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Bone Mineral Density and Fat-Soluble
Vitamin Status in Adults with Cystic
Fibrosis Undergoing Lung Transplantation:
A Pilot Study
GRACE HUBERT, RD BSca; THERESA TAM CHUNG, RD BSca; CONNIE PROSSER, PhD FCACBb; DALE LIEN, MDc;
JUSTIN WEINKAUF, MDc; NEIL BROWN, MDc; MARIANNE GOODVIN, RN BNScd; KATHY JACKSON, RN BNScd;
JOAN TABAK, RNe; JOSETTE SALGADO, RN BNSce; ABEER SALMAN ALZABEN, MScf; DIANA R. MAGER, PhD MSc RDfg
"Nutrition Services, Alberta Health Services, Edmonton, AB; bDepartment of Laboratory Medicine, University of Alberta, Edmonton, AB; 'Division of Pulmonary
Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB; dLung Transplant Program, Alberta Health Services,
Edmonton, AB; "Adult Cystic Fibrosis Clinic, Alberta Health Services, Edmonton, AB; fDepartment of Agricultural, Food and Nutritional Science, University of
Alberta, Edmonton, AB; gDepartment of Pediatrics, University of Alberta, Edmonton, AB
ABSTRACT
RESUME
Purpose: Patients with cystic fibrosis (CF) often experience low bone
Objectif. Les patients atteints de fibrose kystique (FK) ont souvent une
mineral density (BMD) pre- and post-lung transplantation (LTX). The
study purpose was to describe BMD and micronutrient status in adults
with CF pre- and post-LTX.
Methods: Twelve patients with CF (29 ± 8 years) were recruited from
the CF clinic at the University of Alberta Lung Transplant Program.
BMD and vitamins A, D, E, K status, and parathyroid hormone were
measured pre- and post-LTX.
Results: No significant differences pre- and post-LTX were observed at
the different bone sites measured (lumber-spine, femoral-neck (FN),
hip, and femoral-trochlea) (p) 0.05). BMD T-scores «-2) was present
in lumbar-spine, FN, hip, and femoral-trochlea in 33%, 17%, 17%, and
25% of individuals pre-LTX and 58%, 33%, 58%, and 33% of individuals post-LTX, respectively. More than 50% of patients had suboptimal vitamin K levels (PIVKA-li values) 3 ng/mL) pre- and post-LTX.
Conclusion: Adults with CF pre- and post-LTX had reduced BMD and
suboptimal vitamin K status.
(Can I Diet Pract Res. 2016;77:1-4)
(DOl: 10.3148/cjdpr-2016-014)
Published at dcjournal.ca on 19 July 2016.
densite minerale osseuse (DMO) faible avant et apres la transplantation pulmonaire (TP). L'objectif de l'etude etait de decrire la DMO et
l'etat nutritionnel en micronutriments des adultes atteints de FK avant
et apres la TP.
Methodes. Douze patients atteints de FK (29 ± 8 ans) ont ete recrutes
Ii la clinique de FK du programme de transplantation pulmonaire de
l'Universite de l'Alberta. La DMO et l'etat nutritionnel en vitamines A,
D, E et K, et I'hormone parathyro'lde ont ete rnesures avant et apres
la TP.
Resultats. Aucune difference significative n'a ete observee avant et
apres la TP aux differents sites osseux mesures (rachis lombaire, col
femoral, hanche et trochlea femorale) (p ) 0,05). Des scores T de la
DMO « - 2) etaicnt presents dans Ie rachis lombaire, Ie col femoral,
la hanche et la trochlea femorale chez 33 %, 17 %, 17 % et 25 %
des personnes avant la TP et chez 58 %, 33 %, 58 % et 33 % des personnes apres la TP, respectivement. Plus de 50% des patients avaient
des taux de vitamine K sous-optimaux (concentrations de PIVKA-II ) 3
ng/rnl) avant et apres la TP.
Conclusion. Les adultes atteints de FKavaient une DMO reduite et un
taux de vitamine K sous-optimal avant et apres la TP.
(Rev can prat rech dletet. 2016;77: 1-4)
(DOl: 10.3148/cjdpr-2016-014)
Publie au dcjournal.ca Ie 19 juillet 2016.
INTRODUCTION
Maintenance of bone health in patients with cystic fibrosis
(CF) is an ongoing challenge, especially as the disease becomes
more severe and the need for lung transplantation (LTX)
becomes more eminent [1]. Pre-LTX and post-LTX, individuals with CF are at high risk for low bone mineral density
(BMD) related to chronic use of corticosteroid and other
immunosuppressive therapy (such as tacrolimus), antibiotic
use and chronic undernutrition secondary to poor intake,
increased energy expenditure, and pancreatic insufficiency
[2-4). Suboptimal fat-soluble vitamin intake due to inadequate
or poor diet quality and/or noncompliance to prescribed vitamin supplementation can also contribute to low BMD. Several
studies have shown that fat-soluble vitamins can be low preLTX [5-7), whereas post-LTX, hypervitaminnosis A can contribute to low BMD [8).
The University of Alberta Lung Transplant Program provides LTX for patients with end-stage lung disease from
Alberta, including individuals with CF who have a reported
60%-75% 5-year survival rate [9). With increased survival,
Canadian Journal of Dietetic Practice and Research - Vol 77, 2016
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poor bone health is a significant concern, especially as it relates
to increased morbidity and mortality and overall quality of
life [4, 10]. Limited exposure to sunlight in northern climates
also increases the risk for vitamin D (vitD) deficiency and
subsequent poor bone health. For these reasons, patients
are routinely supplemented with commercially available fatsoluble vitamins (A, D, E, and K) pre- and post-LTX.
Although suboptimal vitamin K (vitK) status has been shown
to be a contributor to low bone health in many clinical populations [11], it is currently unknown what the current prevalence of suboptimal vitK status is in adult patients post-LTX.
This is particularly relevant in the CF population, as on-going
fat malabsorption due to pancreatic insufficiency is not corrected or improved by lung transplantation. This pilot study
describes BMD and fat-soluble vitamin status in adult CF subjects, pre- and post -LTX.
METHODS
Ethics approval (Pro 00001737) was obtained from the
Human Research Ethics Board at the University of Alberta
prior to study initiation. Adult CF patients (age> 18 years)
who were referred to the University of Alberta Lung Transplant program between 2005 and 2012 were recruited and
enrolled over a 12-month period. Study inclusion criteria
included those on anti-resorptive therapy, as this is part of
routine clinical care. Exclusion criteria included terminal illness, intensive care unit stay >72 hours, and subjects who
were unable to provide informed consent. A total of 25
patients with CF undergoing lung transplant assessment
were screened for eligibility; 13 were excluded due to coinciding illness requiring hospitalization, early lung TX, and/or
refusal to participate. No Significant differences in demographic or anthropometric variables were noted between those
who agreed to participate in the study and those who did not.
Informed consent was obtained from all participants. Height
and weight were measured using validated techniques.
Blood was collected for measurement of vitamins A, D, E,
and K (protein indicated in vitamin K absence (PIVKA-II))
and parathyroid hormone (PTH) at LTX assessment and at
3, 6, and 12 months post-LTX. The samples were analyzed
according to standardized methodologies in the Core Laboratory at Alberta Health Services [12]. Serum 25-hydroxy vitamin D (25(OH)D) concentrations were assessed according to
the Canadian Endocrine Practice Guidelines «75 nmol/L,
insufficient/suboptimal; >75 nrnol/L, optimal) [13]. BMD
was measured using hologic dual-energy X-ray absorptiometry 450 at LTX assessment and at 9 and 18 months postLTX (whole body, hip, femoral-neck (FN), femoral-trochlea,
lumbar-spine).
Analyses were performed using Statistical Analysis Software (SAS; version 9.4 SAS Institute, Cary, NC, USA). Data
were analyzed by treating individual patient data as single
measures, rather than repeated measures due to the small sample size at each individual time point. Continuous variables
were expressed as mean ± SD. Normality was assessed using
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the Shapiro-Wilk test. Non-parametric variables were log
transformed. Continuous variables were analyzed using
dependent t test to assess differences pre- and post-LTX with
adjustments for potential confounding variables (season, age,
sex). Statistical Significance was determined at P < 0.05.
RESULTS
Demographic, anthropometric, and laboratory data
Anthropometric and demographic data for the 12 patients
pre- and post-LTX are shown in Table 1. No significant age
difference at time of LTX assessment was observed between
sexes (males, 29 ± 10 years vs. females, 31 ± 6 years; P = 0.70).
A total of 42% (n = 5) and 17% (n = 2) of participants
had a mean BMI reflective of suboptimal nutritional status
(BMI < 18.5) pre- and post-LTX, respectively. Laboratory
data are shown in Table 2. Although there was no Significant
difference in estimated glomerular filtration rate (GFR), values
in 58% of patients were indicative of renal insufficiency (GFR
<60; stage 3 chronic kidney disease) post-LTX. In addition,
significant differences in urea, creatinine, and PTH pre- and
post-LTX were noted, indicating worsening renal function
and secondary hyperparathyroidism in 83% of patients postLTX. The majority of patients (67% pre-LTX and 58% postLTX) had optimal 25(OH) vitD levels (>75 nrnol/L), likely
secondary to vitD supplementation (400-8700 IV/d) [13]. A
total of 58% and 55% of patients had suboptimal vitK status
(PIVKA-II values >3 ng/mL) pre- and post-LTX, respectively,
despite routine recommendation for vitK supplementation
Table 1. Anthropometric and bone health variables pre- and
post-LTX in adult patients with cystic fibrosis.
Anthropometrics
Age (y)
Weight (kg)b
Height (m)
BMI (kg/m2)b
Spine BMD
(gm/c2)C
Hip BMD
(gm/cm2)C
Femoral-neck
BMD (grn/crrr')"
Femoraltrochlea BMD
Pre-LTX
(n=12; 7M, 5W
Post-LTX
(n=12; 7M, 5F)a
29 ± 8 (19-49)
54.8 ± 9.0
(39.1-71.0)
1.68 ± 0.08
(1.55-1.81)
19.3 ± 3.2
(15.1- 25.7)
0.86 ± 0.11
(0.69-1.03)
0.82 ± 0.14
(0.57-1.08)
0.71 ± 0.10
(0.56-0.90)
0.60 ± 0.11
(0.43-0.82)
30 ± 8 (19-52)
60.3 ± 5.6
(51.4-67.8)
1.68 ± 0.08
(1.55-1.81)
21.4 ± 2.4
(17.5-25.0)
0.86 ± 0.10
(0.69-1.07)
0.77 ± 0.12
(0.54-1.04)
0.67 ± 0.11
(0.54-0.91)
0.55 ± 0.10
(0.40-0.77)
p
0.371
0.098
>0.05
0.103
0.992
0.262
0.324
0.166
(grn/cm)"
'Dataarepresentedasmean± standarddivision(range).
bThenumberof measurements
post-LTX
was 11.
'Thenumberof repeatedmeasurements
post-LTX
was22.
Note:LTX,lungtransplantation;
M, male;F. female;BMI,bodymassindex;BMD.bone
mineraldensity.
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Table 2. Laboratory variables pre- and post-LTXin adult patients with cystic fibrosis
Biochemical
'<,
o
Pre-LTX(n=12)a
Vitamin A (IJmoI/L)b
PIVKAII (ng/rnl)"
Vitamin E (IJmoI/L)b
Calcium (mrnol/l)''
PTH(prnol/l)"
25(OH)D (nrnol/L)"
Urea (mrnol/L)"
Creatinine (IJmoI/L)f
GFR(ml/min/1.73 m2)g
Hemoglobin A1C (%)h
Post-LTX(n=12)a
1.4 ± 0.3 (0.8-2.0)
80.0 ± 171.9 (0.1-427.8)
26 ± 9 (10-43)
2.25 ± 0.10 (2.08-2.38)
4.4 ± 3.9 (1.4-160)
83 ± 40 (10-154)
4.3 ± 1.5 (1.2-6.8)
64 ± 18 (35-99)
60 ± 0 (60-60)
6.34 ± 0.57 (5.5-7.4)
2.7 ± 0.8 (1.3-4.0)
6.4 ± 14.2 (0.1-64.2)
40 ± 18 (13-86)
2.26 ± 0.13 (2.10-2.80)
9.8 ± 11.9 (2.1-61.0)
85 ± 23 (43-141)
7.1 ± 2.8 (19-10.7)
108 ± 35 (48-166)
53 ± 9 (30-60)
6.11 ± 0.47 (5.4-7.1)
p
Normal reference ranges
1.5-3.5
,,3
12-45
2.10-2.60
1.2-6.8
<75
2.5-8.0
M: 50-115 F: 50-105
>60
<6.1
<0.001
0.206
0.010
0.773
0.025
0.798
0.006
<0.001
0.090
>0.05
'Data are presentedas mean ± standard division (range).
bThenumber of measurementspre-L1Xwas 12; the number of repeated measurementspost-L1Xwas 33
'The number of measurementspre-Llx was 11; the number of repeated measurementspost-Llx was 20.
dThenumber of measurementspre-L1Xwas 12; the number of repeated measurementspost-L1Xwas 34.
'The number of measurementspre-Ux was 12; the number of repeated measurementspost-L1Xwas 13.
rThenumber of measurementspre-Ux was 12; the number of repeated measurementsposH1X was 24.
gThenumber of measurementspre-Llx was 6; the number of repeated measurementsposHTX was 17.
"None of the participants pre-L1Xwere on exogenous insulin vs 83% post-L1Xwho were on exogenousinsulin.
Note: L1X,lung transplantation; PIVKAII, proteins Induced by vitamin K absenceII; PTH,parathyroid hormone; 25(OH)D,25-hydroxy vitamin D; GFR, glomerular filtration rate.
(> 1 mg/d). Significant differences in serum retinol levels and
vitamin E levels were also observed pre- and post- LTX (P <
0.05) with daily vitamin A (26 501 ± 14040 IU/d) and vitamin
E (260 ± 179 IU/d) supplementation. Routine vitamin supplementation was typically in the form of single vitD (>1000 IU)
and/or multivitamin preparations.
Bone mineral density
BMD data are shown in Table 1 and Figure 1. No significant
differences pre- and post-LTX were observed at the different
site measures (lumbar-spine, FN, hip and femoral-trochlea)
(P > 0.05). With the exception of spinal-BMD (absolute;
Figure 1. The average T-score of spine, hip, femoral-neck
and femoral-trochlea pre- (n=12) and post-lung transplant
(LTX)in adult patients with cystic fibrosis (n=12). The
number of measurements post-LTXwas n=22 for hip,
femoral-neck, and femoral-trochlea and n=23 for spine.
0.0
-0.5
-1.0
8 -1.5
Q)
.: -2.0
II
-+---1--1----1--1----1--1--
-2.5
+--I--I-----=.----I----~-3.0+-+-1:-----------3.5L.---------·Spine
Hip
Femoral Neck
_
_
Femoral
Trochlea
Pre-LTX
..Post-LTX
females, 0.91 ± 0.08 vs males, 0.82 ± 0.09 gm/cm/, P = 0.002)
and T scores (females, -1.27 ± 0.79 vs males, -2.25 ± 1.26;
P == 0.015), no Significant differences in absolute or T scores
were observed between sexes at the different sites measured
(P> 0.05). BMD T scores «-2) indicative of osteoporosis
were present in lumbar-spine, hip, FN, and femoral-trochlea
in 33%, 17%, 17%, and 25% individuals pre-LTX, respectively.
In contrast, BMD T scores «-2) were present in lumbarspine, hip, FN and femoral-trochlea in 58%, 33%, 58%, and
33% individuals post-LTX, respectively.
DISCUSSION
This is a descriptive, pilot study that describes fat-soluble vitamin status and BMD in adults with CF pre- and post-LTX in a
northern Canadian LTX program. A Significant finding is that
the majority of patients had reduced BMD and suboptimal
vitK status, despite healthcare practitioner recommendation
for fat-soluble vitamin supplementation. Several factors may
have influenced these findings such as low patient adherence
to prescriber recommendation,
ongoing pancreatic insufficiency and malabsorption
refractive to pancreatic
enzyme replacement therapy, poor diet quality, reduced weightbearing activities, and use of immunosuppressive medications
such as corticosteroids, tacrolimus, and antibiotics (e.g., tobramycin) [14, 15]. Many patients in this cohort were underweight at the time of LTX and hence had suboptimal
nutritional status. Although, weight status improved postLTX, deficits in nutritional intake and weight-bearing activity,
ongoing pancreatic insufficiency and the use of corticosteroid
therapy (typically 10-15 mg/d, but tapered down to alternative
day therapy and/or discontinuation by 6-12 months), and/or
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other medications such as tacrolimus may have contributed to
reduced BMD [9, 15-17].
Suboptimal vitD status is highly prevalent in northern climates like Alberta [18, 19]. Although patients in general had
serum 25(OH)D levels above 75 nmol/L and normal PTH
levels, higher vitD levels in conjunction with weight-bearing
activities may be needed to optimize bone health pre- and
post-LTX. Findings regarding poor bone health are similar
to other LTX centres where ongoing nutritional challenges in
adult LTX recipients place them at high risk for poor bone
health [20]. A major limitation in this study includes the small
sample size, which limits the overall generalizability of the
findings. However, a post-hoc power test indicated sufficient
power (~ > 0.8) to discriminate reduced BMD at the different
sites pre- and post-LTX.
Unique findings include the high prevalence of suboptimal
vitK status post-LTX. These findings underscore the importance of routine follow-up by healthcare practitioners in
patients with CF undergoing LTX. Future studies should focus
on assessing adherence to vitamin therapy, and the impact of
vitK supplementation on bone health parameters.
'<,
o
RELEVANCE TO PRACTICE
Patients with CF are at high risk for poor bone health and
micronutrient insufficiency, This underscores the need for
highly specialized medical teams to address ongoing micronutrient deficiencies in this population. Registered Dietitians are
uniquely positioned to help optimize bone health and micronutrient status by developing effective nutrition care plans
and exploring the barriers and facilitators to achieving nutritional goals in complex care populations.
Acknowledgements
The authors gratefully acknowledge the participants in this
study.
Funding: Canadian Lung Transplantation Study Group.
Personal funding for ASA by the King Abdullah Program
for Scholarship- Saudi Cultural Bureau is also gratefully
acknowledged.
Conflicts of interest: None to report.
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