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

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

0378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
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Table 1 2. Subjects and methods

Inclusion and exclusión criteria.

Inclusion Exclusion 2.1. Inclusion and exclusion criteria

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

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 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

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

HOSPITALIZATION

HISTORY BLOOD ANALYSIS BARTHEL MNA GIJÓN BIA

CHARLSON ANTHROPOMETRICS SF-LLFDI SCALE DYNAMOMETER
WALKING SPEED

EXCLUSION INCLUSION

RANDOMIZATION

CASES CONTROL
(SUPPLEMENT) GROUP

REHABILITATION

DISCHARGE

CHARLSON BLOOD ANALYSIS BARTHEL BIA

SF-LLFDI
MMSE ANTHROPOMETRICS WALKING SPEED DYNAMOMETER

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- of 28.2 kg/m2 in men and 27.1 kg/m2 in women associated with
malized by size (muscle mass in kg/size in m2 ), to give the Skeletal the lowest mortality rates [15]. This outcome could be at the root
Muscle Index (SMI). of the well known obesity paradox, whereby, especially in older
We shall classify patients according to the criteria proposed by people, being overweight (BMI between 25 and 30 kg/m2 ) may even
Janssen in 2006 defining, respectively for men and women: normal become a protective factor. Nevertheless, a BMI above 30 kg/m2 ,
SMI values, ≥10.76 kg/m2 and ≥6.76 kg/m2 ; moderate sarcope- particularly with a fat percentage above 28% in men and 40% in
nia, 8.51–10.75 kg/m2 and 5.76–6.75 kg/m2 ; or severe sarcopenia, women, is still a risk factor for disability and death [44].
≤8.50 kg/m2 and ≤5.75 kg/m2 [40]. Low intake of VitD has been shown to be a risk factor for the loss
We will measure strength in both hands with a JAMAR portable of muscle mass and function [26,45,46]. The mechanism probably
dynamometer. Patients will be asked to press for 3–5 s. The measure involves myoblast proliferation and differentiation [23].
will be repeated after a 30-s rest. The highest score will be regis- A recent review of studies assessing nutritional supplements in
tered. In order to reduce variability, measurements will be taken in the treatment of loss of muscle mass in elderly patients with sar-
a standardized manner [41]. Grip work will be calculated according copenia found that the reported results are not uniform, despite
to the formula proposed by Bautmants and colleagues in 2011 in quite a high correspondence among them [47]. The main limita-
order to study resistance to fatigue [42]. tion in most of the reviewed studies was that they included older
Performance measurements will be carried out using the 4-m people living in the community, with whom the benefits of nutri-
walking test, with values lower than 0.8 m/s considered to be a tional supplements are more difficult to prove. The present study,
reduction in speed, and the FAC (see above). in contrast, will be carried out with an older population admitted
to a specialist rehabilitation unit.

3. Novelty of the study and discussion

4. Conclusions

Two studies have directly compared muscle mass in young and

Dependency and disability are two public health problems with
older people, measuring it with BIA. Thus, Schutz et al. in 2002
a large impact on the quality of life of older people. There are cer-
showed that muscle mass in older healthy people is similar to that
tain factors which can be modified to reduce their prevalence, such
in young subjects, both men and women [3]. They also observed
as loss of muscle mass and strength, sarcopenia, and excess fat or
that fat increases with age in both men and women. Masanes et al.
obesity. We have a duty to attempt to manipulate these factors in
in 2012 found similar results only in men, because the muscle mass
order to improve the health and well-being of older people.
in older women was significantly less than that in younger women
[2].
Some authors have suggested that excess fat accompanied by Contributors
loss of muscle (sarcopenic obesity) may negatively influence the
ability to walk, whilst the loss of muscle mass (sarcopenia) is an VM designed the study and he is the principal investigator and
important limiting factor for more tiring activities [43]. BMI is a risk wrote the first draft. FUO, RI, LGG, MAZ and JAM collaborated
factor for death and disability and many studies have shown that actively in the scientific basis of the protocol, and in drafting and
the relationship appears in the shape of a ‘J’ or a ‘U’, with BMI values editing the manuscript.

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 V. Malafarina et al. / Maturitas 76 (2013) 123–128 127

Competing interest [17] Paillaud E, Bories PN, Le Parco JC, Campillo B. Nutritional status and energy
expenditure in elderly patients with recent hip fracture during a 2-month
follow-up. British Journal of Nutrition 2000;83(2):97–103.
VM has received grants from Abbott Nutrition SA, Avenida de [18] Wyers CE, Breedveld-Peters JJL, Reijven PLM, et al. Efficacy and cost-
Burgos 91, 28050 Madrid, España, and Nestle Health Care SA, effectiveness of nutritional intervention in elderly after hip fracture: design
Avenida Països Catalans 25-51, 08950 Esplugues de Llobregat, of a randomized controlled trial. BMC Public Health 2010;10:212.
[19] Volkert D, Berner YN, Berry E, et al. ESPEN guidelines on enteral nutrition:
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tistical analysis of the results, which are owned by Hospital San [20] Vukovich MD, Stubbs NB, Bohlken RM. Body composition in 70-year-old adults
Juan de Dios of Pamplona, nor in the conclusions of this study. JAM responds to dietary beta-hydroxy-beta-methylbutyrate similarly to that of
young adults. Journal of Nutrition 2001;131(7):2049–52.
and MAZ are member of CIBERobn, physiopathology of obesity and
[21] Flakoll P, Sharp R, Baier S, Levenhagen D, Carr C, Nissen S. Effect of
nutrition. Instituto de Salud Carlos III, Madrid, Spain. beta-hydroxy-beta-methylbutyrate, arginine, and lysine supplementation on
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women. Nutrition 2004;20(5):445–51.
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changes in protein metabolism in elderly men and women supplemented with
a nutrition cocktail of beta-hydroxy-beta-methylbutyrate (HMB), l-arginine,
The San Juan de Dios Hospital has received funding from Abbott and l-lysine. Journal of Parenteral and Enteral Nutrition 2009;33(1):71–82.
Nutrition SA, Avenida de Burgos 91, 28050 Madrid, España. [23] Gonzalez Pardo V, Russo de Boland A. Age-related changes in the response of
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Acknowledgments or postmenopausal women: a 2013 update of the 2008 recommendations
from the European Society for Clinical and Economic Aspects of Osteo-
The authors are grateful to the Head of staff of Hospital San porosis and Osteoarthritis (ESCEO). Current Medical Research and Opinion
2013;29(4):305–13.
Juan de Dios, Pamplona, and the staff of the Fundación Sant Joan de
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Deu, Barcelona, for their efforts and support in the development of status, ankle strength and activity show seasonal variation in older adults:
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