Bone mineral density, bone metabolism and body composition of children with chronic renal failure, with and without growth hormone treatment.
ABSTRACT Osteopenia has been reported in adult patients with chronic renal failure (CRF). Only a few studies have been performed in children. The objective of this study was to evaluate bone mineral density (BMD), bone turnover, body composition in children with CRF and to study the effect of GH on these variables.
Two groups were identified: patients with growth retardation who received GH (GH-group) and patients most of whom were not growth retarded who did not receive GH (no-GH-group). After an observation period of 6 months, the patients in the GH-group started GH treatment. Patients were studied every 6 months during 18 months.
Thirty-six prepubertal patients (27 boys and 9 girls), mean age 7.9 years, with CRF participated in the study. The GH-group consisted of 17 patients of whom 14 completed one year treatment. The no-GH-group consisted of 19 patients, of whom 16 were followed for 6 months, 14 for 12 months and 13 for 18 months.
Lumbar spine BMD, total body BMD and body composition were assessed by dual energy X-ray absorptiometry, compared to age-and sex-matched reference values of the same population and expressed as standard deviation scores (SDS). BMD of appendicular bone was measured by quantitative microdensitometry (QMD). Blood samples were obtained to assess bone metabolism and growth factors.
Baseline mean lumbar spine and total body BMD SDS of all patients were not significantly different from normal. Mean lumbar spine and total body BMD SDS did not change significantly in the GH-group during GH treatment. The change of QMD at the midshaft during the first 6 months of GH treatment was significantly smaller than during the observation period (P < 0.01). Height SDS and biochemical markers of both bone formation and bone resorption increased significantly during GH treatment; 1,25-dihydroxyvitamin D remained stable. Lean tissue mass increased (P < 0.001) and percentage body fat decreased (P < 0.01) during GH treatment. BMD, the biochemical markers of bone turnover which are independent of renal function, and body composition remained stable in the no-GH-group.
Mean lumbar spine and total body BMD of children with chronic renal failure did not differ from healthy controls. The lack of a GH-induced increase in 1,25-dihydroxyvitamin D levels, probably due to treatment with alpha-calcidol, might be linked to the absence of a response in BMD during GH treatment in children with chronic renal failure.
- SourceAvailable from: Justine Shults[show abstract] [hide abstract]
ABSTRACT: The impact of pediatric chronic kidney disease (CKD) on acquisition of volumetric bone mineral density (BMD) and cortical dimensions is lacking. To address this issue, we obtained tibia quantitative computed tomography scans from 103 patients aged 5-21 years with CKD (26 on dialysis) at baseline and 12 months later. Gender, ethnicity, tibia length, and/or age-specific Z-scores were generated for trabecular and cortical BMD, cortical area, periosteal and endosteal circumference, and muscle area based on over 700 reference subjects. Muscle area, cortical area, and periosteal and endosteal Z-scores were significantly lower at baseline compared with the reference cohort. Cortical BMD, cortical area, and periosteal Z-scores all exhibited a significant further decrease over 12 months. Higher parathyroid hormone levels were associated with significantly greater increases in trabecular BMD and decreases in cortical BMD in the younger patients (significant interaction terms for trabecular BMD and cortical BMD). The estimated glomerular filtration rate was not associated with changes in BMD Z-scores independent of parathyroid hormone. Changes in muscle and cortical area were significantly and positively associated in control subjects but not in CKD patients. Thus, children and adolescents with CKD have progressive cortical bone deficits related to secondary hyperparathyroidism and potential impairment of the functional muscle-bone unit. Interventions are needed to enhance bone accrual in childhood-onset CKD.Kidney International advance online publication, 3 October 2012; doi:10.1038/ki.2012.347.Kidney International 10/2012; · 7.92 Impact Factor
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ABSTRACT: Chronic kidney disease (CKD) is associated with increased fracture risk and skeletal deformities. The impact of CKD on volumetric bone mineral density (vBMD) and cortical dimensions during growth is unknown. Tibia quantitative computed tomographic scans were obtained in 156 children with CKD [69 stages 2 to 3, 51 stages 4 to 5, and 36 stage 5D (dialysis)] and 831 healthy participants aged 5 to 21 years. Sex-, race-, and age- or tibia length-specific Z-scores were generated for trabecular BMD (TrabBMD), cortical BMD (CortBMD), cortical area (CortArea) and endosteal circumference (EndoC). Greater CKD severity was associated with a higher TrabBMD Z-score in younger participants (p < .001) compared with healthy children; this association was attenuated in older participants (interaction p < .001). Mean CortArea Z-score was lower (p < .01) in CKD 4-5 [-0.49, 95% confidence interval (CI) -0.80, -0.18)] and CKD 5D (-0.49, 95% CI -0.83, -0.15) compared with healthy children. Among CKD participants, parathyroid hormone (PTH) levels were positively associated with TrabBMD Z-score (p < .01), and this association was significantly attenuated in older participants (interaction p < .05). Higher levels of PTH and biomarkers of bone formation (bone-specific alkaline phosphatase) and resorption (serum C-terminal telopeptide of type 1 collagen) were associated with lower CortBMD and CortArea Z-scores and greater EndoC Z-score (r = 0.18-0.36, all p ≤ .02). CortBMD Z-score was significantly lower in CKD participants with PTH levels above versus below the upper limit of the Kidney Disease Outcome Quality Initiative (KDOQI) CKD stage-specific target range: -0.46 ± 1.29 versus 0.12 ± 1.14 (p < .01). In summary, childhood CKD and secondary hyperparathyroidism were associated with significant reductions in cortical area and CortBMD and greater TrabBMD in younger children. Future studies are needed to establish the fracture implications of these alterations and to determine if cortical and trabecular abnormalities are reversible.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2011; 26(9):2235-44. · 6.04 Impact Factor
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ABSTRACT: BACKGROUND Since childhood cancer survival has increased, long-term effects of treatment have gained interest. Childhood Hodgkin's lymphoma has been treated successfully for decades now. We provide an overview of the literature on long-term endocrine side effects, such as gonadal dysfunction and growth retardation, as a result of childhood Hodgkin's lymphoma treatment. METHODS A comprehensive search of the Pubmed database was performed. RESULTS We identified 16 studies (10 studies: 298 male survivors and 6 studies: 230 female survivors) about gonadal dysfunction. In survivors treated with alkylating agents or pelvic radiotherapy, severe gonadal damage is described. Recovery was rarely described. Seven studies (481 survivors) about bone mineral density (BMD) and growth were identified. The effects on BMD appear to be small. Data on growth are scarce, but show that radiotherapy in a dose of >30 Gy including the spine, especially in pre-pubertal children, results in reduced height. We included 10 studies (4012 survivors) about thyroid complications. Hypothyroidism is the most common thyroid disorder after radiotherapy. There is also a significant incidence in thyroid carcinoma after low-dose radiation. In survivors treated with chemotherapy only, hypothyroidism and thyroid cancer have not been reported. CONCLUSIONS The severity of endocrine toxicity after childhood Hodgkin's lymphoma depends on the type of treatment. Gonadal dysfunction seems to be the most severe endocrine long-term effect, especially after treatment with alkylating agents or pelvic radiotherapy. The knowledge obtained in specific follow-up programmes for paediatric cancer survivors will help to find the optimal balance between curability and long-term side effects.Human Reproduction Update 09/2011; 18(1):12-28. · 9.23 Impact Factor
Bone mineral density and body composition
of children and adolescents
in health and disease
Cover design: Roelinde Boot, Robbeti Zweegman
Copyright 1997 A.M. Boot
Printed by ICG Printing, Dordrecht
No part of this thesis may be reproduced or transmitted in any form, by any means,
electronic or mechanical, including photocopying, recording or any information storage
and retrieval system, without prior written permission of the author, or where appropia·
te, of the publishers of the articles.
Bone mineral density and body compositioh
of children and adolescents
in health and disease
Botdichtheid en Iichaamssamenstelling
bij gezonde en zieke kinderen en adolescenten
Tel' verkrijging van de graad van doctor aan de
Erasmus Universiteit Rotterdam op gezag van de
Prof. Dr P.W.C. Akkermans M.A.
en vol gens het besluit van het College voor Promoties
De openbare verdediging zal plaatsvinden op
woensdag 8 oktober 1997 om 15.45 uur
Annemieke M. Boot
geboren te Amhem
Prof. Dr S.L.S. Drop
Prof. Dr H.A. BUller
Prof. Dr E.P. Krenning
Prof. Dr S.W.I. Lamberts
Co-promotor: Dr S.M.P.F. de Muinck Keizer-Schrama
The printing of this thesis and the studies described were fmancially supported by
Novo Nordisk Farma B.V., Alphen aan de Rijn and Novo Nordisk AlS, Denmark.
Determinants of bone mineral density and body
composition in healthy children and adolescents
Bone mineral density of children and adolescents;
relation to puberty, calcium intake and physical activity.
J elin Endocrinoi Metab 1997; 82: 57-62.
Determinants of body composition, measured by
dual-energy x-ray absorptiometry, in Dutch children
Am J elin Nutr 1997; 66: 232-8.
Bone mineral density and body composition before
and during treatment with gonadotrophin-releasing
hormone agonist in children with central precocious
and early puberty.
Bone mineral density and nutritional status
in children with chronic inflammatory bowel disease.
Bone mine:al density and bone metabolism of
prepubertal children with asthma after long-term
treatment with inhaled corticosteroids.
Ped Puimonoi (in press)
Bone mineral density in children with
acute lymphoblastic leukemia.
Bone mineral density in renal diseases
Renal transplantation and osteoporosis.
Arch Dis Child 1995; 72: 502-6.
Bone mineral density, bone metabolism and
body composition of children with chronic renal failure,
with and without growth hormone treatment.
Changes in hone mineral density, body composition
aud lipid metabolism during growth hormone treatment
in children with growth hormone deficiency.
J Clill Endocrillol Metab 1997; 82: 2423-28.
General discussion and future research
Samenvatting (in Dutch)
Dankwoord (in Dutch)
About the author
Osteoporosis is characterized by low bone mass and microarchitectural deterioration of
bone tissue, leading to enhanced bone fragility and a consequent increase in fracture
risk.' Osteoporosis is a major public health problem involving postmenopausal women
and aging individuals.' The lifetime risk of osteoporotic fractures of the vertebral
bodies (symptomatic), hip, and distal radius is about 40 % for white women and 13 %
for white men.' At present, the best possibility to assess the fracture risk of an
individual is the measurement of bone mass (g) or bone mineral density (BMD, glcm').
Studies in postmenopausal women showed that for each standard deviation decrease in
BMD there was a 2-3 fold increase in fracture risk.'·4 Bone mass later in life is
determined by the peak bone mass acquired during adolescence and the subsequent rate
of bone loss.'·8 Low peak bone mass results in a higher risk of osteoporosis. A high
peak bone mass provides a larger reserve later in life.'
BMD increases during childhood until the peak bone mass is achieved, around the age
of 18 to 20 years."·11 Thereafter, bone mass stabilizes and then decreases progressively
in both sexes after 35 to 40 years of age with a steeper decline in women after the
menopause'·12 (Figure I, adapted from reference 12).
Low ...L_~ __
Schematic lifetime presentation of bone mass and fracture risk.
Children with low BMD have a higher risk of fractures. Besides, they may have a
higher risk of osteoporosis in adult life. In children, osteoporosis and low BMD are
mainly observed in association with diseases or treatments. Disorders associated with
osteoporosis in childhood are listed in Table 1 (adapted from reference 13,14).
Preventive measures for osteoporosis later in life is focussed on factors that may
increase peak BMD. Therefore, knowledge of determinants of BMD during childhood
and adolescence in physiological and pathological conditions is essential with the goal
of optimizing peak bone density. Identifying patients at risk of low BMD is important.
Optimizing bone mass accretion during childhood and the attaimnent of peak bone
mass reduces the risk of osteoporosis.
Classification of osteoporotic conditions of childhood
I. Endocrine :
2. Marrow replacement and expansion
3. Dntgs :
4. Immunologic and inflammatory :
6. Deficiency states :
7. Inborn errors of metabolism:
anemias (sickle cell, thalassemia)
inflammatory bowel disease
idiopathic juvenile osteoporosis
Technique to measure bone mineral density
At present, dual energy x-ray absorptiometry (DXA) is the method of choice to
measure BMD. DXA has low radiation exposure, great precision, and accuracy and is
suitable for children." For children below 30 kg in weight special pediatric software
has been developed. DXA BMD measurements (Lunar DPXLIPED, Wisconsin, USA)
were used in the studies described in this thesis.
Two types of bone can be distinguished in the skeleton : cortical bone, the compact
bone of the appendicular skeleton, and trabecular bone, the primary component of
vertebral bodies of the axial skeleton and flat bones of the skull and pelvis. Eighty %
to 90 % of the volume of compact bone is calcified, whereas 15 % to 25 % of the
trabecular bone is calcified; the remainder is occupied by bone marrow, blood vessels
and connective tissue.I6 Cortical bone fulfills mainly a mechanical and protective
function and trabecular bone a metabolic function.I6 In the studies of this thesis BMD
is measured of the total body, 80 % cortical bone, and of lumbar spine, 50 to 70 %
BMD (glcm') measured by DXA is an area density derived Il'om the bone mineral
content (g) divided by the projected bone image (area, cm') of the region. The COI1'eC-
tion for area removes some, but not all, of the dependency on bone size. Given a fixed
volumetric density, large vellebrae have greater BMD values than small vertebrae.I8 To
correct completely for bone size, we calculated volumetric d e n ~ i t y for lumbar spine in
some studies. Ancillary DXA-derived data were used to calculate the lumbar spine
volumetric bone mineral apparent density (BMAD). The lumbar body was assumed to
have a cylindrical shape and BMAD was calculated as follows : Volume = 1t r' h = 1t
(widthl2)') (area / widthV9 Thus BMAD = BMC / Volume = BMD [4/ (1t width)].I9
The validity of this model was tested by others using magnetic resonance inlaging
measurements of vertebral dimensions.19
Nutritional status is an important indicator of health in children and affects BMD. For
many purposes anthropometric measurements as weight for age, weight for height and
body mass index provide satisfactory infomtation about the nutritional status of
children. However, diseases or treatment may influence body composition which is not
reflected in anthropometry. Changes in body fat and lean body mass occur in many
disorders. Diseases or dmgs which affect bone metabolism may also influence body
composition, like growth hormone deficiency or treatment with corticosteroids.
In the studies described in this thesis body composition was assessed by DXA, which
has been shown to be a precise and accurate method for assessing body compositi-
on,15,20,21 DXA provides a three compartment model : fat mass, lean tissue mass and
bone mineral content.
In two studies, additional bio-electrical impedance was performed, a method which is
cheap and easy to perform. It uses a two compartment model : fat and fat free mass.
The resistance and reactance are measured by applying a pair of electrodes to one arm
and one leg of a subject and using a conduction current of 50 kHz and 800 flA (model
10 I, RJL systems, Detroit, USA). The measurement is based on the fact that fat free
mass contains electrolytes and acts as a conductor while body fat is relatively ion-free
and acts as an insulator.
Bone is an active tissue constantly being remodeled in adults as well as in children.
Old bone is replaced by new bone. The remodelling process takes place at discrete sites
(bone remodelling units). After resorption of a mineralized surface by osteoclasts,
osteoblasts are recruited and secrete new bone matrix and gradually fill in the resorp-
tion cavity." Bone remodelling is higher in trabecular than in cortical bone. Both
systemic and local factors influence bone turnover. In the steady state after growth has
ceased, the coupling of bone formation and resorption maintains bone mass." Any
imbalance may lead to a change of bone mass. In periods of bone loss, rates of
resorption exceed fonnation. During childhood and adolescence growth involves
accumulation of bone called bone modelling. Bone modelling is achieved both by
appositional growth along periostal surfaces and by the calcification of cru1ilage in the
growth plate." Chondrocytes regulate enchondral bone fOlIDation during lineru' growth.
The remodeling of existing mineralized tissue and the modeling of new bone are each
ongoing processes in growing children. Both involve bone formation and bone
resOllltion. The biochemical mru'kers of bone turnover are not specific for either the
process of bone modeling or skeletal remodeling." In children, biochemical bone
markers correlate with growth velocity." The markers are high in periods of increased
growth like the first year of life and during the pubertal grow1h spurt.
Biochemical markers of bone turnover can be measured in blood and urine samples.
Assessment of these markers may provide insight in the pathogenesis of osteopenia.
The following bone formation and resOllltion markers were evaluated in the studies
described in this thesis :
Markers of bone formation :
- serum alkaline phosphatase. Total alkaline phosphatase in serum includes several
isoforms. Alkaline phosphatase is an enzyme not only produced by osteoblasts but also
by other tissues, including liver, intestines, and kidney."
- selUm osteocalcin. Osteocalcin is a small protein synthesized by osteoblasts, odonto-
blasts and chondrocytes. While osteocalcin is primarily deposited in the extracellular
matrix of bone, a small amount enters the circulation." Osteocalcin has a circadian
rhythm with higher nocturnal values in comparison with diurnal values."
- serum carboxytenninal of type I procollagen (PICP). Collagen I represents more than
90 % of the organic bone matrix. It is synthesized by osteoblasts as procollagen with
amino- arid carboxytenninal extension peptides. These extension peptides are cleaved
from the molecules to newly formed collagen." Like osteocalcin, PICP shows a
circadian rhythm." PICP is cleared by the liver.
Markers of bone resorption :
- urinary hydroxyprolin. Hydroxyprolin is an aminoacid found in collagenous pro-
teins." Only about 10 % of hydroxyproline-containing products from collagen break-
down are excreted in the urine, the majority is reabsorbed by the renal tubules and
broken down in the liver." Another disadvantage is that several other sources of
hydroxyproline in addition to bone resorption contribute to urinary hydroxyproline, like
diet (gelatin) and breakdown of soft connective tissue." Dietary influences can be
circumvented by measuring hydroxyproline/creatinine ratio in the fIrst morning void of
urine after an overnight fast.'·
- urinary calcium. The total daily calcium excretion is dependent on calcium intake.
Like hydroxyproline, dietary influence can be minimized by measuring calcium/crea-
tinine ratio in the fIrst morning urine.
- serum cross-linked telopeptide of type I collagen (lCTP). ICTP is released during the
resorption of bone collagen. ICTP shows a circadian rhythm, like osteocalcin and
Scope of the thesis
The overall aim of the studies reported in this thesis was to identify determinants of
BMD during childhood and adolescence in healthy subjects and in patients with
diseases or treated with drugs affecting bone mineralization. Determinants of body
composition were evaluated in healthy children and adolescents. BMD, biochemical
markers of bone turnover and body composition were evaluated in several patient
Knowledge of nonnal physiological variation is necessary to identify pathological
changes. Therefore, we conducted a study in healthy children and adolescents in order
to acquire reference values and to evaluate detenninants of BMD and body compositi-
on in physiological conditions (Chapter 2).
Puberty is an important period for bone mass acquisition. In children with central
precocious pubeliy pubertal development starts prematurely and can be inhibited by the
administration of gonadotrophin-releasing hormone agonist. Chapfer 3 describes BMD,
bone metabolism and body composition of these children before and during treatment
with gonadotrophin-releasing hormone agonist.
In children with inflammatory bowel disease BMD may be negatively influenced by
treatment with cOlticosteroids, malnutrition, or the disease itself. Chapfer 4 describes a
study in children with inflammatory bowel disease.
We evaluated BMD and bone metabolism after long-term treatment with inhaled
corticosteroids in asthmatic children (chapfer 5).
Chapfer 6 presents a study in children with acute lymphoblastic leukemia. BMD in
these children may be affected by the disease or by the treatment of cOlticosteroids and
In chapfer 7 studies in patients with renal diseases are described. Treatment willi
corticosteroids after transplantation or renal osteodystrophy before transplantation may
influence bone metabolism. In chapfer 7.1 BMD of young adult patients who received
a renal transplantation in childhood was assessed. In chapfer 7.2 BMD and bone
metabolism were studied in children with chronic renal insufficiency. Children willi
chronic renal insufficiency and growth retardation were treated with growih hormone
and the effect on BMD, bone turnover and body composition was studied.
In children with growth hormone deficiency BMD, body composition, bone metabolism
and lipid metabolism were studied before and during treatment with growth hormone
Chapfer 9 discusses the presented data and suggestions are made for future research.
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