REVIEW

Nutrition and physical activity in the prevention and treatmentof sarcopenia: systematic review

C. Beaudart1,2 & A. Dawson1& S. C. Shaw1

& N. C. Harvey1 & J. A. Kanis3,4 & N. Binkley5 &

J. Y. Reginster6 & R. Chapurlat7 & D. C. Chan8,9,10& O. Bruyère6 & R. Rizzoli11 &

C. Cooper1,12 & E. M. Dennison1& the IOF-ESCEO Sarcopenia Working Group

Received: 9 January 2017 /Accepted: 31 January 2017 /Published online: 1 March 2017# The Author(s) 2017. This article is published with open access at Springerlink.com

AbstractSummary This systematic review summarizes the effect ofcombined exercise and nutrition intervention on muscle massand muscle function. A total of 37 RCTs were identified.Results indicate that physical exercise has a positive impacton muscle mass and muscle function in subjects aged 65 yearsand older. However, any interactive effect of dietary supple-mentation appears to be limited.Introduction In 2013, Denison et al. conducted a system-atic review including 17 randomized controlled trials(RCTs) to explore the effect of combined exercise andnutrition intervention to improve muscle mass, musclestrength, or physical performance in older people.They concluded that further studies were needed to pro-

vide evidence upon which public health and clinicalrecommendations could be based. The purpose of thepresent work was to update the prior systematic reviewand include studies published up to October 2015.Methods Using the electronic databases MEDLINE andEMBASE, we identified RCTs which assessed the combinedeffect of exercise training and nutritional supplementation onmuscle strength, muscle mass, or physical performance insubjects aged 60 years and over. Study selection and dataextraction were performed by two independent reviewers.Results The search strategy identified 21 additional RCTs giv-ing a total of 37 RCTs. Studies were heterogeneous in terms ofprotocols for physical exercise and dietary supplementation(proteins, essential amino acids, creatine, β-hydroxy-β-

This paper has been endorsed by the Committee of Scientific Advisors ofthe IOF.

* C. Coopercc@mrc.soton.ac.uk

1 MRC Lifecourse Epidemiology Unit, University of Southampton,Southampton General Hospital, Southampton SO16 6YD, UK

2 Department of Public Health, Epidemiology and Health Economics,University of Liège, Liège, Belgium

3 Centre for Metabolic Bone Disease, Medical School, University ofSheffield, Sheffield, UK

4 Institute for Health and Aging, Catholic University of Australia,Melbourne, Australia

5 University of Wisconsin Osteoporosis Clinical Center and ResearchProgram, Madison, WI, USA

6 Department of Public Health, Epidemiology and Health Economics,University of Liège, Liège, Belgium

7 INSERM UMR 1033, Université de Lyon, Hôpital E Herriot,Lyon, France

8 Department of Geriatrics and Gerontology, National TaiwanUniversity Hospital, Taipei, Taiwan

9 Department of Internal Medicine, National Taiwan UniversityHospital, Taipei, Taiwan

10 Superintendent’s Office, National Taiwan University HospitalChu-Tong Branch, Hsinchu City, Taiwan

11 Service of Bone Diseases, Geneva University Hospitals and Facultyof Medicine, Geneva, Switzerland

12 NIHR Musculoskeletal Biomedical Research Unit, Institute ofMusculoskeletal Sciences, University of Oxford, Oxford, UK

Osteoporos Int (2017) 28:1817–1833DOI 10.1007/s00198-017-3980-9

methylbuthyrate, vitamin D, multi-nutrients, or other). In 79%of the studies (27/34 RCTs), muscle mass increased with ex-ercise but an additional effect of nutrition was only found in 8RCTs (23.5%). Muscle strength increased in 82.8% of thestudies (29/35 RCTs) following exercise intervention, and di-etary supplementation showed additional benefits in only asmall number of studies (8/35 RCTS, 22.8%). Finally, themajority of studies showed an increase of physical perfor-mance following exercise intervention (26/28 RCTs, 92.8%)but interaction with nutrition supplementation was only foundin 14.3% of these studies (4/28 RCTs).Conclusion Physical exercise has a positive impact on musclemass and muscle function in healthy subjects aged 60 yearsand older. The biggest effect of exercise intervention, of anytype, has been seen on physical performance (gait speed, chairrising test, balance, SPPB test, etc.). We observed huge vari-ations in regard to the dietary supplementation protocols.Based on the included studies, mainly performed on well-nourished subjects, the interactive effect of dietary supple-mentation on muscle function appears limited.

Keywords Dietary . Intervention . Physical activity .

Sarcopenia

Introduction

Sarcopenia has been defined by the European Working Groupon Sarcopenia in Older People as a progressive and general lossof muscle mass and muscle function (defined either by a lowmuscle strength or a low physical performance) with advancingage [1]. Even though the loss of both is a natural part of theaging process, sarcopenia is defined when muscle mass andfunction falls below defined thresholds. Diagnosis of sarcopeniarequires, therefore, the measurement of muscle mass, musclestrength, and physical performance [2]. Sarcopenia is recog-nized as a major public health problem [3, 4] due to significantclinical, economic, and social consequences. The implementa-tion of preventive and therapeutic interventions has become achallenge due to the growing number of older persons affectedby sarcopenia and its disabling complications.

Physical activity and nutritional supplementation havebeen investigated in several interventional studies. Recently,Cruz-Jentoft et al. [5] published a systematic review summa-rizing studies assessing the effect of physical activity and/ordietary supplementation on sarcopenia. Results indicated thatmost exercise trials showed an improvement of musclestrength and physical performance with physical activity, pre-dominantly resistance training interventions. Results wereconsistent regarding the effect of dietary supplementation onmuscle mass. Some studies have suggested a role of proteins,β-hydroxy β-methylbutyric acid, or amino acid on musclefunction. However, the effects of these exercise and dietary

interventions were assessed separately in this particular re-view; little is known about the combined effects of these twointerventions. For this reason, Denison et al. [6] conducted asystematic review in 2013 to determine the effect of combinedexercise and nutrition interventions on muscle mass, strength,and function in older people. That systematic review com-prised 17 studies involving older (≥ 65 years) adults publishedup to April 2013. The authors concluded that further studieswere required to provide adequate evidence on which to basepublic health and clinical recommendations. The purpose ofthe present work was to provide an update to that systematicreview by including studies published up to October 2015,and to focus on whether additional benefits arose if dietarysupplementation was combined with exercise training.

Methods

Literature search

The literature search was performed in accordance with thePreferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. Using MEDLINE/Ovid andEMBASE/Ovid, we identified randomized controlled studies(RCTs) which assessed the combined effect of exercise trainingand nutritional supplementation on muscle strength, musclemass, or physical performance. We updated the paper byDenison et al. [6] which limited the search strategy toFebruary 2013. Therefore, we searched for any additional stud-ies published betweenApril 2013 andOctober 2015. The searchstrategy and search terms that were used for this research aredetailed in Table 1. Additional studies were identified by a man-ual search of bibliographic references of relevant articles andexisting reviews. Conference abstracts were not included.

Study selection

In the initial screening stage, two investigators independentlyreviewed the title and abstract for each of these references toexclude articles irrelevant to the systematic review. Rigorousinclusion criteria were adhered to (Table 2). In the second step,the two investigators independently read full texts of the arti-cles not excluded in the initial stage, then selected the studiesmeeting the inclusion criteria (Table 2). All differences ofopinion regarding selection of articles were resolved throughdiscussion and consensus.

In order to maintain consistency between this update andthe previous systematic review, the same inclusion criteriawere used [6]. No age restriction was included in the searchstrategy but this review focused only on subjects aged 60 yearsand older. Studies performed on children, adolescents, andyoung adults were therefore excluded. Studies in which thenutritional intervention was energy restriction to promote

1818 Osteoporos Int (2017) 28:1817–1833

weight loss were also excluded. Finally, studies were alsoexcluded if they included populations with a specific healthcondition (e.g., cirrhosis, cancer, diabetes, chronic kidney dis-ease, etc.).

Data extraction

Data were extracted according to a standardized form to in-clude authors, journal name, year of publication, country, ob-jective of the study, length of intervention, type of population,gender ratio, mean age, age range, detailed groups with sam-ple size, adherence to the treatment, % of participants whocompleted the study, adverse events, protocol of exercise in-tervention, protocol of nutritional intervention, muscle massoutcomes, muscle strength outcomes, and physical perfor-mance outcomes.

Methodology quality assessment

The quality of each study was independently assessed by twoauthors using the Jadad Score [7] system. The Jadad score

Table 1 Search strategy (application to MEDLINE Ovid andEMBASE)

1. Sarcopenia/2. Sarcopeni$.tw3. Muscle atrophy/4. Muscle weakness/5. Fat free mass.tw6. Lean body mass.tw7. Muscle mass.tw8. Exp hand strength/9. Grip strength.tw10. Anthropometry/11. Body composition/12. Lean mass.tw13. Or/1-1214. Exp exercise/15. Exp Movement/16. Muscle contraction/17. Muscle Development/18. Physical exertion/19. Exp Physical endurance/20. Exp muscle strength/21. Physical fitness/22. Exp Exercise test/23. Exercise therapy.tw24. Exp Exercise movement techniques/25. Exp Psychomotor performance/26. Muscle contraction/27. Resistance exercise.tw28. Aerobic exercice.tw29. Endurance.tw30. Physical exercise.tw31. Physical performance.tw32. Physical training.tw33. Exercise programme.tw34. Exercise technique.tw35. Muscle mass.tw36. Or/14-3537. Nutrition.tw38. Exp nutrition therapy/39. Exp Nutritional physiological phenomena/40. Exp Diet/41. Exp Diet therapy/42. Exp Dietary fats/43. Exp Dietary proteins/44. Exp Food/45. Exp Food, fortified/46. Exp Micronutrients/47. Exp Dietary supplements/48. Energy intake/49. Nutrition.tw50. Nutrition trial.tw51. Dietary lipids.tw52. Or/37-5153. Randomized controlled trials/54. Randomised controlled trial.tw55. Randomized controlled trial.tw56. Controlled clinical trial/57. Controlled study.tw58. Random allocation/59. Random$.tw60. Randomly allocated.tw61. Double blind method/62. Single blind method/63. Clinical trials.tw64. Clinical trial/65. Trial$.tw66. Intervention studies/

Table 1 (continued)

67. Intervention study.tw68. Interventional study.tw69. Placebo.tw70. Placebo$.tw71. Or/53-7072. And/36,5273. And/13, 71, 7274. (73 and humans/) or (73 not (humans/ or animals/))75. Limit 74 to English language76. Limit 75 to yr. = B2013-Current^ (344 results on PubMed (308 afterdeleting duplicates)– 859 with Embase (819 after remove duplicates)) –total 992 after remove duplicates between the 2 databases

Table 2 Inclusion criteria

Design Randomized controlled trials

Participants Human, men, and women aged 60 years and older

Exposure Studies which include at least two groups ofcomparison: a control group with only exerciseintervention and a treated group with combinedexercise intervention and nutritional intervention.Exercise intervention can be resistance exercise,aerobic exercise, or other. Nutrition interventioninvolves the provision of nutrients supplied witheither a supplement or food

Outcome Outcomes on muscle mass, on muscle strength,or on physical performance

Language English only

Date Studies published between April 2013 andend of October 2015

Osteoporos Int (2017) 28:1817–1833 1819

ranges from 0 to 5 points. Studies were considered to be ofexcellent quality if the score was 5, good quality if the scorewas 3 or 4, and poor quality if otherwise.

Presentation of results

The findings were evaluated in a descriptive manner based onthe information provided by each of the included studies.Because of the huge heterogeneity observed in the protocolsof exercise and dietary supplementation, nometa-analysis wasundertaken.

Results

Included studies

A total of 993 references were identified through the databasesearch. A manual search of the bibliography of 10 relevantsystematic reviews and meta-analyses did not generate anyfurther studies for inclusion. After reading all titles and ab-stracts, 36 RCTs were selected for full-text review, followingwhich 21 were included in this systematic review update.These 21 studies, added to the previous 17 considered byDenison et al. [6], gave a total of 37 RCTs included in thecurrent systematic review (Fig. 1).

Characteristics of the studies are shown in Table 3. Twelvestudies were performed in Europe, 11 in the USA/Canada, 7 inAsia, 4 in South America, and 3 in Australia. The number ofparticipants ranged from 17 [35] to 222 [26] and study dura-tion ranged from 4 weeks [27] to 18 months [42, 43]. Themajority of studies included both male and female participantsbut 10 studies were confined to women only and 5 includedonly men. The mean age of participants varied from59.5 ± 4.5 years [9, 10] to 87.1 ± 0.6 years [39, 40]. TwelveRCTs were graded on the Jadad Scale as having an excellentquality, 15 a good quality, and 10 a poor quality.

Twenty-two studies used a two-group comparison method-ology: one group receiving exercise + nutrition and the othergroup receiving exercise only (with placebo or no interven-tion). Eleven other studies used a four-group comparisonmodel with one control group with no intervention, one groupwith exercise only, one group with nutrition only and finally,one group with combined exercise and nutrition interventions.Three other studies chose to randomize their population intothree groups comprising a control group with no intervention,a group with exercise only, and a group with exercise com-binedwith nutrition. Finally, one study used a five-group com-parison model that included two groups with exercise andnutrition interventions, but used a different nutritional supple-ment in each of these two groups. For this systematic review,we used only results from two groups, one receiving exercise +

nutrition and one receiving exercise only. It has to be notedthat only half of the studies were double blinded.

Regarding nutritional interventions, 10 of the 37 studiesused proteins. One further study used protein combined withessential amino acids, a second used protein combined withvitamin D, and a third used protein combined with creatine.Three studies used essential amino acids alone, five studiesused creatine alone, three studies used β-hydroxy-β-methylbutyrate alone, and two used vitamin D alone. Of theremaining 12 studies, five used multi-nutrient supplementsand six used other products (vitamin and mineral-enhanceddairy and fruit products, green tea, magnesium oxide, milkfat globule membrane, soy isoflavones, and tea catechin).For exercise, the majority of studies used resistance trainingwith the remainder using multicomponent training involvingboth resistance and additional exercises such as walking, fit-ness, aerobics, balance, etc.

Types of nutritional intervention

Results of the interventions are summarized in Table 4.

Fig. 1 Flow chart of literature search

1820 Osteoporos Int (2017) 28:1817–1833

Protein supplementation

Thirteen individual studies assessed the impact of a combinedprotein supplement and exercise intervention on the musclefunction of elderly people. Most of these studies were of goodquality but four were of poor quality [12, 24, 26, 29]. Inthree of the 13 studies, protein was combined with creatine[12], essential amino acids [24], or vitamin D [26].Supplementation protocols were heterogeneous in terms ofstudied population, duration of study, and supplementationdose, which varied from 7.4 to 45 g of protein per day.Twelve studies assessed the effect of the interventions onmus-cle mass and/or muscle strength but only nine reported resultson physical performance.

Muscle mass: Muscle mass increased significantly withexercise in 11 of the 12 included RCTs. An interactive effectof protein supplementation and exercise was reported in onlythree of these studies: one looked at frail individuals [33], asecond has been performed in elderly sarcopenic men [25],and the third enrolled female retirement village residentswhose protein supplementation was lean red meat [22]. Oneother study [8] reported an increase of fat-free mass and ap-pendicular lean mass only in the group supplemented withprotein and exercise but the difference between the groupswas not described.Muscle strength: All studies showed a sig-nificant improvement of leg muscle strength with exercise. Noadditional effect of protein was seen in the majority of thesestudies with the exception of three studies, each one of excel-lent quality: Daly et al. [22] showed significant improvementin leg extension in the group receiving lean red meat (45 g ofprotein/day) and exercise compared to an exercise-only groupand Chalé et al. [17], who showed greater improvement inknee extensor peak power after a supplementation of 40 g ofprotein/day and, finally, Zdzieblik et al. [25] reported thatquadriceps strength of the right leg (effect on the left leg wasnot assessed) increased more in the group taking 15 g of col-lagen peptide as supplement/day. Improvement in handgripstrength was seen in one study [33] but was absent in threeothers [20, 24, 29]. Finally, one study [8] reported an increaseof the 1 repetitionmaximum (1RM) knee extensors only in thegroup with protein combined with exercise; however, the dif-ference between the two groups was not reported. Physicalperformance: All studies showed a significant improvementof at least one physical performance test with exercise. Nostudies showed a significant difference between the groupsreceiving exercise only compared to the group receiving ex-ercise combined with protein.

Summary: Muscle mass increased with exercises in 11/12RCTs but an additional effect of protein was found in only 3/12 RCTs; Muscle strength increased with exercises in 12/12RCTs but an additional effect of protein was found in only 3/12 RCTs; Physical performance increased with exercise, for at

least one outcome, in 9/9 RCTs with no additional effect ofprotein.

Essential amino acids supplementation

Three studies used essential amino acids (EAA) supplemen-tation, 6 g/day for 3 months in sarcopenic community-dwelling older women [36], 10 g/day for 4 weeks in olderadults recruited from nursing homes and adult day-carecenters [27], and 12 g/day for 12 weeks in older men[35]. One study was of poor quality [35]. All three assessedthe effect of intervention on muscle mass and musclestrength and two also measured the effect on physical per-formance [27, 36].

Muscle mass: Two studies reported an increase of musclemass with exercise but did not report any difference betweenthe group receiving EAA supplements and the group who didnot [35, 36]. The third study did not report any increase ofmuscle mass, neither for subjects receiving exercises only, norin the groups of subjects receiving a combination of exerciseand EAA supplements [27].Muscle strength: Knee extensionincreased with exercise in two studies but no interaction wasfound with EAA supplementation. In the third study, no effecton isometric leg strength was observed [27]. Physicalperformance: Walking speed [36] and timed up and go [27]tests improved with exercise with no additional effect of EAAsupplements. Standing balance and chair-stand test did notimprove with treatment [27].

Summary: Muscle mass and muscle strength increasedwith exercise in 2/3 RCTs with no additional effect of EAA;Physical performance (walking speed and SPPB test only)increased with exercise in 2/2 RCTs with no additional effectof EAA.

β-hydroxy-β-methylbutyrate (HMB) supplementation

Three studies of good quality used Ca-HMB [13, 16, 37] asa dietary supplement. In all studies, the treated group re-ceived 3 g of Ca-HMB per day. The study duration varied:24 weeks [13], 12 weeks [37], and 8 weeks [16].Participants were healthy ambulatory older adults in thefirst two studies [13, 37] and healthy adults confined tocomplete bed rest for 10 days for the latter [16]. All studiesassessed the effect on muscle mass and muscle strength butonly two assessed the effect of treatment on physical per-formance [13, 16].

Muscle mass: Effects of Ca-HMB supplementation on mus-cle mass were not consistent across the three studies. Fat-freemass significantly increased with exercise in one study but nodifference was evident between the group with combined exer-cise + Ca-HMB and the group with exercise only [13].Moreover, a significantly greater increase in fat-free mass was

Osteoporos Int (2017) 28:1817–1833 1821

Tab

le3

Characteristicsof

included

studies

Reference

Settin

gs,study

participants,

meanage±SD

Studydesign

Exercisetraining

interventio

nNutritio

nalsupplem

ent

Outcomemeasures

Qualityscore

(Jadad

scale)

Grysonet

al.2014[8]

France.35

healthysedentarymen

60.7

±0.4years

16-w

eekintervention.

Participants

random

ized

in5groups:(i)no

exercise

+placebo,(ii)exercise

+placebo,(iii)

exercise

+fortified

milk,(iv)no

exercise

+fortified

leucine,(v)exercise

+fortified

leucine.Treatmentswere

administrated

doubleblind

Resistanceandaerobicexercises.3

sessions

perweek,non-consecutive

days,45–60

min

foreach

session

Protein.M

ilk-based

supplement

drinks

containing,proteins(total

milk

proteins

10g/dayor

fast

digested

solublemilk

proteins

10g/day),carbohydrates,and

fat.

Placebo

drinks

contains

4gof

totalm

ilkprotein

MM:appendicularmusclemassand

fat-free

massin

thedominant

legM

S:isom

etricstrength

ofthe

knee

extensors

4

Lebon

etal.2014,[9]

Choquetteet

al.2013

[10]

Canada.34

postmenopausal

wom

en59.5

±4.5years

6-month

intervention.Participants

random

ized

intwogroups:(i)

exercise

andisoflavone,(ii)

exercise

andplacebo.Treatmentswere

administereddoubleblind

Com

binedaerobicandresistance

training,3

sessions

perweek(1

h,30

min

ofaerobic,30

min

ofresistance)

Other

(soy

isoflavones).4

capsules

daily

with

either

soyisoflavones

orplacebo.The

70-m

gdaily

dose

ofisoflavonescontained44

mgof

daidzein,16mgof

glycitein,and

10mgof

genisteinextractedfrom

naturalsoy.P

laceboscontained

cellu

lose

MM:w

aistandhipcircum

ference,

musclemassindexM

S:grip

strength,1RM

(leg

press,bench

press,latp

ulldow

n)PP

:chair

standtest

5

Gualano

etal.2014[11]

Brazil.60

vulnerableolder

wom

en.T

reated

67.1

±5.6years/control

63.6

±3.6years

24-w

eekintervention.Participantswere

random

ized

infour

groups:(i)

placebo,(ii)creatin

e,(iii)

placebo+

exercise,(iv)creatine+exercise.

Treatmentswereadministereddouble

blind

Supervised

resistance

training.T

wo

sessions

perweek

Creatine.Su

pplementspackages

20g/dayof

creatinemonohydrate

for5days

dividedinto

four

equal

doses,followed

bysingledaily

dosesof

5gforthenext

23weeks.P

lacebo

was

dextrose

MM:appendicularleanmassMS:leg

press,benchpressPP:

timed-standstests.,T

imed

upand

gotest

4

Villanueva

etal.2014

[12]

USA.22healthymen,

recreationally

active

68.1

±6.1years

12-w

eekintervention.Participantswere

random

ized

inthreegroups:(i)exer-

cise

+creatineandprotein

supplementation,(ii)exercise

only,

(iii)

control.Treatmentadm

inistration

was

notd

oubleblinded

Resistancetraining.3

sessions

perweek

Protein

+creatine.Su

pplemented

group(encapsulatedpowder)

consum

ed0.3g/kg/day

ofcreatin

efor5days

followed

by0.07

g/kg/day

until

completionof

thestudy.The

supplemented

groupalso

consum

edone35-g

liquidproteinready-to-drink

daily

MM:leanbody

massM

S:leg

press,

chestp

ress,strengthendurance.

PP:stairclim

bing

power,

dynamicpower,400-m

walk

2

Stoutetal.2013[13]

USA.48am

bulatory

participants

(22men

and26

wom

en)

73±1years

24-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+placebo,(ii)exercise

+HMB.T

reatmentswereadministered

doubleblind

Supervised

resistance

training.T

hree

sessions

perweek

β-hydroxy-β-m

ethylbuthyrate.CaH

-MB(H

MB,1,5

gCaH

MB+4g

carbohydrate)twicedaily.

Placebo

(200

mgcalcium

+4g

carbohydrates)twice

daily.Participantswereaskedto

mixtheirp

roductinnon-alcoholic

beveragesanddrinkit

MM:totallean

mass,reginalleg

lean

mass,regionalarm

lean

massM

S:handgrip

strength,leg

extension,

benchpress,legpress,leg

extensionstrength.PP:G

etup

and

Go

5

Okazaki

etal.2013[14]

Japan.35

healthymiddle-aged

andolderwom

en.T

reated

60±3years/control

61±3years

5-month

intervention.Participantswere

random

ized

intwogroups:(i)

exercise

only,(ii)

exercise

+post-exercisemacronutrient.

Treatmentadm

inistrationwas

not

doubleblinded

Hom

e-basedintervalwalking

training.4

ormoredays

perweek

Multi-nutrient

(macrunutrient

mixture).215gof

amacronutrient

mixture

within

30min

aftereach

training

session

(com

position200kcal;7

,6g

protein;3

2,5gCHO;4

,4gfat)

MM:totalmuscletissueareaMS:

isom

etricknee

extension,

isom

etricknee

flexion,isokinetic

knee

extension,isokineticknee

flexion

2

Narotzkietal.2013[15]

Israel.13elderlymen

and9

elderlywom

en.

71.1

±1.2years

12-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+greenteaandvitamin

E,

(ii)exercise

+vitamin

Eonly.

Treatmentadm

inistrationwas

not

doubleblinded

Fitness-guided

exercises.6tim

esaweek.

30min

ofdaily

walks

Other

(green

tea).P

articipantswere

askedtobrew

teasachets3tim

esa

dayin240mlofb

oilingwaterfor

3min.O

nevitamin

Ecapsule

composedof

400IU

ofd-alpha-tocopheroladay.Placebo

groupdidnotd

rink

teaand

consum

edacapsuleof

vitamin

Eplaceboaday

MM:w

aistandhipcircum

ference

2

1822 Osteoporos Int (2017) 28:1817–1833

Tab

le3

(contin

ued)

Reference

Settin

gs,study

participants,

meanage±SD

Studydesign

Exercisetraining

interventio

nNutritio

nalsupplem

ent

Outcomemeasures

Qualityscore

(Jadad

scale)

Deutzet

al.2013[16]

USA.24olderadultsconfined

tocompletebedrestfor10

days.

Treated

67.4

±1.4years/control

67.1

±1.7years

8-weekinterventio

n.Participantswere

random

ized

intwogroups:(i)

exercise

+HMB,(ii)

exercise

+placebo.Treatmentswere

administereddoubleblind.Testswere

performed

beforebedrest,afterbed

rest,and

afterthe8weeks

ofrehabilitation

Resistanceexercise

training

rehabilitation.3days

perweek.

Strength

training

during

1h

β-hydroxy-β-m

ethylbuthyrate.2

sachetsof

Ca-HMBperd

ay.E

ach

sachetcontained1.5gof

Ca-HMB,4

gmaltodextrin,and

200mgcalcium.T

hecompositionof

placebowas

identicalwith

theexclusionof

Ca-HMB

MM:leanbody

massM

S:knee

extension,flexor

force,legpress,

standing

plantarflexor

force,and

stairascent

anddescentp

ower.

PP:SPPB

test,G

etup

andGotest,

5-item

SPPB

5

Chaléet

al.2013[17]

USA.80mobility-lim

itedwom

enaged

70–85years.Treated

78.0

±4.0years/control

77.3

±3.9years

6-month

intervention.Participants

random

ized

intwogroups:(i)

exerciseandproteins,(ii)

exerciseand

isocaloriccontrol.Treatmentswere

administereddoubleblind

Supervised

progressiveprogram.3

times

perweekwhich

entailedlegpress,

seated

row,leg

extension,chestp

ress

andlegcurl

Protein(w

heyprotein).W

heyprotein

inpowderform

40g/day(one

servingcontains

20gprotein,

25gmaltodextrin,1gfat,

189kcal)Isocaloriccontrolin

powderform

(45gmaltodextrin,

1gfat,189kcal)

MM:leanmass,totalm

uscle

CSA

MS:

Leg

press,knee

extensionstrength,peakpower

PP:S

tairclim

bing,chairrise

performance,S

PPBtest,400

mwalktim

e

5

Kim

etal.2013[18]

Japan.128community-dwelling

elderlysarcopenicwom

enTreated

81.1

±3.7years

/control

79.6

±4.2years

3-month

intervention.Participantswere

random

ized

infour

groups:(i)

exercise

andteacatechin,(ii)

exercise

only,(iii)tea

catechinonly,(iv)h

ealth

education,control.Treatmentswere

administereddoubleblind

Stretching,m

usclestrengthening,

balanceandgaittraining.T

wo

sessions

perweek.Eachsession

60mins

Other

(tea

catechin).One

bottleper

daycontaining

350mLof

tea

fortifiedwith

540mgof

catechin

MM:leanbody

mass,appendicular

lean

massandlegmusclemass

MS:gripstrength,kneeextension

strength

PP:u

sualandmaxim

umwalking

speed,TUG,balance

ability

4

Aguiaret

al.2013[19]

Brazil.18

healthywom

en64.9

±5.0years

12-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+creatin

e,(ii)exercise

+placebo.Treatmentswere

administereddoubleblind

Resistancetraining.T

hree

sessions

per

week.The

training

volumewas

progressivethroughout

thetraining

program

Creatine.One

capsule(5.0

g/day).

The

placebogroupingested

anidentical-looking

equivalent

amount

ofplacebo,maltodextrin

MM:appendicularmusclemassMS:

benchpress,knee

extension,

biceps

curlstrengthPP:

30-schair

standandarm

curltestandatest

ofgetting

upfrom

lyingon

the

floor

4

Leenderset

al.2014[20]

The

Netherlands.29healthy

e lderlymen

and24

healthy

elderlywom

en70

±1years

24-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+placebo,(ii)exercise

+protein.Treatmentswere

administereddoubleblind

Supervised

resistance

training.T

hree

sessions

perweek

Protein.250

mlb

everages

perday.

Protein

beveragescontains

15g

ofprotein,0.5gfat,7.13

glactose,0.42

gcalcium.P

lacebo

beveragescontainno

proteinor

fat,7.13

glactose,0.42

gcalcium

MM:totalbody

lean

mass,leglean

mass,quadriceps

CSA

MS:

leg

press,legextension,

handgrip

testPP

:sit-to-stand

test

3

Veroneseet

al.2014[21]

Italy.139healthyelderlywom

en.

71.5

±5.2years

12-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+magnesium

oxide,(ii)

exercise

only.T

reatment

administrationwas

notd

ouble

blinded

Mild

fitnessprogram.T

wosessions

per

week

Other

(magnesium

oxide)sachets.

900mg/dof

oralmagnesium

oxidecorrespondingto

300mg

bioavailablemagnesium

MM:appendicularskeletalmuscle

massindexM

S:isom

etricknee

extension,handgrip

strength

PP:

SPPB

test

3

Dalyet

al.2014[22]

Australia.100

wom

enresiding

inretirem

entv

illages.T

reated

72.1

±6.4years/control

73.6

±7.7years

4-month

intervention.Participantswere

random

ized

intwogroups:(i)

exercise

+meat,(ii)exercise

only.

Treatmentadm

inistrationwas

not

doubleblinded

Supervised

progressiveresistance

and

balance-agility

training

program.2

sessions

perweek

Protein

(leanredmeat).220

glean

redmeattobe

consum

ed6days/week=160gcooked

meat/day

(45gprotein).C

ontrol

75gcooked

rice

and/or

pasta/day

(thatp

rovides25–35

carbohydrates/day)

MM:leantissuemassMS:

leg

extensionP

P:4-squarestep

test,

Tim

edUpandGo,30-s

sit-to-stand

test

5

Cooke

etal.2014[23]

Australia.20middleto

older

males

Treated

61.4

±5.0years/control

60.7

±5.4years

12-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+CHO,(ii)

exercise

only.

Treatmentswereadministereddouble

blind

High-intensity

resistance

training

program.3

days

perweek

Creatine

monohydrate-carbohydrates.

Treated

group20

gof

CrM

combinedwith

5gof

glucosefor

7days

follo

wed

by0.1gkg

−1

(average

dosage

of∼8

.8g)

ofCrM

with

5gof

glucoseon

MM:fat-freemassMS:leg

press,

benchpress

4

Osteoporos Int (2017) 28:1817–1833 1823

Tab

le3

(contin

ued)

Reference

Settin

gs,study

participants,

meanage±SD

Studydesign

Exercisetraining

interventio

nNutritio

nalsupplem

ent

Outcomemeasures

Qualityscore

(Jadad

scale)

training

days.P

lacebo

20gof

glucoseonly

for7days

followed

by5gof

glucoseon

training

days

Oesen

etal.2015[24]

Italy.82

olderadultsliv

ingin

retirem

entcarefacilities

82.8

±6.0years

6-month

intervention.Participantswere

random

ized

inthreegroups:(i)

exercise

only,(ii)

exercise

+nutrient

supplementation,

(iii)

cognitive

training

group.Treatment

administrationwas

notd

ouble

blinded

Supervised

resistance

exercise

with

elastic

band.T

wosessions

perweeks

onnon-consecutivedays

(separately

min

48h)

Protein

andessentialaminoacids.

Twonutrient

supplementd

rink

perday.Eachdrinkhadacaloric

valueof

150kcal,20.7gprotein

(3gleucine,>10

gessential

aminoacids),9.3

gcarbohydrates,3gfat,vitamins

andminerals

MS:kneeextensor

peak

torque,knee

flexor

peak

torque,handgrip

strengthPP

:chairstandtest,gait

speed,six-minutewalking

test,

functio

nalreach

test,arm

liftin

gtest

2

Zdzieblik

etal.2015[25]

Germany.53

elderlymen

with

sarcopenia.72.2±4.68

12-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+collagenpeptide,(ii)

exercise

+placebo.Treatmentswere

administereddoubleblind

Guidedtraining

program

onfitness

devices.Three

sessions

aweekovera

period

of60

min

Protein

(collagenpeptide).Treated

groupreceived

15gof

collagen

peptides

each

day.Placebo

group

received

silicon

dioxideas

placebo.Bothweregivenin

powderto

dissolve

in250mlo

fwater.

MM:fat-freemassMS:isokinetic

quadriceps

strength

oftheright

leg

5

Yam

adaet

al.2015[26]

Japan.222community-dwelling

olderadults(142

wom

enand

80men).Treated

76.3

±5.9years/control

75.8

±5.2years

6-month

intervention.Participantswere

random

ized

inthreegroups:(i)

walking

andnutrition,(ii)

walking

only,(iii)control.Treatment

administrationwas

notd

ouble

blinded

Walking

program.U

seof

pedometer-based

walking

programs.

Participantswereinstructed

toincrease

thenumberof

daily

stepsby

10%

each

month

Protein

andvitamin

D.D

aily

supplementscomposedof

200kcal,10.0gof

proteinwith

branched

chainam

inoacids

12.5

mgof

vitamin

D,and

300mgof

calcium

MM:skeletalm

uscleindex

2

Trabaletal.2015[27]

Spain.24olderadultsin

nursing

homes

andadultd

aycare

centers(16wom

enand8

men).Treated

85±8years/control

84±4years

4-weekinterventio

n.Participantswere

random

ized

intwogroups:(i)

exercise

andleucine,(ii)exercise

only.T

reatmentswereadministered

doubleblind

Resistancetraining.T

hree

sessions

ofprogressiveresistance

training

adaptedforolderadultsandone

sessionof

balanceexercise

perweek

Essentialaminoacid

(leucine).

Leucine

10g/dayor

thesame

amount

ofmaltodextrinas

placebo.Bothsupplementsand

placebowereaccompanied

with

alemon

andlim

eflavor

todisguise

thecharacteristictasteof

leucine

MM:calfcircum

ference,waist

circum

ference.MS:

maxim

alisom

etriclegstrength.P

P:

standing

balance,4m

walk,chair

stands

testandTUGtest

5

Ki m

etal.2015[28]

Japan.130community-dwelling

frailw

omen.T

reated

81.0

±2.6years/control

81.1

±2.8years

3-month

intervention.Participantswere

random

ized

infour

groups:(i)

exercise

andmilk

fatg

lobule

mem

brane,(ii)exercise

only,(iii)

milk

fatg

lobulemem

braneonly,(iv)

health

education,control.Treatments

wereadministereddoubleblind

Physicalcomprehensive

training

program

ofmoderateintensity.E

ach

classwas

60min,twiceperweek

Other

(milk

fatg

lobulemem

brane).

The

compositionwas

21.5%

protein,44%

fat,26.5%

carbohydrate,33.3%

phospholipids,6.4%

ash,and

1.6%

moisture.Six

pills

(1gof

MFG

M)ingested

daily.T

heplaceboconsistedof

pills

ofsimilarshape,taste,andtexture

andincluded

milk

powderinstead

ofMFG

M.M

ilkpowderwas

composedof

26.3%

protein,

25.2%fat,39.5%

carbohydrate,

0.286phospholipids,5.7%

ash,

and3,3%

moisture

MM:appendicularmusclemass,leg

musclemassMS:g

ripstrength,

knee

extensionPP

:usualwalking

speed,tim

edup

andgo

5

Shahar

etal.2013[29]

Malaysia.65

elderlieswith

sarcopenia(18wom

enand47

men).67.1

±5.3years

12-w

eekintervention.Participantswere

random

ized

infour

groups:(i)control

group,(ii)exercise

group,(iii)

protein

supplementation,(iv)

exercise

+proteinsupplementation.Treatment

administrationwas

notd

ouble

blinded

Moderatelyintensive,well-roundedac-

tivities

infacilitated

groupsessions.

During60

min,twosessions

per

week

Protein

(soy

protein).20g/dayand

40g/dayof

high

protein

supplementationinapowderform

tomen

andwom

en,respectively.

Control

groupdidnotreceived

placebobuta

relaxatio

nexercise

MM:totalmusclemassandfat-free

massMS:h

andgripstrength,arm

curltestPP

:chairstandtest,chair

sitand

reach,back

scratch,8-ft

andgo,6-m

inwalk

1

1824 Osteoporos Int (2017) 28:1817–1833

Tab

le3

(contin

ued)

Reference

Settin

gs,study

participants,

meanage±SD

Studydesign

Exercisetraining

interventio

nNutritio

nalsupplem

ent

Outcomemeasures

Qualityscore

(Jadad

scale)

program

tomaintaininteraction

andincrease

motivation

Arnarsonet

al.2013[30]

Iceland.161healthy

community-dwellingmen

and

wom

en.(94

wom

enand67

men)Treated

73.3

±6.0/control:

74.6

±5.5,8

12-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+wheyproteinsupplement

or(ii)exercise

only.T

reatment

administrationwas

notd

ouble

blinded

Resistanceexercise

program.

Participantsexercisedthreetim

esper

week

Protein

(wheyprotein).D

rink

(250

mL)providing20

gprotein,

20gcarbohydrate,1

gfat

(169

kcal)(intervention)

oriso-

caloricdrinkcontaining

40g

carbohydrate,1

gfat(control)

consum

edim

mediately

afterex-

ercise

MM:leanbody

mass,appendicular

lean

massMS:

quadriceps

muscle

strength

PP:tim

edup

andgo;

6-min

walkfordistance

5

Rosendahl

etal.[31]

2006,C

arlssonet

al.

2011

[32]

Sweden.191

oldermen

and

wom

enin

residentialcare.

(139

wom

enand52

men)

84.7

±6.5years

3-month

intervention.Participants

random

ized

tofour

groups:(i)

protein-enriched

drink,control

activ

ity,(ii)

exercise

training

+placebodrink,(iii)

protein-enriched

drink

+exercise

training,or(iv)

neith

er(control

activity,placebo

drink).T

reatmentadm

inistrationwas

notd

oubleblinded

High-intensity

multicom

ponent

exercise

program,including

resistance

exercise

training

andbalance

exercises.Participantsexercisedfive

times

perfortnight

Protein

(milk

-based

protein-enriched

drink).D

rink

(200

mL),provid-

ing7.4gprotein,15.7

gcarbohydrate,408

kJper100g.

Placebo

drink(200

mL)

contained0.2gprotein,10.8

gcarbohydrate,191

kJper100g.

Drinksofferedwithin

5min

ofexercise

session

MM:totallean

massM

S:lower-lim

bmusclestrengthPP

:balance

(Berg

Balance

Scale),gaitability(2.4

mtim

edtest)

3

Tieland

etal.2012[33]

The

Netherlands.20frailo

lder

men

and41

frailolderwom

enTreated

78±9years/control:

79±6years

24-w

eekintervention.

Participants

random

ized

intwogroups:(i)

exercise

+proteinsupplementation

or(ii)exercise

+placebodrink.

Treatmentswereadministereddouble

blind

Resistance-type

exercise

training.

Participantsexercisedtwiceperweek

Protein.P

rotein-supplem

enteddrink

(250

mL),(15gprotein,7.1g

lactose,0.4gcalcium)and

placebodrink(noprotein,7.1g

lactose,0.4gcalcium)consum

edtwiceperday

MM:leanmassMS:

legpress,leg

extension,handgripPP

:SPP

Btest

5

Verdijk

etal.2009[34]

The

Netherlands.28healthy

oldermen,living

independently

72±2years

12-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+proteinor

(ii)exercise

+water.T

reatmentswereadministered

doubleblind

Resistance-type

exercise

training.

Participantsexercisedthreetim

esper

weekin

themorning,atsam

etim

eof

day

Protein.P

rotein

drink(10gcasein

hydrolysate,250mL)or

placebo

drink(250

mLwater)given

immediatelybeforeandfollo

wing

exercise

sessions

MM:leanmass,leglean

mass,

cross-sectionalareaof

quadriceps

MS:leg

press,legextension

3

Godardet

al.2002[35]

USA.17oldermen

Treated

70.8

±1.5/control7

2.1±1.9

12-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+EAAor

(ii)exercise

with

nodietarysupplementation(control).

Treatmentadm

inistrationwas

not

doubleblinded

Progressiveknee

extensor

resistance

training

program.P

articipants

exercisedthreetim

esperweek

Essentialaminoacids.Amino

acid-containingdrink(400

mL)

providing12

gessentialamino

acids,72

gfructose

anddextrose;

consum

edim

mediately

after

training

oratsametim

eeach

day

MM:w

holemusclecross-sectional

area

ofrightthigh

MS:knee

extension

1

Kim

etal.2012[36]

Japan.155sarcopenic,

community-dwellingolder

wom

enTreated

79.5

±2.9years/control

79,2

±2,8

3-month

intervention.Participants

random

ized

tofour

groups:(i)EAA,

(ii)exercise

training,(iii)

supplementation+exercise

oriv)

health

education(oncepermonth).

Treatmentadm

inistrationwas

not

doubleblinded

Multicom

ponent

exercise

program

includingresistance

exercise

training.

Participantsexercisedtwiceperweek

Essentialaminoacids.Pow

dered

aminoacid

supplementsprovided

tobe

takentwicedaily

with

water

ormilk,supplying

6gessential

aminoacidsperday

MM:totalmusclemassMS:

knee

extension.PP

:usualand

maxim

umwalking

speed

3

Vukovichet

al.2001[37]

USA.15healthyoldermen

and16healthyolderwom

en70

±1years

8-weekinterventio

n.Participantswere

random

ized

intwogroups:(i)

HMB+exercise

or(ii)aplacebo

supplement+exercise.T

reatments

wereadministereddouble-blind

Multicom

ponent

exercise

training

includingresistance

exercises.

Participantsexercised5days

per

week(2

days

strength

training,

3days

walking

andstretching)

β-hydroxy-β-m

ethylbuthyrate.

Supplem

entcapsulescontained

250mgCa-HMB;p

articipants

consum

edfour

capsules,three

times

perday(3

g/day).P

lacebo

capsules

wereidenticalin

appearance,providing

3g/day

rice

flour

MM:fat-freemass,musclearea.M

S:upperandlower

body

strength

4

Bonnefoyet

al.2003[38]

9-month

intervention.Participants

random

ized

tofour

groups:(i)

Multicom

ponent

exercise

training

includingresistance

exercises.

Multi-nutrient.N

utritionald

rinks

(200

mL)(providing

200kcal,

MM:fat-freemassMS:explosive

leg

extension(pow

er).PP

:gaitspeed,

3

Osteoporos Int (2017) 28:1817–1833 1825

Tab

le3

(contin

ued)

Reference

Settin

gs,study

participants,

meanage±SD

Studydesign

Exercisetraining

interventio

nNutritio

nalsupplem

ent

Outcomemeasures

Qualityscore

(Jadad

scale)

France.57

frailresidentin

retirem

enth

omes

(50wom

enand7men)83

years

nutritionaldrink+controlactivity

(mem

ory),(ii)

exercise

training

+placebodrink,(iii)

nutritional

drink+exercise

training,or(iv)

controlactivity

+placebodrink.

Treatmentadm

inistrationwas

not

doubleblinded

Participantsexercisedthreetim

esper

week.Three

weeklymem

orysessions

served

ascontrolsforexercise

15gprotein,vitaminsand

minerals)or

placebo(providing

nonutrients)giventwicedaily

six-step

stairclim

b,chairrise,

balanceabnorm

alities

Fiataroneet

al.1994,[39]

Fiataroneet

al.1993

[40]

USA.100

frailn

ursing

home

residents,37

men

and63

wom

en87.1

±0.6years

10-w

eekintervention.

Participants

random

ized

tofour

groups:(i)

multi-nutrient

supplementation,(ii)

exercise

training,(iii)

supplementation+exercise

oriv)

neith

er(control).Treatment

administrationwas

notd

ouble

blinded

Progressiveresistance

exercise

training

ofhipandknee

extensors.

Participantsexercised3days

per

week.Other

participantsoffered

alternativerecreationalactivities

Multi-nutrient.N

utritional

supplementp

rovidedas

adaily

drink(240

mL),supplying

360kcal,15gproteinand

vitaminsandminerals.

Participantswho

werenot

supplementedweregivena

minim

allynutritive

drinkof

equal

volume(4

kcal)

MM:thigh

musclearea,fat-freemass

MS:g

ripstrength,hip

andknee

extensorsPP:

gaitspeed,stair

clim

b,balance

2

Miller

etal.2006[41]

Australia.79olderwom

enand

21oldermen

hospitalized

followingafall-related

lower-lim

bfracture

83.5

(82.3–84.7)years

12-w

eekintervention.

Participants

random

ized

tofour

groups:(i)

nutritionalsupplementation,(ii)

exercise

training,(iii)

supplementation+exercise

oriv)

attentioncontrol(homevisitsonly,

generalnutritio

nandexerciseadvice).

Treatmentadm

inistrationwas

not

doubleblinded

Progressiveresistance

exercise

training

program.P

articipantsexercisedthree

times

perweek

Multi-nutrient.C

ompleteoral

nutritionalsupplementp

rescribed

toprovide45%

ofindividually

estim

ated

energy

requirem

ent,

administeredin

four

daily

doses

whilehospitalized

ortwodoses

afterdischargehome

MS:q

uadricepsstrength

PP:g

ait

speed

3

Bunoutetal.2

001,[42]

Bunoutetal.2004

[43]

Chile.108

community-dwelling

poorolderpeople(42men

and

66wom

en).Treated

73.7

±3.0/control7

4.4±3.3

18-m

onth

intervention.Evaluationat12

and18

months.Participantswere

random

ized

intwogroups:(i)

exercise

+nutritional

supplementationor

(ii)exercise

but

nodietarysupplementation.

Treatmentadm

inistrationwas

not

doubleblinded

Resistanceexercise.P

articipants

exercisedtwiceperweek

Multi-nutrient.N

utritionalp

roduct

(preparedas

asoup

orporridge,

givenas

twodaily

snacks),to

provide400kcal,13gprotein,

∼25%

daily

requirem

entsfor

micronutrients

MM:fat-freemassMS:h

andgrip,

quadriceps,bicepsstrength

PP:

walking

capacity

(m)

1

ChinAPawet

al.2001

[44],D

eJong

etal.

2000

[45]

The

Netherlands.217

frail

community-dwellingolder

men

andwom

en(45men

and

172wom

en).Treated

78.9

±6.0/control7

6.2±4.5

17-w

eekintervention.

Participants

random

ized

tofour

groups:(i)

supplementation,(ii)exercise

training,(iii)supplementation+

exercise

oriv)neither

(control).The

nutritionalinterventionwas

double-blin

ded

Multicom

ponent

exercise

training

(gradually

increasing

intensity).

Participantsexercisedtwiceperweek

Other

(vitaminsandminerals).

Supplem

entedgroupaskedto

consum

eonefruitand

onedairy

productenrichedwith

vitamins

andmineralsperday.Other

participantsreceived

same

productsthatwerenotenriched

MM:leanbody

mass,waist

circum

ference,hipcircum

ference

MS:h

andgrip,quadriceps

strengthPP:

gaitspeed,chairrise,

balance,flexibility

4

Binderet

al.1995[46]

USA.25nursinghomeresidents

with

dementia

(16men

and9

wom

en).Treated

87±4.4years/control

88.7

±6.9years

8-weekinterventio

n.Participantswere

random

ized

intwogroups:(i)

exercise

+calcium

carbonate+

vitamin

Dsupplementation,or

(ii)

exercise

+calcium

carbonateonly.

Treatmentadm

inistrationwas

not

doubleblinded

Multicom

ponent

butm

ainly

resistance-typeexercise.P

articipants

exercisedthreetim

esperweek

Vitamin

D.Interventiongroupgiven

bolusdose

(orally)of

100,000U

vitamin

D3atstarto

fstudy,then

weeklysupplements50,000

U

MS:k

neeextensor,low

erextrem

ityPP

:gaitspeed,balance

2

Bunoutetal.2006[47]

Chile.96community-dwelling

oldermen

andwom

en,w

ithlowvitamin

Dstatus

(86

wom

en,10men)76±4years

9-month

intervention.Participants

random

ized

toreceiveexercise

training

orno

training,and

further

random

ized

toreceive

supplementation(doubleblind)

with

vitamin

D/calcium

orcalcium

alone.

Resistanceexercise

training;p

articipants

exercisedtwiceperweek

Vitamin

D.C

ombinedoralvitamin

D/calcium

supplement

(400

IU/800

mg)

orcalcium-only

supplement(800mg)

provided,

tobe

takenin

theevening

MM:leanmassMS:

handgrip,

quadriceps

strength

PP:

TUG,

SPPB

5

1826 Osteoporos Int (2017) 28:1817–1833

found in men from the placebo group. One study did not showany effect of the treatment on fat-free mass but did show anincrease in thigh muscle area with exercise; no inter-group dif-ference was seen [37]. Finally, the third study showed a signif-icantly greater effect of exercise + Ca-HMB in preventing thedecline of lean bodymass over a period of bed rest compared toexercise only [16].Muscle strength: Muscle strength increasedin two studies with exercise but no additional effect of Ca-HMB was found. In the third study [37], no improvement inupper or lower body strength was found. Physicalperformance: The two studies showed an improvement in theperformance of the Timed Up and Go test with exercise but didnot show any added effect of nutritional supplementation andexercise. In a single study, no effect on the Short PhysicalPerformance Battery (SPPB) test was found [16].

Summary: Muscle mass increased with exercise in 3/3RCTs and an interactive effect of HMB was found in 1/3RCTs; Muscle strength increased with exercises in 2/3 RCTswith no additional effect of HMB; Physical performance in-creased with exercise (TUG only) in 2/2 RCTs with no addi-tional effect of HMB.

Multi-nutrient intervention

Five studies reported results of treatment combining multi-nutrients and exercise on muscle strength; four of the fivestudies also looked at muscle mass and physical performance.Studies were performed on community-dwelling participants[14, 42, 43], frail retirement community residents [38], ornursing home residents [39, 40]. The majority of studies wereof poor quality [14, 39, 40, 42, 43].

Muscle mass: Two out of four studies did not report anyimprovement in fat-free mass with exercise or with exercisecombined with multi-nutrient supplementation [38, 42, 43].Two studies reported an increase in muscle mass with exercise[14, 39, 40] but only in the cross-sectional area for the study ofFiatarone et al. [39, 40]. One of these failed to show anyadditional effect of nutritional supplementation [14] and theother did not describe the additional effect of multi-nutrientsupplementation [39, 40]. Muscle strength: Results were het-erogeneous for the five studies that assessed the combinedeffect of exercise and multi-nutrient supplementation on mus-cle strength. Two studies [14, 42] showed a significant im-provement in muscle strength with exercise, one [42] did notreport any additional effect of nutrition whereas the otherstudy [14], reported greater improvement in isometric kneeflexion in the group receiving combined exercise and multi-nutrient supplementation versus only exercise. Fiatarone et al.[39, 40] also reported an increase of muscle strength withexercise but did not describe the difference between the exer-cise only and combined multi-nutrient and exercise group.Finally, two other studies [38, 41] did not report any increaseof muscle strength with treatment. Physical performance:T

able3

(contin

ued)

Reference

Settin

gs,study

participants,

meanage±SD

Studydesign

Exercisetraining

interventio

nNutritio

nalsupplem

ent

Outcomemeasures

Qualityscore

(Jadad

scale)

Treatmentswereadministereddouble

blind

Brose

etal.2003[48]

Canada.30

healthy-community-dwelling

oldermen

andwom

en(15

wom

enand15

men)65+

years.

14-w

eekintervention.Participantswere

random

ized

intwogroups:(i)

exercise

+creatinesupplementor(ii)

exercise

+placebo.Treatmentswere

administereddoubleblind

Resistanceexercise

training.P

articipants

exercisedthreetim

esperweek

Creatine.Dailycreatinemonohydrate

supplement(5g+2gdextrose)

(intervention)

orplacebo(7

gdextrose)(control)

MM:fat-freemassMS:h

andgrip,

ankledorsiflexion,knee

extension,dynamic1R

MPP

:chairrise,stairclim

b,walking

speed

4

Tarnopolskyet

al.2012

[49]

Canada.39

community-dwelling

oldermen

andwom

en(10

wom

en,19men)65+years

6-month

intervention.Participantswere

random

ized

intwogroups:(i)

exercise

+supplementationwith

creatinemonohydrateandconjugated

linoleicacid,(ii)

exercise

+placebo.

Treatmentswereadministereddouble

blind

Resistanceexercise

training

program;

participantsexercisedtwiceperweek

Creatine.Dailysupplementationwith

creatinemonohydrate(5

g)+

conjugated

linoleicacid

(6g)

+2gdextrose

orplacebo(7

gdextrose

+6gsafflower

oil)

MM:fat-freemassMS:h

andgrip,

ankledorsiflexion,kneeextension

strength,endurance

PP:chairrise,

stairclim

b,walking

speed,

balance

5

MM

musclemass,MSmusclestrength,P

Pphysicalperformance,1-RM

onerepetitionmaxim

umtest,IUinternationalunit,HMBβ-hydroxy-β-m

ethylbuthyrate,SPPBshortphysicalperform

ance

battery,

TUGTim

edUpandGo,CSA

cross-sectionalarea,CHOcarbohydrate

Osteoporos Int (2017) 28:1817–1833 1827

Three studies described a significant improvement in physicalperformance with exercise. No additional effect of nutritionwas seen in two studies [38, 42, 43]; one further study did notreport whether there were any additional effect of nutrition[39, 40]. Finally, a fifth study did not show any effect oftreatment on gait speed [41].

Summary: Muscle mass increased with exercises in 2/4RCTs with no additional effect of multi-nutrient; Musclestrength increased with exercises in 3/5 RCTs and an addi-tional effect of multi-nutrient was found in 1/5 RCTs; Physicalperformance increased with exercise in 3/4 RCTs with no ad-ditional effect of multi-nutrient.

Creatine supplementation

Five good-quality studies have reported results of the effects ofcreatine supplementation on muscle mass and muscle strength;four of these also reported effects on physical performance. Theprotocols of supplementation were heterogeneous with threestudies using 5 g/day of creatine while the two other studiesused a higher dose of creatine for the first week followed by5 g/day in one of the study and 0.1 g/kg/day in the second study.The study duration varied from 12 weeks to 6 months.

Muscle mass: four out of the 5 studies showed greater im-provement of muscle mass in the group treated with the com-bination of exercise and creatine compared to the controlgroup with exercise only. The other study showed a significantincrease in muscle mass with exercise but without any addi-tional effect of creatine supplementation. Muscle strength:Muscle strength improved with exercise in all studies, withthe exception of handgrip strength, which remained un-changed in one study [48]. Several studies found additionaleffects of creatine supplementation in addition to exercise on:bench press [11, 19, 23], knee extension [19, 48, 49], bicepscurl performance [19], leg press [19], ankle dorsiflexion [48],isokinetic muscle strength [49], and, finally, endurance ofknee extension [49]. Physical performance: Results were lessconsistent regarding physical performance. Two studies [48,49] reported an improvement in physical performance withexercise but did not report any additional effects of creatinesupplementation. One study reported no improvement inphysical performance with either exercise or exercise pluscreatine [11]. The final study found a greater improvementin the 30-s chair stand test and in an exercise where partici-pants raised themselves from the floor, in the group receivingcombined exercise and creatine [19].

Summary: Muscle mass increased with exercises in 5/5RCTs and an additional effect of creatine was found in 4/5RCTs; Muscle strength increased with exercises in 5/5 RCTsand an additive effect of creatine was found, for some of themuscle strength outcomes, in 4/5 RCTs; Physical performanceincreased with exercises in 3/4 RCTs and an interactive effectof creatine was found in 1/4 RCTs.

Vitamin D supplementation

Two studies [46, 47] reported effects of combined exerciseand vitamin D3 supplementation onmuscle strength and phys-ical performance. One of those studies also reported effect onarm, waist and hip circumferences as well as lean mass [47].The vitamin D3 dose was 400 IU/day for 9 months in the studyof Bunout et al. [47] and 50,000 IU/week (after an initialinjection of 100,000 IU at study entry) for 8 weeks for thestudy of Binder et al. [46]. This last study was graded ashaving a poor quality [46] whereas the study of Bunoutet al. [47] was a good-quality study.

Muscle mass: Only one study reported results on musclemass [47]. No effects of exercise alone or of exercise com-bined with vitamin D supplementation were observed. Indeed,no significant changes in weight, circumferences, or bodycomposition measured by DXA were observed in any of thegroups.Muscle strength: Both studies reported significant im-provement in muscle strength with exercise but did not reportany difference between the exercise-only group and the groupwith combined exercise and vitamin D supplementation.Physical performance: Binder et al. [46] reported improvedbalance with exercise in a population of elderly nursing homeresidents with dementia. No additional effect of vitamin Dsupplementation was found and no improvement in gait speedwas evident in either group. Bunout et al. [47] reported asignificant improvement in the Timed Up and Go test for thegroup with combined vitamin D and exercise but no differ-ence for the SPPB test between groups.

Summary: Muscle mass did not improve with exercise andno additional effect of vitamin D was found; Muscle strengthincreased with exercise in 2/2 RCTs with no additional effectof vitamin D; Physical performance increased, for some of thephysical performance outcomes, in 2/2 RCTs with no addi-tional effect of vitamin D, except for TUG in 1/2 RCTs.

Other supplementation

Our systematic review identified six studies of good quality thatused other types of nutritional supplements: green tea in elderlymen and women [15], magnesium oxide in healthy elderly sub-jects [21], milk fat globule membrane in frail women [28], soyisoflavones in frail older women [9, 10], vitamin and mineral-enhanced dairy and fruit products in frail community-dwellingolder people [44, 45] and finally, tea catechin in sarcopenicwomen [18]. Four studies were 12 weeks in length [15, 18,21, 28], one was 6-months in length [9, 10], and the last onewas 17 weeks in length [44, 45].

Muscle mass: A significant effect of exercise alone onmus-cle mass was seen in various studies: in waist and hip circum-ference in men in the green tea [15] study, hip circumferencein the soy isoflavones [9, 10]study participants, lean mass inthe vitamin and mineral-enhanced dairy and fruit products

1828 Osteoporos Int (2017) 28:1817–1833

[44, 45]study, and leg lean mass in tea catechin [18]. No ad-ditional effects of nutritional supplements were observedacross studies. Muscle strength: Exercise increased benchpress and 1RM leg press without an additional effect of soyisoflavones [9, 10] and knee extension without additional ef-fects of tea catechin [18]. A small increase of quadricepsstrength was also shown in one study but the difference be-tween groups was not described [44, 45]. No effect of treat-ment was found on knee extension and handgrip strength inthe other studies [9, 10, 21, 28]. Physical performance:Exercise combined with magnesium oxide significantly im-proved performance in the SPPB test, the chair stand test, andin the 4-m walking speed in the study of Veronese et al. [21].TUG, usual gait speed, and maximum walking speed signifi-cantly improved in the exercise + tea catechin group comparedto exercise group only in another study of Kim et al. [18]Walking speed and TUG test performance also improved withexercise in the study of Kim et al. [28] but no additional effectof milk fat globule membrane was described. In the study byChin A Paw et al., improvements in physical performancewere described but the additional effect of vitamin- andmineral-enhanced dairy and fruit products was not described[44, 45]. Finally, the chair stand test did not improve withtreatment in two other studies [9, 10, 18].

Summary: Muscle mass increased with exercise in 4/6RCTs and no additional effect of nutrition was found;Muscle strength increased with exercise in 3/5 RCTs and nointeractive effect of nutrition was found; Physical perfor-mance increased with exercise in 4/5 RCTs and an additionaleffect of nutrition was found in 2/5 RCTs.

Discussion

This systematic review aimed to summarize results of RCTsassessing the effect of an intervention combining physicalactivity and dietary supplement on muscle mass and musclefunction of subjects aged 60 years and older. Following asystematic review previously performed in 2013 by Denisonet al. including 17 RCTs, we performed an update of thiscomprehensive systematic review and identified 21 RCTspublished between April 2013 and October 2015. Thus, 37RCTSs assessing the impact of a therapeutic intervention con-taining both physical activity and a nutritional supplement onmuscle parameters were included in the present work. Thestudy protocols were quite heterogeneous. Different types ofphysical activities have been studied in different populationsthat varied in sex, settings, and health status. Moreover, withineach category of dietary supplements, the supplement doseand the length of study differed across RCTs.

Among the 37 RCTs included in the systematic review,34 RCTs assessed the impact of intervention on musclemass in elderly subjects. In almost 80% of the RCTs (27/T

able4

Generalsummaryof

thesystem

aticreview

Musclemass

Musclestrength

Physicalperformance

Significantincrease

with

exercises

Significantadded

effectwith

nutrition

Significant

increase

with

exercises

Significantadded

effectwith

nutrition

Significantincrease

with

exercises

Significantadded

effectwith

nutrition

Protein

11/12RCTs

3/12

RCTs

12/12RCTs

3/12

RCTs

9/9RCTs

0/9RCTs

EAA

2/3RCTs

0/3RCTs

2/3RCTs

0/3RCTs

2/2RCTs

(onlyforSPP

BandTUG)

0/2RCTs

HMB

3/3RCTs

1/3RCTs

2/3RCTs

0/3RCTs

2/2RCTs

(onlyforTUG)

0/2RCTs

Multi-nutrient

2/4RCTs

0/4RCTs

3/5RCTs

1/5RCTs

3/4RCTs

0/4RCTs

Creatine

5/5RCTs

4/5RCTs

5/5RCTs

4/5RCTs

(for

someof

musclestrength

outcom

es)

3/4RCTs

1/4RCTs

Vitamin

D0/1RCTs

0/1RCTs

2/2RCTs

0/2RCTs

2/2RCTs

(for

someof

physicalperformance

outcom

es)

1/2RCTs

(onlyforTUG)

Other

4/6RCTs

0/6RCTs

3/5RCTs

0/5RCTs

4/5RCTs

2/5RCTs

RCTs

random

ized

controlledtrials,SPPBshortp

hysicalp

erform

ance

battery,T

UGtim

edup

andgo

Osteoporos Int (2017) 28:1817–1833 1829

34 RCTs), muscle mass increased with exercise training.In the majority of studies where no effect of exercise wasobserved, these were undertaken in frail subjects, residingin a nursing home, or, subjects with limited mobility. Ahypothesis could be that the physical condition of thesesubjects did not allow them to perform the protocol forthe physical activity intervention correctly. The majorityof studies proposed three sessions per week. Fewer ses-sions may compromise efficacy of the physical activityintervention. An additional effect of nutritional interven-tion on muscle mass was only found in 8 RCTs (23.5%),which were all of high quality (4 or 5 points in the JadadScale), 4 using creatine, 3 using proteins, and 1 usingHMB as dietary supplement. The majority (75%) of stud-ies using creatine as a dietary supplement showed a highereffect on muscle mass once exercise intervention wascombine with creatine. The combination of creatine sup-plementation and resistance training therefore seems to actsynergistically. Only 3 of the 12 RCTs using protein as adietary supplement reported an additional effect of proteinwhen combined with physical activity. These three studiesvaried in type and dose of protein with no specific simi-larity between them that could explain their positive re-sults as distinct from the other nine studies that did notreport an effect on mass muscle with protein. Because ofblunted response in muscle protein synthesis in olderadults and reduced post-prandial inhibition of muscle pro-tein breakdown, some authors recommended increasingprotein intake to 1.2 g/kg body weight/day in older adultsand even more in frail older adults or elderly with acute orchronic disease [50, 51]. Based on these recommenda-tions, we hypothesized a beneficial effect of protein sup-plementation in muscle function in older people.However, it should be discussed that the baseline dietaryintake of protein has not been reported in the differentstudies. Therefore, we do not know if the target of1.2 g/kg/day has been reached or if differences could havebeen observed between populations who reached this tar-get and those who did not. A meta-analysis published in2012 [52] showed a positive effect of protein supplemen-tation on muscle mass gains during prolonged resistance-type exercise training in older subjects. This probablymeans that the type of exercise training could have anon-negligible impact on results. Indeed, in this system-atic review, inclusion criteria were not limited to one par-ticular type of physical exercise. Finally, one out of thethree studies using HMB as a dietary supplement alsoshowed an intergroup difference between subjects under-going exercise intervention and subjects undergoing acombination of exercise and dietary intervention. Of note,this study comprised subjects confined to bedrest.Subjects receiving a combination of exercise and HMBsupplementation were more prevented for decline of lean

body mass over bed rest compared to subjects undergoingexercises only. In this study, HMB supplementation didnot increase muscle mass but prevented its decline.

Muscle strength increased in 82.8% of the studies (29/35RCTs) following an exercise intervention and, once again,dietary supplementation showed additional benefits in only asmall number of studies (8/35 RCTS, 22.8%) principally forcreatine but only at specific muscle sites. In 4 out of the 5RCTs using creatine as a dietary supplement (dose range 5–20 g/day), the group treated with the combination of exerciseand dietary intervention showed greater improvement of mus-cle strength compared to exercise only. Three good-qualityRCTs using protein as a dietary supplement also showed agreater effect on muscle strength when compared to the exer-cise group. These three studies were providing a high amountof protein with, respectively, 45, 40, and 15 g (collagen pep-tide) daily whereas the mean dose of supplementation in otherstudies was approximately 20 g/day. The dose of supplemen-tation is likely to contribute to the inconsistent findings be-tween studies. Handgrip strength, a component of sarcopeniadefinitions, was an outcome in 13 RCTs assessing the effect ofa combined exercise and dietary intervention. Approximatelyhalf of the studies (6/13 RCTs) showed an improvement ingrip strength with exercise. However, none of these RCTsshowed an additional effect of dietary supplementation.Highlighted by these last results, it should be noted that, evenif this systematic review revealed an increase of musclestrength following exercise in the majority of the studies, thisseems particularly true for leg muscle strength.

A total of 29 RCTs also assessed the impact of combinedphysical activity and dietary supplementation on physical per-formance. We observed, in the majority of studies, an im-provement in physical performance outcomes following anexercise intervention (26/28 RCTs, 92.8%). In the two studiesthat did not report an improvement on physical performance,one was performed on frail people and the other one on hos-pitalized people. Physical performance was assessed using avariety of measures in the reported studies. The most com-monly used measures were gait speed (used in 17 RCTs),followed by chair stand test (used in 13 RCTs), Timed Upand Go test (used in 8 RCTs), and SPPB test (used in 6RCTs). The heterogeneity of both the type of exercise inter-vention and physical performance outcomes impedes generalstatements of findings on the association between exercisetraining and improvements in physical performance.Interaction of exercise and nutrition was found in only17.8% of these studies (5/28 RCTs): one study when amulti-nutrient was used as a dietary supplement, another withcreatine, a third study with vitamin D, another with tea cate-chin, and finally, one with magnesium oxide.

This study is an update of an existing systematic reviewand it followed the same rigorous methodology as the previ-ous one. We searched multiple electronic databases to identify

1830 Osteoporos Int (2017) 28:1817–1833

as many studies as possible that would meet our inclusioncriteria. Nevertheless, this review is limited by the disparitybetween the studies. The exercise interventions described inthe RCTs varied in regards of the types of exercises, doses,intensity, and duration. Moreover, adherence to these proto-cols were not reported, which impacts the assessment of thereal effect of exercise on muscle features. Supplementationsprovided also varied, not merely for the dosage, but also forthe duration, the way, and the frequency of administration. Itmust also be noted that half of these studies were not doubleblinded. These parameters are likely to be key factors in mod-ulating the outcomes of studies investigating the potentialbenefit of dietary supplementation to further augment gainsin muscle mass and strength during exercise training.Moreover, the majority of individual RCTs did not take intoaccount the baseline nutritional status of the population. Itmakes perfect sense that elders, close to undernutrition insome of the dietary supplements presented, failed to respondproperly to exercise training meant to increase their musclemass and strength. Even a reasonable dose of the supplementmay be insufficient if participants are very sick, frail, and/ormalnourished at baseline. In the same vein, even if exercisecould have a positive effect, nutritional supplement may notbe effective in very healthy, fit, and/or vigorous elderly.Nutrition supplementation is likely to be more efficient if mal-nutrition is present. The specific elderly subpopulation shouldbe regarded when evaluating the need for nutritional supportduring exercise training. Finally, even if our purpose was toassess combined effects of exercise training and dietary sup-plementation on muscle outcomes in sarcopenic subjects, avery limited number of included studies have been performedspecifically on subjects affected by sarcopenia. Because of thecondition of sarcopenic patients, it is likely that the effectsobserved in this systematic review would have been lesser insolely sarcopenic patients. It was however difficult for thisstudy to focus only on sarcopenic subjects. Indeed, there areno universally accepted criteria for the diagnosis of sarcopeniain an operational sense. Therefore, we chose to focus on el-derly subjects in a broader sense instead of focusing on one ormore restricted definitions of sarcopenia.

In conclusion, physical exercise has a beneficial impact onmuscle mass, muscle strength, or physical performance inhealthy subjects aged 60 years and older. However, the addi-tional effect of dietary supplementation has only been reportedin a limited number of studies. For the majority of studiesincluded in this systematic review, the population was com-posed of healthy older subjects. Studies assessing the impactof a combined exercise intervention and dietary interventionare still lacking in frail and sarcopenic populations, popula-tions suffering from nutritional deficiency, or populations atrisk of malnutrition. Further well-designed and well-conducted studies performed on these types of populationsshould be implemented. It seems likely that nutritional

interventions in populations who are presenting nutritionalor physical deficiencies would be more beneficial than inter-ventions in well-nourished and replete populations. There is aneed of a rigorous documentation of subject’s baseline exer-cise level and nutritional status prior to implement interven-tion regimens in those future studies.

Compliance with ethical standards

Conflict of interest N Binkley received research support from Amgen,GEHealthcare, and Lilly, Merck and consultant/advisory board fees fromAmgen, Astellas, Lilly, Merck, Nestle, and Radius. J-Y Reginster re-ceived consulting fees or paid advisory boards from Servier, Novartis,Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle,Nycomed-Takeda, NPS, IBSA-Genevrier, Theramex, UCB, AsahiKasei, Endocyte, and Radius Health; lecture fees from Merck Sharpand Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier,Roche, GlaxoSmithKline, Merckle, Teijin, Teva, Analis, Theramex,Nycomed, NovoNordisk, Ebewee Pharma, Zodiac, Danone, WillPharma, Amgen, and PharmEvo; and grant support from Bristol MyersSquibb, Merck Sharp & Dohme, Rottapharm, Teva, Roche, Amgen,Lilly, Novartis, GlaxoSmithKline, Servier, Pfizer, Theramex, Danone,Organon, Therabel, Boehringer, Chiltern, and Galapagos. ML Brandi isa consultant and grant recipient from Alexion, Abiogen, Amgen, BrunoFarmaceutici, Eli Lilly, MSD, NPS, Shire, SPA, and Servier. C Beaudart,A Dawson, S Shaw, N Harvey, JA Kanis, R Chapurlat, D Chan, OBruyère, R Rizzoli, C Cooper, EM Dennison, G Adib, T Chevalley, PClark, B Dawson-Hughes, A El Maghraoui, K Engelke, R Fielding, JFoldes, G Guglielmi, JM Kaufman, B Larijani, W Lems, L van Loon,G Lyritis, S Maggi, L Masi, E McCloskey, ODMessina, A Papaioannou,P Szulc, and N Veronese have nothing to declare.

Appendix

the IOF-ESCEO Sarcopenia Working GroupG. AdibM. L. BrandiT. ChevalleyP. ClarkB. Dawson-HughesA. El MaghraouiK. EngelkeR. FieldingA. J. FoldesG. GugliemiJ. M. KaufmanB. LarijaniW. LemsL. J. C. van LoonG. P. LyritisS. MaggiL. MasiE. McCloskeyO. D. MessinaA. PapaioannouP. SzulcN. Veronese

Osteoporos Int (2017) 28:1817–1833 1831

Open Access This article is distributed under the terms of the CreativeCommons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncom-mercial use, distribution, and reproduction in any medium, providedyou give appropriate credit to the original author(s) and the source, pro-vide a link to the Creative Commons license, and indicate if changes weremade.

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