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Efficacy of high dose phylloquinone in correcting vitamin K deficiency in cystic fibrosis
Journal of Cystic Fibrosis 7 (2008) 457 – 459 www.elsevier.com/locate/jcf
Case report
Efficacy of high dose phylloquinone in correcting vitamin K deficiency in cystic fibrosis Donna Drury a,⁎, Vijay Laxmi Grey b , Guylaine Ferland c , Caren Gundberg d , Larry C. Lands a a
Montreal Children's Hospital, McGill University Health Center, 2300 Tupper Avenue, Montreal, Canada H3H-1P3 Pathology and Molecular Medicine, McMaster University, 1200 Main St W, HSC-2N17 Hamilton, Canada L8N 3Z5 Département de Nutrition, Faculté de Médecine, Université de Montréal C.P. 6128, succursale Centre-ville Montréal, Québec, Canada H3C 3J7 d School of Medicine, Yale University, 333 Cedar Street, New Haven, 06510, USA b
c
Received 5 February 2008; received in revised form 20 March 2008; accepted 1 April 2008 Available online 29 May 2008
Abstract Background: Subclinical deficiencies of vitamin K are universally present in unsupplemented cystic fibrosis (CF) patients. The dose required to prevent deficiencies cannot be estimated from the existing literature. The aim of this study is determine if a supplemental dose of 1 mg/day or 5 mg/day vitamin K1 per day would normalize vitamin K status in a population of children with cystic fibrosis. Methods: Fourteen pancreatic insufficient CF children, between the ages of 8 to 18 years old, were randomized to receive either 1 mg/day or 5 mg/day vitamin K1 per day, for one month. Fasting blood tests were done at baseline and after one month of the intervention. The degree of undercarboxylation of osteocalcin (%Glu-OC), and serum vitamin K1, were evaluated by descriptive statistics and nonparametric Wilcoxon matchedpair test and Mann–Whitney U test. Results: Of the 50% of subjects who were below the optimal serum vitamin K1 at baseline, all rose into the normal range with supplementation. Supplementation also significantly reduced the overall %Glu-OC from a median of 46.8 to 29.1% (p b 0.0003). Conclusion: Our results suggest that both 1 mg and 5 mg of vitamin K1, given over a one-month period in pancreatic insufficient pediatric cystic fibrosis patients improve vitamin K status. © 2008 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Nutrition; Vitamin K; Undercarboxylated osteocalcin
1. Introduction Subclinical deficiencies of vitamin K, at levels insufficient to result in hemorrhage but great enough to impair the carboxylation of osteocalcin in bone, are considered universally present in unsupplemented cystic fibrosis (CF) patients [1–3]. In a recent cross-sectional survey, we observed subclinical vitamin K status in 82% of pancreatic insufficient CF pediatric patients despite a mean vitamin intake of 295 ± 184 μg/day [4]. Vitamin K insufficiency in cystic fibrosis is likely secondary to a combination of fat malabsorption and decreased gut bacterial menaquinone (vitamin K2) production because of chronic antibiotic use. Possible liver disease, bowel resections, and ⁎ Corresponding author. Tel.: +1 514 412 4400x22432; fax: +1 514 412 4250. E-mail address: [email protected] (D. Drury).
increased mucous accumulation in the bowel [5] may also increase the risk of vitamin K deficiency. Although it has been concluded that vitamin K supplementation is necessary to prevent vitamin K deficiency in CF, the dose required to prevent deficiencies cannot be estimated from the existing literature and remains elusive. The 2002 consensus report [6], which recommends 0.3–0.5 mg/day of supplemental vitamin K in pediatric CF patients, was based on expert opinion at the time and not on scientific evidence. The aim of this study is to assess the effect of higher doses of supplemental vitamin K on vitamin K status in pediatric CF patients. The 1 mg/day dose was chosen as it is higher than the current recommendations of 0.3–0.5 mg/day. Literature in healthy adults has shown that a high phylloquinone intake of 1 mg/day is required to maximally carboxylate osteocalcin [7]. The 5 mg/day dose was chosen empirically.
1569-1993/$ - see front matter © 2008 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2008.04.001
458
D. Drury et al. / Journal of Cystic Fibrosis 7 (2008) 457–459
Fig. 1. Change in percent undercarboxylated osteocalcin with vitamin K supplementation.
Serum vitamin K reflects recent dietary intakes [8] and provides useful information on the adherence to vitamin K supplement as well as its absorption. Vitamin K is a cofactor for the carboxylation reaction that transforms gamma-glutamyl residuals (Glu) residues to gamma carboxyglutamate (Gla) residues. In subclinical vitamin K deficiency, the undercarboxylated species of the vitamin Kdependent proteins are released into the circulation. The percent undercarboxylated osteocalcin (%Glu-OC) rises when vitamin K status is suboptimal and has been found to be inversely correlated with measures of bone quality [9,10], bone quantity [10], and fracture risk [11]. 2. Subjects and methods Fourteen pancreatic insufficient CF children, between the ages of 8 to 18 years old, were randomized to receive either 1 mg/day, or 5 mg/day, vitamin K1 for 1 month. Since no tablet form of vitamin K1 is currently commercially available in Canada, the injectable formulation of vitamin K1 – phytonadione (Sandoz Canada, Boucherville, Qc) – was diluted to 1 mg/ml and given orally. Injectable vitamin K1, given orally, has recently been shown to be more effective than subcutaneous injections and as effective as intravenous administration [12]. Of the seven subjects in each group, all completed the intervention trial. One subject in the 5 mg group lost consciousness at the time of the second blood procurement and hence no blood work was drawn post-intervention, for this subject. Exclusion criteria included any person who was pancreatic sufficient, persons with known liver disease (diagnosed by ultrasound, liver function tests and/or hepatomegaly) or any one who was already receiving supplemental therapeutic vitamin K K to treat coagulopathies. Informed consent was obtained from a parent or guardian and informed assent was obtained from all children participating in the study. Ethics approval was obtained from the Institutional Review Board of McGill University. Fasting blood tests were done at baseline and after one month of the intervention. All vitamin supplementation was stopped
24 h prior to blood procurement. The degree of undercarboxylation of osteocalcin (%Glu-OC) was the primary outcome measure as it is the most sensitive measure of overall vitamin K nutritional status [13]. Success of the oral vitamin K1 intervention was defined as a %Glu-OC of less than 21%. Undercarboxylated osteocalcin was determined by a standardized hydroxyapatite binding assay and radioimmunoassay (RIA) in the laboratory of Dr. Caren Gundberg [14]. Fasting serum vitamin K levels were measured by high performance liquid chromatography (HPLC) with post-column reduction and fluorimetric detection. This assay is sensitive to a lower limit of 0.03 nmol/L; non-detectable samples were assigned this value. Undercarboxylated osteocalcin and serum vitamin K were analyzed by descriptive statistics and nonparametric Wilcoxon matched-pair test and the Mann–Whitney U test for change at the end of the one-month intervention with either 1 mg/day or 5 mg/day supplementation. The sample size calculation was based on an expected reduction in %Glu-OC of 13% (from 33% down to 20%) [4] with supplementation. The coefficient of variation (CV) of the %Glu-OC assay is reported to be 8%. This study was not powered to detect statistical difference between the 1 mg and 5 mg dose of supplementation. 3. Results All %Glu-OC levels (14/14) were elevated, as defined as greater than 21%, prior to the vitamin K1 supplementation (Fig. 1). Similarly, 50% (7/14) of the baseline vitamin K levels were suboptimal (defined as b 0.3 nmol/L) at baseline with 43% (6/14) of all the vitamin K levels being undetectable (b 0.03 nmol/L) (Fig. 2). Three of these undetectable levels were found in subjects taking a non-vitamin K containing multivitamin and three in those on ADEK™, a multivitamin which provides 150 µg/tablet vitamin K1. Supplementation with vitamin K1 for 1 month significantly reduced the overall %GluOC from a median of 46.8 to 29.1% (p b 0.0003). Three of the 13 (23%) undercarboxylated osteocalcin levels decreased into the normal (Fig. 1)—one in the 5 mg/day group and two in
Fig. 2. Change in vitamin K levels with supplementation.
D. Drury et al. / Journal of Cystic Fibrosis 7 (2008) 457–459
the 1 mg/day group. Serum vitamin K levels improved significantly (p b 0.001) with supplementation and all subjects who were below the optimal range (0.3 nmol/L) rose into the normal range with supplementation (Fig. 2). There was no trend towards a difference between the 5 mg/day vitamin K1 and the 1 mg/day in terms of change in %Glu-OC or in the change in serum vitamin K. 4. Discussion Subclinical deficiencies of vitamin K are widespread in both supplemented and unsupplemented CF patients alike. After one month of supplementation, there was a highly significant improvement in vitamin K status, as assessed by the undercarboxylated osteocalcin (%Glu-OC), but in both the 1 mg/day and the 5 mg/day supplemented groups, the majority of patents remained in the suboptimal range. It is possible that the duration of the supplementation was not long enough to normalize the vitamin K status. In a 3-year vitamin K2 intervention trial in postmenopausal women, the %Glu-OC decreased markedly up until the 3-month intervention period and then remained unchanged until the end of the study [15]. Beker et al. [16] supplemented CF patients with 5 mg vitamin K1 per week for 4 weeks and found that the vitamin K supplementation improved, but did not normalize vitamin K parameters. Nicolaidou et al. [17] supplemented CF patients with 10 mg/week for 1 year and found significant improvement in %Glu-OC, but it is difficult to compare results from different studies using different methods for assessing %Glu-OC. In conclusion, our results suggest that higher doses of vitamin K1 than presently recommended, given over a onemonth period, improve vitamin K status. The 5 mg/day dose did not appear to offer an advantage over the 1 mg/day dose. A longer period of supplementation may be needed to achieve normal vitamin K status. There is a need for long-term vitamin K1 intervention trials to shed further light on preventing and treating this widespread nutrient deficiency affecting CF patients. Acknowledgments We would like to thank the children of the Montreal Children's Hospital Cystic Fibrosis Clinic and their parents for the participation in this study. We would also like to thank Dr. Nurlan Dauletbaev for his help with the graphics. This project was funded by the Canadian Cystic Fibrosis Foundation.
459
References [1] Conway SP, Wolfe S, Brownlee KG, White H, Oldroyd B, Truscott JG, et al. Vitamin K status among children with cystic fibrosis and its relationship to bone mineral density and bone turnover. Pediatrics 2005;115:1325–31. [2] Drury D, Grey V, Ferland G, Lands LC. Bone mineral density and body composition in children from a Northern climate with cystic fibrosis. Pediatr Pulmonol 2003:S25 (abstract 457). [3] Rashid M, Durie P, Andrew M, Kalnins D, Shin J, Corey M, et al. Prevalence of vitamin K deficiency in cystic fibrosis. Am J Clin Nutr 1999;70:378–82. [4] Grey V, Atkinson S, Drury D, Casey L, Ferland G, Gundberg C, et al. Prevalence of low bone mass and deficiencies of vitamin D and K in pediatric cystic fibrosis patients from 3 Canadian centers. Pediatrics (In Press). [5] Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pediatr Pulmonol 2006;41:35–49. [6] Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. JPGN 2002;35:246–59. [7] Binkley NC, Krueger DC, Kawahara TN, Engelke JA, Chappell RJ, Suttie JW. A high phylloquinone intake is required to achieve maximal osteocalcin γcarboxylation. Am J Clin Nutr 2002;76:1055–60. [8] Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr 1998;128:785–8. [9] Sugiyama T, Kawai S. Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. J Bone Miner Metab 2001;19:146–9. [10] Liu G, Peacock M. Age-related changes in serum undercarboxylated osteocalcin and its relationships with bone density, bone quality, and hip fracture. Calcif Tissue Int 1998;62:286–9. [11] Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: a three year follow-up study. Bone 1996;18:487–8. [12] Wilson SE, Watson HG, Crowther MA. Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review. CMAJ 2004;170(5):821–4. [13] Sokoll LJ, Sadowski JA. Comparison of biochemical indexes for assessing vitamin K nutritional status in healthy adult population. Am J Clin Nutr 1996;63:566–73. [14] Gundberg CM, Nieman SD, Abrams S, Rosen H. Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin. J Clin Endocrinol Metab 1998;83:3258–66. [15] Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int 2007;18:963–72. [16] Beker LT, Ahrens RA, Fink RJ, O'Brien ME, Davidson KW, Sokoll LJ, et al. Effect of vitamin K1 supplementation of vitamin K status in cystic fibrosis patients. JPGN 1997;24:512–7. [17] Nicolaidou P, Stavrinadis I, Loukou I, Papadopoulou A, Georgouli H, Douros K, et al. The effect of vitamin K supplementation on biochemical markers of bone formation in children and adolescents with cystic fibrosis. Eur J Pediatr 2006;165:540–5.
Case report
Efficacy of high dose phylloquinone in correcting vitamin K deficiency in cystic fibrosis Donna Drury a,⁎, Vijay Laxmi Grey b , Guylaine Ferland c , Caren Gundberg d , Larry C. Lands a a
Montreal Children's Hospital, McGill University Health Center, 2300 Tupper Avenue, Montreal, Canada H3H-1P3 Pathology and Molecular Medicine, McMaster University, 1200 Main St W, HSC-2N17 Hamilton, Canada L8N 3Z5 Département de Nutrition, Faculté de Médecine, Université de Montréal C.P. 6128, succursale Centre-ville Montréal, Québec, Canada H3C 3J7 d School of Medicine, Yale University, 333 Cedar Street, New Haven, 06510, USA b
c
Received 5 February 2008; received in revised form 20 March 2008; accepted 1 April 2008 Available online 29 May 2008
Abstract Background: Subclinical deficiencies of vitamin K are universally present in unsupplemented cystic fibrosis (CF) patients. The dose required to prevent deficiencies cannot be estimated from the existing literature. The aim of this study is determine if a supplemental dose of 1 mg/day or 5 mg/day vitamin K1 per day would normalize vitamin K status in a population of children with cystic fibrosis. Methods: Fourteen pancreatic insufficient CF children, between the ages of 8 to 18 years old, were randomized to receive either 1 mg/day or 5 mg/day vitamin K1 per day, for one month. Fasting blood tests were done at baseline and after one month of the intervention. The degree of undercarboxylation of osteocalcin (%Glu-OC), and serum vitamin K1, were evaluated by descriptive statistics and nonparametric Wilcoxon matchedpair test and Mann–Whitney U test. Results: Of the 50% of subjects who were below the optimal serum vitamin K1 at baseline, all rose into the normal range with supplementation. Supplementation also significantly reduced the overall %Glu-OC from a median of 46.8 to 29.1% (p b 0.0003). Conclusion: Our results suggest that both 1 mg and 5 mg of vitamin K1, given over a one-month period in pancreatic insufficient pediatric cystic fibrosis patients improve vitamin K status. © 2008 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Nutrition; Vitamin K; Undercarboxylated osteocalcin
1. Introduction Subclinical deficiencies of vitamin K, at levels insufficient to result in hemorrhage but great enough to impair the carboxylation of osteocalcin in bone, are considered universally present in unsupplemented cystic fibrosis (CF) patients [1–3]. In a recent cross-sectional survey, we observed subclinical vitamin K status in 82% of pancreatic insufficient CF pediatric patients despite a mean vitamin intake of 295 ± 184 μg/day [4]. Vitamin K insufficiency in cystic fibrosis is likely secondary to a combination of fat malabsorption and decreased gut bacterial menaquinone (vitamin K2) production because of chronic antibiotic use. Possible liver disease, bowel resections, and ⁎ Corresponding author. Tel.: +1 514 412 4400x22432; fax: +1 514 412 4250. E-mail address: [email protected] (D. Drury).
increased mucous accumulation in the bowel [5] may also increase the risk of vitamin K deficiency. Although it has been concluded that vitamin K supplementation is necessary to prevent vitamin K deficiency in CF, the dose required to prevent deficiencies cannot be estimated from the existing literature and remains elusive. The 2002 consensus report [6], which recommends 0.3–0.5 mg/day of supplemental vitamin K in pediatric CF patients, was based on expert opinion at the time and not on scientific evidence. The aim of this study is to assess the effect of higher doses of supplemental vitamin K on vitamin K status in pediatric CF patients. The 1 mg/day dose was chosen as it is higher than the current recommendations of 0.3–0.5 mg/day. Literature in healthy adults has shown that a high phylloquinone intake of 1 mg/day is required to maximally carboxylate osteocalcin [7]. The 5 mg/day dose was chosen empirically.
1569-1993/$ - see front matter © 2008 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2008.04.001
458
D. Drury et al. / Journal of Cystic Fibrosis 7 (2008) 457–459
Fig. 1. Change in percent undercarboxylated osteocalcin with vitamin K supplementation.
Serum vitamin K reflects recent dietary intakes [8] and provides useful information on the adherence to vitamin K supplement as well as its absorption. Vitamin K is a cofactor for the carboxylation reaction that transforms gamma-glutamyl residuals (Glu) residues to gamma carboxyglutamate (Gla) residues. In subclinical vitamin K deficiency, the undercarboxylated species of the vitamin Kdependent proteins are released into the circulation. The percent undercarboxylated osteocalcin (%Glu-OC) rises when vitamin K status is suboptimal and has been found to be inversely correlated with measures of bone quality [9,10], bone quantity [10], and fracture risk [11]. 2. Subjects and methods Fourteen pancreatic insufficient CF children, between the ages of 8 to 18 years old, were randomized to receive either 1 mg/day, or 5 mg/day, vitamin K1 for 1 month. Since no tablet form of vitamin K1 is currently commercially available in Canada, the injectable formulation of vitamin K1 – phytonadione (Sandoz Canada, Boucherville, Qc) – was diluted to 1 mg/ml and given orally. Injectable vitamin K1, given orally, has recently been shown to be more effective than subcutaneous injections and as effective as intravenous administration [12]. Of the seven subjects in each group, all completed the intervention trial. One subject in the 5 mg group lost consciousness at the time of the second blood procurement and hence no blood work was drawn post-intervention, for this subject. Exclusion criteria included any person who was pancreatic sufficient, persons with known liver disease (diagnosed by ultrasound, liver function tests and/or hepatomegaly) or any one who was already receiving supplemental therapeutic vitamin K K to treat coagulopathies. Informed consent was obtained from a parent or guardian and informed assent was obtained from all children participating in the study. Ethics approval was obtained from the Institutional Review Board of McGill University. Fasting blood tests were done at baseline and after one month of the intervention. All vitamin supplementation was stopped
24 h prior to blood procurement. The degree of undercarboxylation of osteocalcin (%Glu-OC) was the primary outcome measure as it is the most sensitive measure of overall vitamin K nutritional status [13]. Success of the oral vitamin K1 intervention was defined as a %Glu-OC of less than 21%. Undercarboxylated osteocalcin was determined by a standardized hydroxyapatite binding assay and radioimmunoassay (RIA) in the laboratory of Dr. Caren Gundberg [14]. Fasting serum vitamin K levels were measured by high performance liquid chromatography (HPLC) with post-column reduction and fluorimetric detection. This assay is sensitive to a lower limit of 0.03 nmol/L; non-detectable samples were assigned this value. Undercarboxylated osteocalcin and serum vitamin K were analyzed by descriptive statistics and nonparametric Wilcoxon matched-pair test and the Mann–Whitney U test for change at the end of the one-month intervention with either 1 mg/day or 5 mg/day supplementation. The sample size calculation was based on an expected reduction in %Glu-OC of 13% (from 33% down to 20%) [4] with supplementation. The coefficient of variation (CV) of the %Glu-OC assay is reported to be 8%. This study was not powered to detect statistical difference between the 1 mg and 5 mg dose of supplementation. 3. Results All %Glu-OC levels (14/14) were elevated, as defined as greater than 21%, prior to the vitamin K1 supplementation (Fig. 1). Similarly, 50% (7/14) of the baseline vitamin K levels were suboptimal (defined as b 0.3 nmol/L) at baseline with 43% (6/14) of all the vitamin K levels being undetectable (b 0.03 nmol/L) (Fig. 2). Three of these undetectable levels were found in subjects taking a non-vitamin K containing multivitamin and three in those on ADEK™, a multivitamin which provides 150 µg/tablet vitamin K1. Supplementation with vitamin K1 for 1 month significantly reduced the overall %GluOC from a median of 46.8 to 29.1% (p b 0.0003). Three of the 13 (23%) undercarboxylated osteocalcin levels decreased into the normal (Fig. 1)—one in the 5 mg/day group and two in
Fig. 2. Change in vitamin K levels with supplementation.
D. Drury et al. / Journal of Cystic Fibrosis 7 (2008) 457–459
the 1 mg/day group. Serum vitamin K levels improved significantly (p b 0.001) with supplementation and all subjects who were below the optimal range (0.3 nmol/L) rose into the normal range with supplementation (Fig. 2). There was no trend towards a difference between the 5 mg/day vitamin K1 and the 1 mg/day in terms of change in %Glu-OC or in the change in serum vitamin K. 4. Discussion Subclinical deficiencies of vitamin K are widespread in both supplemented and unsupplemented CF patients alike. After one month of supplementation, there was a highly significant improvement in vitamin K status, as assessed by the undercarboxylated osteocalcin (%Glu-OC), but in both the 1 mg/day and the 5 mg/day supplemented groups, the majority of patents remained in the suboptimal range. It is possible that the duration of the supplementation was not long enough to normalize the vitamin K status. In a 3-year vitamin K2 intervention trial in postmenopausal women, the %Glu-OC decreased markedly up until the 3-month intervention period and then remained unchanged until the end of the study [15]. Beker et al. [16] supplemented CF patients with 5 mg vitamin K1 per week for 4 weeks and found that the vitamin K supplementation improved, but did not normalize vitamin K parameters. Nicolaidou et al. [17] supplemented CF patients with 10 mg/week for 1 year and found significant improvement in %Glu-OC, but it is difficult to compare results from different studies using different methods for assessing %Glu-OC. In conclusion, our results suggest that higher doses of vitamin K1 than presently recommended, given over a onemonth period, improve vitamin K status. The 5 mg/day dose did not appear to offer an advantage over the 1 mg/day dose. A longer period of supplementation may be needed to achieve normal vitamin K status. There is a need for long-term vitamin K1 intervention trials to shed further light on preventing and treating this widespread nutrient deficiency affecting CF patients. Acknowledgments We would like to thank the children of the Montreal Children's Hospital Cystic Fibrosis Clinic and their parents for the participation in this study. We would also like to thank Dr. Nurlan Dauletbaev for his help with the graphics. This project was funded by the Canadian Cystic Fibrosis Foundation.
459
References [1] Conway SP, Wolfe S, Brownlee KG, White H, Oldroyd B, Truscott JG, et al. Vitamin K status among children with cystic fibrosis and its relationship to bone mineral density and bone turnover. Pediatrics 2005;115:1325–31. [2] Drury D, Grey V, Ferland G, Lands LC. Bone mineral density and body composition in children from a Northern climate with cystic fibrosis. Pediatr Pulmonol 2003:S25 (abstract 457). [3] Rashid M, Durie P, Andrew M, Kalnins D, Shin J, Corey M, et al. Prevalence of vitamin K deficiency in cystic fibrosis. Am J Clin Nutr 1999;70:378–82. [4] Grey V, Atkinson S, Drury D, Casey L, Ferland G, Gundberg C, et al. Prevalence of low bone mass and deficiencies of vitamin D and K in pediatric cystic fibrosis patients from 3 Canadian centers. Pediatrics (In Press). [5] Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pediatr Pulmonol 2006;41:35–49. [6] Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. JPGN 2002;35:246–59. [7] Binkley NC, Krueger DC, Kawahara TN, Engelke JA, Chappell RJ, Suttie JW. A high phylloquinone intake is required to achieve maximal osteocalcin γcarboxylation. Am J Clin Nutr 2002;76:1055–60. [8] Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr 1998;128:785–8. [9] Sugiyama T, Kawai S. Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. J Bone Miner Metab 2001;19:146–9. [10] Liu G, Peacock M. Age-related changes in serum undercarboxylated osteocalcin and its relationships with bone density, bone quality, and hip fracture. Calcif Tissue Int 1998;62:286–9. [11] Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: a three year follow-up study. Bone 1996;18:487–8. [12] Wilson SE, Watson HG, Crowther MA. Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review. CMAJ 2004;170(5):821–4. [13] Sokoll LJ, Sadowski JA. Comparison of biochemical indexes for assessing vitamin K nutritional status in healthy adult population. Am J Clin Nutr 1996;63:566–73. [14] Gundberg CM, Nieman SD, Abrams S, Rosen H. Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin. J Clin Endocrinol Metab 1998;83:3258–66. [15] Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int 2007;18:963–72. [16] Beker LT, Ahrens RA, Fink RJ, O'Brien ME, Davidson KW, Sokoll LJ, et al. Effect of vitamin K1 supplementation of vitamin K status in cystic fibrosis patients. JPGN 1997;24:512–7. [17] Nicolaidou P, Stavrinadis I, Loukou I, Papadopoulou A, Georgouli H, Douros K, et al. The effect of vitamin K supplementation on biochemical markers of bone formation in children and adolescents with cystic fibrosis. Eur J Pediatr 2006;165:540–5.