REVIEW
Nutrition and physical activity in the prevention and treatment
of 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
# The Author(s) 2017. This article is published with open access at Springerlink.com Abstract
Summary This systematic review summarizes the effect of combined exercise and nutrition intervention on muscle mass and muscle function. A total of 37 RCTs were identified. Results indicate that physical exercise has a positive impact on muscle mass and muscle function in subjects aged 65 years and 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 and nutrition intervention to improve muscle mass, muscle strength, or physical performance in older people. They concluded that further studies were needed to
pro-vide epro-vidence upon which public health and clinical recommendations could be based. The purpose of the present work was to update the prior systematic review and include studies published up to October 2015. Methods Using the electronic databases MEDLINE and EMBASE, we identified RCTs which assessed the combined effect of exercise training and nutritional supplementation on muscle strength, muscle mass, or physical performance in subjects aged 60 years and over. Study selection and data extraction 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 of protocols 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 of the IOF.
* C. Cooper cc@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 of Sheffield, Sheffield, UK
4 Institute for Health and Aging, Catholic University of Australia, Melbourne, Australia
5
University of Wisconsin Osteoporosis Clinical Center and Research Program, 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 Taiwan University Hospital, Taipei, Taiwan
9
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
10 Superintendent’s Office, National Taiwan University Hospital Chu-Tong Branch, Hsinchu City, Taiwan
11
Service of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
12
NIHR Musculoskeletal Biomedical Research Unit, Institute of Musculoskeletal Sciences, University of Oxford, Oxford, UK DOI 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 8 RCTs (23.5%). Muscle strength increased in 82.8% of the studies (29/35 RCTs) following exercise intervention, and di-etary supplementation showed additional benefits in only a small number of studies (8/35 RCTS, 22.8%). Finally, the majority of studies showed an increase of physical perfor-mance following exercise intervention (26/28 RCTs, 92.8%) but interaction with nutrition supplementation was only found in 14.3% of these studies (4/28 RCTs).
Conclusion Physical exercise has a positive impact on muscle mass and muscle function in healthy subjects aged 60 years and older. The biggest effect of exercise intervention, of any type, has been seen on physical performance (gait speed, chair rising 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 Group on Sarcopenia in Older People as a progressive and general loss of muscle mass and muscle function (defined either by a low muscle strength or a low physical performance) with advancing age [1]. Even though the loss of both is a natural part of the aging process, sarcopenia is defined when muscle mass and function falls below defined thresholds. Diagnosis of sarcopenia requires, therefore, the measurement of muscle mass, muscle strength, and physical performance [2]. Sarcopenia is recog-nized as a major public health problem [3,4] due to significant clinical, economic, and social consequences. The implementa-tion of preventive and therapeutic intervenimplementa-tions has become a challenge due to the growing number of older persons affected by sarcopenia and its disabling complications.
Physical activity and nutritional supplementation have been 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/or dietary supplementation on sarcopenia. Results indicated that most exercise trials showed an improvement of muscle strength and physical performance with physical activity, pre-dominantly resistance training interventions. Results were consistent regarding the effect of dietary supplementation on muscle mass. Some studies have suggested a role of proteins, β-hydroxy β-methylbutyric acid, or amino acid on muscle function. 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 two interventions. For this reason, Denison et al. [6] conducted a systematic review in 2013 to determine the effect of combined exercise and nutrition interventions on muscle mass, strength, and function in older people. That systematic review com-prised 17 studies involving older (≥ 65 years) adults published up to April 2013. The authors concluded that further studies were required to provide adequate evidence on which to base public health and clinical recommendations. The purpose of the present work was to provide an update to that systematic review by including studies published up to October 2015, and to focus on whether additional benefits arose if dietary supplementation was combined with exercise training.
Methods
Literature search
The literature search was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. Using MEDLINE/Ovid and EMBASE/Ovid, we identified randomized controlled studies (RCTs) which assessed the combined effect of exercise training and nutritional supplementation on muscle strength, muscle mass, or physical performance. We updated the paper by Denison et al. [6] which limited the search strategy to February 2013. Therefore, we searched for any additional stud-ies published between April 2013 and October 2015. The search strategy and search terms that were used for this research are detailed in Table1. Additional studies were identified by a man-ual search of bibliographic references of relevant articles and existing reviews. Conference abstracts were not included.
Study selection
In the initial screening stage, two investigators independently reviewed the title and abstract for each of these references to exclude articles irrelevant to the systematic review. Rigorous inclusion criteria were adhered to (Table2). In the second step, the two investigators independently read full texts of the arti-cles not excluded in the initial stage, then selected the studies meeting the inclusion criteria (Table 2). All differences of opinion regarding selection of articles were resolved through discussion and consensus.
In order to maintain consistency between this update and the previous systematic review, the same inclusion criteria were used [6]. No age restriction was included in the search strategy but this review focused only on subjects aged 60 years and older. Studies performed on children, adolescents, and young adults were therefore excluded. Studies in which the nutritional intervention was energy restriction to promote
weight loss were also excluded. Finally, studies were also excluded if they included populations with a specific health condition (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 who completed the study, adverse events, protocol of exercise in-tervention, protocol of nutritional inin-tervention, muscle mass outcomes, muscle strength outcomes, and physical perfor-mance outcomes.
Methodology quality assessment
The quality of each study was independently assessed by two authors using the Jadad Score [7] system. The Jadad score Table 1 Search strategy (application to MEDLINE Ovid and
EMBASE) 1. Sarcopenia/ 2. Sarcopeni$.tw 3. Muscle atrophy/ 4. Muscle weakness/ 5. Fat free mass.tw 6. Lean body mass.tw 7. Muscle mass.tw 8. Exp hand strength/ 9. Grip strength.tw 10. Anthropometry/ 11. Body composition/ 12. Lean mass.tw 13. Or/1-12 14. Exp exercise/ 15. Exp Movement/ 16. Muscle contraction/ 17. Muscle Development/ 18. Physical exertion/ 19. Exp Physical endurance/ 20. Exp muscle strength/ 21. Physical fitness/ 22. Exp Exercise test/ 23. Exercise therapy.tw
24. Exp Exercise movement techniques/ 25. Exp Psychomotor performance/ 26. Muscle contraction/ 27. Resistance exercise.tw 28. Aerobic exercice.tw 29. Endurance.tw 30. Physical exercise.tw 31. Physical performance.tw 32. Physical training.tw 33. Exercise programme.tw 34. Exercise technique.tw 35. Muscle mass.tw 36. Or/14-35 37. Nutrition.tw 38. Exp nutrition therapy/
39. Exp Nutritional physiological phenomena/ 40. Exp Diet/
41. Exp Diet therapy/ 42. Exp Dietary fats/ 43. Exp Dietary proteins/ 44. Exp Food/ 45. Exp Food, fortified/ 46. Exp Micronutrients/ 47. Exp Dietary supplements/ 48. Energy intake/
49. Nutrition.tw 50. Nutrition trial.tw 51. Dietary lipids.tw 52. Or/37-51
53. Randomized controlled trials/ 54. Randomised controlled trial.tw 55. Randomized controlled trial.tw 56. Controlled clinical trial/ 57. Controlled study.tw 58. Random allocation/ 59. Random$.tw 60. Randomly allocated.tw 61. Double blind method/ 62. Single blind method/ 63. Clinical trials.tw 64. Clinical trial/ 65. Trial$.tw 66. Intervention studies/ Table 1 (continued) 67. Intervention study.tw 68. Interventional study.tw 69. Placebo.tw 70. Placebo$.tw 71. Or/53-70 72. And/36,52 73. And/13, 71, 72
74. (73 and humans/) or (73 not (humans/ or animals/)) 75. Limit 74 to English language
76. Limit 75 to yr. =B2013-Current^ (344 results on PubMed (308 after deleting 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 of
comparison: a control group with only exercise intervention and a treated group with combined exercise intervention and nutritional intervention. Exercise intervention can be resistance exercise, aerobic exercise, or other. Nutrition intervention involves the provision of nutrients supplied with either 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 and end of October 2015
ranges from 0 to 5 points. Studies were considered to be of excellent quality if the score was 5, good quality if the score was 3 or 4, and poor quality if otherwise.
Presentation of results
The findings were evaluated in a descriptive manner based on the information provided by each of the included studies. Because of the huge heterogeneity observed in the protocols of exercise and dietary supplementation, no meta-analysis was undertaken.
Results
Included studies
A total of 993 references were identified through the database search. A manual search of the bibliography of 10 relevant systematic reviews and meta-analyses did not generate any further studies for inclusion. After reading all titles and ab-stracts, 36 RCTs were selected for full-text review, following which 21 were included in this systematic review update. These 21 studies, added to the previous 17 considered by Denison et al. [6], gave a total of 37 RCTs included in the current systematic review (Fig.1).
Characteristics of the studies are shown in Table3. Twelve studies were performed in Europe, 11 in the USA/Canada, 7 in Asia, 4 in South America, and 3 in Australia. The number of participants ranged from 17 [35] to 222 [26] and study dura-tion ranged from 4 weeks [27] to 18 months [42,43]. The majority of studies included both male and female participants but 10 studies were confined to women only and 5 included only men. The mean age of participants varied from 59.5 ± 4.5 years [9,10] to 87.1 ± 0.6 years [39,40]. Twelve RCTs were graded on the Jadad Scale as having an excellent quality, 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 other group receiving exercise only (with placebo or no interven-tion). Eleven other studies used a four-group comparison model with one control group with no intervention, one group with 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 into three groups comprising a control group with no intervention, a group with exercise only, and a group with exercise bined with nutrition. Finally, one study used a five-group com-parison model that included two groups with exercise and nutrition 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 noted that only half of the studies were double blinded.
Regarding nutritional interventions, 10 of the 37 studies used proteins. One further study used protein combined with essential amino acids, a second used protein combined with vitamin D, and a third used protein combined with creatine. Three studies used essential amino acids alone, five studies used creatine alone, three studies used β-hydroxy-β-methylbutyrate alone, and two used vitamin D alone. Of the remaining 12 studies, five used multi-nutrient supplements and six used other products (vitamin and mineral-enhanced dairy and fruit products, green tea, magnesium oxide, milk fat globule membrane, soy isoflavones, and tea catechin). For exercise, the majority of studies used resistance training with the remainder using multicomponent training involving both resistance and additional exercises such as walking, fit-ness, aerobics, balance, etc.
Types of nutritional intervention
Results of the interventions are summarized in Table4. Fig. 1 Flow chart of literature search
Protein supplementation
Thirteen individual studies assessed the impact of a combined protein supplement and exercise intervention on the muscle function of elderly people. Most of these studies were of good quality but four were of poor quality [12, 24,26, 29]. In three of the 13 studies, protein was combined with creatine [12], essential amino acids [24], or vitamin D [26]. Supplementation protocols were heterogeneous in terms of studied population, duration of study, and supplementation dose, which varied from 7.4 to 45 g of protein per day. Twelve studies assessed the effect of the interventions on mus-cle mass and/or musmus-cle strength but only nine reported results on physical performance.
Muscle mass: Muscle mass increased significantly with exercise in 11 of the 12 included RCTs. An interactive effect of protein supplementation and exercise was reported in only three of these studies: one looked at frail individuals [33], a second has been performed in elderly sarcopenic men [25], and the third enrolled female retirement village residents whose protein supplementation was lean red meat [22]. One other study [8] reported an increase of fat-free mass and ap-pendicular lean mass only in the group supplemented with protein and exercise but the difference between the groups was not described. Muscle strength: All studies showed a sig-nificant improvement of leg muscle strength with exercise. No additional effect of protein was seen in the majority of these studies with the exception of three studies, each one of excel-lent quality: Daly et al. [22] showed significant improvement in leg extension in the group receiving lean red meat (45 g of protein/day) and exercise compared to an exercise-only group and Chalé et al. [17], who showed greater improvement in knee extensor peak power after a supplementation of 40 g of protein/day and, finally, Zdzieblik et al. [25] reported that quadriceps strength of the right leg (effect on the left leg was not assessed) increased more in the group taking 15 g of col-lagen peptide as supplement/day. Improvement in handgrip strength was seen in one study [33] but was absent in three others [20,24,29]. Finally, one study [8] reported an increase of the 1 repetition maximum (1RM) knee extensors only in the group with protein combined with exercise; however, the dif-ference between the two groups was not reported. Physical performance: All studies showed a significant improvement of at least one physical performance test with exercise. No studies showed a significant difference between the groups receiving exercise only compared to the group receiving ex-ercise combined with protein.
Summary: Muscle mass increased with exercises in 11/12 RCTs but an additional effect of protein was found in only 3/ 12 RCTs; Muscle strength increased with exercises in 12/12 RCTs 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 of protein.
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 older adults recruited from nursing homes and adult day-care centers [27], and 12 g/day for 12 weeks in older men [35]. One study was of poor quality [35]. All three assessed the effect of intervention on muscle mass and muscle strength and two also measured the effect on physical per-formance [27, 36].
Muscle mass: Two studies reported an increase of muscle mass with exercise but did not report any difference between the group receiving EAA supplements and the group who did not [35,36]. The third study did not report any increase of muscle mass, neither for subjects receiving exercises only, nor in the groups of subjects receiving a combination of exercise and EAA supplements [27]. Muscle strength: Knee extension increased with exercise in two studies but no interaction was found with EAA supplementation. In the third study, no effect on isometric leg strength was observed [27]. Physical performance: Walking speed [36] and timed up and go [27] tests improved with exercise with no additional effect of EAA supplements. Standing balance and chair-stand test did not improve with treatment [27].
Summary: Muscle mass and muscle strength increased with 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 effect of EAA.
β-hydroxy-β-methylbutyrate (HMB) supplementation Three studies of good quality used Ca-HMB [13,16,37] as a 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 the first two studies [13, 37] and healthy adults confined to complete bed rest for 10 days for the latter [16]. All studies assessed the effect on muscle mass and muscle strength but only 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-free mass significantly increased with exercise in one study but no difference was evident between the group with combined exer-cise + Ca-HMB and the group with exerexer-cise only [13]. Moreover, a significantly greater increase in fat-free mass was
Ta b le 3 C h ar act er isti cs of inc lude d studie s Referen ce S ettings, study participants, me an age ± SD Study des ign Exercise training intervention Nutr itional supp lement Outcome m easures Q u ality score (J ada d scal e) Grys on et al . 2014 [ 8 ] F ra nce. 35 health y sedentary men 60.7 ± 0.4 y ears 16-week int er v en tio n. P arti cipant s ra n domized in 5 group s: (i) no ex er cise + p lace b o , (i i) exercise + placebo, (iii ) ex er ci se + fo rtifi ed m ilk, (iv ) no exercis e + fort ified leucine, (v) exercise + fortif ie d leucine. T reatments w er e ad m inis trated doub le bli n d Resistance and aerobic exercises.3 sess ions p er w eek, non -c o nsecuti ve days , 45 –6 0 mi n fo r ea ch se ss io n P rot ein. Milk -based suppl em ent drinks con taini ng, prot ei ns (to tal m ilk prot eins 10 g/ day or fa st digest ed solu ble m ilk p ro teins 10 g /day), carbohydrat es , and fat . P lac ebo d rinks cont ains 4 g of to ta l m il k p ro tei n MM : app en dicul ar m uscl e m ass and fat-free m ass in the domin an t legMS: is om et ric streng th of the knee extenso rs 4 Lebo n et al . 2 014, [ 9 ] Choquet te et al . 2 013 [ 10 ] Canada. 34 post m enopausal women 59.5 ± 4.5 y ears 6-m o nth in terventi on. Pa rt icip an ts ra n domized in tw o groups: (i) ex er ci se an d isofl avone, (ii) exercise an d p lacebo. T reatments w ere ad m inis tered doubl e bl ind Combined aerobic and resistance trai ning , 3 ses sion s per w ee k (1 h, 30 min of aerobic, 30 min of resistance) Other (soy isoflavo nes). 4 ca ps ules daily w ith ei ther soy is oflavon es or pl ac ebo . The 70-mg dai ly dose of is ofl av ones contai ned 4 4 m g of daidzein, 16 mg of glyci tein, and 10 mg of genis tein ex tracted from natural so y. P lacebos cont ained ce ll ul ose MM : w ai st and h ip circumfere n ce , muscle mass ind ex M S : grip st re n g th, 1 RM (l eg pres s, bench press, la t pull down) PP: chair st an d te st 5 Gualano et al. 2 014 [ 11 ] B razil. 6 0 v u lnerable older w o m en . T rea te d 67.1 ± 5.6 years/co ntrol 63.6 ± 3.6 y ears 24-week int er v en tio n. P arti cipant s were ra n domized in four gro ups: (i ) placebo, (ii) creatine, (iii) plac eb o + ex er ci se , (i v ) cr ea ti n e + ex er ci se . T rea tm en ts were admin ist er ed d ouble blin d Supervised re si stance tra inin g . T wo sess ions p er w eek C reatine. Supp lements p ackages 20 g /day of creati ne m ono hydrate for 5 days divi ded into four eq ual doses, fol lowed by si ngl e dai ly doses of 5 g for the next 2 3 w eek s. Pl ace b o w as d ex tr o se MM :a ppendi cu lar lean mass MS :l eg press, bench press P P : ti m ed-s tands te sts., T im ed up and go test 4 V il lanueva et al . 2014 [ 12 ] U SA . 2 2 h eal th y m en , re cr ea tio n al ly acti v e 68.1 ± 6.1 y ears 12-week int er v en tio n. P arti cipant s were ra n domized in th re e group s: (i) exer -ci se + creatine an d protein suppl em ent atio n, (i i) exercise onl y, (iii ) co ntrol . T rea tme n t admini strat ion was not dou ble bli nded Resist ance traini ng. 3 sessi ons per w eek P rot ein + crea ti ne. S uppl em ent ed group (encapsul at ed powder) co nsumed 0.3 g/kg/ day of cr eatine for 5 day s follo wed by 0.07 g/kg/ day u ntil compl et ion of the stu dy . T he suppl em ent ed group also con sumed one 35-g liq uid prot ein ready-to-d rink dai ly MM : lea n b ody ma ss MS : leg press, chest p ress, strength en durance. PP : stair cli m bing po wer , dynamic pow er , 400-m w alk 2 Stou t et al . 2013 [ 13 ] U S A . 4 8 am b u latory p articipants (2 2m ena n d2 6w o m en ) 73 ± 1 years 24-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er cise + p lace b o , (i i) exercise + HM B . T reatments w ere administered doubl e bl ind Supervised re si stance tra inin g . T hree sess ions p er w eek β -h ydroxy-β -methy lbut hyrate.Ca H -M B (HMB , 1 ,5 g C aHMB + 4 g ca rbo hydrate) twi ce d ai ly . P lac eb o (2 0 0 m g calciu m + 4 g ca rbo hydrates) twice daily .Partic ip ants we re asked to m ix their p ro duct in n on-alcohol ic bevera g es an d d rink it MM : total lean mass, re g inal leg lean mass, regional arm lean massMS: handgri p strengt h, leg extens ion, bench p ress, leg p res s, leg extens ion strengt h. PP :G et up and Go 5 Okazaki et al. 201 3 [ 14 ] Japan. 3 5 h ealthy m iddle-aged an d o lder women. T reated 60 ± 3 years/cont rol 61 ± 3 years 5-m o nth in terventi on. Pa rt icip an ts were ra n domized in tw o groups: (i) ex er cise only , (ii) exercise + post -e xerci se macronut rient . T rea tm en t adminis trati on w as not doubl e bl inded Home-based interval walking tra in ing . 4 or more days per w ee k M u lt i-nutri en t (ma cr un utrient m ixture). 215 g of a m acronu trient mi xture w it hi n 30 min after each training session (c o m p o sit ion 20 0 k cal ; 7 ,6 g protei n ; 32,5 g CHO ; 4,4 g fat ) MM : total musc le tissue ar eaMS: is om et ric knee ex tensi on, is om et ric knee fl exion , isoki netic knee extensi on, iso kinet ic knee flexion 2 Narot zki et al. 2013 [ 15 ] Israe l. 13 elderly m en and 9 el derly w omen. 71.1 ± 1.2 y ears 12-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er ci se + g re en tea an d v it am in E , (ii) exercise + vitam in E only . T rea tm en t adminis trati on w as not doubl e bl inded Fit ness-gui ded ex er cises. 6 times a week. 30 min of dail y walks Other (green tea). P articipants w ere as ked to b rew tea sachets 3 times a day in 240 ml of boi li ng water for 3 m in. O ne v itamin E capsule co m p osed of 400 IU of d-alpha-to copherol a day . Placebo group di d n ot drin k tea and co nsumed a caps ule of vit am in E placebo a d ay MM : w ai st and h ip circumfere n ce 2
Ta b le 3 (c onti nue d) Referen ce S ettings, study participants, me an age ± SD Study des ign Exercise training intervention Nutr itional supp lement Outcome m easures Q u ality score (J ada d scal e) Deut z et al. 201 3 [ 16 ] U S A . 2 4 o ld er adul ts confi n ed to co m p le te b ed rest fo r 1 0 d ay s. Tr ea te d 67.4 ± 1.4 years/co ntrol 67.1 ± 1.7 y ears 8-week intervention . P artic ipants w ere ra n domized in tw o groups: (i) ex er cise + H M B , (ii) exercise + placebo. T reatments w ere ad m inis tered d ouble bl ind. T ests w er e perf o rm ed b efore b edrest, afte r bed re st , and after the 8 w ee k s of re h ab ili tati on Resistance exercise training rehabil it at ion . 3 days per w eek. Strengt h traini ng duri ng 1 h β -h ydroxy-β -methy lbut hyrate. 2 sachets o f C a-HM B p er day . Each sachet contained 1 .5 g o f Ca-HMB, 4 g m alto dextrin , and 200 m g calci um. T he co mp o si ti o n o f p la ce b o w as ident ical wit h the exclus ion of Ca -H M B MM : lea n b ody ma ss MS : knee extension, flexo r force, leg p ress, st an ding pl antar flexor force, an d st ai r as ce n t and descent power . PP :S P P B tes t, Get up and Go te st, 5-it em SPP B 5 Chalé et al . 2013 [ 17 ] U S A .8 0 m o b ili ty -l im it ed w o men ag ed 7 0– 85 years. T rea te d 78.0 ± 4.0 years/co ntrol 77.3 ± 3.9 y ears 6-m o nth in terventi on. Pa rt icip an ts ra n domized in tw o groups: (i) ex er cise and p roteins, (ii) exercise and is o cal ori c co n tro l. T re atm en ts w ere ad m inis tered doubl e bl ind Supervis ed progres sive p rogram. 3 ti mes per w eek which entailed leg press, seated row , leg ext en sion , chest press and leg curl P rot ein (whey prot ein). W hey prot ei n in powd er form 40 g/day (on e serving con tains 2 0 g prot ein, 25 g m alt odext rin, 1 g fa t, 189 kcal) Isocalori c cont rol in powder form (45 g m alt odext ri n, 1g fa t, 1 8 9k ca l) MM : lea n m ass, total m usc le CS AM S : Le g p re ss , k ne e extens ion st rength, peak power PP : S ta ir climbing, chair rise performance , SPP B test, 4 0 0 m walk ti me 5 Ki m et al. 201 3 [ 18 ] Japan. 128 comm u nit y-dwell ing el derly sarcopeni c w ome n T rea te d 81.1 ± 3.7 y ears /contro l 79.6 ± 4 .2 years 3-m o nth in terventi on. Pa rt icip an ts were ra n domized in four gro ups: (i ) ex er cise an d tea catechin, (ii) exercise only , (ii i) tea ca te ch in onl y, (i v) h ea lth ed uca tion , cont rol. T reatments w ere ad m inis tered doubl e bl ind Stretchi ng, muscle st re n gtheni ng, balance and gait traini ng. T w o sess ions p er w eek. E ach sess ion 60 mins Other (tea catechin). One bottle p er day co ntain ing 350 mL of tea fortified w ith 540 m g o f catechin MM : lea n b ody ma ss , appendicul ar lean mass and leg muscle mass MS : grip st re n gth, knee extens ion str en g th PP : u sual and m aximum walking speed, T UG, b al ance abil ity 4 Agu iar et al. 2 013 [ 19 ] B ra zi l. 18 he alt h y w om en 64.9 ± 5.0 y ears 12-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er cise + creatine, (ii) exercise + placebo. T reatments w ere ad m inis tered doubl e bl ind Resist ance tr aini ng. Three sessi ons per week. T he trai ning vo lume was prog re ss ive th roughou t the train ing prog ra m C reatine. One capsule (5.0 g/day). The p lacebo g roup ingeste d an ident ical-lo oking equ ivalent am ou nt of placebo, malto dextrin MM : appendicul ar m uscle m ass M S : bench press, knee extens ion, biceps curl st re n gth P P : 30-s chair st an d and arm curl tes t and a test of gett ing up from lyi ng on th e floo r 4 Leenders et al. 201 4 [ 20 ] T he N etherlands . 2 9 hea lt hy el d er lym ena n d2 4h ea lt h y el derly w omen 70 ± 1 years 24-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er cise + p lace b o , (i i) exercise + protein . T re at m ent s were ad m inis tered doubl e bl ind Supervised re si stance tra inin g . T hree sess ions p er w eek P rot ein. 250 ml beverages p er day . P rotein b everages conta ins 15 g of protein , 0.5 g fat, 7.13 g lactose , 0.42 g calciu m . P lacebo bevera g es co ntain no p ro tein or fa t, 7.1 3 g lacto se, 0.42 g ca lcium MM : total b ody lean ma ss , leg lean mass, quadriceps C SA M S : leg press, le g ext ensio n, h an dgrip test P P : sit-t o-st an d test 3 V eronese et al. 2014 [ 21 ] Italy . 139 healt hy elderl y women. 71.5 ± 5.2 y ears 12-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er ci se + m agnesi um oxide, (ii ) ex er cise only . T reatment ad m inis trati on was not do uble blin ded Mil d fi tness program. T w o sessi ons per week Other (magnesiu m oxi de)sachets. 900 m g /d of oral magnesiu m oxide correspon ding to 300 m g bioavai lable magnesiu m MM : app en dicul ar sk el etal m uscl e mass ind ex M S : is ometric knee extens ion, handgri p streng th PP : SP P B test 3 Daly et al. 2 0 1 4 [ 22 ] A ust ra lia. 100 women residi ng in re ti rement vi llages. T reated 72.1 ± 6.4 years/co ntrol 73.6 ± 7.7 y ears 4-m o nth in terventi on. Pa rt icip an ts were ra n domized in tw o groups: (i) ex er cise + meat, (ii) ex ercise only . T rea tm en t adminis trati on w as not doubl e bl inded Supervis ed progressi ve re si st ance and balance-agi lit y traini ng program. 2 sess ions p er w eek P rotein (lean red me at). 2 20 g lean re d m eat to b e cons ume d 6days/ w ee k = 16 0 g cook ed m eat/ day (45 g protei n). C ont rol 75 g cook ed rice and/or past a/ day (that prov ides 25 –35 ca rbo hydrates/ day) MM : lea n ti ssue m ass M S : le g extens ionPP: 4-squ ar e st ep test, T im edU pa n d G o ,3 0 -s si t-to-s tand tes t 5 Cooke et al. 2014 [ 23 ] A ust ra lia. 20 m iddl e to older ma les T rea te d 61.4 ± 5.0 years/co ntrol 60.7 ± 5.4 y ears 12-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er cise + C HO, (ii) exer cise only . T rea tm en ts were admin ist er ed d ouble blin d Hi gh-int ensi ty resis tance traini ng prog ra m. 3 d ays p er week C reatine m o nohydrat e-carboh ydrates. T rea te d g roup 20 g o f C rM co m b ined wit h 5 g of g lucose for 7 d ay sf o ll o w edb y0 .1 g k g − 1 (a v er age dos ag e of ∼ 8.8 g ) o f C rMw it h5 go fg lu co se o n MM : fat-fre e m ass M S : leg p ress, bench p ress 4
Ta b le 3 (c onti nue d) Referen ce S ettings, study participants, me an age ± SD Study des ign Exercise training intervention Nutr itional supp lement Outcome m easures Q u ality score (J ada d scal e) training days. P lacebo 20 g of glucos e on ly for 7 d ays foll owed by 5 g of g lucose on traini ng days Oesen et al. 201 5 [ 24 ] Italy . 8 2 o ld er adul ts li vi ng in re ti rement care facilities 82.8 ± 6.0 y ears 6-m o nth in terventi on. Pa rt icip an ts were ra n domized in th re e group s: (i) ex er cise only , (ii) exercise + nutrient suppl em en ta tio n, (i ii ) cogn iti ve traini ng group. T reatment ad m inis trati on was not do uble blin ded Supervised re si stance exercise with elast ic band. T w o sess ions per w ee ks on non -c o nsecutive d ay s (separately min 48 h) P rot ein and essent ial amino acid s. T w o nutri ent sup plement drin k per d ay . E ach drin k h ad a caloric value of 150 kcal, 20.7 g protei n (3 g le u cine, > 10 g essential am in o aci d s) , 9 .3 g ca rbo hydrates, 3 g fat, vit am ins an d m in erals MS : knee ext en sor p eak to rque, k n ee flexor peak to rq ue, h an dgrip str en g thPP: chair sta n d test, g ait speed, si x-m inut e w al king te st, functional reach test, arm lifting test 2 Zd zi ebli k et al . 2 015 [ 25 ] G er ma n y. 5 3 el d er ly me n w it h sarcopenia. 72.2 ± 4 .68 12-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er ci se + col lagen pept ide, (ii) ex er cise + p lace b o . T rea tme n ts w ere ad m inis tered doubl e bl ind Gui ded train ing program on fit ness devi ce s. Three ses sion s a week over a perio d of 6 0 mi n P rotein (collagen peptide). T re at ed group received 15 g of co llagen pepti d es ea ch day . P lace b o group re ce ived silicon d io xide as placebo. Bo th were given in powder to di ssol ve in 250 ml of water . MM : fat-fre e m ass M S : isok inetic quadri ce ps strengt h of the right leg 5 Y ama d a et al. 2015 [ 26 ] Japan. 222 comm u nit y-dwell ing older adult s (142 women and 80 m en). T reated 76.3 ± 5.9 years/co ntrol 75.8 ± 5.2 y ears 6-m o nth in terventi on. Pa rt icip an ts were ra n domized in th re e group s: (i) walki n g an d nutri tio n, (i i) walk ing only , (ii i) control . T rea tm en t ad m inis trati on was not do uble blin ded Wa lk in g p ro g ra m . U se o f pedometer -based walking p rograms. P artici pants were ins truct ed to in cr ease th e nu m b er of dail y steps by 10% ea ch mont h P rot ein and vi tamin D . D ail y suppl em en ts composed of 200 kcal, 10.0 g of protein w ith branched ch ai n am ino acids 12.5 m g of vitamin D, and 300 m g o f calcium MM : skeletal m us cl e index 2 T rabal et al. 201 5 [ 27 ] S p ai n . 2 4 o lder adul ts in n u rsing homes an d ad u lt day care ce nt ers (16 women and 8 m en). T reated 85 ± 8 years/cont rol 84 ± 4 years 4-week intervention . P artic ipants w ere ra n domized in tw o groups: (i) ex er ci se an d le u ci n e, (i i) ex er ci se only . T reatments w er e admini stered doubl e bl ind Resist ance tr aini ng. Three sessi ons of prog re ss ive resi stance traini ng adapted for ol der adu lts and o ne session o f b ala n ce exercise per w eek Essent ial amino aci d (l eucine). Leucine 10 g/d ay o r the sam e am ou nt of ma lt od ex trin as placebo. Bo th supp lements and placebo w ere accom p an ied w ith a lemon and lime flavor to disgu ise th ec h ar ac te ri st ict as te o f le u ci n e MM : calf circumference, waist circumference . MS: m ax imal is om et ric leg stre n gth. P P : st an ding balance, 4 m walk, chair st an ds test and T UG test 5 Ki m et al. 201 5 [ 28 ] Japan. 130 comm u nit y-dwell ing fr ail w omen. T reated 81.0 ± 2.6 years/co ntrol 81.1 ± 2.8 y ears 3-m o nth in terventi on. Pa rt icip an ts were ra n domized in four gro ups: (i ) ex er ci se an d m il k fat gl obule m embrane, (ii) exercise on ly , (i ii) m ilk fat gl obule m embrane on ly , (iv) hea lth educati on, contro l. T reatments were admin ist er ed do uble bli nd P h y si cal co mp reh en si v e tr ai n in g prog ra m of m oderate int en sit y. E ac h class w as 60 m in, twic e p er week Other (mil k fat g lobul e m em brane). The composit ion w as 2 1 .5% protei n, 4 4% fat, 26.5% ca rbo hydrate, 33.3% phosph oli pids , 6.4 % ash, and 1.6% mois ture. S ix pil ls (1 g of M F GM) ingest ed daily . Th e placebo consisted of pills o f simil ar shape, taste, and text ure an d includ ed m il k powder in stead of M F GM. M il k powd er w as co m p osed of 26.3% pro tein, 25.2%fat , 3 9 .5% carbohydrat e, 0.286 phos phol ipid s, 5.7% ash, an d 3,3% m ois ture MM : app en dicul ar m uscl e m ass, le g muscle mass MS : grip stre n gth, knee extensi on PP : usual wal king speed, tim ed up and g o 5 Shahar et al. 2 013 [ 29 ] M al aysia. 65 elderlies w ith sarcopenia (18 women an d 4 7 m en). 67.1 ± 5.3 y ea rs 12-week int er v en tio n. P arti cipant s were ra n domized in four grou ps: (i) cont rol group, (ii ) exercis e grou p, (i ii ) prot ein suppl em ent atio n, (i v) exerc ise + protein suppl em ent at ion . T reat m ent ad m inis trati on was not do uble blin ded Moderately intens ive, well -r o unded ac-ti vit ies in facil it ated group sess ions . Duri ng 60 min, two sessio ns per week P rot ein (soy p rotein). 20 g/ day an d 40 g /day o f h ig h p rotein suppl em ent atio n in a powder form to men an d wome n , resp ec tively . Con trol gro up did not re ce ived placebo but a relaxation exercise MM : total mus cl e mass and fat-fre e mass MS : h an dgrip st rength , arm curl test PP: chair stand te st , chair si t and re ac h, back scratch, 8-ft and go, 6-min w al k 1
Ta b le 3 (c onti nue d) Referen ce S ettings, study participants, me an age ± SD Study des ign Exercise training intervention Nutr itional supp lement Outcome m easures Q u ality score (J ada d scal e) p ro g ram to ma in ta in in te ract io n an d increase m o ti vat ion Arnars on et al . 2 013 [ 30 ] Ic el an d. 161 health y co m m uni ty-d welli ng men an d women. (9 4 w omen and 6 7 m en) T reated 73.3 ± 6.0/ control : 74.6 ± 5.5,8 12-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er ci se + w hey protein suppl em ent or (ii) exercise only . T reatm ent ad m inis trati on was not do uble blin ded Resistance exercise p ro g ram . Participants exercise d three times p er week P rot ein (whey prot ein). D ri nk (250 m L ) p rovidi ng 20 g protei n, 20 g carboh ydrate, 1 g fat (169 kca l) (int er v en tion ) o r iso-ca loric drin k con taini ng 40 g ca rbo hydrate, 1 g fa t (c o ntrol ) co nsumed immediately after ex-er ci se MM : lea n b ody ma ss , appendicul ar lean m ass MS: quadriceps m uscle st re n gth PP : timed up and go; 6 -m inw al kf o r d is ta n ce 5 Rosendahl et al . [ 31 ] 200 6, Carls son et al. 201 1 [ 32 ] Sw ed en . 1 9 1 o ld er m en an d women in residential care. (139 women and 52 me n ) 84.7 ± 6.5 y ears 3-m o nth in terventi on. Pa rt icip an ts ra n domized to four gro ups: (i ) protein -e n riched drink , cont rol ac tivity , (ii) exercise training + placebo drink , (iii) pro tein-enric h ed drink + exerc ise train ing, or (iv) neither (cont rol activ ity , pl ac ebo drink). T reatment admin ist ration w as not doub le bli nded Hi gh-int ensi ty m ult icomponent exerci se prog ra m, incl udin g res ist an ce exercise training and b alance exercises. Partic ip ants ex er cised five time s p er fortnig h t P rotein (milk-based protein-enriched drink). D ri nk (200 mL), provid -in g7 .4 gp ro te in ,1 5 .7 g ca rbo hydrate, 408 kJ per 100 g. P lac ebo d rink (200 mL) co ntain ed 0 .2 g prot ein, 10.8 g ca rbo hydrate, 191 kJ per 100 g. Drinks of fered w it hin 5 min of ex er ci se sessi on M M: to ta l le an m as sMS : lo w er -l im b muscle stre n g th PP :b alance (Ber g B alan ce Sca le ), g ait ab il it y (2 .4 m ti me d tes t) 3 T ieland et al. 2012 [ 33 ] T he N etherlands . 2 0 fra il old er m en and 41 frail older w omen T rea te d 7 8 ± 9 y ears/control: 79 ± 6 years 24-week int er v en tio n. P arti cipant s ra n domized in tw o groups: (i) ex er ci se + p ro te in su p p le m en ta ti o n or (ii) exercise + p lacebo d rink. T rea tm en ts were admin ist er ed d ouble blin d Resistance-type exercise training. Participants exercised twice per w eek P rot ein. Protei n-suppl em ent ed drink (250 m L ), (1 5 g pro tein, 7.1 g lactose , 0.4 g calcium) and placebo drink (n o p rotein , 7.1 g lactos e, 0.4 g calcium) consu m ed twi ce per day MM : lea n mass M S: leg p ress, leg extens ion, handgrip PP :S PP B test 5 V erdi jk et al. 2009 [ 34 ] T he N etherlands . 2 8 hea lt hy older m en, livi ng independent ly 72 ± 2 y ea rs 12-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er ci se + p ro te in o r (i i) ex erc is e + water . T reatments w er e administe red doubl e bl ind Resistance-type exercise training. Participants exercise d three times p er week in the m orni ng, at sa m e ti me of day P rotein. Protein d rink (10 g casein hydrolysate, 250 mL) o r p lacebo drink (250 mL wat er ) gi ven imme d iately b efore and following ex er ci se sessi ons MM : lea n m ass, leg lean m ass, cross-s ec tional area of quadriceps MS : leg press, leg exten sion 3 God ard et al. 2 0 0 2 [ 35 ] U S A . 1 7 o lder men T re at ed 70.8 ± 1.5/ control 72.1 ± 1.9 12-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er cise + E AA or (ii) exercise with no dietary su pplementat ion (cont rol). T rea tm en t adminis trati on w as not doubl e bl inded Progressi ve knee ext ensor resi stance trai ning pro gram . Partici pants exercised three times p er wee k Essent ial amino aci ds. A mino ac id-contai ning dri nk (400 mL) provid ing 12 g essent ial amino ac ids, 72 g fructose and dext rose; co nsumed immediately after traini ng or at same ti me ea ch day MM : w hole m uscle cross -section al area of rig h t thi gh MS : knee extens ion 1 Ki m et al. 201 2 [ 36 ] Japan. 155 sarcopeni c, co m m uni ty-d welli ng old er women T re at ed 79.5 ± 2.9 years/co ntrol 79,2 ± 2,8 3-m o nth in terventi on. Pa rt icip an ts ra n domized to four gro ups: (i ) E AA, (ii) exercise training , (iii) suppl em ent atio n + exercis e or iv) hea lth educati o n (once p er mon th). T rea tm en t adminis trati on w as not doubl e bl inded Mult icomponent ex er ci se program in cl uding resistance exercise training. Participants exercised twice per w eek Essent ial amino aci ds. P o w dered am ino ac id supp leme n ts provi ded to be taken twice dail y w it h w ater or m ilk, sup plyi ng 6 g es senti al am in o aci d s p er d ay MM : total mus cl e mass MS: knee extension. PP : u sual and maximum w alki ng speed 3 V ukovi ch et al . 2001 [ 37 ] U S A . 1 5 h ea lt hy ol der m en an d16 health y older women 70 ± 1 years 8-week intervention . P artic ipants w ere ra n domized in tw o groups: (i) HM B + exer cise or (ii) a p lacebo suppl em en t + exercis e. T reat m ent s were admin ist er ed do uble-bl ind Mult icomponent ex er ci se traini ng in cl uding re si stance exercises. Participants exercise d 5 days p er week (2 days st re n gth trai ning, 3 days w alk ing and stretchin g) β -h ydroxy-β -methy lbut hyrate. S u p plement capsul es co ntain ed 250 m g Ca-HMB; p ar ti ci pants co nsumed four capsul es , th ree times p er day (3 g /day). Placebo ca psules were identical in ap pea rance, provi ding 3 g /d ay rice flour MM : fa t-free m ass , m u scle area. MS: upper and low er bo dy strengt h 4 Bonnefoy et al . 2003 [ 38 ] 9 -m o n th in terventi on. P ar ticip an ts ra n domized to four gro ups: (i ) Mult icomponent ex er ci se traini ng in cl uding re si stance exercises. M u lt i-nutri en t. Nut ri ti onal dri nks (200 m L ) (p rovidi ng 200 kcal, MM : fat-fre e m ass M S : explos ive leg extension (power). PP : g ait speed, 3
Ta b le 3 (c onti nue d) Referen ce S ettings, study participants, me an age ± SD Study des ign Exercise training intervention Nutr itional supp lement Outcome m easures Q u ality score (J ada d scal e) F rance. 57 frail resi dent in re ti rement homes (50 w omen an d 7 men) 83 years nutri tio nal drink + cont rol acti vity (m em ory), (ii ) exerci se traini ng + placebo drink , (iii) nu tritional drink + exercise trai ning, or (iv ) co ntrol activity + placebo d rink . T rea tm en t adminis trati on w as not doubl e bl inded Participants exercise d three times p er week. T hree wee k ly me m o ry session s served as controls for exercise 15 g p rotein , vi tamins and m inerals) or placebo (prov iding no nutrients) g iven twice d aily si x-step st air climb, chair ris e, balance abnormalit ies Fiataron e et al . 1994, [ 39 ] Fiataron e et al. 199 3 [ 40 ] US A . 1 00 fra il nurs ing home re si dent s, 37 m en and 63 women 87.1 ± 0.6 y ears 10-week int er v en tio n. P arti cipant s ra n domized to four gro ups: (i ) m u lt i-nutri ent supp lementati on, (ii) ex er ci se traini ng, (iii ) suppl em ent atio n + exercis e or iv) neither (cont rol). T reatment ad m inis trati on was not do uble blin ded Progressive re si stance exercise trainin g of hi p and k nee ext en sors. Participants exercise d 3 days p er week. O th er part icipant s of fered alternative recrea ti on al ac tivities M u lt i-n u trie n t. N u tr it io n al suppl em ent provid ed as a dail y drink (240 mL), sup plyi ng 360 kcal, 15 g p rotein and vita m ins and m inerals. P articipants who w ere not suppl em en te d w ere g iv en a m inimall y n utrit ive drink of equal volume (4 kca l) MM : thigh mus cl e area, fa t-free m ass MS : g rip st re n gth, hi p and k nee extensors P P : g ai t speed, stair climb, bal an ce 2 Mil ler et al .2006 [ 41 ] A u st ral ia . 7 9 o ld er w o me n an d 21 older m en hospi tali ze d follo wing a fall -r el ated lower -l imb fracture 83.5 (82.3 –84.7 ) years 12-week int er v en tio n. P arti cipant s ra n domized to four gro ups: (i ) nutri tio nal suppl em en tati on, (ii) ex er ci se traini ng, (iii ) suppl em ent atio n + exercis e or iv) at tent ion cont rol (home visi ts on ly , genera l n utri tion and exercis e advi ce ). T rea tm en t adminis trati on w as not doubl e bl inded Progressive re si stance exercise trainin g prog ra m. Pa rticip an ts exercised three ti me s per w ee k M u lt i-n u trie n t. C o m plet e o ral nutri tio nal supp leme n t prescribed to provi de 45% of ind ivi duall y es ti ma ted en er g y req u ir em en t, ad m inis tered in four dail y doses whil e h ospi tali ze d o r tw o doses af ter d ischar g e home MS : q uadriceps st rength PP: gait speed 3 Bunout et al . 2 0 01, [ 42 ] Bunout et al . 2 0 0 4 [ 43 ] Chi le. 108 communit y-dwell ing poor old er peop le (42 men an d 66 women). T rea ted 73.7 ± 3.0/ control 74.4 ± 3.3 18-month intervent ion. Eval uati on at 12 an d 1 8 m ont hs. P artici pants were ra n domized in tw o groups: (i) ex er ci se + n u tr it io n al suppl em ent atio n o r (i i) exercise but no dietary su pplementat ion. T rea tm en t adminis trati on w as not doubl e bl inded Resistance exercise. P articipants exercised twice per w ee k M u lt i-nutri en t. Nut ri ti onal produ ct (prepare d as a soup o r po rridge, given as tw o daily snac k s), to provid e 40 0 kcal , 13 g prot ein, ∼ 2 5% dail y requirements for m icronutri ents MM : fat -fre e m ass M S : handgrip , quadri ce p s, b iceps st re n gth PP: walking capacity (m) 1 Chin A P aw et al . 2001 [ 44 ], De Jon g et al. 200 0 [ 45 ] The N etherlands . 2 17 frail co m m uni ty-d welli ng old er m ena n dw o m en( 4 5m ena n d 172 women). T reated 78.9 ± 6.0/ control 76.2 ± 4.5 17-week int er v en tio n. P arti cipant s ra n domized to four gro ups: (i ) suppl em ent atio n, (i i) exercise traini ng, (iii ) suppl em en ta tio n + ex er cise or iv) n either (control). T h e nutri tio nal int er v en tio n w as doubl e-b lind ed Mult icomponent ex er ci se traini ng (gradual ly increasi n g int ensit y ). Participants exercised twice per w eek Other (vit amins and m inerals ). S u p p lemented group as ked to co nsume one fruit and on e dai ry product enri ch ed w ith vi tamins an d m in erals p er day . Other participants received same products that were not enri ch ed MM : lea n b ody ma ss , w aist circumference , hip ci rcumfe rence MS : h an dgrip, quad ri ceps str en g th P P : g ait speed, chair rise, balance, flexib ility 4 Binder et al. 1995 [ 46 ] U S A . 2 5 nursin g home resi dents w it h d em en ti a (1 6m en an d9 women). T re at ed 87 ± 4 .4 years/con trol 88.7 ± 6.9 y ears 8-week intervention . P artic ipants w ere ra n domized in tw o groups: (i) ex er cise + calcium carbon at e + vitami n D suppl em ent at ion , or (i i) ex er cise + calcium carbon at e o nly . T rea tm en t adminis trati on w as not doubl e bl inded Mult icomponent but mainl y resistance-typ e exercise . P artic ipants exercised three times p er wee k V itamin D . Intervent ion gro up given bolus dose (orally ) o f 10 0,000 U vit am in D3 at start o f stu dy , then weekly sup plements 50 ,000 U MS : k nee ext ensor , lower extremit y PP : g ai t spe ed , b al an ce 2 Bunout et al . 2 0 0 6 [ 47 ] C hi le. 9 6 comm u nity -dwell ing older m en and w ome n , w ith low v it amin D st atus (86 women, 10 me n ) 7 6 ± 4 yea rs 9-m o nth in terventi on. Pa rt icip an ts ra n domized to receive exerc ise traini ng or no train ing, and furth er ra n domized to receive suppl em en ta tio n (d ouble b li nd) wi th vitamin D /calciu m or calciu m alo ne. Resistance exercise tr aini ng; parti cipant s exercised twice per w ee k V itamin D . C om b ined oral vi tamin D/calci um supplement (400 IU/800 mg) or calcium-on ly suppl em ent (800 m g ) pro vided, to be taken in the eveni ng MM : lea n mass M S: handgri p , quadri ce ps strengt h P P : T UG, SP P B 5
found in men from the placebo group. One study did not show any effect of the treatment on fat-free mass but did show an increase 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 the decline of lean body mass over a period of bed rest compared to exercise only [16]. Muscle strength: Muscle strength increased in two studies with exercise but no additional effect of Ca-HMB was found. In the third study [37], no improvement in upper or lower body strength was found. Physical performance: The two studies showed an improvement in the performance of the Timed Up and Go test with exercise but did not show any added effect of nutritional supplementation and exercise. In a single study, no effect on the Short Physical Performance Battery (SPPB) test was found [16].
Summary: Muscle mass increased with exercise in 3/3 RCTs and an interactive effect of HMB was found in 1/3 RCTs; Muscle strength increased with exercises in 2/3 RCTs with 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 five studies also looked at muscle mass and physical performance. Studies were performed on community-dwelling participants [14,42, 43], frail retirement community residents [38], or nursing home residents [39,40]. The majority of studies were of poor quality [14,39,40,42,43].
Muscle mass: Two out of four studies did not report any improvement in fat-free mass with exercise or with exercise combined 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 of Fiatarone et al. [39, 40]. One of these failed to show any additional effect of nutritional supplementation [14] and the other did not describe the additional effect of multi-nutrient supplementation [39,40]. Muscle strength: Results were het-erogeneous for the five studies that assessed the combined effect 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 not report any additional effect of nutrition whereas the other study [14], reported greater improvement in isometric knee flexion 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 with exercise but did not describe the difference between the exer-cise only and combined multi-nutrient and exerexer-cise group. Finally, two other studies [38,41] did not report any increase of muscle strength with treatment. Physical performance:
Ta b le 3 (c onti nue d) Referen ce S ettings, study participants, me an age ± SD Study des ign Exercise training intervention Nutr itional supp lement Outcome m easures Q u ality score (J ada d scal e) T rea tm en ts were admin ist er ed d ouble blin d Brose et al . 2003 [ 48 ] C anada. 30 hea lthy -c ommuni ty-dw el li ng older m en and w ome n (15 women an d 1 5 m en) 65+ y ea rs. 14-week int er v en tio n. P arti cipant s were ra n domized in tw o groups: (i) ex er ci se + creati ne suppl em ent or (ii) ex er cise + p lace b o . T rea tme n ts w ere ad m inis tered doubl e bl ind Resistance exercise training. Participants exercised three times p er wee k Creati ne. Dai ly cr eati ne m ono hydrate suppl em ent (5 g + 2 g dextros e) (int er vent ion ) o r pl ace b o (7 g dextros e) (cont rol) MM : fat -fre e m ass M S : handgrip , ankle dors iflexi on, knee extens ion, dynamic 1 RM PP: chair rise , stair climb, w alking speed 4 T arnopo lsky et al. 201 2 [ 49 ] Canada. 39 comm u nit y-dwell ing older m en and w ome n (10 women, 1 9 m en) 65+ years 6-m o nth in terventi on. Pa rt icip an ts were ra n domized in tw o groups: (i) ex er ci se + supplement at ion wi th cr eati ne m ono hydrate an d conj ugated lino leic acid, (ii) exercise + p lac eb o . T rea tm en ts were adminis tered doubl e blin d Resistance exercise training program; participants exerc ised twice per w eek C reatine. Da il y su pplementation with cr eat ine m onohydrat e (5 g ) + co njugat ed lino leic acid (6 g) + 2 g dextrose or placebo (7 g dextros e + 6 g saf flo w er o il) MM : fat -fre e m ass M S : handgrip , ankle dorsi flexi on, k nee extens ion st re n g th, endurance PP: chair rise, sta ir cl imb, w alking speed, balance 5 MM musc le mass, MS muscle strength, PP phys ical performance, 1-RM one re pe tit ion m ax imum te st, IU intern ational unit, HMB β -hy d roxy-β -methylbuthyrate, SPPB short physical perf ormance battery , TU G T im edU pa n d G o , CSA cr oss-se cti onal area , CHO carbohydrate
Three studies described a significant improvement in physical performance with exercise. No additional effect of nutrition was seen in two studies [38,42,43]; one further study did not report whether there were any additional effect of nutrition [39, 40]. Finally, a fifth study did not show any effect of treatment on gait speed [41].
Summary: Muscle mass increased with exercises in 2/4 RCTs with no additional effect of multi-nutrient; Muscle strength increased with exercises in 3/5 RCTs and an addi-tional effect of multi-nutrient was found in 1/5 RCTs; Physical performance 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 of creatine supplementation on muscle mass and muscle strength; four of these also reported effects on physical performance. The protocols of supplementation were heterogeneous with three studies using 5 g/day of creatine while the two other studies used a higher dose of creatine for the first week followed by 5 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 control group with exercise only. The other study showed a significant increase in muscle mass with exercise but without any addi-tional effect of creatine supplementation. Muscle strength: Muscle strength improved with exercise in all studies, with the exception of handgrip strength, which remained un-changed in one study [48]. Several studies found additional effects of creatine supplementation in addition to exercise on: bench press [11,19,23], knee extension [19,48,49], biceps curl performance [19], leg press [19], ankle dorsiflexion [48], isokinetic muscle strength [49], and, finally, endurance of knee extension [49]. Physical performance: Results were less consistent regarding physical performance. Two studies [48, 49] reported an improvement in physical performance with exercise but did not report any additional effects of creatine supplementation. One study reported no improvement in physical performance with either exercise or exercise plus creatine [11]. The final study found a greater improvement in the 30-s chair stand test and in an exercise where partici-pants raised themselves from the floor, in the group receiving combined exercise and creatine [19].
Summary: Muscle mass increased with exercises in 5/5 RCTs and an additional effect of creatine was found in 4/5 RCTs; Muscle strength increased with exercises in 5/5 RCTs and an additive effect of creatine was found, for some of the muscle strength outcomes, in 4/5 RCTs; Physical performance increased with exercises in 3/4 RCTs and an interactive effect of creatine was found in 1/4 RCTs.
Vitamin D supplementation
Two studies [46,47] reported effects of combined exercise and vitamin D3supplementation on muscle strength and phys-ical performance. One of those studies also reported effect on arm, waist and hip circumferences as well as lean mass [47]. The vitamin D3dose was 400 IU/day for 9 months in the study of Bunout et al. [47] and 50,000 IU/week (after an initial injection of 100,000 IU at study entry) for 8 weeks for the study of Binder et al. [46]. This last study was graded as having a poor quality [46] whereas the study of Bunout et al. [47] was a good-quality study.
Muscle mass: Only one study reported results on muscle mass [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 body composition measured by DXA were observed in any of the groups. Muscle strength: Both studies reported significant im-provement in muscle strength with exercise but did not report any difference between the exercise-only group and the group with combined exercise and vitamin D supplementation. Physical performance: Binder et al. [46] reported improved balance with exercise in a population of elderly nursing home residents with dementia. No additional effect of vitamin D supplementation was found and no improvement in gait speed was evident in either group. Bunout et al. [47] reported a significant improvement in the Timed Up and Go test for the group with combined vitamin D and exercise but no differ-ence for the SPPB test between groups.
Summary: Muscle mass did not improve with exercise and no additional effect of vitamin D was found; Muscle strength increased with exercise in 2/2 RCTs with no additional effect of vitamin D; Physical performance increased, for some of the physical 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 that used other types of nutritional supplements: green tea in elderly men and women [15], magnesium oxide in healthy elderly sub-jects [21], milk fat globule membrane in frail women [28], soy isoflavones in frail older women [9,10], vitamin and mineral-enhanced dairy and fruit products in frail community-dwelling older people [44,45] and finally, tea catechin in sarcopenic women [18]. Four studies were 12 weeks in length [15,18, 21,28], one was 6-months in length [9,10], and the last one was 17 weeks in length [44,45].
Muscle mass: A significant effect of exercise alone on mus-cle mass was seen in various studies: in waist and hip circum-ference in men in the green tea [15] study, hip circumference in the soy isoflavones [9,10]study participants, lean mass in the vitamin and mineral-enhanced dairy and fruit products
[44,45]study, and leg lean mass in tea catechin [18]. No ad-ditional effects of nutritional supplements were observed across studies. Muscle strength: Exercise increased bench press and 1RM leg press without an additional effect of soy isoflavones [9,10] and knee extension without additional ef-fects of tea catechin [18]. A small increase of quadriceps strength 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 in the 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, and in 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 compared to exercise group only in another study of Kim et al. [18] Walking speed and TUG test performance also improved with exercise in the study of Kim et al. [28] but no additional effect of milk fat globule membrane was described. In the study by Chin A Paw et al., improvements in physical performance were described but the additional effect of vitamin- and mineral-enhanced dairy and fruit products was not described [44,45]. Finally, the chair stand test did not improve with treatment in two other studies [9,10,18].
Summary: Muscle mass increased with exercise in 4/6 RCTs and no additional effect of nutrition was found; Muscle strength increased with exercise in 3/5 RCTs and no interactive effect of nutrition was found; Physical perfor-mance increased with exercise in 4/5 RCTs and an additional effect of nutrition was found in 2/5 RCTs.
Discussion
This systematic review aimed to summarize results of RCTs assessing the effect of an intervention combining physical activity and dietary supplement on muscle mass and muscle function of subjects aged 60 years and older. Following a systematic review previously performed in 2013 by Denison et al. including 17 RCTs, we performed an update of this comprehensive systematic review and identified 21 RCTs published between April 2013 and October 2015. Thus, 37 RCTSs assessing the impact of a therapeutic intervention con-taining both physical activity and a nutritional supplement on muscle parameters were included in the present work. The study protocols were quite heterogeneous. Different types of physical activities have been studied in different populations that varied in sex, settings, and health status. Moreover, within each category of dietary supplements, the supplement dose and the length of study differed across RCTs.
Among the 37 RCTs included in the systematic review, 34 RCTs assessed the impact of intervention on muscle mass in elderly subjects. In almost 80% of the RCTs (27/
Ta b le 4 General summary o f th es y st em at icr ev ie w Muscle mass Mus cle st rength P hysical performance Si gni fi ca nt in cr ea se w ith ex erc ise s Significant added ef fect w ith nutr it ion Sign ifican t increase wi th exer ci ses Significant added ef fec t wit h n u tri tion S ignificant increase wi th ex er ci ses Significant added ef fect w ith nut rit ion Protein 1 1 /12 RCT s 3/12 RCT s 12/ 12 RCT s 3/ 12 RCT s 9/ 9 R CT s 0/9 RCT s EA A 2 /3 RCT s 0/3 R CT s 2/3 RCT s 0/ 3 RCT s 2/ 2 R CT s (onl y for S P PB and T U G ) 0/2 RCT s HMB 3 /3 RCT s 1/3 R CT s 2 /3 RCT s 0 /3 RCT s 2/ 2 R CT s (onl y for TUG) 0/2 R CT s M u lt i-nut rient 2 /4 RC T s 0/4 R CT s 3 /5 R C T s 1 /5 RC T s 3/ 4 R C T s 0 /4 R C T s Cre at ine 5 /5 R CT s 4/5 RCT s 5/5 RCT s 4/ 5 RCT s (for some of m us cle strengt h outcomes) 3/ 4 R CT s 1/4 RCT s V itamin D 0 /1 R CT s 0/1 RCT s 2/2 RCT s 0/ 2 RCT s 2/ 2 R CT s (for some of physi cal performa n ce out come s) 1/2 R CT s (o nly for T U G ) Other 4 /6 R C T s 0/ 6 R C T s 3 /5 RCT s 0 /5 R C T s 4/5 R CT s 2 /5 RC T s RC T s randomized controlled trials, SPPB short physical perf ormance battery , TU G timed up and g o
34 RCTs), muscle mass increased with exercise training. In the majority of studies where no effect of exercise was observed, these were undertaken in frail subjects, residing in a nursing home, or, subjects with limited mobility. A hypothesis could be that the physical condition of these subjects did not allow them to perform the protocol for the physical activity intervention correctly. The majority of studies proposed three sessions per week. Fewer ses-sions may compromise efficacy of the physical activity intervention. 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 Jadad Scale), 4 using creatine, 3 using proteins, and 1 using HMB as dietary supplement. The majority (75%) of stud-ies using creatine as a dietary supplement showed a higher effect on muscle mass once exercise intervention was combine with creatine. The combination of creatine sup-plementation and resistance training therefore seems to act synergistically. Only 3 of the 12 RCTs using protein as a dietary supplement reported an additional effect of protein when combined with physical activity. These three studies varied 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 not report an effect on mass muscle with protein. Because of blunted response in muscle protein synthesis in older adults and reduced post-prandial inhibition of muscle pro-tein breakdown, some authors recommended increasing protein intake to 1.2 g/kg body weight/day in older adults and even more in frail older adults or elderly with acute or chronic 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 dietary intake of protein has not been reported in the different studies. Therefore, we do not know if the target of 1.2 g/kg/day has been reached or if differences could have been observed between populations who reached this tar-get and those who did not. A meta-analysis published in 2012 [52] showed a positive effect of protein supplemen-tation on muscle mass gains during prolonged resistance-type exercise training in older subjects. This probably means that the type of exercise training could have a non-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 the three studies using HMB as a dietary supplement also showed an intergroup difference between subjects under-going exercise intervention and subjects underunder-going a combination of exercise and dietary intervention. Of note, this study comprised subjects confined to bedrest. Subjects receiving a combination of exercise and HMB supplementation were more prevented for decline of lean
body mass over bed rest compared to subjects undergoing exercises only. In this study, HMB supplementation did not increase muscle mass but prevented its decline.
Muscle strength increased in 82.8% of the studies (29/35 RCTs) following an exercise intervention and, once again, dietary supplementation showed additional benefits in only a small number of studies (8/35 RCTS, 22.8%) principally for creatine but only at specific muscle sites. In 4 out of the 5 RCTs using creatine as a dietary supplement (dose range 5– 20 g/day), the group treated with the combination of exercise and dietary intervention showed greater improvement of mus-cle strength compared to exercise only. Three good-quality RCTs using protein as a dietary supplement also showed a greater effect on muscle strength when compared to the exer-cise group. These three studies were providing a high amount of protein with, respectively, 45, 40, and 15 g (collagen pep-tide) daily whereas the mean dose of supplementation in other studies 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 sarcopenia definitions, was an outcome in 13 RCTs assessing the effect of a combined exercise and dietary intervention. Approximately half of the studies (6/13 RCTs) showed an improvement in grip strength with exercise. However, none of these RCTs showed an additional effect of dietary supplementation. Highlighted by these last results, it should be noted that, even if this systematic review revealed an increase of muscle strength following exercise in the majority of the studies, this seems particularly true for leg muscle strength.
A total of 29 RCTs also assessed the impact of combined physical activity and dietary supplementation on physical per-formance. We observed, in the majority of studies, an im-provement in physical performance outcomes following an exercise intervention (26/28 RCTs, 92.8%). In the two studies that 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 a variety 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 Up and Go test (used in 8 RCTs), and SPPB test (used in 6 RCTs). The heterogeneity of both the type of exercise inter-vention and physical performance outcomes impedes general statements of findings on the association between exercise training and improvements in physical performance. Interaction of exercise and nutrition was found in only 17.8% of these studies (5/28 RCTs): one study when a multi-nutrient was used as a dietary supplement, another with creatine, 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 review and it followed the same rigorous methodology as the previ-ous one. We searched multiple electronic databases to identify
