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Indian Pediatr 2017;54:
545-549 |
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Bone Mineral Density of Indian Children and
Adolescents with Cystic Fibrosis
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Sumita Gupta, Aparna Mukherjee,
*Rajesh Khadgawat, Madhulika
Kabra, Rakesh Lodha and Sushil K Kabra
From Departments of Pediatrics and *Endocrinology,
All India Institute of Medical Sciences, New Delhi, India.
Correspondence to: Prof SK Kabra, Professor,
Department of Pediatrics, 3067, Teaching Block, All India Institute of
Medical Sciences, Ansari Nagar, New Delhi 110 029, India.
Email: [email protected]
Received: May 27, 2016;
Initial review: August 28, 2016;
Accepted: April 13, 2017.
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Objective: To document bone
mineral density of children and adolescents with cystic fibrosis.
Design: Cross-sectional study.
Setting: Tertiary-care center of
Northern India, July 2012 to August 2015.
Participants: 52 children aged
6-18 years with cystic fibrosis and 62 healthy controls of similar age
and sex.
Methods: Both patients and
controls were stratified into two groups, as pre-pubertal and peri-/post-pubertal,
and compared for whole body bone mineral density, measured using dual
energy X-ray absorptiometry. Serum levels of calcium, phosphate,
alkaline phosphatase, 25-hydroxyvitamin D and parathyroid hormone were
measured in children with cystic fibrosis.
Results: Compared with controls,
the mean (SD) bone mineral density of children with cystic fibrosis was
significantly lower in both the pre-pubertal (0.7 (0.1) g/cm2 vs
0.9 (0.1) g/cm2; P<0.001)) and peri-/post-pubertal groups (0.9
(0.1) g/cm2 vs 1.1 (0.1) g/cm2; P<0.001). Also, the mean
(SD) bone mineral apparent density of pre-pubertal and peri-/post-pubertal
cystic fibrosis patients was lower than the controls (P <0.001
and P= 0.01, respectively). Thirty-seven (71.2%) cystic fibrosis
patients had serum 25-hydroxyvitamin D level below 15 ng/mL.
Conclusion: Bone mineral density
of children with cystic fibrosis was significantly lower than controls;
majority of them were vitamin-D deficient. Intervening at an early stage
of the disease and providing optimal therapy involving simultaneous
management of the several factors affecting bone mineral accretion may
be beneficial in improving bone health of these patients.
Keywords: Bone health, Chronic illness, Dual
energy X-ray absorptiometry, Vitamin D.
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W
ith increased survival, individuals with cystic
fibrosis (CF) develop disease-related long-term complications, among
which, one is low bone mineral density (BMD). Factors that contribute to
low BMD in CF include malnutrition, chronic respiratory inflammation,
delayed puberty, reduced physical activity, exocrine insufficiency and
glucocorticoid usage [1].
Clinical profile of Indian CF patients is almost
similar to Caucasians but the disease severity is higher, mainly due to
delayed diagnosis and delayed implementation of appropriate management
resulting from lack of awareness about the disease or lack of diagnostic
facilities [2,3]. Studies on children and adolescents with CF from
developed countries suggest low BMD [4-6]. Over past two decades, there
is increasing awareness about CF in India but there are no studies on
BMD in Indian children with CF. We conducted this study with the
objective of documenting BMD in children with CF being followed up in a
large tertiary-care hospital of Northern India.
Methods
This study was carried out in the Department of
Pediatrics, All India Institute of Medical Sciences in New Delhi, India,
from July 2012 to August 2015. Children (age 6-18 y) with confirmed
diagnosis of CF (clinical phenotype with sweat chloride
³60 mEq/L), not
having any primary bone disease were included in this cross-sectional
study. Healthy controls included children of similar age and sex, not
having any chronic illness affecting bone density or a period of
immobility of more than two weeks in the preceding 12 weeks. They were
either friends of CF participants or children of healthcare personnel of
the center. Study was approved by the Institutional Ethics Committee of
AIIMS. Written informed consent was obtained from parents and guardians
of all eligible children.
All participants’ weight was measured using
calibrated scales, and height was measured to nearest 0.1 cm using a
standardized stadiometer. Body mass index (BMI) was calculated. Z scores
were calculated using WHO Anthroplus software [7].
Pubertal development was determined by a
self-assessment questionnaire using drawings and written descriptions of
Tanners’ breast, genital and pubic hair classification [8].
Whole body dual energy X-ray absorptiometry
(DXA) scan (Hologic QDR 4500A, Hologic Inc., Bedford, MA, USA) was
performed and the measurements included whole body bone mineral content
(in g), area (in cm 2), and
areal density (in g/cm2).
Since there are substantial changes in bone dimensions during childhood
and BMD measured by DXA scan does not take into account thickness of
bone, bone mineral apparent density (BMAD), which is bone mineral
content normalized to a derived bone reference value, was calculated
using methods suggested by Katzman, et al. [9]. BMAD minimizes
effect of bone geometry and allows comparisons of mineral status among
bones of similar shape but different size.
In addition, use of inhaled and oral bronchodilators
and other medication was recorded in children with CF. Fasting blood
samples of patients were collected to assess bone-related biochemical
parameters. Serum calcium, phosphorous, and alkaline phosphatase were
measured by Hitachi Modular P 800 autoanalyser,and 25-hydroxyvitamin D
(25 (OH) D) was measured using chemiluminescent immunoassay (DiaSorin
LIAISON, Minnesote, USA). Parathyroid hormone (PTH) levels in serum were
measured with electrochemiluminescence method (Roche COBAS e411, Japan).
The reference range of serum 25 (OH) D was taken as: sufficient (20-100
ng/mL); insufficient (15-19 ng/mL); and deficient (<15 ng/mL) [10].
Spirometric parameters (FEV 1
and FVC (% predicted) were measured in the CF patients with a portable
spirometer (Super Spiro Micromedics, Rochester, UK), using standard
method for test performance recommended by American Thoracic Society and
European Respiratory Society [11]. Physical activity level of these
patients was estimated using Habitual Activity Estimation Scale (HAES)
[12]. Participants were asked to recall one usual weekday and one usual
weekend day separately from past two weeks. Sum of ‘somewhat active’ and
‘active’ scores was taken as total activity in hours.
Statistical analysis: As accelerated bone
acquisition occurs during the initial few years of life and then during
the pubertal spurt, children were divided into prepubertal and peri-/post-pubertal
strata based on self-assessed Tanner stage. Stratified analysis was
performed to compare demographic characteristics and DXA parameters
between CF patients and controls separately in the two strata of
children. Multivariable linear regression analysis was performed to
assess factors associated with whole body BMD, which was the dependent
variable. Independent covariates were presence of CF, age, sex and
height.
Results
Fifty-two children with CF and 62 controls were
enrolled in the study. Baseline characteristics of participants are
shown in Table I. Mean (SD) age of CF group was 149.8
(37.8) months with 30 boys and that of controls was 148.6 (36.3) months
with 35 boys. There were 28 patients and 29 controls in the pre-pubertal
stratum and 24 patients and 33 controls in the peri-/post-pubertal
stratum. The height, weight and the BMI of patients were significantly
lower as compared to controls (Table I).
TABLE I Baseline Characteristics of Patients with Cystic Fibrosis Subjects and Healthy Controls
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Group/ |
Cystic fibrosis |
Controls |
P value |
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Characteristics |
(n = 52) |
(n = 62) |
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Pre-pubertal |
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Number |
28 |
29 |
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Age (months) |
122.8 (25.9) |
116.3 (18.1) |
0.28 |
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Female/Male (n) |
9/19 |
12/17 |
0.47 |
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Weight (kg) |
22.9 (7.7) |
36.3 (10.2) |
< 0.001 |
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Height (cm) |
128.0 (11.4) |
140.9 (9.3) |
< 0.001 |
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Height for age Z score |
-1.8 (1.4) |
-0.4 (1.2) |
< 0.001 |
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BMI (Kg/m2) |
13.6 (2.7) |
18.2 (4.2) |
< 0.001 |
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BMI for age Z score |
-2.5 (1.7) |
0.3 (1.4) |
< 0.001 |
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Peri-/post-pubertal |
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Number |
24 |
33 |
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Age (mo) |
181.3 (21.4) |
176.9 (21.5) |
0.44 |
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Female/Male (n) |
13/11 |
15/18 |
0.52 |
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Weight (kg) |
36.0 (9.9) |
55.4 (12.5) |
< 0.001 |
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Height (cm) |
149.7 (9.4) |
158.8 (10.0) |
< 0.001 |
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Height for age Z score |
-1.9 (1.2) |
0.4 (1.2) |
< 0.001 |
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BMI (Kg/m2) |
15.8 (3.1) |
21.9 (4.7) |
< 0.001 |
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BMI for age Z score |
-2.3 (2.0) |
0.5 (1.7) |
< 0.001 |
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All values as Mean (SD) unless specified; BMI: Body mass index. |
Children with CF had median (IQR) vitamin D levels of
9.0 (6,15.5) ng/mL, PTH 47.3 (38.6, 73.9) pg/mL, and serum alkaline
phosphatase 528.5 (376.5, 674.5) IU/L. Mean (SD) serum calcium and
phosphate were 9.2 (0.5) mg/dL and 4.7 (0.7) mg/dL, respectively. Mean
(SD) FEV 1 and FVC (%
predicted) were 61.2 (24.6)% and 67.3 (20.1)%, respectively. Three
(5.7%) children with CF were vitamin-D sufficient, 12 (23.1%) had
insufficiency and 37 (71.2%) were deficient.
Thirty-three (63.5%) children had FEV 1
(% predicted) <70%, twenty-seven (52%) were colonized with
Pseudomonas and 20 children were moderately severely malnourished
(height for age Z score <2). Using HAES, average activity level
of CF boys was 6.5 hours and of girls was 5.8 hours. Of 52 enrolled CF
children, 46 were taking inhaled glucocorticoids, 5 were on long term
oral glucocorticoids and 5 had taken oral corticosteroids for short
durations.
Compared with controls, mean (SD) whole body BMD Z
score was significantly lower in CF patients, difference being more
marked in peri-/post-pubertal stratum (Table II). ‘Z’
score of -2 and below was present in 11 (38%) children and 14 (58%)
adolescents with CF. Ten (36%) children and 5 (21%) adolescents with CF
had Z score between -1and -2.
TABLE II Comparison of Whole Body Bone Mineral Parameters in Patients with Cystic Fibrosis and Healthy Controls
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Parameter |
Cystic |
Control |
P-value |
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fibrosis |
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Pre-pubertal (n) |
28 |
29 |
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Bone mineral |
-1.8 (1.1) |
1.1 (0.9) |
< 0.001 |
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density ‘Z’ score |
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Difference (95% CI) |
-2.9 (-3.5, -2.4) |
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Bone mineral density (g/cm2) |
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Unadjusted |
0.7 (0.1) |
0.9 (0.1) |
<0.001 |
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Adjusted, Mean (SE) |
0.7 (0.0) |
0.8 (0.0) |
<0.001 |
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Difference (95% CI) |
-0.1 (-0.2, -0.1) |
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Bone mineral apparent |
0.08 (0.01) |
0.09 (0.01) |
<0.001 |
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density (g/cm3) |
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Peri-/post-pubertal (n) |
24 |
33 |
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Bone mineral |
-2.4 (1.9) |
0.9 (1.0)) |
<0.001 |
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density ‘Z’ score |
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Difference (95% CI) |
-3.4 (-4.2, -2.6) |
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Bone mineral density (g/cm2) |
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Unadjusted |
0.9 (0.1) |
1.1 (0.1)) |
<0.001 |
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Adjusted, Mean (SE) |
0.9 (0.0) |
1.1 (0.0)) |
<0.001 |
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Difference (95% CI) |
-0.2 (-0.3, -0.1) |
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Bone mineral apparent density (g/cm3) |
0.09 (0.01) |
0.1 (0.01)) |
0.01 |
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All values as Mean (SD) unless specified; Difference in means
calculated by (CF – Control) with 95% CI; Adjusted for age, sex
and height; SE: Standard error. |
Controls had a significantly higher mean (SD) BMD
as compared to CF patients, both in pre-pubertal
and peri-/post-pubertal strata (Table II). As there was a
significant difference in height between the two groups, BMD was
adjusted for age, sex and height and difference in means between
controls and CF for the two strata was reported (Table II).
Mean (SE) BMD of controls was significantly higher than CF in both
strata. Also mean BMAD of pre-pubertal, as well as, peri-/post-pubertal
controls remained significantly higher than that in CF patients (Table
II).
Discussion
In our study, children with CF were relatively
leaner, shorter and lighter than their healthy counterparts. Whole body
BMD of both children and adolescents with CF was significantly lower
than that of controls, even after adjustment for height, age and sex.
The major limitation of the study was that blood
sampling of healthy controls could not be carried out for comparison
with CF patients’ bone-related biochemical parameters, especially
vitamin D status. Also, the referral nature of hospital might have
introduced bias of inclusion of CF patients with more severe disease
profile.
Literature regarding low bone mass in children with
CF is controversial, with most of the studies reporting normal BMD in
well-nourished CF children. Hardin, et al. [13] found that total
body BMD of 13 pre-pubertal CF children was significantly lower when
compared with age- and gender-matched controls, but no difference was
found when compared with controls matched for lean tissue mass, height,
age and gender. Buntain, et al. [14] found that age-, sex- and
height-adjusted total body, lumbar spine and femoral neck BMD of 32
well-nourished CF children was comparable to 40 controls of similar age
and sex.
Some studies suggest that bone mineral deficit in CF
children starts in early childhood. Ujhelyi and colleagues [15] observed
lower Z scores of BMD in lumbar spine and femoral neck of 11
children with CF. In a Canadian study including 81 CF children, Z
score for bone mineral content between -1 and -2 was observed for whole
body in 38% of children and for lumbar spine in 28% of children; Z
score of less than -2 was observed in 7 children for both the
measures [16]. Findings of our study are consistent with the
observations of these studies, where the whole body BMD Z score of -2
and below was observed in 11 (38%) children and 14 (58%) adolescents
with CF as compared to none in healthy cohort.
Bone mass in CF patients is inversely related to
disease severity, wherein, decrease in FEV 1
is associated with decrease in bone mass and increased
glucocorticoid usage is associated with decreased bone mass [5,6,14].
Studies on Indian CF patients report increased
disease severity due to delayed diagnosis [2]. Studies also suggest that
pulmonary involvement is the most prominent and the severest
manifestation in Indian CF patients [2,17]. Majority (63.5 %) of CF
children enrolled in present study had moderate to severe lung disease
and a large number of them were malnourished. These factors might have
contributed to low BMD in our patients. As the disease severity observed
in Indian CF patients and our study population is higher than
Caucasians, use of glucocorticoids could be higher than the western
world, which may be compromising the bone mineral accretion of our CF
group. The oral glucocorticoids use showed a negative relation with mean
whole body BMD and whole body BMD Z score. Using habitual
activity estimation scale, in our study, average activity level of boys
with CF was 6.5 hours and of girls was 5.8 hours which was lower than
the documented activity levels by Boucher, et al.
[18]. The lower activity levels of our CF cohort
may be due to increased disease severity that might have affected bone
mineral accretion. Some rare and novel mutations identified in Asian
population could be another contributing factor to increased disease
severity and thereby reduced bone mass of our CF population [2,19].
Influence of suboptimal levels of vitamin D and
calcium homeostasis on bone metabolism of CF patients remains unclear.
In the current study it was observed that majority of CF subjects were
vitamin D-deficient and in 15 patients parathyroid hormone levels were
above the normal limits. These findings are consistent with findings of
Haworth, et al. [4] and Aris, et al. [20], and could be
contributing to low bone mass in the present CF cohort.
The results of this study stress on implementation of
vigorous strategies to manage skeletal health of CF children from early
childhood. We conclude that in children with CF, several factors
concomitantly adversely affect bone mineral accretion. The beneficial
effects of improving/altering any one factor on bone mass may be masked
by other factors. Therefore, intervening at an early stage of the
disease and providing optimal therapy involving simultaneous management
of several factors affecting bone mineral accretion in CF patients may
have a positive impact on their skeletal health.
Contributors: SG: development of protocol, data
collection, data analysis and manuscript writing; AM: in data analysis
and manuscript writing; RK and MK: protocol development and manuscript
writing; RL and SKK: protocol development, data analysis and manuscript
writing; SKK will act as guarantor.
Funding: None; Competing interest: None
stated.
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What is Already Known?
• There is reduced bone mineral density in
children with cystic fibrosis.
What This Study Adds?
• Majority of Indian children with cystic fibrosis are
vitamin D - deficient and have low bone mineral density.
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References
1. Cystic Fibrosis Trust, 2007. Bone mineralization
in cystic fibrosis. Report of the UK Cystic Fibrosis Trust Bone
Mineralisation Working group. Bromley, London; Cystic Fibrosis Trust.
2. Kabra SK, Kabra M, Lodha R, Shastri S. Cystic
fibrosis in India. Pediatr Pulmonol. 2007;42:1087-94.
3. Kabra SK, Kabra M, Shastri S, Lodha R. Diagnosing
and managing cystic fibrosis in the developing world. Paediatr Respir
Rev. 2006;7S:S147-50.
4. Haworth CS, Selby PL, Webb AK, Dodd ME, Musson H,
Niven RM, et al. Low bone mineral density in adults with cystic
fibrosis. Thorax. 1999; 54:961-7.
5. Conway SP, Morton AM, Oldroyd B, Truscott JG,
White H, Smith AH, et al. Osteoporosis and osteopenia in adults
and adolescents with cystic fibrosis: prevalence and associated factors.
Thorax. 2000;55:798-804.
6. Elkin SL, Fairney A, Burnett S, Kemp M, Kyd P,
Burgess J, et al. Vertebral deformities and low bone mineral
density in adults with cystic fibrosis: A cross-sectional study.
Osteoporos Int. 2001;12:366-72.
7. WHO Anthroplus software version 1.0.4 (based on
WHO growth reference 2007 for 2009)). Available from:
http:/www.who.int/childgrowth/software/en. Accessed January 12,
2015.
8. Tanner JM, Whitehouse RH. Clinical longitudinal
standards for height, weight, height velocity, weight velocity, and
stages of puberty. Arch Dis Child. 1976;51:172-9.
9. Katzman DK, Bachrach LK, Carter DR, Marcus R.
Clinical and anthropometric correlates of bone mineral acquisition in
healthy adolescents girls. J Clin Endocrinol Metab. 1991;73:1332-9.
10. Misra M, Pacaud D, Petryk A, Collett-Solberg PF,
Kappy M. Vitamin D deficiency in children and its management: Review of
current knowledge and recommendations. Pediatrics. 2008;122:398-417.
11. Millar MR, Hankinson J, Brusasco V, Burgos F,
Casaburi R, Coates A, et al. Standardisation of spirometry. Eur
Respir J. 2005;26:319-38.
12. Hay JA, Cairney J. Development of the Habitual
Activity Estimation scale for clinical research: A systematic approach.
Pediatr Exer Sci. 2006;18:193-202.
13. Hardin DS, Arumugam R, Seilheimer DK, LeBlanc A,
Ellis KJ. Normal bone mineral density in cystic fibrosis. Arch Dis
Child. 2001;84:363-8.
14. Buntain HM, Greer RM, Schluter PJ, Wong JCH,
Batch JA, Potter JM, et al. Bone mineral density in Australian
children, adolescents and adults with cystic fibrosis: A controlled
cross sectional study. Thorax. 2004;59: 149-55.
15. Ujhelyi R, Treszl A, Vásárhelyi B, Holics K, Tóth
M, Arató A, et al. Bone mineral density and bone acquisition in
children and young adults with cystic fibrosis: A follow-up study. J
Pediatr Gastroenterol Nutr. 2004;38:401-6.
16. Grey V, Atkinson S, Drury D, Casey L, Ferland G,
Gundberg C, et al. Prevalence of low bone mass and deficiencies
of vitamins D and K in pediatric patients with cystic fibrosis from 3
Canadian centers. Pediatrics. 2008;122:1014-20.
17. Ashavaid TF, Raghavan R, Dhairyawan P, Bhawalkar
S. Cystic fibrosis in India: A systematic review. J Assoc Physicians
India. 2012;60:39-41.
18. Boucher GP, Lands LC, Hay JA, Hornby L. Activity
levels and the relationship to lung function and nutritional status in
children with cystic fibrosis. Am J Phy Med Rehab. 1997;76:311-5.
19. Shastri SS, Kabra M, Kabra SK, Pandey RM, Menon
PS. Characterisation of mutations and genotype-phenotype correlation in
cystic fibrosis: experience from India. J Cyst Fibros. 2008;7:110-5.
20. Aris RM, Ontjes DA, Buell HE, Blackwood AD, Lark
RK, Caminiti M, et al. Abnormal bone turnover in cystic fibrosis
adults. Osteoporos Int. 2002;13:151-7.
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