Maturitas 76 (2013) 123–128

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Maturitas
journal homepage: www.elsevier.com/locate/maturitas

Study protocol: High-protein nutritional intervention based on

␤-hydroxy-␤-methylbutirate, vitamin D3 and calcium on obese and
lean aged patients with hip fractures and sarcopenia. The
HIPERPROT-GER study夽
Vincenzo Malafarina a,∗ , Francisco Uriz-Otano a , Lucía Gil-Guerrero b , Raquel Iniesta c ,
M. Angeles Zulet d,e , J. Alfredo Martinez d,e
a
Department of Geriatrics, Hospital San Juan de Dios, Calle Beloso Alto 3, 31006 Pamplona, Spain
b
Department of Internal Medicine, Hospital San Juan de Dios, Calle Beloso Alto 3, 31006 Pamplona, Spain
c
Servicio de soportes estadístico, Fundació Sant Joan de Deu, Carrer Santa Rosa 39-57, Level 3, 08950 Esplugues de Llobregat, Barcelona, Spain
d
Department of Nutrition, Food Science and Physiology, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain
e
CIBERobn, Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Loss of muscle strength is associated with falls, which, in turn, are the main cause of hip
Received 21 May 2013 fractures in elderly people. The factors that most influence loss of strength in elderly people are a decrease
Received in revised form 6 June 2013 in muscle mass, i.e. sarcopenia, and an increase in fat, i.e. obesity.
Accepted 8 June 2013
Methods: A prospective randomized clinical trial among patients who have undergone an operation for
a traumatic hip fracture and who are aged 65 or above will be implemented. We shall compare a control
diet against a high-protein diet enriched with ␤-hydroxy-␤methylbutirate, calcium and vitamin D. The
Keywords:
diet will be administered during 30 days of hospitalization in the orthopaedic geriatric rehabilitation
Sarcopenia
Obesity
unit. There will be 50 patients in each arm of the study. The main objective is to assess whether the
␤-Hydroxy-␤-methylbutirate experimental diet, together with rehabilitation, improves functional recovery, measured on the Barthel
Hip fracture index. Secondary objectives are to assess changes in body composition and the prevalence of sarcopenia,
Older people obesity and mortality one year after the hip fracture. We shall also assess whether there is a relationship
High protein between specific inflammatory markers, sarcopenia and functional recovery.
Conclusions: Ageing is accompanied by changes in body composition that increase the risk of falls and
progressive functional loss. These factors are a public health problem because they are highly associated
with disability in older people. The present study seeks to gain knowledge of those factors that are most
often associated with the onset of disability and those that can be modified through diet.
© 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction dual-energy X-ray absorptiometry (DXA) or with bioelectrical

Sarcopenia, defined as a loss of strength, function and mass of
skeletal muscle, is associated with ageing [1]. Few studies have
attempted to establish the ‘normal’ amount of muscle mass in
elderly people who are independent or who have few functional
limitations [2,3]; there are thus no universally accepted criteria
or cut-off points for sarcopenia. Nevertheless, there is a consen-
sus among most international groups on the following guidelines
for the diagnosis: (1) a decrease in muscle mass, measured with
夽 Trial registration www.clinicaltrials.gov (NCT01404195, registered 26 July
2011).
∗ Corresponding author. Tel.: +34 948 231800; fax: +34 948230607.
E-mail address: vmalafarina@gmail.com (V. Malafarina).
impedance analysis (BIA); (2) a decrease in strength, measured with
a dynamometer (hand grip strength); and (3) a decrease in muscle
function, measured as walking speed [4,5].
Sarcopenia in elderly people is not always associated with a
decrease in body mass index (BMI), because the loss of muscle
mass is commonly accompanied by an increase in fat mass [6–8].
An increase with age in the proportion of people who are over-
weight is common in developed countries [9,10]. The combination
in an individual of a decrease in muscle mass and an increase in fat
mass is known as sarcopenic obesity (SO) [11]. SO has been shown
to directly reduce the autonomy of elderly people, as it is broadly
acknowledged as a risk factor for the onset of functional limitations
[12,13]. The many studies that have assessed the effect of BMI on
mortality in elderly people have tended to find either J-shaped or
U-shaped relationships [14,15].

0378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.maturitas.2013.06.016

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124 V. Malafarina et al. / Maturitas 76 (2013) 123–128
Table 1
Inclusion and exclusión criteria.
Inclusion Exclusion
≥65 years Barthel index < 40 in the previous six months
Traumatic hip fracture IMC < 21 kg/m2 , MNA < 11 or serum
undergone surgerya albumin < 2.1 g/dL
Join for rehabilitation IMC > 40 kg/m2
Diabetes
Liquid dysphagia
Pathological hip fracture or cancer disease in
active phase or undergoing treatment
(radiotherapy or chemotherapy)
Serious clinical conditions that compromise
and endanger the patient’s life
Charlson index ≥ 6
a
It is considered traumatic fracture resulting from an accidental fall, fall defining
any unexpected event that determines that the patient reaches a lower level than
where it was originally.
Hip fractures are a common health problem for elderly people.
In Spain, there are between 50 000 and 60 000 hip fractures a year,
representing an annual incidence rate of 100 cases/100 000 popu-
lation [16]. The female:male ratio is 4:1 and the incidence of hip
fractures increases with age. Hip fractures have important impli-
cations for the ability to walk but also greatly restrict many other
daily activities.
Inadequate protein intake is one of the main risk factors for
sarcopenia [17]. The dietary intake of a group of patients under-
going orthopaedic surgery was shown to be insufficient in terms of
energy, proteins and micronutrients [18]. This situation is often due
to a hypermetabolic state secondary to inflammation, to a reduction
of food intake due to lack of appetite and to patients being confined
to bed. For all these reasons, the European Society of Parenteral
and Enteral Nutrition (ESPEN) recommends, with the highest grade
of evidence (grade A), the use of nutritional supplements in older
people who have experienced a hip fracture [19]. Many studies
have demonstrated that muscle metabolism improves with HMB
supplements, and that there is also a decrease in protein deteriora-
tion and a significant increase in free fatty mass [20–22]. However,
few studies have reported significant results in their assessment of
functional parameters.
A deficiency of vitamin D3 (vitD) (in its active form 1␣,
25(OH)2 D3 ) is very prevalent among elderly people [23,24]. Despite
the fact that vitD receptors are present in many organs and tis-
sues, recommendations about vitD intake refer only to bone tissue
[25]. VitD plays an important role in protein synthesis and low
levels are associated with a decrease in muscle strength and an
increase of the risk of developing mobility limitations and disabil-
ity [26]. VitD supplements may help to improve muscle function
as well as strength and to reduce the risk of falls and mortality
[27].
This paper describes a prospective randomized clinical trial
presently being conducted among patients who have undergone
an operation for a traumatic hip fracture and who are aged 65
or above (the HIPERPROT-GER study). We aim to compare a
control diet against a high-protein diet enriched with ␤-hydroxy-
␤-methylbutirate (HMB), calcium and vitamin D3 (cholecalciferol).
The diet will be administered during 30 days of hospitaliza-
tion in the orthopaedic geriatric rehabilitation unit. There will be
50 patients in each arm of the study. The main objective is to
assess whether the experimental diet, together with rehabilita-
tion, improves functional recovery. The secondary aims are: (1)
to gain knowledge of body composition and calculate the preva-
lence of sarcopenia and obesity; (2) to assess whether there is a
relationship between inflammatory indexes and sarcopenia; (3) to
evaluate whether there is an increase in muscle mass; and (4) to
assess mortality and morbidity.
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2. Subjects and methods
2.1. Inclusion and exclusion criteria
The inclusion and exclusion criteria used in the present study
are listed in Table 1. The HIPERPROT-GER study has been approved
by the appropriate ethics committee (Comité Ético de Investigación
Clínica de la Comunidad Foral de Navarra) (62/2011) and has been
designed in accordance with the European Union requirements
for good clinical practice and the review of the Declaration of
Helsinki. Informed consent will be obtained from all participants.
This trial has been registered at www.clinicaltrials.gov with code
NCT01404195.
2.2. Statistical analysis
2.2.1. Descriptive analysis
The data will be defined at the descriptive level, and presented
according to the type of variable: using measures of centrality
(mean and median) and measures of dispersion (standard devi-
ation) for quantitative data; and using percentages (of the study
group) for qualitative variables. The distribution of the data (nor-
mality) will be taken into account in the selection of the appropriate
statistical tests.
2.2.2. Univariate analysis
A homogeneity analysis will be undertaken of the sample’s
baseline characteristics. Any associations between different mea-
surements taken at the scheduled times for the intervention group
and the control group will be assessed using the appropriate para-
metric and non-parametric tests. All inter-subject quantitative
comparisons will be carried out with the Student t-test for indepen-
dent samples or the Mann–Witney U-test. Associations between
qualitative variables will be determined with the chi-square or
Fisher’s exact test, depending on the distribution of the data.
Intra-subject and within-group comparisons (longitudinal tests for
changes over time) will be made using the paired Student t-test for
quantitative variables or the McNemar test for qualitative variables.
2.2.3. Multivariate analysis
Multivariate models will be considered for the purpose of
adjusting for confounding factors. Cross-sectional analyses will be
adjusted using binary logistic regression models. The results will be
presented as adjusted ORs (odds ratios), accompanied by p values
and confidence intervals. Repeated-measures analysis of variance
(ANOVA) will be used to assess longitudinal change; in particu-
lar, mixed-effects models (fixed and random) will be used. We will
adjust for confounding variables in these models, and then exam-
ine time × group interaction terms. We plan to apply a statistical
significance of 0.05 for population inference. The study design is
intention to treat. Analysis will be carried out using SPSS 19 and R
2.13.0.
2.2.4. Estimation of sample size
Sample size has been calculated in terms of the main objective
of this study: to find significant differences in functional improve-
ment following a nutritional intervention for patients with a hip
fracture, measured with the Barthel index. For the present study,
we estimated that a sample size will be needed of 50 patients in the
intervention group and 50 in the control group. The standard devia-
tion in ratings of such patients on the Barthel index was around ±30
in a pilot study (unpublished data). Using this figure in the calcula-
tion of sample size, and a level of statistical significance set at 0.05
(5%), a sample made up of two groups of 45 patients has a statistical
power of 80% to pick up a 10-point difference between groups on
the Barthel index. Estimating a loss to follow-up of 10%, the total
 V. Malafarina et al. / Maturitas 76 (2013) 123–128 125

Table 2 28050 Madrid, Spain) has the following characteristics: 1.5 kcal/ml,
Determinations and assessment scales in patients included.
22% protein origin (8.3 g/100 ml), 29% fat (4.8 g/100 ml), 47% carbo-
Admission 30 days hydrates (17 g/100 ml), 1% FOS (0.75 g/100 ml). The supplement is
Weight X X enriched with HMB 0.55 g/100 ml, vitD3 227 UI/100 ml and calcium
Height X 160 mg/100 ml. In order to assess whether the patients genuinely
Arm circumference X X follow the treatment, they will be given a register on which to note
Calf circumference X X their daily intake of the supplement.
Triceps skinfold X X
Inflammatory markersa X X
Hormonesb X Xc 2.6. Assessment of functional abilities
Hepatic funtiond X X
Renal functione X X
The scale used most often studies of autonomy in daily life
Proteinsf X X
Lipidg X X activities is the Barthel index, which was developed in 1965 by
Blood count X X Mahoney and Barthel [28]. It addresses 10 variables: feeding,
Vitaminsh X Xi bathing, dressing, grooming, urinary and faecal continence, toi-
Fast blood glycaemia X X
let use, chair-to-bed transfer, walking and stairs. The score is on
Gijón scale X
MNA X
a scale of 0–100, where 100 indicates total independence and 0
SF-LLFDI X X total dependence.
MMSE X Function will be assessed using the Short Form-Late Life Func-
BARTHEL indexi X X tion and Disability Index (SF-LLFDI), which has a very low floor
FAC X X
effect, whereas no ceiling effect has been observed in previous
CHARLSON index X X
studies [29,30].
a
IL1, IL6, PCR, TNF-a.
b
We will evaluate the ability to walk with the Functional Ambu-
TSH, FT3, FT4, cortisol, insulin.
c
Cortisol, insulin.
lation Category (FAC), which places patients into six categories:
d
Transaminases, bilirubin total and fractions, alkaline phosphatase, lactic dehy- 0 = non-functional or no walking; 1 = walks with a lot of physical
drogenase, g-glutamyl transferase. help from another person; 2 = walks with light manual contact from
e
Creatinine, uraemia, uric acid, MDRD. another person; 3 = requires supervision but no physical contact;
f
Albumin, transtiretin.
g 4 = independent on a flat surface; 5 = independent on flat surface
Cholesterol, HDL, LDL, triglyceride.
h
B-12, 25-OH-Vit-D. and stairs. It can be applied via direct observation or via medical
i
Barthel index pre-fracture. history [31].
Cognitive assessment will be carried out using the Mini Men-
tal State Examination (MMSE) [32], which will be applied once
sample size is about 100 individuals. The relatively low percentage
the processes that may influence cognitive assessment have been
loss is due to the fact that the patients will be in hospital for the
stabilized, in order to ensure the validity of the results as far as
duration of the study.
possible.

2.3. Study design

This is a prospective, randomized, controlled clinical trial.
Patients admitted to the orthopaedic geriatric unit at the San Juan
de Dios Hospital in Pamplona (Spain) from 9 January 2012 were
due to be prospectively included.
Assessment shall be carried out within 72 h of admission and
shall be repeated upon discharge (Fig. 1). After assessment and
randomization, patients will begin their rehabilitation programme.
A summary of the assessments and scales used, and when, can
be found in Table 2.
2.4. Hypothesis
The hypothesis for our study is that the addition of a hypercaloric
and hyperproteic diet enriched with HMB, calcium and vitD is more
effective than conventional methods alone in treating sarcopenia
in older patients with hip fractures and improves recovery.
2.5. Intervention
Once patients are included in the study, they shall be randomly
split into two groups. Group 1 (G1), the intervention group, will
receive the nutritional intervention, which is an oral hypercaloric
and hyperproteic liquid supplement enriched with HMB, calcium
and vitD. Group 2 (G2), the control group, will receive standard
care.
Patients in Group 1 shall be given two bottles of Ensure® Plus
Advance per day, one with breakfast and one mid-afternoon, 7 days
a week, during the 30 days of their stay in hospital. Ensure® Plus
Advance 220 ml, Abbott Laboratorios SA (Avenida de Burgos 91,
2.7. Nutritional assessment
Nutritional assessment is key to the diagnosis of sarcopenia [33].
There are numerous scales for the nutritional assessment of older
patients. The most widely used is the Mini Nutritional Assessment
(MNA), which will be used in the present study [34,35]. Patients will
be classified as malnourished (MNA score <17), as being at risk of
malnutrition (score 17–23.5), or as having an adequate nutritional
status (score ≥24) [36].
2.8. Assessment of comorbidity
The Charlson index, originally designed to predict mortality, is
the comorbidity index most widely used in both Spanish and inter-
national studies. It has been translated into Spanish and validated
for use with Spanish subjects [37,38].
2.9. Assessment of sarcopenia
To assess sarcopenia we shall use the criteria proposed by the
European Working Group on Sarcopenia in Older People (EWG-
SOP) [5]. Bioelectrical impedance analysis (BIA) will be carried out
between 08:00 and 09:00 h, with patients in a fasting state, in a
supine position and with an empty bladder. We shall use a BIA-
101, RJL System, Akern SRL (Via Lisbona 32/34, 50 065 Pontassieve,
Firenze, Italia). Measurements will be taken with the electrodes
placed on the patients’ wrists and ankles on the same side.
Muscle mass (MM) in kg shall be calculated as: MM = [(size2 /BIA-
resistance × 0.401) + (sex × 3.825) + (age × −0.071)] + 5.102, where
size is in centimetres, BIA-resistance is in ohms, sex is rated male = 1

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126 V. Malafarina et al. / Maturitas 76 (2013) 123–128
HISTORY BLOOD ANALYSIS
CHARLSON ANTHROPOMETRICS
EXCLUSION
CASES
(SUPPLEMENT)
CHARLSON BLOOD ANALYSIS
MMSE ANTHROPOMETRICS
Fig. 1. Work plan for each patient during the study. BIA: bioelectrical impedance analysis; MMSE: Mini Mental State Examination; MNA: Mini Nutritional Assessment;
SF-LLDI: Short Form-Late Life Function and Disability Index.
and female = 0, and age is in years [39]. Muscle mass will be nor-
malized by size (muscle mass in kg/size in m2 ), to give the Skeletal
Muscle Index (SMI).
We shall classify patients according to the criteria proposed by
Janssen in 2006 defining, respectively for men and women: normal
SMI values, ≥10.76 kg/m2 and ≥6.76 kg/m2 ; moderate sarcope-
nia, 8.51–10.75 kg/m2 and 5.76–6.75 kg/m2 ; or severe sarcopenia,
≤8.50 kg/m2 and ≤5.75 kg/m2 [40].
We will measure strength in both hands with a JAMAR portable
dynamometer. Patients will be asked to press for 3–5 s. The measure
will be repeated after a 30-s rest. The highest score will be regis-
tered. In order to reduce variability, measurements will be taken in
a standardized manner [41]. Grip work will be calculated according
to the formula proposed by Bautmants and colleagues in 2011 in
order to study resistance to fatigue [42].
Performance measurements will be carried out using the 4-m
walking test, with values lower than 0.8 m/s considered to be a
reduction in speed, and the FAC (see above).
3. Novelty of the study and discussion
Two studies have directly compared muscle mass in young and
older people, measuring it with BIA. Thus, Schutz et al. in 2002
showed that muscle mass in older healthy people is similar to that
in young subjects, both men and women [3]. They also observed
that fat increases with age in both men and women. Masanes et al.
in 2012 found similar results only in men, because the muscle mass
in older women was significantly less than that in younger women
[2].
Some authors have suggested that excess fat accompanied by
loss of muscle (sarcopenic obesity) may negatively influence the
ability to walk, whilst the loss of muscle mass (sarcopenia) is an
important limiting factor for more tiring activities [43]. BMI is a risk
factor for death and disability and many studies have shown that
the relationship appears in the shape of a ‘J’ or a ‘U’, with BMI values
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HOSPITALIZATION
BARTHEL MNA GIJÓN BIA
SF-LLFDI SCALE DYNAMOMETER
WALKING SPEED
INCLUSION
RANDOMIZATION
CONTROL
GROUP
REHABILITATION
DISCHARGE
BARTHEL BIA
SF-LLFDI
WALKING SPEED DYNAMOMETER
of 28.2 kg/m2 in men and 27.1 kg/m2 in women associated with
the lowest mortality rates [15]. This outcome could be at the root
of the well known obesity paradox, whereby, especially in older
people, being overweight (BMI between 25 and 30 kg/m2 ) may even
become a protective factor. Nevertheless, a BMI above 30 kg/m2 ,
particularly with a fat percentage above 28% in men and 40% in
women, is still a risk factor for disability and death [44].
Low intake of VitD has been shown to be a risk factor for the loss
of muscle mass and function [26,45,46]. The mechanism probably
involves myoblast proliferation and differentiation [23].
A recent review of studies assessing nutritional supplements in
the treatment of loss of muscle mass in elderly patients with sar-
copenia found that the reported results are not uniform, despite
quite a high correspondence among them [47]. The main limita-
tion in most of the reviewed studies was that they included older
people living in the community, with whom the benefits of nutri-
tional supplements are more difficult to prove. The present study,
in contrast, will be carried out with an older population admitted
to a specialist rehabilitation unit.
4. Conclusions
Dependency and disability are two public health problems with
a large impact on the quality of life of older people. There are cer-
tain factors which can be modified to reduce their prevalence, such
as loss of muscle mass and strength, sarcopenia, and excess fat or
obesity. We have a duty to attempt to manipulate these factors in
order to improve the health and well-being of older people.
Contributors
VM designed the study and he is the principal investigator and
wrote the first draft. FUO, RI, LGG, MAZ and JAM collaborated
actively in the scientific basis of the protocol, and in drafting and
editing the manuscript.
 V. Malafarina et al. / Maturitas 76 (2013) 123–128
Competing interest
VM has received grants from Abbott Nutrition SA, Avenida de
Burgos 91, 28050 Madrid, España, and Nestle Health Care SA,
Avenida Països Catalans 25-51, 08950 Esplugues de Llobregat,
Barcelona. The sponsor of the study, not participate nor in the sta-
tistical analysis of the results, which are owned by Hospital San
Juan de Dios of Pamplona, nor in the conclusions of this study. JAM
and MAZ are member of CIBERobn, physiopathology of obesity and
nutrition. Instituto de Salud Carlos III, Madrid, Spain.
Funding
The San Juan de Dios Hospital has received funding from Abbott
Nutrition SA, Avenida de Burgos 91, 28050 Madrid, España.
Acknowledgments
The authors are grateful to the Head of staff of Hospital San
Juan de Dios, Pamplona, and the staff of the Fundación Sant Joan de
Deu, Barcelona, for their efforts and support in the development of
this protocol. The authors thank specially to Pau Ferrer Salvans for
advice and availability in the early stages of protocol development.
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