficiency in CF Patients

In children, severe vitamin D deficiency results in rickets, but its clinical presentation in CF is more subtle. Studies from non-CF populations show that vitamin D deficiency in adults causes secondary hyperparathyroidism, resulting in mobilization of mineral and matrix from the skeleton, and precipitating or causing osteomalacia, but this condition has rarely been described in CF [8]. Nonetheless, several studies have shown abnormally high PTH levels in CF, reduced numbers of osteoblasts on bone biopsies, and some evidence of prolonged mineralization lag times in some CF adults suggesting that mineralization defects, short of true rickets/osteomalacia, do occur [54].

The complete impact of low vitamin D levels in CF patients is yet to be determined. Though vitamin D likely has roles in muscle function, innate immunity, cardiovascular disease, diabetes, and some malignancies [55], there is no information on these outcomes in CF. In fact, vitamin D has been mainly studied in the context of CF bone disease. A recent meta-analysis by the University of Ottawa Evidence Based Practice Center (EPC) suggested a fair correlation between low vitamin D levels and Bone Mass Density (BMD) in healthy adolescents and adults, but such correlations have been hard to demonstrate in CF [56]. Inconsistent correlation may also be due to a myriad of nonvitamin D factors in CF that affect bone health as well as the known seasonal and lifetime variations in serum 25OHD levels.

5. Role of Vitamin D Deficiency in Bone Health in CF

While the connection between low 25OHD levels and low bone density in CF has been hard to verify, it seems highly likely that low vitamin D levels play a role in poor bone health that is very frequently seen in adults with CF. In 1979, 2 independent studies reported a decrease in bone mineral content in patients with CF as compared to age-matched controls [24, 25]. Dozens of additional reports of low bone mass and frank osteoporosis in patients with CF, particularly in adolescents and adults, have been written over the past 30 years [15, 16, 18, 43, 4650, 57, 58]. The US CF Foundation 2007 Patient Registry of 24,000 CF individuals reported a rate of bone disease in adults with CF of 21% (along with 0.5% for bone fractures), a number which has increased by an order of magnitude in the last 7 years largely due to better screening and recognition of bone disease [1].

Despite better screening, large careful cross-sectional studies indicate that these rates almost certainly underestimate the true prevalence due to continued under-reporting. Studies from at least 7 countries have found that low BMD is common in both children and adults with CF, although adults tend to be more affected. In some studies, up to 69% of patients have been reported to have low bone mass, with 57% displaying bone density greater than 2 standard deviations below the mean for age-matched controls [15, 16, 20, 46, 49, 50, 57, 58].

Bone mineral accrual in CF is likely inadequate [18, 54, 59], especially from late childhood through young adulthood, when measured volumetrically by quantitative computed tomography (QCT) [59] or when corrected for bone volume (bone mineral apparent density (BMAD)). Here in particular, there is a concern that inadequate vitamin D contributes to poor bone health in CF.

Markers of bone formation and breakdown have improved the understanding of CF bone disease, which include the osteoblast markers bone-specific alkaline phosphatase and osteocalcin in addition to the osteoclast markers pyridinoline crosslinks and collagen N-telopeptides. Though these markers display significant variability with age, puberty, season, time of day, menstrual cycle, and amount of lung infection, they support the histomorphometric data demonstrating both increased bone breakdown and inadequate formation [16, 21, 42, 43, 6063]. These data, when taken as a whole, then suggest that low BMD in CF is a result of inadequate bone formation and increased bone resorption, with low vitamin D as a likely contributor.

Both the degree of bone disease and degree of vitamin D deficiency appear to increase with age and severity of lung disease. A recent study showed a correlation between 25OHD levels and decreased FEV1 (forced expiratory volume in 1 second, an important measure of lung function) and nutritional status [64]. Several studies have demonstrated positive correlation of BMD with FEV1 [15, 43, 47, 48, 59]. Increases in fracture rates may occur as early as the late teens and early twenties, decades before increases are seen in the general population. While increased fractures are not solely due to vitamin D deficiency, this problem does contribute. Similar to the general population, fractures appear to occur earlier in CF women [48]. While fractures tend to affect the axillary skeleton to a greater extent than the appendicular skeleton, no site is unaffected. Resultant chest wall deformities and “splinting” due to pain from thoracic vertebral and rib fractures can inhibit effective cough and airway clearance. Ultimately, this may accelerate the decline in lung function in patients with CF.

Most end-stage CF patients get referred for lung transplantation in developed countries. Few data are available regarding the impact of lung transplantation on 25OHD. One study reported that 25OHD levels went up slowly after transplant suggesting that lung disease and systemic ramifications of chronic inflammation affect the absorption of precursor molecule or the 25-hydroxylase enzyme [42]. Unfortunately most patients already suffer from severe osteoporosis before transplant [19, 6567]. Post lung transplant patients carry additional fracture risk [19, 65], which may be attributed to increased lung function and activity level. Transplant recipients appear to develop high-turnover osteoporosis, which appears to be linked to immunosuppressants rather than vitamin D insufficiency. This causes decreases in spine and femur BMD as high as 10% in posttransplant CF patients [19, 35, 66, 68, 69] and pathologic fracture rates after transplant as high as 37% to 42% [66, 70]. Regardless of the etiology, maximizing vitamin D status in the years before transplant will likely be key to improving bone health post-transplant.

6. Treatment of Vitamin D Deficiency

It is recommended that all CF patients target an optimum 25OHD level in the range of 75–150 nmol/L (30–60 ng/mL), but levels up to 250 nmol/L (100 ng/mL) are probably still safe. These targets are based on data outside of CF that demonstrate that parathyroid hormone (PTH) levels (a sensitive marker of serum ionized calcium levels) start to rise when 25OHD levels fall below 75 nmol/L (30 ng/mL) [69].

Trials have further reinforced the need to update vitamin D supplementation algorithms. A summary of all vitamin D related intervention research studies in the CF population is shown in Table 2. Most early trials failed to significantly change participants’ serum 25OHD levels. Stephenson et al. were able to achieve 25OHD levels 50 nmol/l (20 ng/mL) in 92% of patients treated with, on average, 1800 IU D3; however only 18% of these participants reached the ideal 75 nmol/L (30 ng/mL) level [35]. Gronowitz et al. had encouraging results with the use of UVB lamps combined with D3 supplementation, raising the mean serum 25OHD level in this group of patients from 55 nmol/L (22 ng/mL) to 125 nmol/L (50 ng/mL) in 12 weeks [72]. However a recent trial by Khazai et al. saw only that 55% of patients reach repletion levels using UVB due to difficulties with compliance. Khazai et al. also showed a promising method in which 100% of participants treated with 50,000 IU D3 weekly for 3 months reached the target serum 25OHD level of 75 nmol/L (30 ng/mL) [29]. They also demonstrated some success with 50,000 IU D2, but to a lesser extent. Due to the limited sample size and short duration of this study, further research is needed in order to determine if this strategy will be beneficial for most CF patients.

tab2
Table 2: Vitamin D Therapy Trials in CF.

The Khazai study illustrates the important point that vitamin D2 and D3 supplementation may not be equivalent. Non-CF patients receiving equipotent doses of D2 and D3 had similar initial 25OHD levels, though the levels declined more rapidly in those receiving D2 [73]. The superiority of D3 to maintain adequate 25OHD levels has also been suggested in earlier literature although this remains controversial [7376].

No superior supplementation strategy has been adequately validated by randomized controlled trials; so current strategies are based on expert review of available data. We suggest a modified and updated version of a previously published algorithm recommended by a recent consensus conference on CF-related bone health [77], which is outlined in Figure 3. Children younger than 1 year of age with low 25OHD levels should receive 8000 IU vitamin D per week; individuals older than 1 year should routinely receive 800 IU or more vitamin D per day. If circulating 25OHD concentrations are still 75 nmol/L (30 ng/mL) and patients are considered adherent to treatment, patients 5 years or older may be given the Medium Dose Regimen, which we define as 50,000 IU vitamin D once per week for 12 weeks. Patients younger than 5 years should be given 12,000 IU vitamin D once per week for 12 weeks. It is critical to recheck the 25OHD level while on supplemental therapy and not to allow a lapse in the repletion effort before the 25OHD level is rechecked. All treatments requires close follow-up to ensure that the 25OHD levels respond. Seasonal variation may need to be accounted for in the long-term repletion effort and considerable interindividual variation in the amount needed to achieve the goal level should be expected. Patients not responding to the Medium Dose Regimen, after adherence has been confirmed, should be given the High Dose Regimen, defined as 50,000 IU (or 12 000 IU for patients younger than 5 years) vitamin D biweekly and reassessment done after 12 weeks. The evolving data suggest that vitamin D amounts in the range of 3000–5000 IU/day may be needed for most adults with CF and this amount may be dosed daily or weekly. We currently favor vitamin D3 supplementation over vitamin D2 until further data are available.

218691.fig.003
Figure 3: Suggested Vitamin D supplementation algorithm.

Some patients will have inadequate levels despite these efforts. Increased exposure to sunlight or phototherapy without sun-blocking lotions may also be considered. Sunlight exposure should be short enough to prevent sunburn. Hands, face, and arms, or arms and legs should be exposed 2 or 3 times a week in the spring, summer, and fall to an amount of sunlight that is equivalent to about 20% to 25% of the amount it would take to cause a mild pinkness to the skin. Phototherapy with artificial ultraviolet lights such as a tanning bed or portable tanning units may be used, provided that the phototherapy unit has the component of UV-B that is responsible for making vitamin D in the skin. The manufacturer’s guidelines for exposure dependent on skin type should be followed. It should be noted that adherence to this regimen is critical, as poor compliance has been implicated as a culprit in most negative studies.

7. Future Directions in Research

Despite our increasing knowledge about vitamin D, basic understanding regarding the association between vitamin D and BMD or fracture risk is still not completely clear. Studies are needed to determine the amount of orally administered vitamin D needed to maintain circulating concentrations of 25OHD above the target level of 75 nmol/L (30 ng/mL), but optimal dosing for clinically useful endpoints (e.g., fracture prevention and improving/stabilizing BMD) is needed. In all likelihood, caregivers will have to individualize doses to some extent to meet the needs of all of their patients. More research is needed to determine the short- and long-term consequences of vitamin D insufficiency in CF. The role of vitamin D repletion in inflammation in CF needs to be explored. Vitamin D ligands (VDLs) are upregulated in inflammatory disease states in various cell lines, and vitamin D’s anti-inflammatory role has been documented in many diseases such as multiple sclerosis, rheumatoid arthritis, type I and II diabetes mellitus, lupus, psoriasis, and prostate cancer. While it is expected that findings from general populations with regard to low vitamin D status ramify to CF individuals, there is also concern that the anti-inflammatory activity of vitamin D levels may be even more important in CF vis a vis chronic lung infection and the systemic response that results. Phototherapy studies are also needed to better define the amount of exposure to UV-B radiation that is needed to maintain 25OHD levels 75 nmol/L (30 ng/mL) without causing toxicity.

8. Conclusions

CF patients have a particularly difficult time maintaining adequate vitamin D levels for a host of environmental, genetic, and circumstantial reasons. Added to this is a predisposition to osteoporosis compounding the impact of low vitamin D levels on morbidity and mortality. Physicians caring for CF patients should be proactive in monitoring 25OHD levels with aggressive treatment of those with low levels in an effort to prevent adverse long-term consequences. Consultants in endocrinology will be very helpful to CF pulmonologists in the management of difficult to treat CF patients as their knowledge of vitamin D metabolism is considerable. Current guidelines for repletion are similar to those in the general population (25OHD levels 75 nmol/L [30 ng/mL]).

Acknowledgments

The authors would like to thank the Clinical Translational Research Center (1U54RR024383), the NHLBI (5T32HL007106-33), and the Cystic Fibrosis Foundation for funding this project.

References

  1. Cystic Fibrosis Foundation, Patient Registry 2004 Annual Report, Cystic Fibrosis Foundation, Bethesda, Md, USA, 2005.
  2. B. P. O'Sullivan and P. Flume, “The clinical approach to lung disease in patients with cystic fibrosis,” Seminars in Respiratory and Critical Care Medicine, vol. 30, no. 5, pp. 505–513, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. CFTR Mutation Database, http://www.genet.sickkids.on.ca/cftr/app.
  4. Cystic Fibrosis Foundation, “Frequently asked questions,” April 2009, http://www.cff.org/AboutCF/Faqs.
  5. L. T. Beker, E. Russek-Cohen, and R. J. Fink, “Stature as a prognostic factor in cystic fibrosis survival,” Journal of the American Dietetic Association, vol. 101, no. 4, pp. 438–442, 2001. View at Scopus
  6. J. A. Dodge and D. Turck, “Cystic fibrosis: nutritional consequences and management,” Best Practice and Research: Clinical Gastroenterology, vol. 20, no. 3, pp. 531–546, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. H.-C. Lai, M. R. Kosorok, S. A. Sondel, et al., “Growth status in children with cystic fibrosis based on the National Cystic Fibrosis Patient Registry Data: evaluation of various criteria used to identify malnutrition,” Journal of Pediatrics, vol. 132, no. 3, pp. 478–485, 1998. View at Publisher · View at Google Scholar · View at Scopus
  8. M. F. Holick, “Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health,” Current Opinion in Endocrinology and Diabetes, vol. 9, no. 1, pp. 87–98, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. M. P. Boyle, M. L. Noschese, S. L. Watts, M. E. Davis, S. E. Stenner, and N. Lechtzin, “Failure of high-dose ergocalciferol to correct vitamin D deficiency in adults with cystic fibrosis,” American Journal of Respiratory and Critical Care Medicine, vol. 172, no. 2, pp. 212–217, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. A. J. Rovner, V. A. Stallings, J. I. Schall, M. B. Leonard, and B. S. Zemel, “Vitamin D insufficiency in children, adolescents, and young adults with cystic fibrosis despite routine oral supplementation,” American Journal of Clinical Nutrition, vol. 86, no. 6, pp. 1694–1699, 2007. View at Scopus
  11. I. Sermet-Gaudelus, M. Castanet, G. Retsch-Bogart, and R. M. Aris, “Update on cystic fibrosis-related bone disease: a special focus on children,” Paediatric Respiratory Reviews, vol. 10, no. 3, pp. 134–142, 2009. View at Publisher · View at Google Scholar · View at PubMed
  12. R. T. L. Couper, M. Corey, D. J. Moore, L. J. Fisher, G. G. Forstner, and P. R. Durie, “Decline of exocrine pancreatic function in cystic fibrosis patients with pancreatic sufficiency,” Pediatric Research, vol. 32, no. 2, pp. 179–182, 1992.
  13. R. K. Lark, G. E. Lestet, D. A. Ontjes, et al., “Diminished and erratic absorption of ergocalciferol in adult cystic fibrosis patients,” American Journal of Clinical Nutrition, vol. 73, no. 3, pp. 602–606, 2001.
  14. L. Dorlöchter, L. Aksnes, and G. Fluge, “Faecal elastase-1 and fat-soluble vitamin profiles in patients with cystic fibrosis in Western Norway,” European Journal of Nutrition, vol. 41, no. 4, pp. 148–152, 2002. View at Publisher · View at Google Scholar · View at PubMed
  15. R. C. Henderson and C. D. Madsen, “Bone density in children and adolescents with cystic fibrosis,” Journal of Pediatrics, vol. 128, no. 1, pp. 28–34, 1996. View at Publisher · View at Google Scholar
  16. T. Rochat, D. O. Slosman, C. Pichard, and D. C. Belli, “Body composition analysis by dual-energy X-ray absorptiometry in adults with cystic fibrosis,” Chest, vol. 106, no. 3, pp. 800–805, 1994.
  17. R. M. Aris, G. E. Lester, S. Dingman, and D. A. Ontjes, “Altered calcium homeostasis in adults with cystic fibrosis,” Osteoporosis International, vol. 10, no. 2, pp. 102–108, 1999. View at Publisher · View at Google Scholar
  18. G. S. Bhudhikanok, M.-C. Wang, R. Marcus, A. Harkins, R. B. Moss, and L. K. Bachrach, “Bone acquisition and loss in children and adults with cystic fibrosis: a longitudinal study,” Journal of Pediatrics, vol. 133, no. 1, pp. 18–27, 1998. View at Publisher · View at Google Scholar
  19. E. Shane, S. J. Silverberg, D. Donovan, et al., “Osteoporosis in lung transplantation candidates with end-stage pulmonary disease,” American Journal of Medicine, vol. 101, no. 3, pp. 262–269, 1996. View at Publisher · View at Google Scholar
  20. L. K. Bachrach, C. W. Loutit, R. B. Moss, and R. Marcus, “Osteopenia in adults with cystic fibrosis,” American Journal of Medicine, vol. 96, no. 1, pp. 27–34, 1994. View at Publisher · View at Google Scholar
  21. A. A. Ionescu, L. S. Nixon, W. D. Evans, et al., “Bone density, body composition, and inflammatory status in cystic fibrosis,” American Journal of Respiratory and Critical Care Medicine, vol. 162, no. 3, part 1, pp. 789–794, 2000.
  22. G. I. Baroncelli, F. De Luca, G. Magazzu, et al., “Bone demineralization in cystic fibrosis: evidence of imbalance between bone formation and degradation,” Pediatric Research, vol. 41, no. 3, pp. 397–403, 1997.
  23. F. Salamoni, M. Roulet, F. Gudinchet, M. Pilet, D. Thiebaud, and P. Burckhardt, “Bone mineral content in cystic fibrosis patients: correlation with fat-free mass,” Archives of Disease in Childhood, vol. 74, no. 4, pp. 314–318, 1996.
  24. E. H. Mischler, P. J. Chesney, R. W. Chesney, and R. B. Mazess, “Demineralization in cystic fibrosis detected by direct photon absorptiometry,” American Journal of Diseases of Children, vol. 133, no. 6, pp. 632–635, 1979.
  25. T. J. Hahn, A. E. Squires, L. R. Halstead, and D. B. Strominger, “Reduced serum 25-hydroxyvitamin D concentration and disordered mineral metabolism in patients with cystic fibrosis,” Journal of Pediatrics, vol. 94, no. 1, pp. 38–42, 1979.
  26. D. Coppenhaver, F. Kueppers, D. Schidlow, et al., “Serum concentrations of vitamin D-binding protein (group-specific component) in cystic fibrosis,” Human Genetics, vol. 57, no. 4, pp. 399–403, 1981. View at Scopus
  27. N. E. Cooke and J. G. Haddad, “Vitamin D binding protein (Gc-globulin),” Endocrine Reviews, vol. 10, no. 3, pp. 294–307, 1989. View at Scopus
  28. M. F. Holick, “McCollum award lecture, 1994: vitamin D: new horizons for the 21st century,” American Journal of Clinical Nutrition, vol. 60, no. 4, pp. 619–630, 1994.
  29. N. B. Khazai, S. Judd, L. Jeng, et al., “Treatment and prevention of vitamin D insufficiency in cystic fibrosis Patients: comparative efficacy of ergocalciferol, cholecalciferol and UV light,” The Journal of Clinical Endocrinology & Metabolism, vol. 94, no. 6, pp. 2037–2043, 2009. View at Publisher · View at Google Scholar · View at PubMed
  30. M. S. Fewtrell, C. Benden, J. E. Williams, et al., “Undercarboxylated osteocalcin and bone mass in 8–12 year old children with cystic fibrosis,” Journal of Cystic Fibrosis, vol. 7, no. 4, pp. 307–312, 2008. View at Publisher · View at Google Scholar · View at PubMed
  31. M. M. Speeckaert, C. Wehlou, S. Vandewalle, Y. E. Taes, E. Robberecht, and J. R. Delanghe, “Vitamin D binding protein, a new nutritional marker in cystic fibrosis patients,” Clinical Chemistry and Laboratory Medicine, vol. 46, no. 3, pp. 365–370, 2008. View at Publisher · View at Google Scholar · View at PubMed
  32. L. S. Hillman, J. T. Cassidy, M. F. Popescu, J. E. Hewett, J. Kyger, and J. D. Robertson, “Percent true calcium absorption, mineral metabolism, and bone mineralization in children with cystic fibrosis: effect of supplementation with vitamin D and calcium,” Pediatric Pulmonology, vol. 43, no. 8, pp. 772–780, 2008. View at Publisher · View at Google Scholar · View at PubMed
  33. L. L. Wolfenden, S. E. Judd, R. Shah, R. Sanyal, T. R. Ziegler, and V. Tangpricha, “Vitamin D and bone health in adults with cystic fibrosis,” Clinical Endocrinology, vol. 69, no. 3, pp. 374–381, 2008. View at Publisher · View at Google Scholar · View at PubMed
  34. C. M. Gordon, E. J. Anderson, K. Herlyn, et al., “Nutrient status of adults with cystic fibrosis,” Journal of the American Dietetic Association, vol. 107, no. 12, pp. 2114–2119, 2007. View at Publisher · View at Google Scholar · View at PubMed
  35. A. Stephenson, M. Brotherwood, R. Robert, E. Atenafu, M. Corey, and E. Tullis, “Cholecalciferol significantly increases 25-hydroxyvitamin D concentrations in adults with cystic fibrosis,” American Journal of Clinical Nutrition, vol. 85, no. 5, pp. 1307–1311, 2007.
  36. R. J. Chavasse, J. Francis, I. Balfour-Lynn, M. Rosenthal, and A. Bush, “Serum vitamin D levels in children with cystic fibrosis,” Pediatric Pulmonology, vol. 38, no. 2, pp. 119–122, 2004. View at Publisher · View at Google Scholar · View at PubMed
  37. C. S. Haworth, A. M. Jones, J. E. Adams, P. L. Selby, and A. K. Webb, “Randomised double blind placebo controlled trial investigating the effect of calcium and vitamin D supplementation on bone mineral density and bone metabolism in adult patients with cystic fibrosis,” Journal of Cystic Fibrosis, vol. 3, no. 4, pp. 233–236, 2004. View at Publisher · View at Google Scholar · View at PubMed
  38. S. A. Brown, D. A. Ontjes, G. E. Lester, et al., “Short-term calcitriol administration improves calcium homeostasis in adults with cystic fibrosis,” Osteoporosis International, vol. 14, no. 5, pp. 442–449, 2003. View at Publisher · View at Google Scholar · View at PubMed
  39. E. Leifke, M. Friemert, M. Heilmann, et al., “Sex steroids and body composition in men with cystic fibrosis,” European Journal of Endocrinology, vol. 148, no. 5, pp. 551–557, 2003. View at Publisher · View at Google Scholar
  40. E. Gronowitz, M. Garemo, A. Lindblad, D. Mellström, and B. Strandvik, “Decreased bone mineral density in normal-growing patients with cystic fibrosis,” Acta Paediatrica, vol. 92, no. 6, pp. 688–693, 2003. View at Publisher · View at Google Scholar
  41. F. Flohr, A. Lutz, E. M. App, H. Matthys, and M. Reincke, “Bone mineral density and quantitative ultrasound in adults with cystic fibrosis,” European Journal of Endocrinology, vol. 146, no. 4, pp. 531–536, 2002.
  42. R. M. Aris, D. A. Ontjes, H. E. Buell, et al., “Abnormal bone turnover in cystic fibrosis adults,” Osteoporosis International, vol. 13, no. 2, pp. 151–157, 2002. View at Publisher · View at Google Scholar
  43. S. L. Elkin, A. Fairney, S. Burnett, et al., “Vertebral deformities and low bone mineral density in adults with cystic fibrosis: a cross-sectional study,” Osteoporosis International, vol. 12, no. 5, pp. 366–372, 2001. View at Publisher · View at Google Scholar
  44. V. Grey, L. C. Lands, H. Pall, and D. Drury, “Monitoring of 25-OH vitamin D levels in children with cystic fibrosis,” Journal of Pediatric Gastroenterology and Nutrition, vol. 30, no. 3, pp. 314–319, 2000. View at Publisher · View at Google Scholar
  45. L. A. Mortensen, G. M. Chan, S. C. Alder, and B. C. Marshall, “Bone mineral status in prepubertal children with cystic fibrosis,” Journal of Pediatrics, vol. 136, no. 5, pp. 648–652, 2000.
  46. S. P. Conway, A. M. Morton, B. Oldroyd, et al., “Osteoporosis and osteopenia in adults and adolescents with cystic fibrosis: prevalence and associated factors,” Thorax, vol. 55, no. 9, pp. 798–804, 2000. View at Publisher · View at Google Scholar
  47. C. S. Haworth, P. L. Selby, A. K. Webb, et al., “Low bone mineral density in adults with cystic fibrosis,” Thorax, vol. 54, no. 11, pp. 961–967, 1999.
  48. R. M. Aris, J. B. Renner, A. D. Winders, et al., “Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis,” Annals of Internal Medicine, vol. 128, no. 3, pp. 186–193, 1998.
  49. G. S. Bhudhikanok, J. Lim, R. Marcus, A. Harkins, R. B. Moss, and L. K. Bachrach, “Correlates of osteopenia in patients with cystic fibrosis,” Pediatrics, vol. 97, no. 1, pp. 103–111, 1996.
  50. A. B. Grey, R. W. Ames, R. D. Matthews, and I. R. Reid, “Bone mineral density and body composition in adult patients with cystic fibrosis,” Thorax, vol. 48, no. 6, pp. 589–593, 1993.
  51. R. J. Stead, S. Houlder, J. Agnew, et al., “Vitamin D and parathyroid hormone and bone mineralisation in adults with cystic fibrosis,” Thorax, vol. 43, no. 3, pp. 190–194, 1988.
  52. R. J. Stead, S. Houlder, J. Agnew, et al., “Erratum in: Vitamin D and parathyroid hormone and bone mineralisation in adults with cystic fibrosis,” Thorax, vol. 43, no. 5, p. 424, 1988.
  53. J. G. Hanly, M. J. McKenna, C. Quigley, R. Freaney, F. P. Muldowney, and M. X. FitzGerald, “Hypovitaminosis D and response to supplementation in older patients with cystic fibrosis,” Quarterly Journal of Medicine, vol. 56, no. 219, pp. 377–385, 1985.
  54. S. L. Elkin, S. Vedi, S. Bord, N. J. Garrahan, M. E. Hodson, and J. E. Compston, “Histomorphometric analysis of bone biopsies from the iliac crest of adults with cystic fibrosis,” American Journal of Respiratory and Critical Care Medicine, vol. 166, no. 11, pp. 1470–1474, 2002. View at Publisher · View at Google Scholar · View at PubMed
  55. M. F. Holick, “The vitamin D epidemic and its health consequences,” Journal of Nutrition, vol. 135, no. 11, pp. 2739S–2748S, 2005.
  56. A. Cranney, T. Horsley, S. O'Donnell, et al., “Effectiveness and safety of vitamin D in relation to bone health,” Evidence Report/Technology Assessment, no. 158, pp. 1–235, 2007.
  57. D. T. Gibbens, V. Gilsanz, M. I. Boechat, D. Dufer, M. E. Carlson, and C.-I. Wang, “Osteoporosis in cystic fibrosis,” Journal of Pediatrics, vol. 113, no. 2, pp. 295–300, 1988.
  58. N. Shaw, C. Bedford, D. Heaf, H. Carty, and J. Dutton, “Osteopenia in adults with cystic fibrosis,” American Journal of Medicine, vol. 99, no. 6, pp. 690–692, 1995.
  59. C. S. Haworth, P. L. Selby, A. W. Horrocks, E. B. Mawer, J. E. Adams, and A. K. Webb, “A prospective study of change in bone mineral density over one year in adults with cystic fibrosis,” Thorax, vol. 57, no. 8, pp. 719–723, 2002. View at Publisher · View at Google Scholar
  60. P. Szulc, E. Seeman, and P. D. Delmas, “Biochemical measurements of bone turnover in children and adolescents,” Osteoporosis International, vol. 11, no. 4, pp. 281–294, 2000. View at Publisher · View at Google Scholar
  61. H. W. Woitge, C. Scheidt-Nave, C. Kissling, et al., “Seasonal variation of biochemical indexes of bone turnover: results of a population-based study,” The Journal of Clinical Endocrinology & Metabolism, vol. 83, no. 1, pp. 68–75, 1998. View at Publisher · View at Google Scholar
  62. H. K. Nielsen, K. Brixen, and L. Mosekilde, “Diurnal rhythm and 24-hour integrated concentrations of serum osteocalcin in normals: influence of age, sex, season, and smoking habits,” Calcified Tissue International, vol. 47, no. 5, pp. 284–290, 1990.
  63. H. K. Nielsen, K. Brixen, R. Bouillon, and L. Mosekilde, “Changes in biochemical markers of osteoblastic activity during the menstrual cycle,” The Journal of Clinical Endocrinology & Metabolism, vol. 70, no. 5, pp. 1431–1437, 1990.
  64. P. N. Black and R. Scragg, “Relationship between serum 25-hydroxyvitamin D and pulmonary function in the Third National Health and Nutrition Examination Survey,” Chest, vol. 128, no. 6, pp. 3792–3798, 2005. View at Publisher · View at Google Scholar · View at PubMed
  65. R. M. Aris, I. P. Neuringer, M. A. Weiner, T. M. Egan, and D. Ontjes, “Severe osteoporosis before and after lung transplantation,” Chest, vol. 109, no. 5, pp. 1176–1183, 1996.
  66. E. Shane, A. Papadopoulos, R. B. Staron, et al., “Bone loss and fracture after lung transplantation,” Transplantation, vol. 68, no. 2, pp. 220–227, 1999. View at Publisher · View at Google Scholar
  67. D. S. Donovan Jr., A. Papadopoulos, R. B. Staron, et al., “Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease,” American Journal of Respiratory and Critical Care Medicine, vol. 157, no. 6, part 1, pp. 1892–1899, 1998.
  68. S. L. Ferrari, L. P. Nicod, J. Hamacher, et al., “Osteoporosis in patients undergoing lung transplantation,” European Respiratory Journal, vol. 9, no. 11, pp. 2378–2382, 1996. View at Publisher · View at Google Scholar
  69. M.-C. Chapuy, P. Preziosi, M. Maamer, et al., “Prevalence of vitamin D insufficiency in an adult normal population,” Osteoporosis International, vol. 7, no. 5, pp. 439–443, 1997. View at Publisher · View at Google Scholar
  70. M. Aringer, H. P. Kiener, M. D. Koeller, et al., “High turnover bone disease following lung transplantation,” Bone, vol. 23, no. 5, pp. 485–488, 1998. View at Publisher · View at Google Scholar
  71. D. Green, K. Carson, A. Leonard, et al., “Current treatment recommendations for correcting vitamin D deficiency in pediatric patients with cystic fibrosis are inadequate,” Journal of Pediatrics, vol. 153, no. 4, pp. 554–559, 2008. View at Publisher · View at Google Scholar · View at PubMed
  72. E. Gronowitz, O. Larkö, M. Gilljam, et al., “Ultraviolet B radiation improves serum levels of vitamin D in patients with cystic fibrosis,” Acta Paediatrica, vol. 94, no. 5, pp. 547–552, 2005. View at Publisher · View at Google Scholar · View at PubMed
  73. L. A. G. Armas, B. W. Hollis, and R. P. Heaney, “Vitamin D2 is much less effective than vitamin D3 in humans,” The Journal of Clinical Endocrinology & Metabolism, vol. 89, no. 11, pp. 5387–5391, 2004. View at Publisher · View at Google Scholar · View at PubMed
  74. L. Tjellesen, L. Hummer, C. Christiansen, and P. Rødbro, “Serum concentration of vitamin D metabolites during treatment with vitamin D2 and D3 in normal premenopausal women,” Bone and Mineral, vol. 1, no. 5, pp. 407–413, 1986.
  75. H. M. Trang, D. E. C. Cole, L. A. Rubin, A. Pierratos, S. Siu, and R. Vieth, “Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2,” American Journal of Clinical Nutrition, vol. 68, no. 4, pp. 854–858, 1998.
  76. M. F. Holick, “Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease,” The American Journal of Clinical Nutrition, vol. 80, no. 6, supplement, pp. 1678S–1688S, 2004.
  77. R. M. Aris, P. A. Merkel, L. K. Bachrach, et al., “Guide to bone health and disease in cystic fibrosis,” The Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 3, pp. 1888–1896, 2005. View at Publisher · View at Google Scholar · View at PubMed