Clinical Nutrition ESPEN 50 (2022) 162e169

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Clinical Nutrition ESPEN

journal homepage: http://www.clinicalnutritionespen.com

Original article

Bone mineral density and nutrition in long-term survivors of

childhood brain tumors
Janne Anita Kvammen a, b, *, Einar Stensvold b, c, Kristin Godang d, Jens Bollerslev d, c,
Tor Åge Myklebust e, f, Petter Brandal g, h, Christine Henriksen a, Anne Grete Bechensteen b
a
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
b
Department of Pediatric Medicine, Oslo University Hospital, Oslo, Norway
c
Department of Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
d
Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway
e
Department of Registration, Cancer Registry of Norway, Oslo, Norway
f
Department of Research and Innovation, More og Romsdal Hospital Trust, Ålesund, Norway
g
Department of Oncology, Oslo University Hospital, Oslo, Norway
h
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway

a r t i c l e i n f o s u m m a r y

Article history: Background and aims: Childhood cancer survivors are at risk of unwanted late effects. The primary aim of
Received 30 November 2021 this study was to assess bone mineral density Z-scores (BMDz) in long-term survivors of childhood
Accepted 31 May 2022 medulloblastoma (MB) or central nervous system supratentorial primitive neuroectodermal tumor (CNS-
PNET). Secondary aims were to describe nutrient intake, vitamin D status, physical activity and explore
Keywords: potential risk factors for decreased BMDz.
Bone
Methods: All MB and CNS-PNET survivors treated at Oslo University Hospital from 1974 to 2013 were
Brain tumors
invited to participate in a cross-sectional study. Dual-energy x-ray absorptiometry (Lunar Prodigy)
Childhood cancer survivors
Nutrition
assessed BMDz lumbar spine, BMDz total body, and lean body mass. Decreased BMDz was defined as a
Physical activity combination of low BMDz
1 to
1.99 and very low BMDz 
2. Lean body mass index (LMI) was
calculated by dividing lean body mass by the squared height. Nutrient intake was assessed by a 3-day
food record. Serum 25(OH)D was analyzed. Physical activity was reported by a questionnaire. Descrip-
tive statistics and multivariable Cox regression analyses were applied.
Results: Fifty survivors with a median age of 25.5 years (5.5e51.9) and a median follow-up time of 19.5
years (3.2e40.5) were included. Mean BMDz lumbar spine was
0.8 (SD 1.1, 95% CI:
1.1 to
0.4), and
BMDz total body was
0.6 (SD 1.1, 95% CI:
0.9 to
0.3). Decreased BMDz was detected in 48% of the
lumbar spine and 34% of the total body measurements. In all, 62% had low calcium, and 69% had low
vitamin D intake. 26% of participants had serum 25(OH)D < 50 nmol/L, and 62% reported an inactive
lifestyle. Male sex, higher age at diagnosis, and lower LMI were potential risk factors for decreased BMDz.
Conclusions: Long-term survivors of childhood MB and CNS-PNET had decreased BMDz, and risk factors
were male sex, higher age at diagnosis, and lower LMI. Inadequate calcium and vitamin D intake, an
inactive lifestyle, and a high prevalence of 25(OH)D  50 nmol/L were detected.
© 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and
Metabolism. This is an open access article under the CC BY license (http://creativecommons.org/licenses/
by/4.0/).

Abbreviations: BMD, bone mineral density (g/cm2); BMDz, bone mineral density Z-score; BMI, body mass index, kg/m2; BMR, basal metabolic rate; CSI, craniospinal
irradiation; CNS, central nervous system; CNS-PNET, central nervous system supratentorial primitive neuroectodermal tumor; DXA, dual-energy x-ray absorptiometry; Htz,
height Z-score; LMI, lean mass index, kg/m2; MB, medulloblastoma; OUH, Oslo University Hospital; RI, recommended intake, referring to Nordic Nutrition Recommendations
2012; UiO, University of Oslo.
* Corresponding author. Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway.
E-mail address: j.a.kvammen@medisin.uio.no (J.A. Kvammen).

https://doi.org/10.1016/j.clnesp.2022.05.025
2405-4577/© 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
J.A. Kvammen, E. Stensvold, K. Godang et al.
1. Introduction
Increased knowledge regarding the role of nutrition and
physical activity in childhood cancer survivors is required to
optimize the quality of life during survivorship. One-third of
cancers in children are in the central nervous system (CNS) [1].
Medulloblastoma (MB) and central nervous system supra-
tentorial primitive neuroectodermal tumor (CNS-PNET) are ma-
lignant embryonal tumors, and they represent approximately
20% of all pediatric CNS tumors [2]. Treatment involves surgery,
craniospinal irradiation (CSI), chemotherapy, and in some cases,
autologous stem cell transplantation. Five-year survival has
improved during the last decades, and the estimated 5-year
overall survival for standard-risk MB is above 80%, 40e60% for
high-risk MB, and 50e70% for CNS-PNET [3]. However, the
recognition of unwanted late side effects among the cancer
survivors is increasing, and childhood brain tumor survivors
have a high burden of unwanted late effects [4]. Health problems
are related to the neoplastic disease, treatment, and the
maturing brain’s vulnerability [5].
Peak bone mass is the maximal attained bone mass during
life and is reached by the end of the second or early in the third
decade of life, depending on the skeletal site [6]. Peak bone mass
is highly dependent on genetics, which influences 60e80% of the
variability in bone mass between individuals, and modifiable
lifestyle factors (e.g., diet, physical activity, and more) influence
20e40% of the reached adult peak bone mass. Gaining a high
peak bone mass is crucial as there is a strong relationship be-
tween bone mineral density (BMD) and the risk of osteoporosis
during life [7,8]. Studies have detected decreased BMD in brain
tumor survivors [9e16], but few studies of long-term survivors
have been conducted. Decreased BMD is a risk factor for fragility
fractures in all ages [10,14,17,18] and reduced quality of life
[9,11,18]. Factors explaining compromised musculoskeletal
health might be present during illness (e.g., cancer, inflamma-
tion, glucocorticoids, irradiation, chemotherapy, malnutrition,
inactivity) and survivorship (e.g., malnutrition, inactivity, endo-
crine disturbances) [19e21]. The mechanisms for detrimental
effects on the musculoskeletal tissues can be multifactorial. Tu-
mor tissue infiltration, cancer-related inflammation, and altered
secretion of cytokines have adverse effects. Chemotherapy can
alter cell functions, or negatively impact kidney, liver, or bowel
functions, and result in loss or malabsorption of nutrients. Drugs
can also induce endocrine deficits [19,21]. CSI, a cornerstone in
the treatment for MB and CNS-PNET, renders these patients even
more vulnerable than other childhood cancer survivors to
detrimental effects on the skeleton [22]. Cranial irradiation can
damage the hypothalamicepituitary axis and reduce the pro-
duction of hormones (growth hormone, sex steroids, insulin-like
growth factors) imperative for developing the skeleton and
muscle mass [23,24]. Hence, BMD surveillance for childhood
cancer survivors is essential to prevent the negative conse-
quences of fractures and is recommended for irradiated patients
[22].
Studies of childhood cancer survivors report poor dietary
quality and unhealthy lifestyles [25]. However, few studies have
investigated lifestyle-related health parameters in long-term
childhood brain tumor survivors. So, our main objective was to
assess bone mineral density Z-scores (BMDz) in long-term sur-
vivors of MB and CNS-PNET. Secondary aims were to describe
nutrient intake, vitamin D status, and physical activity. Further,
we wanted to explore potential risk factors for impaired bone
health.
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Clinical Nutrition ESPEN 50 (2022) 162e169
2. Methods
2.1. Design and subjects
This study is part of a more extensive investigation of survivors
treated for childhood MB or CNS-PNET at Oslo University Hospital
(OUH) from January 1, 1974, until December 31, 2013. During this
period, 123 MB and 34 CNS-PNET patients younger than 22 years of
age at primary diagnosis were treated [26]. We invited all survivors,
except one who had emigrated from Norway (n ¼ 63), to participate
in a cross-sectional, follow-up study performed from August 2016
to October 2018. There were no further exclusion criteria. Clinical
and demographic data were obtained from clinical examinations,
medical records, and questionnaires. Overall study design and
some previous results have been published [26e28].
2.2. Anthropometry
We measured all participants in light clothing. Weight (kg) was
measured by Seca weight (model 770 Seca GmbHbh & co. kg Ger-
many) and standing height (cm) by a stadiometer (Holtain Limited,
Britain). The body mass index (BMI) was calculated by dividing
weight by the square of the height (kg/m2). For the young partic-
ipants (age <18 years), Z-scores for height for age (Htz), and BMI for
age (BMIz) were calculated based on the Norwegian reference
population [29]. Stunted growth was defined as Htz < e2 in young.
Short stature in adults was defined as <150 cm in women and
<160 cm in men [30]. For participants below the age of 18 years, we
defined undernutrition (thinness) as BMIz <e2, normal weight as
BMIz e2 to 1, overweight as BMIz >1, and obesity as BMIz >2
[31,32]. For adults, we defined underweight as BMI <18.5, normal
BMI 18.5e24.9, overweight BMI 25e29.9, and obesity BMI >30 [33].
In the results, overweight and obesity were combined and pre-
sented as overweight.
2.3. Bone mineral density and body composition
Dual-energy x-ray absorptiometry (DXA) was used to assess
bone mineral density (BMD). The measurements were done at the
Department of Specialized Endocrinology, OUH, with a narrow fan-
beam DXA densitometer (Lunar Prodigy) and software enCORE
version 16 (both GE Healthcare, Corp., Madison, WI, USA). We
measured the participants’ BMD (g/cm2) for anterior-posterior
lumbar L2eL4 spine and total body by The International Society
For Clinical Densitometry (ISCD) Official Positions [34]. BMDz was
calculated according to reference materials in the software [35]. For
two stunted girls with available hand radiographs, BMDz were
adjusted according to bone age. Decreased BMDz was defined as a
combination of low BMDz
1 to
1.99 and very low BMDz 
2
[22]. The same DXA was used to assess lean body mass (kg), and
lean body mass index (LMI) was calculated by dividing the lean
body mass by the square of the height (kg/m2).
2.4. Dietary assessment
Participants completed a 3-day food record [36], preferably on
one weekend day and two weekdays. The study had one assigned
registered dietitian responsible for all parts of the dietary assess-
ment. Participants/parents/guardians received written information
on how to fill out the diet records, and the study’s registered die-
titian was available for questions during the study period. Partici-
pants were instructed to maintain their usual diet and register all
foods, liquids, and dietary supplements. Household measures were
J.A. Kvammen, E. Stensvold, K. Godang et al.
recorded. A pictorial booklet of typical dishes with different portion
sizes was used to describe dietary intake [37]. Information on
homemade foods, including cooking methods and receipts, was
noted in the diary. Composite items were analyzed by dividing
them into separate components. An online nutrition analysis tool
(DietistPro), based on the Norwegian Food Composition Table [38],
was used to calculate the mean energy- and nutrient intake for each
participant. Recommended intake (RI) refers to the age and gender-
appropriate reference for healthy persons, given by the Nordic
Nutrition Recommendations 2012 [39]. We calculated all macro-
and micronutrient results individually and compared the results to
appropriate references. Results were presented as the % of RI.
Nutrient intakes (medians, 25e75 percentiles) were also presented
for young (<18 years), adults, and all participants. To estimate basal
metabolic rate (BMR), we used the age and gender appropriate
Oxford equations from Henry 2005 [40], with each participant’s
weight.
2.5. Physical activity
Physical activity was assessed with a study-made questionnaire
where the participants scored their usual activity level. The fre-
quency of physical activity was described as: “never”, “less than
once per week”, “once per week”, “2e3 times per week”, or “almost
every day”. The intensity was described as: “easy without getting
out of breath or sweat”, “so much that you get out of breath or
sweat”, or “exhausted”. Based on answers from the questionnaire,
we categorized the participants’ lifestyles into two groups: an
“active lifestyle” and an “inactive lifestyle”. An “active lifestyle”
required “a frequency of 2e3 times or more per week and a
perceived intensity equal to so much that you get out of breath or
sweat, or exhausted”. If less, it was categorized as having an
“inactive lifestyle”. Our definition of an “inactive lifestyle” corre-
sponds to the physical activity category classified as “low activity”
described by Rangul et al. [41].
2.6. Serum vitamin D
One fasting morning blood sample was collected from each
participant according to routine procedures at the hospital visit.
According to the Vitamin D Standardization Program, the Hormone
Laboratory performed the serum 25(OH)D analyses. Vitamin
25(OH)D was quantified by liquid chromatography-tandem mass
spectrometry with a determination of 25-hydroxyvitamin D2
(25(OH)D2) and 25-hydroxyvitamin D3 (25(OH)D3) levels. The sum
of 25(OH)D2 and 25(OH)D3 levels are referred to as 25(OH)D. The
coefficients of variation were 10e17% [42]. Vitamin D sufficiency
was defined as a total of 25(OH)D > 50 nmol/L [43].
2.7. Endocrine deficits
A medical record review and consecutive plasma analysis of
hormones by standard methods at the Department of Medical
Biochemistry, OUH, were used to assess endocrine deficits [27].
Clinically significant lack of the production of at least one hormone,
including growth hormone, thyroxine, gonadal hormones, and
cortisone requiring hormone replacement therapy, was defined as
an endocrine deficit.
2.8. Statistics
Descriptive statistics are presented as mean and standard de-
viation (SD) if normally distributed and median with 25the75th
percentile or minimumemaximum if non-normal. Categorical data
are presented as absolute and relative frequencies. A one-sample t-
164
Clinical Nutrition ESPEN 50 (2022) 162e169
test was used to test BMDz values against the software’s reference
population (Z-score ¼ 0). The independent samples t-test was used
to test mean BMDz values between the young (<18 years) and adult
(>18 years) groups. Chi-square or Fisher Exact test was used to
explore differences in categorical variables between young and
adults. Following patients from the time of diagnosis and to the
time of the survey, we estimated multivariable Cox proportional
hazard regressions to investigate potential risk factors for subop-
timal or low BMDz L2eL4 and BMDz total body. Due to the sample
size, we limited the number of covariates to five. Using predictors
from previously published studies combined with results from
simple correlations, we selected a subset of covariates deemed
most relevant for the multivariable analyses (sex, age at diagnosis,
LMI, endocrine deficit, and calcium intake). Statistical analyses
were performed using IBM SPSS Statistics for Windows, version 26
(Armonk, New York), and Stata version 16.1 (StataCorp. 2019. Stata
Statistical Software: Release 16. College Station, TX: StataCorp LLC).
Ethical statement
Ethical standards of the Declaration of Helsinki were followed.
All participants were given written information about the study,
and informed consent was obtained. For children <16 years of age
and adults with moderate or severe intellectual disability, care-
givers gave consent on the participant’s behalf. The Regional
Committees for Medical and Health Research Ethics of the South-
Eastern Norway Regional Health Authority (#2015/2362) and the
Data Protection Officer at OUH approved the study protocol. The
study was registered in ClinicalTrials.gov (NCT02851355).
3. Results
3.1. Subjects
Fifty of the 63 survivors (79%) were included. Participant char-
acteristics are presented in Table 1. The participants did not differ
from the 13 nonparticipants in age at first surgery, gender, histol-
ogy, and treatment with irradiation (data not shown). At the time of
the survey, the median age of all participants was 25.5 years
(5.5e51.9), and the median follow-up time since diagnosis was 19.5
years (3.2e40.5). The majority (84%) of participants were MB sur-
vivors. All participants had been treated with surgery, 88% with CSI,
and 84% with chemotherapy. A combination of CSI and chemo-
therapy had been used in 72%. Details on participants and treat-
ment have been published earlier [27].
3.2. Bone mineral density
Mean BMDz L2-L4 was
0.8 (SD 1.1, 95% CI:
1.1 to
0.4), and
BMDz total body was
0.6 (SD 1.1, 95% CI:
0.9 to
0.3). Both pa-
rameters were significantly lower than the mean of the reference
population. No difference between the young and the adult patient
group was found for BMDz L2eL4 (
1.1 vs.
0.7, P ¼ 0.260) or
BMDz total body (
0.4 vs.
0.7, P ¼ 0.518). The prevalence of
normal, low, and very low BMDz values is presented in Fig. 1. The
prevalence of decreased (low and very low) BMDz was found in 48%
for lumbar spine and 34% for the total body. No differences between
young and adults were detected (data not shown).
3.3. Growth and body composition
The prevalence of stunted height was 19% in the young and 15%
of the adults had short stature. A significantly higher proportion of
adults vs. young (59% vs. 6%, P ¼ 0.001) were overweight. Under-
weight was found in one adult and two young participants.
J.A. Kvammen, E. Stensvold, K. Godang et al. Clinical Nutrition ESPEN 50 (2022) 162e169

Table 1
Participant characteristics.

Young Adults All

<18 years (n ¼ 16) >18 years (n ¼ 34) (n ¼ 50)

Age, years a
at study 14.2 (5.5e17.1) 31.7 (19.4e51.9) 25.5 (5.5e51.9)
at diagnosis 5.3 (0.2e13.1) 7.9 (1.3e19.2) 7.1 (0.2e19.2)
time since primary surgery 7.4 (3.2e15.9) 23.4 (4.0e40.5) 19.5 (3.2e40.5)
Male/female, n 7/9 18/16 25/25
Caucasian/other ethnicities, n 16 33/1 49/1
Diagnosis, n (%)
Medulloblastoma 10 (63) 32 (94) 42 (84)
CNS-PNET 6 (37) 2 [6] 8 [16]
Treatment history, n (%)
surgery þ chemotherapy 4 [25] 2 [6] 6 [12]
surgery þ CSI 0 8 [24] 8 [16]
surgery þ chemotherapy þ CSI 12 (75) 24 (70) 36 (72)
Anthropometrics b
weight, kg 42.4 (14.6) 71.5 (13.9)
height, cm 148.0 (18.1) 164.6 (10.6)
BMI, kg/m2 18.8 (3.2) 26.5 (5.3)
LMI, kg/m2
Male 12.8 (2.5) 16.1 (2.1)
Female 11.4 (1.3) 14.4 (1.4)

Abbreviations: CNS-PNET, central nervous system supratentorial primitive neuroectodermal tumor; CSI, craniospinal irradiation (proton therapy in one); BMI, body mass
index; LMI, lean body mass index; SD, standard deviation.
a
Median (minimumemaximum).
b
Mean (SD).

Fig. 1. Prevalence of normal, low, and very low BMD Z-score for A) lumbar spine L2eL4 (n ¼ 50) and B) total body (n ¼ 48) in long-term survivors of childhood medulloblastoma or
CNS-PNET (central nervous system supratentorial primitive neuroectodermal tumor).

3.4. Dietary intake BMR  1.1 (0.9e1.3) for the group, which is below the expected for
persons with a low physical activity level. An energy intake below the
Daily intake of energy and macronutrients for young, adults and estimated BMR was reported by 33% of all participants. The macro-
all participants are presented in Table 2. Energy intake was median nutrient composition of the diet (energy-% from carbohydrates, fat,

165
J.A. Kvammen, E. Stensvold, K. Godang et al.
Table 2
Daily energy and macronutrient intake in long-term survivors of childhood medulloblastoma or CNS-PNET (median, 25the75th percentiles).
Young <18 years (n ¼ 13)
Energy, KJ 6180 (5685e7370)
Energy, kcal 1476 (1355e1751)
Energy, kcal/kg 34 (30e42)
Fat, energy-% 33.5 (29.7e35.3)
Saturated fat, energy-% 12.2 (10.7e13.0)
Carbohydrates, energy-% 51.4 (49.2e53.5)
Sugar, energy-% 10.3 (8.0e11.4)
Fiber, g/MJa 1.8 (1.4e2.2)
Protein, energy-% 15.0 (13.4e18.1)
Protein, g/kg 1.5 (1.1e1.7)
Abbreviations: CNS-PNET, central nervous system supratentorial primitive neuroectodermal tumor; RI, recommended intake (Nordic Nutrition Recommendations 2012) [39];
KJ, kilojoule; kcal/kg, kilocalories/kilogram; g/MJ, gram/megajoule; g/day, gram/day; g/kg, gram/kilo.
a
2e3 g/MJ from the age of 2 years, and 3 g/MJ for adolescents and adults.
and proteins) and protein intake (g/kg) were compliant with RI for
the total group. Saturated fat (energy-%) was above RI in 91% of all
participants. The sugar energy-% for the total group was in line with
RI, but sugar intake was higher than recommended in 44% of the
young and 24% of adults. Fiber intake was low, whereas 76% of all
participants did not meet RI (g/MJ).
Figure 2 presents total micronutrient intake (including dietary
supplements) vs. RI. Median calcium intake was 700 mg/day, cor-
responding to 83% of RI on the group level. Median vitamin D intake
was 3.9 mg/day, corresponding to 39% of RI. Vitamin D supplements
were used by 29% of all participants, but 69% did not reach RI. 62% of
all participants did not reach RI for calcium. The intake of iodine
and folate was very low. The intake of iron, selenium, magnesium,
vitamin A, vitamin B6, and vitamin C was also below RI. Details on
micronutrient intakes in both groups are presented in
Supplemental Table S1.
3.5. Physical activity
The majority (62%) of participants had an inactive lifestyle. No
difference between age groups was detected (P ¼ 0.952).
3.6. Vitamin D status
Vitamin 25(OH)D status was sufficient, with a mean level of
66 nmol/L (SD 24). However, vitamin D insufficiency was found in
26% (young 19% vs. adults 29%, P ¼ 0.508).
3.7. Endocrine deficits
The majority (66%) of participants had one or more endocrine
deficits [27], and no difference between young and adults was
found (63% vs. 68%, P ¼ 0.720). For all participants, 58% had hy-
pothyroidism, 50% had growth hormone deficiency, 28% had
hypogonadism, and 26% had panhypopituitarism. Further, 16% had
isolated hypothyroidism, 16% had a combination of hypothyroidism
and growth hormone deficiency, and 8% had isolated growth hor-
mone deficiency. None had sole gonadotropic or corticotropic
failure [27].
3.8. Risk factors for decreased BMDz
Multivariable Cox-regression models exploring potential risk
factors for decreased BMDz L2eL4 and total body are presented in
Table 3. Out of selected covariates we found that male sex, higher
age at diagnosis, and lower LMI were associated with increased risk
of low or very low BMDz L2eL4. Higher age at diagnosis and lower
LMI were also associated with increased risk of low or very low
166
Clinical Nutrition ESPEN 50 (2022) 162e169
Adults >18 years (n ¼ 32) All (n ¼ 45) RI
7229 (6221e8614)
1732 (1484e2055)
25 (19e30)
38.0 (34.5e43.6) 36.3 (32.9e42.0) 25e40
14.2 (11.5e17.7) 12.9 (11.4e16.2) <10
42.8 (37.1e49.3) 46.1 (38.7e51.4) 45e60
6.4 (1.9e10.5) 8.1 (2.6e11.1) <10
2.3 (1.9e3.0) 2.1 (1.7e2.9) 2e3
16.6 (15.6e19.4) 16.3 (14.8e18.7) 10e20
1.1 (0.8e1.3) 1.2 (0.9e1.4) 0.9
BMDz for the total body. Additionally, endocrine deficit was asso-
ciated with increased risk of low or very low BMDz for the total
body.
4. Discussion
This cross-sectional study revealed a risk of impaired bone
health in long-term survivors of childhood MB or CNS-PNET. Risk
factors associated with decreased BMDz were male sex, higher age
at diagnosis, and lower LMI. Insufficient calcium and vitamin D
intake, an inactive lifestyle, and a high prevalence of 25(OH)
D  50 nmol/L were detected.
BMDz L2-L4 and total body were significantly below the mean
value of the reference population integrated in the DXA software.
Nearly half of the participants (48%) had decreased BMDz in the
lumbar spine and one-third (34%) in the total body. Out of these,
very low BMDz <
2 was found in 16% of lumbar spine and 15% of
total body measurements. These results support the finding of 24%
with very low BMDz in a national cohort of Finnish adult long-term
survivors of pediatric brain tumors [14]. Studies with shorter
follow-up have also reported compromised BMD in various
measured sites in groups of survivors of pediatric brain tumors
[9e13,15,16]. Recent published evidence-based recommendations
from the International Late Effects of Childhood Cancer Guideline
Harmonization Group [22] conclude that we have high-quality
evidence for very low BMD in patients treated with cranial irradi-
ation or CSI. They recommend BMD surveillance routinely by DXA
in these survivors to prevent fragility fractures.
Lower LMI was a significant risk factor for decreased BMDz in
the explorative models. Muscles and bones share the loading
environment and the genes regulating body size [44], and a positive
association between lean body mass, muscular strength, and bone
health is well known [8,45]. Muscle depletion and impaired func-
tion are related to chronic diseases, malnutrition, and inactivity at
all ages. An inactive lifestyle was prevalent in our participants. This
is essential to address as physical activity stimulates muscle mass
and BMD accrual and prevents osteoporosis [46]. We also found
insufficient calcium and vitamin D intakes, and a fourth had 25(OH)
D  50 nmol/L. Suboptimal vitamin D status is commonly seen in
the Nordic countries due to lack of sun exposure at high latitudes
and limited intake of vitamin D [47]. Optimal bone health depends
on calcium and vitamin D [7,8], and we suggest that advice on
nutrition during survivorship can improve dietary intake and
positively impact bone health.
Male sex and older age at diagnosis were associated with the
risk of decreased BMDz in our explorative models, supporting the
findings from previous studies [10,14,15]. During growth and
maturation, the muscle mass increases, particularly for boys, during
J.A. Kvammen, E. Stensvold, K. Godang et al. Clinical Nutrition ESPEN 50 (2022) 162e169

Fig. 2. Median daily micronutrient intake in the percentage of recommended intake (RI) in long-term survivors of childhood medulloblastoma or CNS-PNET. Abbreviations: RI,
recommended intake (Nordic Nutrition Recommendations 2012) [39], CNS-PNET, central nervous system supratentorial primitive neuroectodermal tumor.

Table 3
Explorative multivariable Cox-regression models for predicting decreased (low or very low) bone mineral density Z-scores for lumbar spine L2eL4 and total body.

Parameter BMDz L2eL4 BMDz total body

HR 95% CI P-value HR 95% CI P-value

Female vs. male 0.27 0.08e0.95 0.042 0.17 0.03e1.07 0.059

Age at diagnosis, years 1.17 1.01e1.37 0.042 1.45 1.14e1.83 0.002
Endocrine deficit vs. no deficita 3.52 0.67e18.39 0.137 23.51 1.79e309.18 0.016
Lean mass index, kg/m2 0.50 0.35e0.71 <0.001 0.33 0.17e0.61 <0.001
Calcium, mg in % of RI 0.99 0.97e1.01 0.146 0.98 0.95e1.01 0.265

Abbreviations: BMDz, bone mineral density Z-score; L2-L4; lumbar spine L2-L4; HR, hazard ratio; vs., versus; RI, recommended intake (Nordic Nutrition Recommendations
2012) [39].
a
Clinically significant lack of the production of at least one hormone, including growth hormone, thyroxine, gonadal hormones, and cortisone, resulting in the need for
hormone replacement therapy.

puberty [48]. Muscle and bone mass accrual depend on sex hor-
mones, growth hormones, and insulin-like growth factors [23,24].
Our findings indicate an increased risk for decreased BMDz with
endocrine deficits, but the uncertainty in the effect estimates is
considerable due to the small study group. Nevertheless, our results
suggest that clinicians should be aware of bone health during
follow-up.
In adults, 59% were overweight. Interestingly, the risk of being
overweight was present even though the energy intake was below
the customarily expected in persons with a low activity level.
Underreporting cannot be ruled out to explain these findings [49].
Cognitive- and memory impairments were frequent in our study
group [28] and could cause under-reporting even though parents
and guardians contributed as much as possible. However, inactivity,
low lean body mass, and adiposity might reduce energy needs.
Many participants had affection on the hypothalamusepituitary
axis, verified by the endocrine deficits. Damage to this axis may
decrease energy metabolism [50], potentially explaining low en-
ergy requirements. However, further studies on energy metabolism
are needed to verify this.
The World Cancer Research Fund/American Institute for Cancer
Research [51] emphasizes the importance of healthy lifestyle habits
for cancer prevention. Brain tumor survivors also are at increased
risk of lifestyle-related health problems like cardiovascular
diseases, obesity, and new cancers [4]. Previously, Stensvold et al.
[27] reported that 30% of our study participants had been diag-
nosed with one or more second primary neoplasms. In the present
study, we revealed a potential for optimization of nutrition and
physical activity. Hence, survivors should be informed on healthy
lifestyle choices to prevent second cancers, secondary osteoporosis,
overweight, metabolic syndrome, cardiovascular disease and to
improve their quality of life. The lifestyle aspects become even
more critical as the number and age of long-term survivors
increase.
This study’s major strength was the homogenous group of brain
tumors, including only survivors of childhood MB or CNS-PNET. We
had a high participation rate, and the risk of selection bias was low.
Other strengths were standardized methods, trained personnel,
one dietitian did all parts of the diet assessments, and our partici-
pants received help from parents/guardians to register dietary
intake when needed. However, the risk of underreporting is present
with diet recording and could impact results [49]. To minimize
errors in the estimation of portion sizes, we used a pictorial booklet
validated for an adult population [52]. Limitations were the small
sample size and the lack of data on puberty, fractures, glucocorti-
costeroids/medication, and information on sun exposure regarding
vitamin D status. Importantly, stunted growth and short stature
might impact BMD results due to the theory that smaller bones will

167
J.A. Kvammen, E. Stensvold, K. Godang et al.
result in lower BMD results by the two-dimensional DXA method
[53]. This could have resulted in an overreporting of low or very low
BMDz. We did not measure energy expenditure, or physical activity,
and we lacked a healthy reference group to compare results. A
cross-sectional study design is a limitation, and results must be
interpreted with caution. Our findings should not be considered
representative for survivors of all pediatric brain tumors. MB and
CNS-PNET have had a high burden of treatment, including irradi-
ation. We suggest a prospective, randomized controlled trial to
investigate lifestyle interventions that can influence rehabilitation
and health outcomes of survivors of childhood brain tumors.
5. Conclusion
Long-term survivors of childhood MB and CNS-PNET had
decreased BMDz, and risk factors were male sex, higher age at
diagnosis, and lower LMI. Inadequate calcium and vitamin D intake,
an inactive lifestyle, and a high prevalence of 25(OH)D  50 nmol/L
were detected. Overweight was found in adults even though their
energy intake was low. Further studies on lifestyle interventions to
optimize brain tumor survivors’ rehabilitation and health outcomes
are needed.
Funding statement
The Norwegian Childhood Cancer Society, The Norwegian Brain
Tumor Association, The Throne Holst Foundation at the University
of Oslo, Støtteforeningen for kreftrammede, and Barnestiftelsen
Oslo University Hospital supported the study.
Author contributions
All authors met the authorship criteria. JAK participated in the
study’s conception and design, collected the data, did the dietary
assessments, carried out the final analyses, and drafted the
manuscript. ES was responsible for the conception, design, and data
collection, did the medical examinations, and contributed to the
data analyses. KG and JB contributed to the design and were liable
for DXA scanning. TÅM was responsible for the statistical analysis.
PB participated in the conception and design, and supervised the
study. CH contributed to the data analyses and supervised this part
of the study. AGB was involved in the conception, design, and the
data analyses and supervised the study. All authors participated in
interpreting results, reviewed, and revised the manuscript. All au-
thors read and approved the final manuscript.
Declaration of competing interest
The authors declare that they have no conflict of interest.
Acknowledgments
We thank all the participants, parents, and guardians for
participating in our study. We also thank the research nurses Karin
Sylte Hammeren and Elna Hamilton Larsen for their valuable
collaboration, the Hormone Laboratory, and The Department of
Medical Biochemistry, OUH, for the blood analyses.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.clnesp.2022.05.025.
168
Clinical Nutrition ESPEN 50 (2022) 162e169
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